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Sample records for renal toxicity nephrotoxicity

  1. Gentamicin Nephrotoxicity in Subclinical Renal Disease.

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    Frazier, Donita L.

    The purpose of the present study was to examine the pharmacokinetic disposition of gentamicin and to define the mechanisms which predispose to nephrotoxicity in subclinical renal disease. Subtotally nephrectomized beagle dogs were used as a model for human beings with compromised renal function secondary to a reduced number of functional nephrons. Using ultrastructural morphometry, light microscopy and clinical chemistry data, the model was defined and the nephrotoxic responses of intact dogs administered recommended doses of drug were compared to the response of subtotally nephrectomized dogs administered reduced doses based on each animal's clearance of drug. Lysosomal and mitochondrial morphometric changes suggested mechanisms for increased sensitivity. To determine if increased sensitivity in this model was dependent on altered serum concentrations, variable rate infusions based on individual pharmacokinetic disposition of drug were administered using computer-driven infusion pumps. Identical serum concentration-time profiles were achieved in normal dogs and subtotally nephrectomized dogs, however, toxicity was significantly greater in nephrectomized dogs. The difference in the nephrotoxic response was characterized by administering supratherapeutic doses of drug to dogs. Nephrectomized dogs given a recommended dose of gentamicin became oliguric during the second week of treatment and increasingly uremic after withdrawal of drug. In contrast, intact dogs administered 2 times the recommended dose of gentamicin become only slightly polyuric during week 4 of treatment. The need to individualize dosage regimens based on drug clearance and not serum creatinine nor creatinine clearance alone was substantiated by describing the pharmacokinetic disposition of gentamicin in spontaneously occurring disease states. Four individualized dosage regimens with differing predicted efficacy were then administered to nephrectomized dogs to determine their relative nephrotoxic

  2. Adefovir nephrotoxicity in a renal allograft recipient

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    N George

    2015-01-01

    Full Text Available Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.

  3. [Renal toxicity of antiviral drugs].

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    Frasca', Giovanni M; Balestra, Emilio; Tavio, Marcello; Morroni, Manrico; Manarini, Gloria; Brigante, Fabiana

    2012-01-01

    Highly effective and powerful antiviral drugs have been introduced into clinical practice in recent years which are associated with an increased incidence of nephrotoxicity. The need of combining several drugs, the fragility of the patients treated, and the high susceptibility of the kidney are all factors contributing to renal injury. Many pathogenetic mechanisms are involved in the nephrotoxicity of antiviral drugs, including drug interaction with transport proteins in the tubular cell; direct cytotoxicity due to a high intracellular drug concentration; mitochondrial injury; and intrarenal obstruction or stone formation due to the low solubility of drugs at a normal urinary pH. As a result, various clinical pictures may be observed in patients treated with antiviral drugs, ranging from tubular dysfunction (Fanconi syndrome, renal tubular acidosis, nephrogenic diabetes insipidus) to acute renal failure (induced by tubular necrosis or crystal nephropathy) and kidney stones. Careful attention should be paid to prevent renal toxicity by evaluating the glomerular filtration rate before therapy and adjusting the drug dosage accordingly, avoiding the combination with other nephrotoxic drugs, and monitoring renal parameters on a regular basis while treating patients.

  4. Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection.

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    Yasuhiro Kidera

    Full Text Available Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity.We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m2 of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%.Cisplatin-induced nephrotoxicity was observed in 127 patients (32%. Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004 and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs (risk ratio, 1.357; P = 0.047 were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004. The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025. Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012.A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further

  5. Renal Toxicities of Targeted Therapies.

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    Abbas, Anum; Mirza, Mohsin M; Ganti, Apar Kishor; Tendulkar, Ketki

    2015-12-01

    With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents be well-recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. This review will focus on these renal toxicities from commonly used targeted agents. This review discusses the mechanisms of these side effects and management strategies. Anti-vascular endothelial growth factor (VEGF) agents including the monoclonal antibody bevacizumab, aflibercept (VEGF trap), and anti-VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) all cause hypertension, whereas some of them result in proteinuria. Monoclonal antibodies against the human epidermal growth factor receptor (HER) family of receptors, such as cetuximab and panitumumab, cause electrolyte imbalances including hypomagnesemia and hypokalemia due to the direct nephrotoxic effect of the drug on renal tubules. Cetuximab may also result in renal tubular acidosis. The TKIs, imatinib and dasatinib, can result in acute or chronic renal failure. Rituximab, an anti-CD20 monoclonal antibody, can cause acute renal failure following initiation of therapy because of the onset of acute tumor lysis syndrome. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, can result in proteinuria. Discerning the renal adverse effects resulting from these agents is essential for safe treatment strategies, particularly in those with pre-existing renal disease.

  6. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

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    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  7. NSAID nephrotoxicity revisited: acute renal failure due to parenteral ketorolac.

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    Perazella, M A; Buller, G K

    1993-12-01

    The success of ketorolac as a nonnarcotic analgesic is likely to propagate its widespread use to control moderate to severe postoperative pain. Indeed, of the patients treated with ketorolac and described in the medical literature, nearly 90% had had a major surgical procedure. Since any such procedure may be associated with significant third-spacing of the fluid and result in renal hypoperfusion, care must be taken in administering ketorolac. Close attention to urine output and parameters of renal function must be maintained. Moreover, postoperative ketorolac therapy should be avoided in patients who have conditions that predispose to NSAID nephrotoxicity (as in our Case 1). Likewise, in nonsurgical patients the same degree of caution should be used with ketorolac as with any oral NSAID. Finally, since ketorolac is excreted almost entirely by the kidney, either elderly patients or patients with underlying renal insufficiency must have an adjustment of the dosing interval, or this medication should be avoided in such patients altogether.

  8. 3,4,5-Trichloroaniline nephrotoxicity in vitro: potential role of free radicals and renal biotransformation.

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    Racine, Christopher; Ward, Dakota; Anestis, Dianne K; Ferguson, Travis; Preston, Deborah; Rankin, Gary O

    2014-11-13

    Chloroanilines are widely used in the manufacture of drugs, pesticides and industrial intermediates. Among the trichloroanilines, 3,4,5-trichloroaniline (TCA) is the most potent nephrotoxicant in vivo. The purpose of this study was to examine the nephrotoxic potential of TCA in vitro and to determine if renal biotransformation and/or free radicals contributed to TCA cytotoxicity using isolated renal cortical cells (IRCC) from male Fischer 344 rats as the animal model. IRCC (~4 million cells/mL; 3 mL) were incubated with TCA (0, 0.1, 0.25, 0.5 or 1.0 mM) for 60-120 min. In some experiments, IRCC were pretreated with an antioxidant or a cytochrome P450 (CYP), flavin monooxygenase (FMO), cyclooxygenase or peroxidase inhibitor prior to incubation with dimethyl sulfoxide (control) or TCA (0.5 mM) for 120 min. At 60 min, TCA did not induce cytotoxicity, but induced cytotoxicity as early as 90 min with 0.5 mM or higher TCA and at 120 min with 0.1 mM or higher TCA, as evidenced by increased lactate dehydrogenase (LDH) release. Pretreatment with the CYP inhibitor piperonyl butoxide, the cyclooxygenase inhibitor indomethacin or the peroxidase inhibitor mercaptosuccinate attenuated TCA cytotoxicity, while pretreatment with FMO inhibitors or the CYP inhibitor metyrapone had no effect on TCA nephrotoxicity. Pretreatment with an antioxidant (α-tocopherol, glutathione, ascorbate or N-acetyl-L-cysteine) also reduced or completely blocked TCA cytotoxicity. These results indicate that TCA is directly nephrotoxic to IRCC in a time and concentration dependent manner. Bioactivation of TCA to toxic metabolites by CYP, cyclooxygenase and/or peroxidase contributes to the mechanism of TCA nephrotoxicity. Lastly, free radicals play a role in TCA cytotoxicity, although the exact nature of the origin of these radicals remains to be determined.

  9. Influence of Tyrosine Kinase Inhibitors on Hypertension and Nephrotoxicity in Metastatic Renal Cell Cancer Patients

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    Aleksandra Semeniuk-Wojtaś

    2016-12-01

    Full Text Available Renal cell carcinoma (RCC is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was to analyze the medical literature for hypertension and renal toxicities as the adverse events of the vascular endothelial growth factor (VEGF signaling pathway inhibitor (anti-VEGF therapy. Relevant studies were identified in PubMed and ClinicalTrials.gov databases. Eligible studies were phase III and IV prospective clinical trials, meta-analyses and retrospective studies that had described events of hypertension or nephrotoxicity for patients who received anti-VEGF therapy. A total of 48 studies were included in the systematic review. The incidence of any grade hypertension ranged from 17% to 49.6%. Proteinuria and increased creatinine levels were ascertained in 8% to 73% and 5% to 65.6% of patients, respectively. These adverse events are most often mild in severity but may sometimes lead to treatment discontinuation. Nephrotoxicity and hypertension are related to multiple mechanisms; however, one of the main disturbances in those patients is VEGF inhibition. There is a significant risk of developing hypertension and renal dysfunction among patients receiving anti-VEGF treatment; however, there is also some evidence that these side effects may be used as biomarkers of response to antiangiogenic agents.

  10. [Intensity of lipid peroxidation in the kidneys in nephrotoxic acute renal failure (experimental study)].

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    Makarenko, V S; Zhiznevskaia, N G; Koltygina, T I; Gapanovich, V M; Makarenko, E V

    2000-01-01

    Mercury chloride was injected cubcutaneously in rats to induce nephrotoxic acute renal failure (ARF). Renal dysfunction in ARF occurs under intensification of lipid peroxidation in the kidneys. Pretreatment with antioxidant ionol diminishes lipid peroxidation intensity in the kidneys in ARF and restricts the severity of renal dysfunction.

  11. Role of renal prostaglandins in the modulation of cisplatinum nephrotoxicity

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    Noordewier, B.; Danielson, P.W.; Noordewier, E.R.; Bredehoeft, S.J.

    1986-03-01

    Indomethacin (I) inhibition of renal prostaglandin (PG) synthesis potentiates the nephorotoxic effects of cis-dichlorodiamine platinum (Cis-Pt). The purpose of this study was to determine if this potentiation was unique to I or was shared by other inhibitors of PG synthesis. Male Fischer 344 rats were fed a purified diet replete (Repl) or deplete (Depl) in sodium. After 5 days on this diet, the rats were given saline or cis-Pt (10 mg/kg, iv) with or without tolmetin (Tol) (2 x 10 mg/kg, ip then iv). Toxicity was assessed 2 days after the injections. Cis-Pt given alone increased BUN and plasma creatinine (Cr) in both Depl (BUN = 43 mg/dl, Cr = 1.3 mg/dl) and Repl (BUN = 45, Cr = 1.3) groups. Tol produced a moderate increase in cis-Pt toxicity in Repl rats (BUN = 62, Cr = 1.5) and a marked increase in Depl rats (BUN = 138, Cr = 2.6). These biochemical changes were accompanied by concurrent changes in renal histology. Rats given cis-Pt alone had focal areas of toxicity marked by evidence of necrosis and vacuolation. Tol enhancement of toxicity was characterized by an increased extent of damage with the appearance of tubular protein and some mineralization. The effects of Tol mimic those of I indicating a role for renal prostaglandins in the renal toxicity of Cis-Pt.

  12. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

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    Manchandani, Pooja; Zhou, Jian; Babic, Jessica T.; Ledesma, Kimberly R.; Truong, Luan D.

    2017-01-01

    ABSTRACT Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. PMID:28096166

  13. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity.

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    Manchandani, Pooja; Zhou, Jian; Babic, Jessica T; Ledesma, Kimberly R; Truong, Luan D; Tam, Vincent H

    2017-04-01

    Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. Copyright © 2017 American Society for Microbiology.

  14. Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

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    Sahu, Bidya Dhar; Rentam, Kiran Kumar Reddy; Putcha, Uday Kumar; Kuncha, Madhusudana; Vegi, Ganga Modi Naidu; Sistla, Ramakrishna

    2011-12-01

    Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (PGSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (PGSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.

  15. Lithium nephrotoxicity.

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    Oliveira, Jobson Lopes de; Silva Júnior, Geraldo Bezerra da; Abreu, Krasnalhia Lívia Soares de; Rocha, Natália de Albuquerque; Franco, Luiz Fernando Leonavicius G; Araújo, Sônia Maria Holanda Almeida; Daher, Elizabeth de Francesco

    2010-01-01

    Lithium has been widely used in the treatment of bipolar disorder. Its renal toxicity includes impaired urinary concentrating ability and natriuresis, renal tubular acidosis, tubulointerstitial nephritis progressing to chronic kidney disease and hypercalcemia. The most common adverse effect is nephrogenic diabetes insipidus, which affects 20-40% of patients within weeks of lithium initiation. Chronic nephropathy correlates with duration of lithium therapy. Early detection of renal dysfunction should be achieved by rigorous monitoring of patients and close collaboration between psychiatrists and nephrologists. Recent experimental and clinical studies begin to clarify the mechanisms by which lithium induces changes in renal function. The aim of this study was to review the pathogenesis, clinical presentation, histopathological aspects and treatment of lithium-induced nephrotoxicity.

  16. Molecular Mechanisms of Renal Cellular Nephrotoxicity due to Radiocontrast Media

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    Ashour Michael

    2014-01-01

    Full Text Available Modern iodinated radiocontrast media are all based on the triiodinated benzene ring with various chemical modifications having been made over the last few decades in order to reduce their toxicity. However, CIN remains a problem especially in patients with pre-existing renal failure. In vitro studies have demonstrated that all RCM are cytotoxic. RCM administration in vivo may lead to a decrease in renal medullary oxygenation leading to the generation of reactive oxygen species that may cause harmful effects to renal tissue. In addition, endothelin and adenosine release and decreased nitric oxide levels may worsen the hypoxic milieu. In vitro cell culture studies together with sparse in vivo rat model data have shown that important cell signalling pathways are affected by RCM. In particular, the prosurvival and proproliferative kinases Akt and ERK1/2 have been shown to be dephosphorylated (deactivated, whilst proinflammatory/cell death molecules such as the p38 and JNK kinases and the transcription factor NF-κB may be activated by RCM, accompanied by activation of apoptotic mediators such as caspases. Increasing our knowledge of the mechanisms of RCM action may help to develop future therapies for CIN.

  17. Sida rhomboidea.Roxb leaf extract ameliorates gentamicin induced nephrotoxicity and renal dysfunction in rats.

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    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Devkar, Ranjitsinh V; Ramachandran, A V

    2010-10-28

    Sida rhomboidea.Roxb (SR) known as "Mahabala" in Ayurveda and marketed as "Shahadeyi" is used in ethnomedicine to treat ailments such as dysuria and urinary disorders. To evaluate nephroprotective potential of SR against gentamicin (GM) induced nephrotoxicity and renal dysfunction. Nephrotoxicity was induced in rats with GM (100 mg/kg bodyweight (i.p.) for 8 days) and were treated with SR extract (200 and 400 mg/kg bodyweight (p.o.) for 8 days) or 0.5% carboxymethyl cellulose (vehicle). Plasma and urine urea and creatinine, renal enzymatic and non-enzymatic antioxidants along with lipid peroxidation were evaluated in various experimental groups. GM treatment induced significant elevation (p<0.05) in plasma and urine urea, creatinine, renal lipid peroxidation along with significant decrement (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR treatment to GM treated rats (GM+SR) recorded significant decrement (p<0.05) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR leaf extract ameliorates GM induced nephrotoxicity and renal dysfunction and thus validates its ethnomedicinal use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models

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    Liu, Senyan [Kidney Institute and Division of Nephrology, Changzheng Hospital, Shanghai 200003 (China); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States); Yao, Yunyi; Lu, Shijun; Aldous, Kenneth; Ding, Xinxin [Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States); Mei, Changlin, E-mail: chlmei1954@126.com [Kidney Institute and Division of Nephrology, Changzheng Hospital, Shanghai 200003 (China); Gu, Jun, E-mail: jungu@wadsworth.org [Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States)

    2013-10-01

    The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200 mg/kg. Blood, liver and kidney samples were obtained at 24 h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity. - Highlights: • New mouse models were developed with varying P450 activities in the proximal tubule. • These mouse models were treated with chloroform, a nephrotoxicant. • Studies showed the importance of local P450s in chloroform-induced nephrotoxicity.

  19. Alterations in renal heme biosynthesis during metal nephrotoxicity.

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    Oskarsson, A; Fowler, B A

    1987-01-01

    The regulation of the heme biosynthetic pathway in the kidney by various metals has been reviewed. In addition, a study on the effects of lead on renal heme biosynthesis after acute treatment of rats has been reported. Chronic low-level lead exposure in rats results in relatively small effects on renal heme biosynthetic pathway enzymes. After acute treatment of rats with lead, no effects on ALAD or UROS and mild, transitory effects on ALAS and ferrochelatase are observed. The intracellular binding of lead within intranuclear inclusion bodies in the proximal tubule cells and to high-affinity cytosolic lead-binding proteins probably protects sensitive subcellular systems, such as the heme pathway, from lead toxicity. Chronic exposure to methyl mercury results in increased urinary excretion of uro- and coproporphyrins in rats, mediated via inhibition of ferrochelatase and UROS and stimulation of ALAS. A tissue-specific inhibition of ALAD occurs in the kidney after treatment of rats with indium. Acute treatment of rats with nickel, platinum, tin, antimony, bismuth, and cobalt results in induction of heme oxygenase, followed by decreased microsomal heme content and ALAS stimulation in the kidney.

  20. Nephroprotective activity ofSolanum xanthocarpum fruit extract against gentamicin-induced nephrotoxicity and renal dysfunction in experimental rodents

    Institute of Scientific and Technical Information of China (English)

    Talib Hussain; Ramesh K Gupta; K Sweety; Bavani Eswaran; M Vijayakumar; Chandana Venkateswara Rao

    2012-01-01

    Objective:To evaluate nephroprotective potential ofSolanum xanthocarpum(S. xanthocarpum) fruit extract(SXE) against gentamicin(GM) induced nephrotoxicity and renal dysfunction. Methods:Twenty-fourWistar rats were divided into four groups(n=6).Control rats that received normal saline(i.p.) and0.5% carboxymethyl cellulose(p.o.) per day for8 d.Nephrotoxicity was induced in rats by intraperitoneal administration ofGM(100 mg/kg/d for8 d) and were treated withSXE(200 and400 mg/kg/d(p.o.) for8 d).Plasma and urine urea and creatinine, kidney weight, urine output, blood urea nitrogen, renal enzymatic and non-enzymatic antioxidants and lipid peroxidation was evaluated along with histopathological investigation in various experimental groupsof rats.Results:It was observed that theGM treatment induced significant elevation(P<0.001) in plasma and urine urea, creatinine, kidney weight, blood urea nitrogen, renal lipid peroxidation along with significant decrement(P<0.001) in urine output, renal enzymatic and non-enzymatic antioxidants.SXE200 and400 mg/kg treatment toGM treated rats recorded significant decrement(up toP<0.001) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment(up toP<0.001) in renal enzymatic and non-enzymatic antioxidants.Histological observations of kidney tissues too correlated with the biochemical observations.Conclusions:These finding powerfully supports thatS. xanthocarpum fruit extract acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects ofGM both in the biochemical and histopathological parameters and thus validates its ethnomedicinal use.

  1. Erythrophagocytosis of Lead-Exposed Erythrocytes by Renal Tubular Cells: Possible Role in Lead-Induced Nephrotoxicity

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    Kwon, So-Youn; Bae, Ok-Nam; Noh, Ji-Yoon; Kim, Keunyoung; Kang, Seojin; Shin, Young-Jun; Lim, Kyung-Min; Chung, Jin-Ho

    2014-01-01

    Background: Nephrotoxicity associated with lead poisoning has been frequently reported in epidemiological studies, but the underlying mechanisms have not been fully described. Objectives: We examined the role of erythrocytes, one of the major lead reservoirs, in lead-associated nephrotoxicity. Methods and results: Co-incubation of lead-exposed human erythrocytes with HK-2 human renal proximal tubular cells resulted in renal tubular cytotoxicity, suggesting a role of erythrocytes in lead-induc...

  2. Amphotericin B nephrotoxicity.

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    Deray, Gilbert

    2002-02-01

    The use of amphotericin B limited by dose-dependent nephrotoxicity. Elevated creatinine associated with amphotericin B is not only a marker for renal dysfunction, but is also linked to an increase in hospital costs and a substantial risk for the use of haemodialysis and a higher mortality rate. Therefore, amphotericin B nephrotoxicity is not a benign complication and its prevention is essential. Several manipulations have been proposed to minimize amphotericin B-induced nephrotoxicity. Mannitol and frusemide administration are reported to be protective based on anecdotal observational reports. Small prospective and randomized trials do not suggest a protective effect. Three new formulations have been developed in attempts to improve both efficacy and tolerability: amphotericin B in a lipid complex (ABLC; Abelcet); amphotericin B colloidal dispersion; and liposomal amphotericin B (AmBisome). Three prospective randomized studies have clearly shown that AmBisome is less nephrotoxic than amphotericin B. In a double-blind randomized trial significantly fewer patients receiving AmBisome had nephrotoxic effects. This significant reduction in azotaemia was also observed among subgroups of patients receiving concomitant therapy with nephrotoxic agents. Moreover, there were fewer patients with hypokalaemia in the group receiving AmBisome. A recent multicentre double-blind study has shown that AmBisome (3 or 5 mg/kg/day) has a better safety profile than Abelcet (5 mg/kg). Patients in both AmBisome treatment groups experienced less chills/rigors, less nephrotoxicity based on a doubling of serum creatinine, and fewer toxic reactions resulting in discontinuation of therapy. In conclusion, amphotericin B nephrotoxicity is observed frequently. It clearly increases patient mortality. Nephrotoxicity must be recognized early, based on tubular abnormalities and a mild increase in serum creatinine. Its prevention relies on the detection and suppression of risk factors and the use of AmBisome.

  3. Erdosteine against acetaminophen induced renal toxicity.

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    Isik, Bunyamin; Bayrak, Reyhan; Akcay, Ali; Sogut, Sadik

    2006-07-01

    Acetaminophen (APAP) induced toxicities have been a major problem in clinical practice. The aim of the present study was to demonstrate a possible protective role of erdosteine, a mucolytic agent having antioxidant properties via its active metabolites, on APAP induced renal damage in rats. Female Wistar Albino rats were divided into groups including control, erdosteine (150 mg/kg, oral), APAP (1 g/kg, oral) APAP+erdosteine (150 mg/kg, oral) and APAP+erdosteine (300 mg/kg, oral). APAP treatment caused lipid peroxidation as well as high NO level in renal tissue. Also, APAP treated rats had decreased activities of CAT and GSH-Px, but not SOD. In addition, tubular epithelial degeneration, vacuolization and cell desquamation were clearly observed in the APAP treated rats. The cellular debris in the proximal tubules and cortical interstitial congestions were prominent in the kidneys of APAP treated rats. BUN and creatinine levels were increased after APAP administration. All these pathological changes were reversed after erdosteine treatments. Erdosteine treated APAP groups showed milder tubular degeneration, epithelial vacuolization in the proximal tubules, lesser cellular desquamation and better morphology when compared with APAP groups. In conclusion, erdosteine may be a choice of preventive treatment against APAP induced nephrotoxicity.

  4. Tc-99m DTPA scans in renal allograft rejection and cyclosporine nephrotoxicity

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    Gedroyc, W.; Taube, D.; Fogleman, I.; Neild, G.; Cameron, S.; Maisey, M.

    1986-11-01

    Renal allograft dysfunction arising from rejection or cyclosporine (CsA) nephrotoxicity can currently only be distinguished reliably by allograft biopsy. We have assessed Technetium (Tc)-99m diethylamine pentacetic acid (DTPA) scanning in 30 CsA-treated patients with allograft dysfunction. Scintigrams were performed during 20 biopsy-proved episodes of rejection and during 14 episodes of CsA nephrotoxicity. These results were compared with the scintigrams of 15 allografts showing stable function. Quantitative indices expressing allograft perfusion (flow index) and function (uptake index) derived from the DTPA scintigrams showed no significant differences between the groups of patients with rejection, CsA nephrotoxicity, or stable or improving function. Similarly, the flow and uptake indices of individual allografts obtained during periods of stable or improving function and then during episodes of dysfunction due to rejection or CsA nephrotoxicity did not significantly change. We conclude that Tc-99m DTPA scintigrams are of limited value in the management of allograft dysfunction in patients immunosuppressed with CsA.

  5. Renal oxidative stress status and histology in gentamicin nephrotoxicity: The effects of antioxidant vitamins

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    R. Ghaznavi

    2006-07-01

    Full Text Available Background: In recent publications, several mechanisms have been implicated in gentamicin (GM nephrotoxicity. Reactive oxygen species have been proposed as one of the causative factors of the drug renal side effects. This study was designed to evaluate the protective effects of the antioxidant vitamins against GM-mediated nephropathy in insitu isolated rat kidneys. Methods: Male Sprague-Dawley rats were randomly assigned to one of the following groups of seven rats: Group 1 (control was tyrode perfused kidneys. Group 2 (GM, 200µg/ml gentamicin was added to the perfusate. Group 3 (GM + Vit C, the same as group 2 but vitamin C (200 mg/L was added to the drinking water for 3 days and 100 mg/L to the perfusate. Group 4 (GM + Vit E, the same as group 2 but vitamin E (100 mg/100 g BW, ip was injected 12 h before experiments. Group 5 (GM + Vit C + Vit E the same as group 2 but Vit E and C were co-administered (same as Group 3 & 4. Urinary N-acetyle-B-D-glucosaminidas (NAG and renal cortex superoxide dismutase (SOD levels were measured and tissue histological evaluations were performed. Results: Gentamicin caused a significant nephrotoxicity demonstrated by increase in urinary NAG. Decline in SOD contents were observed comparing to controls. Vit C or Vit E inhibited the gentamicin-induced increased releases of NAG into urine but did not show a significant effect on the SOD levels. Conclusion: Co-administration of VitC&E significantly prevented the GM nephrotoxicity demonstrating by preservation of SOD levels and prevention of increase in urinary enzyme activities. Histological studies of renal tissues provided additional evidences for protective effects of antioxidant vitamins. We concluded that moderate doses of Vit C & E have protective effects in gentamicin nephrotoxicity and co-administration of these vitamins have additional beneficial effects.

  6. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

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    Rubera, I.; Duranton, C; Melis, N; Cougnon, M; Mograbi, B.; Tauc, M

    2013-01-01

    The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl− channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whe...

  7. Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model

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    José Sereno

    2014-05-01

    Full Text Available Cyclosporin A (CsA, a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day treatments (3 and 9 weeks, respectively. Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA, transforming growth factor beta 1 (TGF-β1, factor nuclear kappa B (NF-κβ and Tumor Protein P53 (TP53 kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR and the antigen identified by monoclonal antibody Ki-67 (Mki67, accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy.

  8. N-acetylcysteine improves renal hemodynamics in rats with cisplatin-induced nephrotoxicity.

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    Abdelrahman, Aly M; Al Salam, Suhail; AlMahruqi, Ahmed S; Al husseni, Ishaq S; Mansour, Mohamed A; Ali, Badreldin H

    2010-01-01

    This work investigated the effect of N-acetylcysteine (NAC), on renal hemodynamics in cisplatin (CP)-induced nephrotoxicity in Wistar-Kyoto (WKY) rats. The animals were divided into four groups (n = 5 or 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) N-acetylcysteine (500 mg kg(-1) per day for 9 days), respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (5 mg kg(-1)) and an i.p. injection of CP (5 mg kg(-1)) together with i.p. NAC (500 mg kg(-1) per day for 9 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE) for measurement of renal vasoconstrictor responses. CP caused a significant reduction in renal blood flow but did not affect NE-induced renal vasoconstriction. In addition, CP significantly increased plasma concentrations of urea and creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and kidney relative weight. CP decreased body weight and creatinine clearance. Histopathologically, CP caused remarkable renal damage compared with control. NAC alone did not produce any significant change in any of the variables measured. However, NAC significantly ameliorated CP-induced hemodynamic, biochemical and histopathological changes. The concentration of platinum in the kidneys of CP ? NAC treated rats was less than in CP-treated rats by 37%. The results show that administration of i.p. NAC (500 mg kg(-1) per day for 9 days) reversed the renal hemodynamic changes as well as the biochemical and histopathological indices of CP-induced nephrotoxicity in WKY rats.

  9. The ischemic/nephrotoxic acute kidney injury and the use of renal biomarkers in clinical practice.

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    Andreucci, Michele; Faga, Teresa; Pisani, Antonio; Perticone, Maria; Michael, Ashour

    2017-04-01

    The term Acute Renal Failure (ARF) has been replaced by the term Acute Kidney Injury (AKI). AKI indicates an abrupt (within 24-48h) decrease in Glomerular Filtraton Rate, due to renal damage, that causes fluid and metabolic waste retention and alteration of electrolyte and acid-base balance. The renal biomarkers of AKI are substances or processes that are indicators of normal or impaired function of the kidney. The most used renal biomarker is still serum creatinine that is inadequate for several reasons, one of which is its inability to differentiate between hemodynamic changes of renal function ("prerenal azotemia") from intrinsic renal failure or obstructive nephropathy. Cystatin C is no better in this respect. After the description of the pathophysiology of "prerenal azotemia" and of Acute Kidney Injury (AKI) due to ischemia or nephrotoxicity, the renal biomarkers are listed and described: urinary NAG, urinary and serum KIM-1, serum and urinary NGAL, urinary IL-18, urinary L-FABP, serum Midkine, urinary IGFBP7 and TIMP2, urinary α-GST and π-GST, urinary ɣGT and AP, urinary β2M, urinary RBP, serum and urinary miRNA. All have been shown to appear much earlier than the rise of serum Creatinine. Some of them have been demonstrated to predict the clinical outcomes of AKI, such as the need for initiation of dialysis and mortality.

  10. Chemopreventive efficacy of hesperidin against chemically induced nephrotoxicity and renal carcinogenesis via amelioration of oxidative stress and modulation of multiple molecular pathways.

    Science.gov (United States)

    Siddiqi, Aisha; Hasan, Syed Kazim; Nafees, Sana; Rashid, Summya; Saidullah, Bano; Sultana, Sarwat

    2015-12-01

    In the present study, chemopreventive efficacy of hesperidin was evaluated against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in wistar rats. Nephrotoxicity was induced by single intraperitoneal injection of Fe-NTA (9 mg Fe/kg b.wt). Renal cancer was initiated by the administration of N-nitrosodiethylamine (DEN 200mg/kg b.wt ip) and promoted by Fe-NTA (9 mg Fe/kg b.wt ip) twice weekly for 16 weeks. Efficacy of hesperidin against Fe-NTA-induced nephrotoxicity was assessed in terms of biochemical estimation of antioxidant enzyme activities viz. reduced renal GSH, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, superoxide dismutase and renal toxicity markers (BUN, Creatinine, KIM-1). Administration of Fe-NTA significantly depleted antioxidant renal armory, enhanced renal lipid peroxidation as well as the levels of BUN, creatinine and KIM-1. However, simultaneous pretreatment of hesperidin restored their levels in a dose dependent manner. Expression of apoptotic markers caspase-3, caspase-9, bax, bcl-2 and proliferative marker PCNA along with inflammatory markers (NFκB, iNOS, TNF-α) were also analysed to assess the chemopreventive potential of hesperidin in two-stage renal carcinogenesis model. Hesperidin was found to induce caspase-3, caspase-9, bax expression and downregulate bcl-2, NFκB, iNOS, TNF-α, PCNA expression. Histopathological findings further revealed hesperidin's chemopreventive efficacy by restoring the renal morphology. Our results provide a powerful evidence suggesting hesperidin to be a potent chemopreventive agent against renal carcinogenesis possibly by virtue of its antioxidant properties and by modulation of multiple molecular pathways.

  11. Inhibitory effect of tea polyphenols on renal cell apoptosis in rat test subjects suffering from cyclosporine-induced chronic nephrotoxicity

    Institute of Scientific and Technical Information of China (English)

    施邵华; 郑树森; 朱有法; 贾长库; 谢海洋

    2003-01-01

    Objective To investigate the inhibitory effect of tea polyphenols on renal cell apoptosis in rat test subjects suffering from cyclosporine A (CsA)-induced chronic nephrotoxicity. Methods Four groups of rats with CsA-induced chronic nephrotoxicity were respectively treated with vehicle olive oil, tea polyphenols, CsA and tea polyphenols plus CsA. At the end of the 28th day of treatment, 24 hours urine and blood samples were obtained, and the animals were then sacrificed. The serum and urine samples were analysed for creatinine clearance, and kidney tissue was used for pathologic analysis of renal tubular injury and interstitial fibrosis. The TUNEL assay, apoptosis-related enzyme caspase-3 mRNA detected by RT-PCR, and its enzymatic activity were analysed for the possible detections of cell apoptosis.Results CsA-treated rats displayed increased apoptosis of the tubular and interstitial cells, in comparison with vehicle-treated controls (18.3±4.6 vs 4.8±1.3 cells/mm2, P<0.05). In comparision with animals treated by CsA, animals treated with CsA plus tea polyphenols demonstrated significantly improved levels of creatinine clearance (0.12±0.03 vs 0.22±0.02 ml*min-1*100g-1 body weight, P<0.05), tubular injury (2.29±0.43 vs 1.42±0.26, P<0.05), and interstitial fibrosis (2.83±0.20 vs 1.46±0.19, P<0.05), and showed a statistically significant decrease in tubular and interstitial cell apoptosis (18.3±4.6 vs 7.7±2.1 cells/mm2, P<0.05). The expression of caspase-3 mRNA and caspase-3 activity was significantly higher in the CsA-treated group than that of the CsA plus tea polyphenols (TP)-treated group (P<0.05).Conclusion These results suggested that tea polyphenols significantly inhibits apoptosis of the tubular and interstitial cells in rats with cyclosporine-induced chronic nephrotoxicity, and that tea polyphenols may be useful to prevent CsA-associated kidney toxicity.

  12. In vivo evidence suggesting a role for purine-catabolizing enzymes in the pathogenesis of cisplatin-induced nephrotoxicity in rats and effect of erdosteine against this toxicity.

    Science.gov (United States)

    Söğüt, Sadik; Kotuk, Mahir; Yilmaz, H Ramazan; Ulu, Ramazan; Ozyurt, Hüseyin; Yildirim, Zeki

    2004-01-01

    The aim of this experimental study was to investigate the possible role of adenosine deaminase (AD) and xanthine oxidase (XO) in the pathogenesis of cisplatin-induced nephrotoxicity and the effect of erdosteine in decreasing the toxicity. The intraperitoneal injection of cisplatin (7 mg kg(-1) body weight) induced a significant increase in plasma creatinine level and blood urea nitrogen (BUN), and plasma and damaged renal tissue activities of AD and XO in rats. Co-treatment with erdosteine (10 mg kg(-1)day(-1)) attenuated the increase in the plasma creatinine and BUN levels, and significantly prevented the increase in tissue and plasma AD and XO activities (Perdosteine may have protective potential in this process and it will become a promising drug in the prevention of this undesired side-effect of cisplatin, but further studies are needed to illuminate the exact protection mechanism of erdosteine against cisplatin-induced nephrotoxicity.

  13. Cyclosporine nephrotoxicity and early posttransplant hyperkalemia in living-donor renal recipients: report of 4 cases.

    Science.gov (United States)

    Pavleska-Kuzmanovska, Svetlana; Popov, Zivko; Ivanovski, Ognen; Ristovska, Vesna; Masin-Spasovska, Jelka; Rambabova-Busljetic, Irena; Ivanovski, Ninoslav

    2014-10-01

    Hyperkalemia is an electrolyte disorder that may occur during the first few months after a renal transplant, in patients undergoing cyclosporine immunosuppression. We present our experience with cyclosporine-associated hyperkalemia in living-donor renal transplant recipients, with isolated clinically relevant hyperkalemia soon after surgery. We report 4 living-donor renal recipients with hyperkalemia soon after transplant. Severe unexpected hyperkalemia (7.5- 9.4 mmol/L) was noted in our patients 12, 20, 22, and 34 days after transplant. The C2 cyclosporine concentration was within recommended range or slightly greater than 1200 ng/mL. The hypertonic glucose/insulin treatment along with potassium diet was without results. A reduction in daily cyclosporine dosages, along with 1- to 2-week administration of fludrocortisone was effective. The patients became normokalemic taking a standard, triple-drug immunosuppression protocol, and were discharged home with normal renal function. There were no repeat episodes of hyperkalemia in any of the patients during 12 months of follow-up. Cyclosporine should be considered a cause of hyperkalemia in renal transplant recipients. Successful treatment with fludrocortisone confirms that transitional pseudohypoaldosteronism has a potential nephrotoxic effect of cyclosporine. We recommend close monitoring of the cyclosporine concentration and administering fludrocortisone when treating hyperkalemia in renal transplant recipients.

  14. Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines.

    Science.gov (United States)

    Mahmoud, Mona F; El Shazly, Shimaa M

    2013-01-01

    Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated. Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.

  15. Interventions to improve chronic cyclosporine A nephrotoxicity through inhibiting renal cell apoptosis: a systematic review

    Institute of Scientific and Technical Information of China (English)

    XIAO Zheng; LI Cheng-wen; SHAN Juan; LUO Lei; FENG Li; LU Jun; LI Sheng-fu

    2013-01-01

    Objective To reveal interventions for chronic cyclosporine A nephrotoxicity (CCN) and provide new targets for further studies,we analyzed all relevant studies about interventions in renal cell apoptosis.Data sources We collected all relevant studies about interventions for cyclosporine A (CsA)-induced renal cell apoptosis in Medline (1966 to July 2010),Embase (1980 to July 2010) and ISI (1986 to July 2010),evaluated their quality,extracted data following PICOS principles and synthesized the data.Study selection We included all relevant studies about interventions in CsA-induced renal cell apoptosis no limitation of research design and language) and excluded the duplicated articles,meeting abstracts and reviews without specific data.Results There were three kinds of intervention,include anti-oxidant (sulfated polysaccharides,tea polyphenols,apigenin,curcumin,spirulina,etc),biologics (recombinant human erythropoietin (rhEPO),a murine pan-specific transforming growth factor (TGF)-beta-neutralizing monoclonal antibody1D11,cartilage oligomeric matrix protein (COMP)-angiopoietin-1 and hepatocyte growth factor (HGF) gene),and other drugs (spironolactone,rosiglitazone,pirfenidone and colchicine).These interventions significantly improved the CCN,renal cell apoptosis and renal dysfunction through intervening in four apoptotic pathways in animals or protected renal cells from apoptosis induced by CsA and increased cell survival through respectively four pathways in vitro.Conclusions There are three group interventions for CCN.Especially anti-oxidant drugs can significantly improve CCN,renal cell apoptosis and renal dysfunction.Many drugs can improve CCN through intervening in Fas/Fas ligand or mitochondrial pathway with sufficient evidences.Angiotensin Ⅱ,nitric oxide (NO) and endoplasmic reticulum (ER) pathways will be new targets for CCN.

  16. Protective Effect of Carvacrol on Renal Functional and Histopathological Changes in Gentamicin-Induced-Nephrotoxicity in Rats

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    Hassan Ahmadvand

    2016-04-01

    Full Text Available Background Nephrotoxicity is one of the most important side effects of the use of gentamicin sulphate (GS resulted in reactive oxygen species generation. Antioxidant compounds played effective roles in reduction of renal injuries caused by using of gentamicin. Carvacrol is a strong antioxidant compound. Objectives The aim of this study is to explore the effect of carvacrol inhibition in lesions of gentamicin-induced nephrotoxicity. Materials and Methods In this experimental study, 32 male mature Sprague-Dawley rats were divided into 4 groups of 8; group1: control, group 2 sham received daily carvacrol injection (74 mg/kg for 12 days, group 3 received daily GS injection (100 mg/kg for 12 days, group 4 received daily GS (100 mg/kg and carvacrol (74 mg/kg for 12 days. After 12 days, rats were anaesthetized, blood sample were obtained and kidneys were removed then stained with hematoxylin and eosin method and then were studied histophatologically. Serum creatinine and urea were measured. Results Flow treatment of nephrotoxic animals with carvacrol could significantly inhibit leukocyte infiltration (9.42% and tubular necrosis (38.18% in comparison with the nephrotoxic untreated group. Carvacrol significantly decreased the levels of urea and creatinine in treated group compared with the nephrotoxic untreated group. Conclusions The findings showed that carvacrol alleviates loss of leukocyte infiltration (9.42% and tubular necrosis and exerts beneficial effects on kidney function test in nephrotoxic group.

  17. Prospective Study to Assess Progression of Renal Markers after Interruption of Tenofovir due to Nephrotoxicity

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    Anna Bonjoch

    2016-01-01

    Full Text Available Background. Prospective studies about the reversibility of tenofovir disoproxil fumarate- (TDF- related renal impairment remain scarce. Methods. This is an observational prospective study including all patients that presented at our HIV Unit who interrupted TDF owing to nephrotoxicity. We assessed the evolution of renal parameters after discontinuation of this drug. Results. We included 59 patients, who were followed up for 72 weeks. Most were male (41, 69.5%, median (IQR age was 53 (44; 58 years, and median time receiving TDF-containing regimens was 55.4 (28; 87.7 months. Most patients were receiving PI-based treatments (67%. At the final visit, most of the subjects showed complete recovery (35, 59.3% or improvement (13 subjects, 22%. Significant improvements were observed in creatinine levels (from 84.9 [73.8; 97.5] to 78 [69.6; 91] μmol/L, p=0.013, estimated glomerular filtration rate (eGFR, CKD EPI equation, from 87.7 [67; 99] to 89.9 [73.6; 99.3] mL/min/1.73 m2, p=0.017, and number of patients with eGFR <60 mL/min/1.73 m2 (from 9 [15.3%] to 1 [1.7%], p=0.031. A trend toward significance was observed in abnormal urine proteinuria/creatinine ratio (from 22 [37%] to 8 [13.6%], p=0.057. Conclusions. Our results corroborate the high frequency of complete or partial renal recovery in patients receiving TDF-containing regimens who discontinued therapy owing to nephrotoxicity.

  18. Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    El-Kashef, Dalia H; El-Kenawi, Asmaa E; Abdel Rahim, Mona; Suddek, Ghada M; Salem, Hatem A

    2016-03-01

    The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.

  19. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Rubera, I; Duranton, C; Melis, N; Cougnon, M; Mograbi, B; Tauc, M

    2013-10-03

    The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl(-) channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR(inh)-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR(inh)-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR(inh)-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR(inh)-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR(inh)-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.

  20. Protective effect of pomegranate flower extract against gentamicin-induced renal toxicity in male rats

    OpenAIRE

    Sadeghi, Ferdos; Nematbakhsh, Mehdi; Noori-Diziche, Ali; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Nasri, Hamid; Mansouri, Azam; Dehghani, Aghdas; Saberi, Shadan; Shirdavani, Soheila; Ashrafi, Farzaneh

    2015-01-01

    Introduction: Gentamicin (GM) as an antibiotic is used in clinic. However, its administration is limited by side effects such as nephrotoxicity. Herbal extracts could be used in therapeutic approaches. Objectives: The present study was planned to investigate whether pomegranate flower extract (PFE) could ameliorate GM-induced renal toxicity in male rats. Materials and Methods: Twenty eight male Wistar rats were divided into 5 groups. Groups 1 and 2 respectively received PFE 25 and 50 mg/kg fo...

  1. Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity.

    Science.gov (United States)

    Matzke, G R; Frye, R F

    1997-03-01

    Renal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient's degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency. The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficiency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function. Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium

  2. Aminoglycoside nephrotoxicity: modeling, simulation, and control.

    Science.gov (United States)

    Rougier, Florent; Claude, Daniel; Maurin, Michel; Sedoglavic, Alexandre; Ducher, Michel; Corvaisier, Stéphane; Jelliffe, Roger; Maire, Pascal

    2003-03-01

    The main constraints on the administration of aminoglycosides are the risks of nephrotoxicity and ototoxicity, which can lead to acute, renal, vestibular, and auditory toxicities. In the present study we focused on nephrotoxicity. No reliable predictor of nephrotoxicity has been found to date. We have developed a deterministic model which describes the pharmacokinetic behavior of aminoglycosides (with a two-compartment model), the kinetics of aminoglycoside accumulation in the renal cortex, the effects of aminoglycosides on renal cells, the resulting effects on renal function by tubuloglomerular feedback, and the resulting effects on serum creatinine concentrations. The pharmacokinetic parameter values were estimated by use of the NPEM program. The estimated pharmacodynamic parameter values were obtained after minimization of the least-squares objective function between the measured and the calculated serum creatinine concentrations. A simulation program assessed the influences of the dosage regimens on the occurrence of nephrotoxicity. We have also demonstrated the relevancy of modeling of the circadian rhythm of the renal function. We have shown the ability of the model to fit with 49 observed serum creatinine concentrations for a group of eight patients treated for endocarditis by comparison with 49 calculated serum creatinine concentrations (r(2) = 0.988; P < 0.001). We have found that for the same daily dose, the nephrotoxicity observed with a thrice-daily administration schedule appears more rapidly, induces a greater decrease in renal function, and is more prolonged than those that occur with less frequent administration schedules (for example, once-daily administration). Moreover, for once-daily administration, we have demonstrated that the time of day of administration can influence the incidence of aminoglycoside nephrotoxicity. The lowest level of nephrotoxicity was observed when aminoglycosides were administered at 1:30 p.m. Clinical application of this

  3. Nephrotoxicity of methadone: a systematic review

    OpenAIRE

    Alinejad, Samira; Ghaemi, Kazem; Abdollahi, Mohammad; Mehrpour, Omid

    2016-01-01

    Background Methadone is commonly administered for chronic pain relief and treatment of opioid dependence. Concurrent with its increased consumption, toxicities and fatalities have increased. One of the adverse effects of opioid analgesics, including methadone, is that of nephrotoxicity. Opioids can have an effect on renal function through several different mechanisms. Methods We searched common bibliographical databases for the terms methadone, toxicity, poisoning, kidney, renal, and nephroto...

  4. Nephrotoxicity of Bence-Jones proteins: interference in renal epithelial cell acidification

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    Nicastri A.L.

    2002-01-01

    Full Text Available The aim of the present study was to evaluate the acidification of the endosome-lysosome system of renal epithelial cells after endocytosis of two human immunoglobulin lambda light chains (Bence-Jones proteins, BJP obtained from patients with multiple myeloma. Renal epithelial cell handling of two BJP (neutral and acidic BJP was evaluated by rhodamine fluorescence. Renal cells (MDCK were maintained in culture and, when confluent, were incubated with rhodamine-labeled BJP for different periods of time. Photos were obtained with a fluorescence microscope (Axiolab-Zeiss. Labeling density was determined on slides with a densitometer (Shimadzu Dual-Wavelength Flying-Spot Scanner CS9000. Endocytosis of neutral and acidic BJP was correlated with acidic intracellular compartment distribution using acridine orange labeling. We compared the pattern of distribution after incubation of native neutral and acidic BJP and after complete deglycosylation of BJP by periodate oxidation. The subsequent alteration of pI converted neutral BJP to acidic BJP. There was a significant accumulation of neutral BJP in endocytic structures, reduced lysosomal acidification, and a diffuse pattern of acidification. This pattern was reversed after total deglycosylation and subsequent alteration of the pI to an acidic BJP. We conclude that the physicochemical characteristics of BJP interfere with intracellular acidification, possibly explaining the strong nephrotoxicity of neutral BJP. Lysosomal acidification is fundamental for adequate protein processing and catabolism.

  5. Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer.

    Science.gov (United States)

    Knijnenburg, Sebastiaan L; Mulder, Renée L; Schouten-Van Meeteren, Antoinette Y N; Bökenkamp, Arend; Blufpand, Hester; van Dulmen-den Broeder, Eline; Veening, Margreet A; Kremer, Leontien C M; Jaspers, Monique W M

    2013-10-08

    Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival. However, childhood cancer survivors (CCS) are at great risk for developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is one of these known (acute) side effects of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate impairment, proteinuria, tubulopathy and hypertension. However, evidence about the long-term effects of these treatments on renal function remains inconclusive. To reduce the number of (long-term) nephrotoxic events in CCS, it is important to know the risk of, and risk factors for, early and late renal adverse effects, so that ultimately treatment and screening protocols can be adjusted. To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment. We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011). With the exception of case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment) in children and adults who were treated for a paediatric malignancy (aged 18 years or younger at diagnosis) with cisplatin, carboplatin, ifosfamide, radiation including the kidney region and/or a nephrectomy. Two review authors independently performed study selection, risk of bias

  6. The Effects of Nifedipine on Renal Perfusion Pressure and Kidney During Cisplatin-Induced Nephrotoxicity in Rats

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    Meral Erdinç

    2007-01-01

    Full Text Available Cisplatin is one of the most effective cancer chemotherapeutic agent used against various solid tumors. Nephrotoxicity is one of the major dose-limiting side effects of cisplatin. It has been known that different mechanisms as oxidative stress may play an important role in cisplatin induced nephrotoxicity resulted with changes in renal haemodynamics. This study was performed to investigate the effect of nifedipine –one of the dihydropyridine calcium antagonist on changes in renal perfusion pressures and kidneys of rats with cisplatin nephrotoxicity. Male wistar albino rats were divided into 3 groups (n=8:1-Control group(1 ml saline. i.p 2-Cisplatin group (a single dose of cisplatin (5 mg/kg, i.p 3- A single dose of cisplatin (5 mg/kg, i.p + Nifedipine (2 mg/kg/day, i.p for five days. When those pre-treated groups compared with control group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels were found significantly higher in cisplatin group (p<0.001. Histopathological examination showed widespread tubular necrosis and dilatation in cisplatin-treated group versus other groups. In cisplatin + nifedipine pretreated group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels found significantly lower than cisplatin group (p<0. 001 and less tubular dilatation and necrosis was observed. As a result it was demonstrated that Nifedipine has protective effects against cisplatin nephrotoxicity. We suggest that this is partly provided by the beneficial effects of nifedipine on altered renal haemodynamics during cisplatin nephrotoxicity.

  7. Relationship between cisplatin or nedaplatin-induced nephrotoxicity and renal accumulation.

    Science.gov (United States)

    Kawai, Yoshiko; Taniuchi, Saburo; Okahara, Shigeki; Nakamura, Masuhisa; Gemba, Munekazu

    2005-08-01

    Nedaplatin is known to exhibit antitumor activity similar to that of cisplatin. However, concerning side effects, nedaplatin causes renal toxicity less frequently than cisplatin. In this study, we compared the incidence of renal toxicity between cisplatin and nedaplatin by investigating the difference in kidney tissue accumulation. Kidney tissue accumulation of cisplatin administered at 3.75 mg/kg was similar to that of nedaplatin administered at 24 mg/kg. At these doses, the plasma creatinine level and urinary excretion of glucose and N-acetyl-beta-D-glucosaminidase (NAG) similarly increased. There was a correlation between kidney accumulation of cisplatin and nedaplatin and the increases in plasma creatinine level and urinary excretion of NAG. Therefore, our results suggest that nedaplatin less frequently causes renal toxicity in comparison to cisplatin due to lower kidney accumulation.

  8. Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis.

    Science.gov (United States)

    Xia, Yumin; Campbell, Sean R; Broder, Anna; Herlitz, Leal; Abadi, Maria; Wu, Ping; Michaelson, Jennifer S; Burkly, Linda C; Putterman, Chaim

    2012-11-01

    Previously it was shown that the TNF superfamily member TWEAK (TNFSF12) acts through its receptor, Fn14, to promote proinflammatory responses in kidney cells, including the production of MCP-1, RANTES, IP-10 and KC. In addition, the TWEAK/Fn14 pathway promotes mesangial cell proliferation, vascular cell activation, and renal cell death. To study the relevance of the TWEAK/Fn14 pathway in the pathogenesis of antibody-induced nephritis using the mouse model of nephrotoxic serum nephritis (NTN), we induced NTN by passive transfer of rabbit anti-glomerular antibodies into Fn14 knockout (KO) and wild type (WT) mice. Severe proteinuria as well as renal histopathology were induced in WT but not in Fn14 KO mice. Similarly, a pharmacologic approach of anti-TWEAK mAb administration into WT mice in the NTN model significantly ameliorated proteinuria and improved kidney histology. Anti-TWEAK treatment did not affect the generation of mouse anti-rabbit antibodies; however, within the kidney there was a significant decrease in glomerular immunoglobulin deposition, as well as macrophage infiltrates and tubulointerstitial fibrosis. The mechanism of action is most likely due to reductions in downstream targets of TWEAK/Fn14 signaling, including reduced renal expression of MCP-1, VCAM-1, IP-10, RANTES as well as Fn14 itself, and other molecular pathways associated with fibrosis in anti-TWEAK treated mice. Thus, TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the NTN model, apparently mediating a cascade of pathologic events locally in the kidney rather than by impacting the systemic immune response. Disrupting TWEAK/Fn14 interactions may be an innovative kidney-protective approach for the treatment of lupus nephritis and other antibody-induced renal diseases.

  9. Lithium-induced Nephrotoxicity: A Case Report of Renal Cystic Disease Presenting as a Mass Lesion

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    Yvonne McCartney

    2014-11-01

    Full Text Available Lithium is an effective therapeutic agent used in the management of bipolar disorder. However, lithium is also associated with several side effects, including renal toxicity. We present a case of a symptomatic cystic mass lesion in the kidney of a patient who had a history of lithium therapy for the management of bipolar disorder.

  10. Far infrared radiation promotes rabbit renal proximal tubule cell proliferation and functional characteristics, and protects against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Chiang, I-Ni; Pu, Yeong-Shiau; Huang, Chao-Yuan; Young, Tai-Horng

    2017-01-01

    Far infrared radiation, a subdivision of the electromagnetic spectrum, is beneficial for long-term tissue healing, anti-inflammatory effects, growth promotion, sleep modulation, acceleration of microcirculation, and pain relief. We investigated if far infrared radiation is beneficial for renal proximal tubule cell cultivation and renal tissue engineering. We observed the effects of far infrared radiation on renal proximal tubules cells, including its effects on cell proliferation, gene and protein expression, and viability. We also examined the protective effects of far infrared radiation against cisplatin, a nephrotoxic agent, using the human proximal tubule cell line HK-2. We found that daily exposure to far infrared radiation for 30 min significantly increased rabbit renal proximal tubule cell proliferation in vitro, as assessed by MTT assay. Far infrared radiation was not only beneficial to renal proximal tubule cell proliferation, it also increased the expression of ATPase Na+/K+ subunit alpha 1 and glucose transporter 1, as determined by western blotting. Using quantitative polymerase chain reaction, we found that far infrared radiation enhanced CDK5R1, GNAS, NPPB, and TEK expression. In the proximal tubule cell line HK-2, far infrared radiation protected against cisplatin-mediated nephrotoxicity by reducing apoptosis. Renal proximal tubule cell cultivation with far infrared radiation exposure resulted in better cell proliferation, significantly higher ATPase Na+/K+ subunit alpha 1 and glucose transporter 1 expression, and significantly enhanced expression of CDK5R1, GNAS, NPPB, and TEK. These results suggest that far infrared radiation improves cell proliferation and differentiation. In HK-2 cells, far infrared radiation mediated protective effects against cisplatin-induced nephrotoxicity by reducing apoptosis, as indicated by flow cytometry and caspase-3 assay.

  11. N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity.

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    Leonardo Victor Barbosa Pereira

    Full Text Available The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC. Male Wistar rats were submitted to 5/6 nephrectomy (Nx to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine was administrated (1.5 mM/KgBW, intravenously 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1--Nx (n = 7; 2--Nx+NAC (n = 6; 3--Nx+Gd (n = 7; 4--Nx+NAC+Gd (4.8 g/L in drinking water, initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6. This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW, proteinuria (mg/24 hs, serum iron (µg/dL; serum ferritin (ng/mL; transferrin saturation (%, TIBC (µg/dL and TBARS (nmles/ml. Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.

  12. [PK/PD modeling of aminoglycoside nephrotoxicity].

    Science.gov (United States)

    Rougier, F; Corvaisier, S; Ducher, M; Claude, D; Jelliffe, R W; Maire, P

    2003-06-01

    Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

  13. Renal liver-type fatty acid binding protein (L-FABP) attenuates acute kidney injury in aristolochic acid nephrotoxicity.

    Science.gov (United States)

    Matsui, Katsuomi; Kamijo-Ikemorif, Atsuko; Sugaya, Takeshi; Yasuda, Takashi; Kimura, Kenjiro

    2011-03-01

    Injection of aristolochic acid (AA) in mice causes AA-induced nephrotoxicity, in which oxidative stress contributes to development of tubulointerstitial damage (TID). Liver-type fatty acid binding protein (L-FABP) is expressed in human proximal tubules and has an endogenous antioxidative function. The renoprotection of renal L-FABP was examined in a model of AA-induced nephrotoxicity. Established human L-FABP (hL-FABP) transgenic (Tg) mice and wild-type (WT) mice were treated with AA for up to 5 days. Mice were sacrificed on days 1, 3, and 5 after the start of AA injection. Although mouse L-FABP was not expressed in proximal tubules of WT mice, hL-FABP was expressed in proximal tubules of Tg mice. The expression of renal hL-FABP was significantly increased in Tg mice administered AA (Tg-AA), compared with the control (saline-treated Tg mice). In WT-AA mice, there was high urinary excretion of N(ε)-(hexanoyl)-lysine, the production of heme oxygenase-1 and receptor for advanced glycation end products increased, and TID was provoked. In contrast, renal hL-FABP in Tg-AA mice suppressed production of N(ε)-(hexanoyl)lysine, heme oxygenase-1, and receptor for advanced glycation end products. Renal dysfunction was significantly milder in Tg-AA mice than in WT-AA mice. The degree of TID was significantly attenuated in Tg-AA mice, compared with WT-AA. In conclusion, renal hL-FABP reduced the oxidative stress in AA-induced nephrotoxicity and attenuated TID.

  14. Mentha piperita in nephrotoxicity - a possible intervention to ameliorate renal derangements associated with gentamicin

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    Naveed Ullah

    2014-01-01

    Full Text Available Objective: Free radical generation has a strong role in the pathogenesis of renal damage associated with the use of gentamicin. Therefore, the present study was carried out to evaluate the renoprotective effect of Mentha piperita against gentamicin induced nephrotoxicity. Materials and Methods: A total of 24 male rabbits were divided into 4 groups receiving normal saline, gentamicin, M. piperita extract and co-therapy of extract and gentamicin respectively. Gentamicin was provided as 80 mg/kg/day intramuscularly and extract was given 200 mg/kg/day orally for a period of 21 days. Serum and urinary biochemical parameters and histological changes were studied for each group. The impact of the extract on the antibacterial action of gentamicin was also evaluated. Results: Animals treated with gentamicin showed derangements in serum and urinary biochemical parameters. These alterations were reversed by treatment with M. piperita extract. The histological changes showed in gentamicin group were also reverted by treatment with the extract. Further the plant did not influence the efficacy of gentamicin with respect to its antimicrobial properties. Conclusion: Co-therapy of M. piperita with gentamicin successfully attenuated biochemical kidney functioning derangements and morphological changes associated with gentamicin.

  15. Cell- and biomarker-based assays for predicting nephrotoxicity.

    Science.gov (United States)

    Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A

    2014-12-01

    Drug-induced nephrotoxicity contributes to the failure rate of investigational drugs during clinical trials. We are still not able to accurately predict drug-induced nephrotoxicity during early drug discovery and development. There is an urgent need for a robust screening system that can identify nephrotoxic compounds before they reach the clinic. This review discusses traditional and emerging kidney injury biomarkers that are used for the determination of nephrotoxicity and for evaluation and diagnosis of other kidney diseases. The potential for in vivo biomarkers to predict renal toxicity in high-throughput in vitro screening assays is discussed. We also compare cell types and highlight novel three-dimensional (3D) culture technologies with potential for in vitro prediction of nephrotoxicity. Traditional cell culture methods and cytotoxicity assays are well established as in vitro tests for nephrotoxicity but the correlation with in vivo results is extremely poor. Recently validated renal biomarkers show promise for early in vivo detection of nephrotoxicity, but have yet to be successfully applied for in vitro prediction of drug-induced nephrotoxicity. Advanced culture technologies 'kidney-on-a-chip' and 3D culture can produce biomarker signatures from relevant kidney cell types that show promise as better predictive systems.

  16. Renal toxicity of the anticancer drug fostriecin

    NARCIS (Netherlands)

    de Vries, EGE; Meijer, S; Mulder, NH; de Jong, Paul; de Jong, Robert

    Purpose: Fostriecin is an inhibitor of topoisomerase II catalytic activity. In a phase I trial we observed renal toxicity, documented as a rise in serum creatinine, which was reversible and non-dose-limiting. The purpose of this study was a detailed analysis of this toxicity. Methods: A total of 20

  17. Disparity in actions of rosiglitazone against cisplatin-induced nephrotoxicity in female Sprague-Dawley rats.

    Science.gov (United States)

    Kumar, Parveen; Prashanth, Krishna Shastrula; Gaikwad, Anil Bhanudas; Vij, Mohit; Barua, Chandana C; Bezbaruah, Babul

    2013-11-01

    Cisplatin is one of the most common chemotherapeutic drugs used against various solid, tumours. Despite of its therapeutic benefits, its use in clinical practice is often limited because of dose, related toxicity. The nephrotoxic potential of cisplatin has been ascribed to its accumulation in the, renal tubular cells generating reactive oxygen species (ROS), activation of Bax, increased secretion of, TNFα and activation of certain inflammatory mediators like cytokines. The present investigation was, undertaken with an objective to study the effect of rosiglitazone against cisplatin induced, nephrotoxicity. Pretreatment of rosiglitazone prevents cisplatin induced nephrotoxicity which was, clearly evident from the renal biochemical parameters like reduced BUN, creatinine and TNFα levels, and increased albumin levels, which was also supported by histopathological studies of the kidneys. In contrast, posttreatment of rosiglitazone was not able to protect the renal damage in cisplatin induced, renal toxicity. These results showed the variation of pre & posttreatment effects of rosiglitazone, against the cisplatin induced nephrotoxicity.

  18. Nephrotoxicity of HAART

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    Robert Kalyesubula

    2011-01-01

    Full Text Available Highly active antiretroviral therapy (HAART and other medical therapies for HIV-related infections have been associated with toxicities. Antiretroviral therapy can contribute to renal dysfunction directly by inducing acute tubular necrosis, acute interstitial nephritis, crystal nephropathy, and renal tubular disorders or indirectly via drug interactions. With the increase in HAART use, clinicians must screen patients for the development of kidney disease especially if the regimen employed increases risk of kidney injury. It is also important that patients with chronic kidney disease (CKD are not denied the best combinations, especially since most drugs can be adjusted based on the estimated GFR. Early detection of risk factors, systematic screening for chronic causes of CKD, and appropriate referrals for kidney disease management should be advocated for improved patient care. The interaction between immunosuppressive therapy and HAART in patients with kidney transplants and the recent endorsement of tenofovir/emtricitabine by the Centers for Disease Control (CDC for preexposure prophylaxis bring a new dimension for nephrotoxicity vigilance. This paper summarizes the common antiretroviral drugs associated with nephrotoxicity with particular emphasis on tenofovir and protease inhibitors, their risk factors, and management as well as prevention strategies.

  19. Age-related differences in susceptibility to cisplatin-induced renal toxicity.

    Science.gov (United States)

    Espandiari, P; Rosenzweig, B; Zhang, J; Zhou, Y; Schnackenberg, L; Vaidya, V S; Goering, P L; Brown, R P; Bonventre, J V; Mahjoob, K; Holland, R D; Beger, R D; Thompson, K; Hanig, J; Sadrieh, N

    2010-03-01

    Limited experimental models exist to assess drug toxicity in pediatric populations. We recently reported how a multi-age rat model could be used for pre-clinical studies of comparative drug toxicity in pediatric populations. The objective of this study was to expand the utility of this animal model, which previously demonstrated an age-dependent sensitivity to the classic nephrotoxic compound, gentamicin, to another nephrotoxicant, namely cisplatin (Cis). Sprague-Dawley rats (10, 25, 40 and 80 days old) were injected with a single dose of Cis (0, 1, 3 or 6 mg kg(-1) i.p.). Urine samples were collected prior and up to 72 h after treatment in animals that were >or= 25 days old. Several serum, urinary and 'omic' injury biomarkers as well as renal histopathology lesions were evaluated. Statistically significant changes were noted with different injury biomarkers in different age groups. The order of age-related Cis-induced nephrotoxicity was different than our previous study with gentamicin: 80 > 40 > 10 > 25 day-old vs 10 >or= 80 > 40 > 25-day-old rats, respectively. The increased levels of kidney injury molecule-1 (Kim-1: urinary protein/tissue mRNA) provided evidence of early Cis-induced nephrotoxicity in the most sensitive age group (80 days old). Levels of Kim-1 tissue mRNA and urinary protein were significantly correlated to each other and to the severity of renal histopathology lesions. These data indicate that the multi-age rat model can be used to demonstrate different age-related sensitivities to renal injury using mechanistically distinct nephrotoxicants, which is reflected in measurements of a variety of metabolite, gene transcript and protein biomarkers.

  20. Gadolinium contrast media are more nephrotoxic than iodine media. The importance of osmolality in direct renal artery injections

    Energy Technology Data Exchange (ETDEWEB)

    Elmstaahl, Barbara; Leander, Peter; Almen, Torsten [Malmoe University Hospital, Lund University, Department of Diagnostic Radiology, Malmoe (Sweden); Nyman, Ulf [Lasarettet Trelleborg, Department of Radiology, Trelleborg (Sweden); Chai, Chun-Ming [Malmoe University Hospital, Lund University, Department of Experimental Research, Malmoe (Sweden); Golman, Klaes [Biosciences, GE Health, Malmoe (Sweden); Bjoerk, Jonas [University Hospital, Lund University, Competence Center for Clinical Research, Lund (Sweden)

    2006-12-15

    A study was undertaken of the role of osmotoxicity in gadolinium (Gd) and iodine contrast media (CM) nephrotoxicity in ischemic porcine kidneys. Test solutions: mannitol iso-osmotic to 0.5 M gadopentetate (1.96 Osm/kg H{sub 2}O), 0.5 M gadodiamide (0.78 Osm/kg H{sub 2}O) and 0.5 M iohexol (190 mg I/ml, 0.42 Osm/kg H{sub 2}O). Each solution was injected [3 ml/kg body weight (BW)] into the balloon-occluded (10 min) renal artery of eight left-sided nephrectomized pigs. The plasma half-life of a glomerular filtration rate (GFR) marker was used to compare their effects on GFR 1-3 h post-injection. The median half-lives of the GFR marker after injection of gadopentetate (1,730 min) and mannitol 1.96 Osm/kg H{sub 2}O (2,782 min) did not differ statistically (P=0.28), but were significantly longer than after all other solutions (P<0.001). There was no significant difference (P=0.06) between gadodiamide (218 min) and mannitol 0.82 Osm/kg H{sub 2}O (169 min), while there was (P=0.03) between iohexol (181 min) and mannitol 0.43 Osm/kg H{sub 2}O (148 min). The difference between gadodiamide and iohexol was significant (P=0.01). Reduction in GFR, as a marker of nephrotoxicity, induced by gadopentetate correlated with its high osmolality, while the effect of gadodiamide and iohexol may include chemotoxicity. Iohexol molecules were less nephrotoxic than the Gd-CM molecules and contain three-times the number of attenuating atoms per molecule. (orig.)

  1. L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake

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    Yakup Yürekli

    2011-04-01

    Full Text Available Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake. Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1 Control (saline; 5 ml/kg intraperitoneally; 2 L-carnitine (CAR; 300 mg/kg intraperitoneally; 3 Amifostine (AMI; 200 mg /kg intraperitoneally; 4 Cisplatin (CIS;7 mg/kg intraperitoneally; 5 Cisplatin plus L-carnitine (CIS + CAR; 6 Cisplatin plus amifostine (CIS + AMI. L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA and reduced glutathione (GSH in kidney tissue homogenates. Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01, in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002. A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue. Conclusion: The results showed that L-carnitine significantly

  2. Melamine-induced renal toxicity is mediated by the gut microbiota.

    Science.gov (United States)

    Zheng, Xiaojiao; Zhao, Aihua; Xie, Guoxiang; Chi, Yi; Zhao, Linjing; Li, Houkai; Wang, Congrong; Bao, Yuqian; Jia, Weiping; Luther, Mike; Su, Mingming; Nicholson, Jeremy K; Jia, Wei

    2013-02-13

    Melamine poisoning has become widely publicized after a recent occurrence of renal injury in infants and children exposed to melamine-tainted milk in China. This renal damage is believed to result from kidney stones formed from melamine and uric acid or from melamine and its cocrystallizing chemical derivative, cyanuric acid. However, the composition of the stones and the mechanism by which the stones are formed in the renal tubules are unknown. We report that cyanuric acid can be produced in the gut by microbial transformation of melamine and serves as an integral component of the kidney stones responsible for melamine-induced renal toxicity in rats. Melamine-induced toxicity in rats was attenuated and melamine excretion increased after antibiotic suppression of gut microbial activity [corrected]. We further demonstrated that melamine is converted to cyanuric acid in vitro by bacteria cultured from normal rat feces; Klebsiella was subsequently identified in fecal samples by 16S ribosomal DNA sequencing. In culture, Klebsiella terrigena was shown to convert melamine to cyanuric acid directly. Rats colonized by K. terrigena showed exacerbated melamine-induced nephrotoxicity. Cyanuric acid was detected in the kidneys of rats administered melamine alone, and the concentration after Klebsiella colonization was increased. These findings suggest that the observed toxicity of melamine may be conditional on the exact composition and metabolic activities of the gut microbiota.

  3. Mesenchymal stem cell-conditioned medium accelerates regeneration of human renal proximal tubule epithelial cells after gentamicin toxicity.

    Science.gov (United States)

    Moghadasali, Reza; Mutsaers, Henricus A M; Azarnia, Mahnaz; Aghdami, Nasser; Baharvand, Hossein; Torensma, Ruurd; Wilmer, Martijn J G; Masereeuw, Rosalinde

    2013-07-01

    Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity to regenerate renal tubule epithelia and repair renal function without fusing with resident tubular cells. The goal of the present project was to investigate the role of MSCs secreted cytokines on tubule cell viability and regeneration after a toxic insult, using a conditionally immortalized human proximal tubule epithelial cell (ciPTEC) line. Gentamicin was used to induce nephrotoxicity, and cell viability and migration were studied in absence and presence of human MSC-conditioned medium (hMSC-CM) i.e. medium containing soluble factors produced and secreted by MSCs. Exposure of ciPTEC to 0-3000 μg/ml gentamicin for 24 h caused a significant dose-dependent increase in cell death. We further demonstrated that the nephrotoxic effect of 2000 μg/ml gentamicin was recovered partially by exposing cells to hMSC-CM. Moreover, exposure of ciPTEC to gentamicin (1500-3000 μg/ml) for 7 days completely attenuated the migratory capacity of the cells. In addition, following scrape-wounding, cell migration of both untreated and gentamicin-exposed cells was increased in the presence of hMSC-CM, as compared to exposures to normal medium, indicating improved cell recovery. Our data suggest that cytokines secreted by MSCs stimulate renal tubule cell regeneration after nephrotoxicity. Copyright © 2012 Elsevier GmbH. All rights reserved.

  4. EVALUATION OF NEPHRO-PROTECTIVE AND ANTI-NEPHRO-TOXIC PROPERTIES OF RAKTA PUNARNAVA ROOTS (Boerhaavia diffusa, L. GOKSHUR FRUITS (Tribulus terrestris, L. IN DRUG INDUCED NEPHROTOXICITY

    Directory of Open Access Journals (Sweden)

    Kulkarni Yogini Ramachandra

    2012-07-01

    Full Text Available Kwath of Rakta Punarnava roots (Boerhaavia diffusa, L. and Gokshur fruits (Tribulus terrestris,L. were tried for their Nephro-protective and anti-nephro-toxic properties by using Gentamycin induced Nephro-toxic model in Wistar strain Albino Rats. The effects were assessed on the basis of Biochemical and Histo-pathological investigations. Both the selected drugs have proven statistically significant results as Nephro-protective agent whereas Punarnava has got pronounced anti-nephro-toxic action too.

  5. Toxicity testing of saponin-containing Yucca schidigera Roetzl. juice in relation to hepato- and nephrotoxicity of Narthecium ossifragum (L.) Huds.

    Science.gov (United States)

    Wisløff, Helene; Uhlig, Silvio; Scheie, Eldri; Loader, Jared; Wilkins, Alistair; Flåøyen, Arne

    2008-01-01

    Yucca schidigera juice in doses of 1.5 g (63 mg sapogenin) and 3.0 g (126 mg sapogenin) per kg live weight was administered intraruminally to 30 lambs for 21 days to investigate whether the saponins in Y. schidigera were toxic to lambs and whether they could cause hepatogenous photosensitisation. Twelve lambs died or had to be euthanised. The main pathological findings in the diseased lambs were acute tubular necrosis in the kidneys, dehydration and watery content in the gastrointestinal tract. Fifteen lambs were euthanised at the end of the study, and the main pathological findings in dosed animals were accumulation of homogeneous pale PAS-positive material in the hepatocytes. There was a rise in serum creatinine and urea concentrations in the lambs with renal lesions the day before they died. Major Y. schidigera-related saponins were found in the liver and kidney samples from all lambs that were dosed with Y. schidigera juice. The results of the present study demonstrate that un-hydrolysed saponins can be absorbed from the gastrointestinal tract. The possible role of saponins in causing nephrotoxicity is discussed.

  6. Tenofovir Nephrotoxicity: 2011 Update

    Directory of Open Access Journals (Sweden)

    Beatriz Fernandez-Fernandez

    2011-01-01

    Full Text Available Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study.

  7. Engineered renal tissue as a potential platform for pharmacokinetic and nephrotoxicity testing.

    Science.gov (United States)

    Davies, Jamie

    2014-06-01

    Pharmacology and regenerative medicine interact in two ways. One is the use of drugs to promote tissue regeneration. The other, less obvious but with great potential, is the use of techniques developed for regenerative medicine to engineer realistic human organoids for drug screening. This review focuses on testing for nephrotoxicity, often a problem with drugs and poorly predicted in animals. Current human-based screens mainly use proximal tubule cells growing in 2D monolayers. Realism might be improved by collagen-based culture systems that encourage proximal tubule cells to grow as tubules. More realistic would be a recently developed technique for engineering functioning 'mini-kidneys' from suspensions of stem cells, a technique that works in mouse but that could also be applied to humans. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Toxicity of uranium on renal cells

    Energy Technology Data Exchange (ETDEWEB)

    Thiebault, C.; Carriere, M.; Gouget, B. [CEA Saclay, CNRS, UMR9956, Lab Pierre Sue, F-91191 Gif Sur Yvette, (France)

    2007-07-01

    Kidney and bone are the main retention organs affected by uranium toxicity. Although the clinical effects of uranium poisoning are well known, only few studies dealt with cellular mechanisms of toxicity. The purpose of this study was to investigate the cyto- and genotoxicity of uranium (U) on renal cells. The cell death was also studied in this conditions of exposure. The effects of U were evaluated in acute and chronic exposure. The acute effects were evaluated after 24 h exposure to strong U concentrations (200-700{mu}M). The chronic exposure was observed on renal cells incubated with low U concentrations (0.1-100 {mu}M) until 70 days then with high uranium concentrations (400-500 {mu}M) during 24 h. U induces apoptosis cell death mainly by the intrinsic pathway. The high U concentrations (600-700 {mu}M) lead to necrosis. U induces DNA damages (single, double strand breaks, as well as alkali labile sites) from 300{mu}M. The cytotoxicity and intracellular accumulation of uranium were less important in cells previously exposed to low uranium concentrations when compared to non-exposed cells. In the same time, DNA damage observed after acute exposure of uranium decreased with the increase of chronic uranium concentrations. These results suggest that renal cells became resistant to uranium, probably due to a cellular transformation process. In conclusion, high U concentrations (300-700{mu}M) induce apoptosis cell death and DNA damages. Cells previously exposed to low U concentrations present also DNA damages and a cellular transformation. (authors)

  9. Evidence for renal ischaemia as a cause of mercuric chloride nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Girardi, G. [Farmacologia, Facultad de Ciencias Bioquimicas y Farmaceuticas, Rosario (Argentina); Elias, M.M. [Farmacologia, Facultad de Ciencias Bioquimicas y Farmaceuticas, Rosario (Argentina)

    1995-09-01

    The present study was undertaken to investigate if the source of oxidative stress and the renal injury produced by mercuric chloride could be renal ischaemia. Verapamil Vp was used because it was described that calcium channel blockers protect cells from nephrotoxicants and from ischaemia. Vp (75 {mu}g/kg, i.v.; 30 min before HgCl{sub 2} injection) prevented mercuric chloride renal injury observed 1 h post-HgCl{sub 2} injection as measured by clearance techniques. Vp also prevented the diminution of non-protein-sulfhydryls (NPSH) and the increased lipd peroxidation (LPO) induced by HgCl{sub 2} in renal tissue. Hg{sup 2+} toxicokinetic alterations were not observed in Vp plus HgCl{sub 2} treated rats, nor was Vp ability found as a free radical scavenger in renal tissue homogenates. The results described in this study give some evidence for the role of renal ischaemia in the production of oxidative stress, generating LPO and functional and morphological renal injury described in mercuric chloride treated rats. (orig.)

  10. Total antioxidant and oxidant status of plasma and renal tissue of cisplatin-induced nephrotoxic rats: protection by floral extracts of Calendula officinalis Linn.

    Science.gov (United States)

    Verma, Pawan Kumar; Raina, Rajinder; Sultana, Mudasir; Singh, Maninder; Kumar, Pawan

    2016-01-01

    The present study was aimed to determine the total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) of plasma and renal tissue in cisplatin (cDDP) induced nephrotoxic rats and its protection by treatments with floral extracts of Calendula officinalis Linn. Treatment with cDDP elevated (p GSH) and antioxidant enzymes compared to the control group. Pre- and post-treatments of ethanolic floral extract of C. officinalis along with cDDP restored (p > 0.05) CR, albumin, TOS, GSH and activities of antioxidant enzymes in blood and renal tissue. Ethanolic extract treatments reduced (p < 0.05) MDA level in renal tissue without restoring the erythrocyte MDA level following cDDP treatment. These observations were further supported by the histopathological findings in renal tissue. Observations of the present study have shown that treatments with ethanolic floral extract of C. officinalis protect cDDP induced nephrotoxicity by restoring antioxidant system of the renal tissue.

  11. Nephrotoxicity of recreational party drugs.

    Science.gov (United States)

    Berney-Meyer, Linda; Putt, Tracey; Schollum, John; Walker, Robert

    2012-02-01

    N-benzylpiperazine (BZP) is the active ingredient in recreational 'party' pills with a stimulant, euphoric mechanism of action akin to that of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). Many people (ab)use BZP-based party pills usually without any significant toxic effects. However, nephrotoxicity secondary to hyperthermia and rhabdomyolysis has been reported. Another serious renal-related side-effect is hyponatraemia with acute cerebral oedema. There is also evidence that these agents may have a specific toxic effect producing acute kidney injury. Thus, acute kidney injury either direct or secondary to the effects of BZP or MDMA need to be considered when any individual presents with symptoms of a recreational party drug overdose.

  12. Eruca sativa seeds possess antioxidant activity and exert a protective effect on mercuric chloride induced renal toxicity.

    Science.gov (United States)

    Sarwar Alam, M; Kaur, Gurpreet; Jabbar, Zoobi; Javed, Kaleem; Athar, Mohammad

    2007-06-01

    Mercuric chloride (HgCl(2)) is a well-known nephrotoxic agent. Increasing number of evidences suggest the role of oxidative stress in HgCl(2) induced nephrotoxicity. Eruca sativa is widely used in folklore medicines and has a good reputation as a remedy of renal ailments. In the present study, the antioxidant potential of ethanolic extract of E. sativa seeds was determined and its protective effect on HgCl(2) induced renal toxicity was investigated. The extract was found to possess a potent antioxidant effect, with a large amount of polyphenols and a high reducing ability. HPLC analysis of the extract revealed glucoerucin and flavonoids to be the major antioxidants present in it. E. sativa extract significantly scavenged several reactive oxygen species (ROS) and reactive nitrogen species (RNS). Feeding of the extract to rats afforded a significant protection against HgCl(2) induced renal toxicity. Subcutaneous administration of 4 mg/kg body weight HgCl(2) induced renal injury evident as a marked elevation in serum creatinine and blood urea nitrogen levels, and histopathological changes such as necrosis, oedema and congestion of stroma and glomeruli. Oxidative modulation of renal tissues following HgCl(2) exposure was evident from a significant elevation in lipid peroxidation and attenuation in glutathione (GSH) contents and activities of antioxidant enzymes viz., catalase (CAT), glutathione peroxidase (GPX), superoxide dismutase (SOD) and glutathione reductase (GR). Oral administration of E. sativa extract to rats at a dose regimen: 50-200 mg/kg body weight for 7 days prior to HgCl(2) treatment significantly and dose dependently protected against alterations in all these diagnostic parameters. The data obtained in the present study suggests E. sativa seeds to possess a potent antioxidant and renal protective activity and preclude oxidative damage inflicted to the kidney.

  13. Lithium nephrotoxicity revisited.

    Science.gov (United States)

    Grünfeld, Jean-Pierre; Rossier, Bernard C

    2009-05-01

    Lithium is widely used to treat bipolar disorder. Nephrogenic diabetes insipidus (NDI) is the most common adverse effect of lithium and occurs in up to 40% of patients. Renal lithium toxicity is characterized by increased water and sodium diuresis, which can result in mild dehydration, hyperchloremic metabolic acidosis and renal tubular acidosis. The concentrating defect and natriuretic effect develop within weeks of lithium initiation. After years of lithium exposure, full-blown nephropathy can develop, which is characterized by decreased glomerular filtration rate and chronic kidney disease. Here, we review the clinical and experimental evidence that the principal cell of the collecting duct is the primary target for the nephrotoxic effects of lithium, and that these effects are characterized by dysregulation of aquaporin 2. This dysregulation is believed to occur as a result of the accumulation of cytotoxic concentrations of lithium, which enters via the epithelial sodium channel (ENaC) on the apical membrane and leads to the inhibition of signaling pathways that involve glycogen synthase kinase type 3beta. Experimental and clinical evidence demonstrates the efficacy of the ENaC inhibitor amiloride for the treatment of lithium-induced NDI; however, whether this agent can prevent the long-term adverse effects of lithium is not yet known.

  14. Insuficiência renal aguda nefrotóxica: prevalência, evolução clínica e desfecho Nephrotoxic acute renal failure: prevalence, clinical course and outcome

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    Patrícia S. Pinto

    2009-09-01

    Full Text Available INTRODUÇÃO: A insuficiência renal aguda (IRA nefrotóxica é frequente e importante causa de morbimortalidade. OBJETIVO: Avaliar a prevalência, o curso clínico e o desfecho da IRA nefrotóxica. PACIENTES e MÉTODOS: Coorte histórica realizada em um hospital de ensino terciário, no período de fevereiro a novembro de 1997. Foram incluídos pacientes acima de 12 anos, com diagnóstico de IRA, acompanhados pela equipe de Interconsulta de Nefrologia. Foram excluídos transplantados renais, portadores de insuficiência renal crônica, dialisados por intoxicação exógena e aqueles transferidos de hospital durante o tratamento. RESULTADOS: Dos 234 pacientes acompanhados, 12% apresentaram IRA nefrotóxica e 24%, IRA multifatorial associada ao uso de drogas nefrotóxica. Entre as comorbidades mais prevalentes, estão hipertensão arterial, hepatopatias, neoplasias, insuficiência cardíaca congestiva e diabetes mellitus. Quinze por cento necessitaram de diálise, e o tipo mais frequentemente usado foi hemodiálise venovenosa contínua; 42% eram oligúricos, 44,7% evoluíram para óbito e 33% recuperaram a função renal. Antibióticos, AINH e contraste radiológico foram as drogas nefrotóxicas mais prevalentes.Os medicamentos nefrotóxicos implicados foram, em ordem de frequência, vancomicina, aminoglicosídeos, aciclovir, quimioterápicos e contraste radiológico. Hepatopatia foi a única variável com significância estatística (p = 0,03, IC = 1,08 a 6,49 em análise multivariada. Na comparação entre IRA nefrotóxica e não nefrotóxica, houve aumento da mortalidade proporcionalmente aos dias de internação. CONCLUSÃO: IRA nefrotóxica é frequente, grave e deve ser continuamente monitorada, tanto ambulatorialmente quanto no ambiente intra-hospitalar.INTRODUCTION: Nephrotoxic acute renal failure (ARF is a frequent and important cause of morbidity and mortality. OBJECTIVE: To assess the prevalence, clinical course, and outcome of

  15. Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity

    Science.gov (United States)

    Venkataraman, Balaji; Kurdi, Amani; Mahgoub, Eglal; Sadek, Bassem

    2016-01-01

    Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals) to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage.

  16. Vitamin E mitigates cisplatin-induced nephrotoxicity due to reversal of oxidative/nitrosative stress, suppression of inflammation and reduction of total renal platinum accumulation.

    Science.gov (United States)

    Darwish, Mostafa A; Abo-Youssef, Amira M; Khalaf, Marwa M; Abo-Saif, Ali A; Saleh, Ibrahim G; Abdelghany, Tamer M

    2017-01-01

    Cisplatin (CP) is one of the most effective chemotherapeutic agents. Unfortunately, CP-induced nephrotoxicity hampered its use. This study aims to investigate the effect of vitamin E (Vit E) on CP-induced nephrotoxicity. Male white albino rats were divided to four group's six rats each and received either, 1% tween 80 in normal saline or Vit E (75 mg/kg) per day for 14 consecutive days or a single injection of CP (6 mg/kg) alone or CP (6 mg/kg) together with Vit E (75 mg/kg per day for 14 consecutive days). Five days after the CP injection, rats were euthanized; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly increased serum levels of creatinine and urea. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CP treatment. Vit E successfully lowered serum levels of urea and creatinine, enhanced creatinine clearance and diuresis, and normalized relative kidney/body weight. Furthermore, Vit E successfully normalized renal MDA and nitrite concentrations, elevated GSH level, and restored CAT and SOD activities in renal tissues. Histopathological examination of rat kidney revealed that Vit E significantly mitigated CP-induced renal damage. Importantly, administration of Vit E reduced kidney total platinum concentration indicating a role of platinum renal accumulation on the ability of Vit E to protect against CP nephrotoxicity.

  17. The molecular clock: a focus on chronopharmacological strategies for a possible control of aminoglycoside renal toxicity

    Directory of Open Access Journals (Sweden)

    Rebuelto M

    2012-01-01

    Full Text Available Marcela RebueltoFarmacología, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires, ArgentinaAbstract: Chronotherapy applies biological rhythmicity in order to optimize clinical treatments, relating the dosing time of the drugs to the daily variations of their therapeutic and unwanted side effects due to the fluctuations in physiological processes involved in their pharmacokinetics and/or pharmacodynamics. The goal of chronotherapy is to administer treatments at the time of day that enhances both their effectiveness and tolerance. This review intends to (1 provide the theoretical rationale behind the use of aminoglycosides during extended interval schedule chronotherapy in clinical practice and (2 target the underlying molecular mechanisms of renal toxicity, the main unwanted side effect. Previous reports suggest that aminoglycoside therapy may benefit from a chronopharmacological approach. Temporal variations in the renal blood flow and glomerular filtration rate and several clock-dependent molecular mechanisms contributing to the daily changes in electrolyte and water urinary excretion have been reported. Daily differences in aminoglycoside toxicity and kinetic disposition have been found in laboratory animals and human patients. Nephrotoxicity and renal cortical accumulation are higher when drugs are administered during the rest phase than during the active phase. Active translocation of aminoglycosides into renal cells is mediated by the megalin/cubilin receptor complex located at the luminal epithelial cell membrane. The complex regulation of this endocytic mechanism deserves further study, in order to dilucidate the molecular bases that may be involved in chronotherapeutic strategies developed for minimizing aminoglycoside accumulation in the renal cells, and thus, increasing their tolerance.Keywords: biological rhythms, chronopharmacology, chronotherapeutics, aminoglycosides

  18. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus.

    Science.gov (United States)

    Karras, Alexandre; Lafaurie, Matthieu; Furco, André; Bourgarit, Anne; Droz, Dominique; Sereni, Daniel; Legendre, Christophe; Martinez, Frank; Molina, Jean-Michel

    2003-04-15

    We report 3 cases of renal toxicity associated with use of the antiviral agent tenofovir. Renal failure, proximal tubular dysfunction, and nephrogenic diabetes insipidus were observed, and, in 2 cases, renal biopsy revealed severe tubular necrosis with characteristic nuclear changes. Patients receiving tenofovir must be monitored closely for early signs of tubulopathy (glycosuria, acidosis, mild increase in the plasma creatinine level, and proteinuria).

  19. The use of pharmacokinetically guided indinavir dose reductions in the management of indinavir-associated renal toxicity.

    NARCIS (Netherlands)

    Boyd, M.A.; Siangphoe, U.; Ruxrungtham, K.; Reiss, P.; Mahanontharit, A.; Lange, J.M.A.; Phanuphak, P.; Cooper, D.A.; Burger, D.M.

    2006-01-01

    OBJECTIVES: Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therape

  20. Myoclonus in renal failure: Two cases of gabapentin toxicity

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    Kenneth R. Kaufman

    2014-01-01

    Full Text Available Gabapentin, an AED approved for the adjunctive treatment of partial seizures with/without secondary generalization and for the treatment of postherpetic neuralgia, is frequently used off-label for the treatment of both psychiatric and pain disorders. Since gabapentin is cleared solely by renal excretion, dosing requires consideration of the patient's renal function. Myoclonic activity may occur as a complication of gabapentin toxicity, especially with acute kidney injury or end-stage renal disease. We report 2 cases of myoclonic activity associated with gabapentin toxicity in the setting of renal disease which resolved with discontinuation of gabapentin and treatment with hemodialysis and peritoneal dialysis. As gabapentin has multiple indications and off-label uses, an understanding of myoclonus, neurotoxicity, and renal dosing is important to clinicians in multiple specialties.

  1. Differential effects of grape juice on gastric emptying and renal function from cisplatin-induced acute adverse toxicity.

    Science.gov (United States)

    Ko, J-L; Tsai, C-H; Liu, T-C; Lin, M-Y; Lin, H-L; Ou, C-C

    2016-08-01

    Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity. © The Author(s) 2015.

  2. Limited Link between Oxidative Stress and Ochratoxin A—Induced Renal Injury in an Acute Toxicity Rat Model

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    Liye Zhu

    2016-12-01

    Full Text Available Ochratoxin A (OTA displays nephrotoxicity and hepatotoxicity. However, in the acute toxicity rat model, there is no evidence on the relationship between OTA and nephrotoxicity and hepatotoxicity. Based on this, the integrated analysis of physiological status, damage biomarkers, oxidative stress, and DNA damage were performed. After OTA treatment, the body weight decreased and AST, ALP, TP, and BUN levels in serum increased. Hydropic degeneration, swelling, vacuolization, and partial drop occurred in proximal tubule epithelial cells. PCNA and Kim-1 were dose-dependently increased in the kidney, but Cox-2 expression and proliferation were not found in the liver. In OTA-treated kidneys, the mRNA expressions of Kim-1, Cox-2, Lcn2, and Clu were dose-dependently increased. The mRNA expressions of Vim and Cox-2 were decreased in OTA-treated livers. Some oxidative stress indicators were altered in the kidneys (ROS and SOD and livers (SOD and GSH. DNA damage and oxidative DNA damage were not found. In conclusion, there is a limited link between oxidative stress and OTA-induced renal injury in an acute toxicity rat model.

  3. Limited Link between Oxidative Stress and Ochratoxin A—Induced Renal Injury in an Acute Toxicity Rat Model

    Science.gov (United States)

    Zhu, Liye; Yu, Tao; Qi, Xiaozhe; Gao, Jing; Huang, Kunlun; He, Xiaoyun; Luo, Haoshu; Xu, Wentao

    2016-01-01

    Ochratoxin A (OTA) displays nephrotoxicity and hepatotoxicity. However, in the acute toxicity rat model, there is no evidence on the relationship between OTA and nephrotoxicity and hepatotoxicity. Based on this, the integrated analysis of physiological status, damage biomarkers, oxidative stress, and DNA damage were performed. After OTA treatment, the body weight decreased and AST, ALP, TP, and BUN levels in serum increased. Hydropic degeneration, swelling, vacuolization, and partial drop occurred in proximal tubule epithelial cells. PCNA and Kim-1 were dose-dependently increased in the kidney, but Cox-2 expression and proliferation were not found in the liver. In OTA-treated kidneys, the mRNA expressions of Kim-1, Cox-2, Lcn2, and Clu were dose-dependently increased. The mRNA expressions of Vim and Cox-2 were decreased in OTA-treated livers. Some oxidative stress indicators were altered in the kidneys (ROS and SOD) and livers (SOD and GSH). DNA damage and oxidative DNA damage were not found. In conclusion, there is a limited link between oxidative stress and OTA-induced renal injury in an acute toxicity rat model. PMID:27983637

  4. Biotransformation, transport and toxicity studies in rat renal proximal tubular cells.

    NARCIS (Netherlands)

    Haenen, H.E.M.G.

    1996-01-01

    SummaryRenal proximal tubular (RPT) cells can be exposed apically to glomerulary filtrated and basolaterally to non-filtrated nephrotoxic compounds. To excrete these compounds via the urine, RPT cells are equipped with transport systems able to transport nephrotoxicants from the basolateral to the a

  5. A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

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    Mehdi Nematbakhsh

    2013-01-01

    Full Text Available Background: Cisplatin (cis-diamminedichloroplatinum II; CP is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr and blood urea nitrogen (BUN. This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity. Materials and Methods: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later. Results: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant. Conclusion: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats.

  6. Hydrogen sulfide: A novel nephroprotectant against cisplatin-induced renal toxicity.

    Science.gov (United States)

    Dugbartey, George J; Bouma, Hjalmar R; Lobb, Ian; Sener, Alp

    2016-07-01

    Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury.

  7. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat.

    OpenAIRE

    Agmon, Y; Peleg, H; Greenfeld, Z; Rosen, S.; Brezis, M

    1994-01-01

    Human radiocontrast nephrotoxicity is predicted by the presence of multiple risk factors, often associated with compromised renal circulation. To produce a simple model of radiocontrast nephropathy, rats were pretreated with indomethacin and N omega-nitro-L-arginine methyl ester (L-NAME, to inhibit nitric oxide synthesis) before the administration of iothalamate. Acute renal failure consistently developed, with a decline in creatinine clearance from 1.05 +/- 0.10 to 0.27 +/- 0.05 ml/min (P < ...

  8. Effect of commercial (vimang and hydroalcoholic extract of Mangifera indica (Mango on gentamicin-induced nephrotoxicity in rat

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    Abolfazl Khajavi Rad

    2011-09-01

    Conclusion: Mango products were able to improve kidney function in an established model of GM-induced nephrotoxicity in the rat. The beneficial effects of Mango on the rat kidney seem to be dose and time-dependent. However, more investigations are needed to elucidate Mango action on GM-induced renal toxicity.

  9. Use of urinary renal biomarkers to evaluate the nephrotoxic effects of melamine or cyanuric acid in non-pregnant and pregnant rats.

    Science.gov (United States)

    Bandele, O J; Stine, C B; Ferguson, M; Black, T; Olejnik, N; Keltner, Z; Evans, E R; Crosby, T C; Reimschuessel, R; Sprando, R L

    2014-12-01

    Although traditional assessments of renal damage detect loss of kidney function, urinary renal biomarkers are proposed to indicate early changes in renal integrity. The recent adulteration of infant formula and other milk-based foods with melamine revealed a link between melamine ingestion and nephropathy. Thus, the effects of melamine and related analogs (e.g., cyanuric acid) should be assessed in other potentially sensitive groups. We evaluated whether urinary Kim-1, clusterin, and osteopontin could detect the effects of high doses of melamine or cyanuric acid in pregnant and non-pregnant female rats gavaged with 1000 mg/kg bw/day for 10 days. We demonstrate that these biomarkers can differentiate the severity of effects induced by melamine or cyanuric acid. All melamine-treated animals experienced adverse effects; however, pregnant rats were most sensitive as indicated by increased SCr, BUN, and kidney weights, decreased body weight, and presence of renal crystals. These effects coincided with elevated urinary biomarker levels as early as day 2 of exposure. One cyanuric acid-treated rat displayed effects similar to melamine, including increased urinary biomarker levels. This work illustrates that these biomarkers can detect early effects of melamine or cyanuric acid crystal-induced nephropathy and further supports the use of urinary protein immunoassays as a powerful, non-invasive method to assess nephrotoxicity.

  10. [Nephrotoxicity of amphotericin B].

    Science.gov (United States)

    Deray, G; Mercadal, L; Bagnis, C

    2002-01-01

    Amphotericin B is widely used for severe life threatening fungal infections. Its use is limited by a dose-dependent nephrotoxicity manifested by a reduction in glomerular filtration rate and tubular dysfunction. An elevated creatinine associated with amphotericin B is not only a marker for renal dysfunction but is also linked to a substantial risk for the use of hemodialysis and a higher mortality rate; therefore amphotericin B nephrotoxicity is not a benign complication and its prevention is essential. Several manipulations have been proposed to try and minimize amphotericin B induced nephrotoxicity. Systematic hydration is crucial to minimize amphotericin B. Mannitol or intralipids administration were once suggested as protective based on anecdotal observational reports. Small prospective and randomized trials, however did not support a protective effect. Three new formulations have been developed in an attempts to improse both efficacy and tolerability: amphotericin B in lipid complex (ABLC, Abelcet). Colloidal dispersion (ABCD, Amphotec and amphotericin B liposome (Ambisome). Three prospectives randomized studies have clearly shown that Ambisome is less nephrotoxic than amphotericin B. Unfortunately the only randomized trial comparing Abelcet with amphotericin B is an open-label treatment of invasive candidiasis which was presented 5 years ago but never published as a full paper. Furthermore in a recent multicenter double-blind study it has been shown that Ambisome has a better safety profile than Abelcet with less chills/rigors and less nephrotocixity.

  11. Nephrotoxicity of over-the-counter analgesics, natural medicines, and illicit drugs.

    Science.gov (United States)

    Blowey, Douglas L

    2005-02-01

    Toxic nephropathy is a disorder whose primary feature is impairment of the normal functions of the kidney. The clinical manifestations of toxic nephropathy vary from a mild reduction in renal function to hematuria, proteinuria, and urolithiasis to a severe progressive toxicity culminating in end-stage renal disease. Although it is commonplace for adolescents to use supplemental treatments such as natural medicines and over-the-counter (OTC) analgesics, they do not often reveal the use of such treatments to physicians, nor do they fully understand their potential adverse effects. This article reviews the nephrotoxic effects of OTC analgesics, natural medicines, and illicit drugs.

  12. Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment.

    Science.gov (United States)

    Ledeganck, Kristien J; Boulet, Gaëlle A; Horvath, Caroline A; Vinckx, Marleen; Bogers, Johannes J; Van Den Bossche, Rita; Verpooten, Gert A; De Winter, Benedicte Y

    2011-09-01

    Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thébault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.

  13. Melatonin prevents acetaminophen-induced nephrotoxicity in rats.

    Science.gov (United States)

    Ilbey, Yusuf Ozlem; Ozbek, Emin; Cekmen, Mustafa; Somay, Adnan; Ozcan, Levent; Otünctemur, Alper; Simsek, Abdulmuttalip; Mete, Fatih

    2009-01-01

    Nephrotoxicity is a major complication of acetaminophen (APAP), a widely used analgesic and antipyretic drug, and there is no specific treatment for APAP-induced renal damage. It has been reported that reactive oxygen metabolites or free radicals are important mediators of APAP toxicity. In this study, the protective role of melatonin (MLT) on APAP-induced nephrotoxicity was investigated in rats. For this purpose, nephrotoxicity was induced in male Wistar albino rats by intraperitoneal (i.p.) administration of a single dose of 1,000 mg/kg APAP. Some of these rats also received i.p. melatonin (10 mg/kg) 20 min after administration of APAP. The rats were sacrificed 24 h after administration of APAP. Urea and creatinine levels were measured in the blood, and levels of malondialdehyde (MDA) and glutathione (GSH), and glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity were determined in renal tissue. Serum urea and creatinine levels increased significantly as a result of APAP nephrotoxicity. A significant increase in MDA and decreases in GSH level and GSH-Px, CAT, and SOD activity indicated that APAP-induced renal damage was mediated through oxidative stress. Significant beneficial changes were noted in serum and tissue oxidative stress indicators in rats treated with MLT. These biochemical observations were supplemented by histopathological examination of kidney sections, which revealed that MLT also reduced the severity of APAP-induced histological alterations in the kidney. These results indicate that administration of APAP causes oxidative stress to renal tissue and that MLT protects against the oxidative damage associated with APAP.

  14. Low renal toxicity of lipoplatin compared to cisplatin in animals.

    Science.gov (United States)

    Devarajan, Prasad; Tarabishi, Ridwan; Mishra, Jaya; Ma, Qing; Kourvetaris, Andreas; Vougiouka, Maria; Boulikas, Teni

    2004-01-01

    Cisplatin is one of the most widely used and effective chemotherapeutic agents for the treatment of several human malignancies. Although the effectiveness of cisplatin is high, its toxicities justify the demand for improved formulations of this drug. A liposomal formulation of cisplatin, Lipoplatin, was developed in order to reduce the systemic toxicity of cisplatin. Mice and rats injected with cisplatin developed renal insufficiency with clear evidence of tubular damage, but those injected with the same dose of Lipoplatin were almost completely free of kidney injury. The maximum levels of total platinum in rat kidneys after intraperitoneal bolus injection of cisplatin or Lipoplatin at similar doses were similar, but the steady state accumulation of total platinum in the kidney was 5 times higher for cisplatin compared to Lipoplatin. This is proposed as one mechanism to explain the low renal toxicity of Lipoplatin.

  15. Antioxidant activity of simvastatin prevents ifosfamide-induced nephrotoxicity.

    Science.gov (United States)

    Mhaidat, Nizar Mahmoud; Ali, Reem Mustafa; Shotar, Ali Muhammad; Alkaraki, Almuthanna Khalaf

    2016-03-01

    Ifosfamide is an anticancer agent used largely in treatment of solid tumors. The mainstay dose-limiting toxicity of ifosfamide is nephrotoxicity. This is largely believde to be a result of ifosfamide-induced oxidative stress. In this study, we investigated the antioxidant activity of simvastatin and the possible protective role of simvastatin against ifosfamide induced nephrotoxicity. Thirty Sprague-Dawely rats were divided into five groups and given orally different drug combinations. Group I and II were regarded as control groups and received 0.1% DMSO and normal saline, respectively. Group III received ifosfamide at 50 mg/kg, group IV received simvastatin at 0.3 mg/kg and group V received both ifosfamide and simvastatin. All animals were decapitated 2 days after the last ifosfamide administration. Findings revealed that ifosfamide induced nephrotoxicity as indicated by a significant increase in plasma creatinine and lipid per oxidation. This increase was significantly inhibited in animals pretreated with simvastatin. Histopathological observations were in correlation with the biochemical parameters in that simvastatin minimized ifosfamide-induced renal tubular damage. The above results promote a future use of simvastatin in combination with ifosfamide in treatment of cancer patients to indicate that simvastatin protectics against ifosfamide-induced nephrotoxicity in terms of oxidative stress and might be given in combination.

  16. Prevalence of renal and hepatobiliary disease, laboratory abnormalities, and potentially toxic medication exposures among persons with COPD

    Directory of Open Access Journals (Sweden)

    Mapel DW

    2013-03-01

    Full Text Available Douglas W Mapel,1 Jenõ P Marton21Lovelace Clinic Foundation, Albuquerque, New Mexico, NM, USA; 2Health Economics and Outcomes Research, Pfizer Inc, New York, NY, USABackground: The purpose of this study was to describe the prevalence of renal and hepatic disease, related laboratory abnormalities, and potentially hepatotoxic and nephrotoxic medication use in a population-based cohort of persons with chronic obstructive pulmonary disease (COPD.Methods: This was a retrospective case-control cohort analysis of COPD patients enrolled in one regional health system for at least 12 months during a 36-month study period (n = 2284. Each COPD patient was matched by age and gender to up to three persons not diagnosed with COPD (n = 5959.Results: The mean age for cases and controls was 70.3 years, and 52.5% were women. The COPD cohort had significantly higher prevalences (cases/100 of acute, chronic, and unspecified renal failure as compared with controls (1.40 versus 0.59, 2.89 versus 0.79, and 1.09 versus 0.44, respectively. Among the cases, 31.3% had at least one renal or urinary tract diagnosis during the study period, as compared with 21.1% of controls. COPD cases also had more gallbladder disease (2.76 versus 1.63 and pancreatic disease (1.40 versus 0.60, but not hepatic disease. COPD patients were more likely to have at least one serum creatinine level (5.1 versus 2.1 or liver aspartate aminotransferase level (4.5 versus 2.7 that was more than twice the upper limit of normal. COPD patients had prescription fills for an average of 17.6 potentially nephrotoxic and 27.4 hepatotoxic drugs during the study period, as compared with 13.6 and 19.9 for the controls (P value for all comparisons < 0.01.Conclusion: COPD patients have a substantially increased prevalence of renal, gallbladder, and pancreatic diseases, as well as abnormal renal and hepatic laboratory values, but not diagnosed liver disease. COPD patients are also more likely to be prescribed

  17. Characterization of N-diethylnitrosamine-initiated and ferric nitrilotriacetate-promoted renal cell carcinoma experimental model and effect of a tamarind seed extract against acute nephrotoxicity and carcinogenesis.

    Science.gov (United States)

    Vargas-Olvera, Chabetty Y; Sánchez-González, Dolores Javier; Solano, José D; Aguilar-Alonso, Francisco A; Montalvo-Muñoz, Fernando; Martínez-Martínez, Claudia María; Medina-Campos, Omar N; Ibarra-Rubio, María Elena

    2012-10-01

    Renal cell carcinoma (RCC), the commonest malignancy in adult kidney, lacks of early signs, resulting often in metastasis at first diagnosis. N-Diethylnitrosamine (DEN)-initiated and ferric nitrilotriacetate (FeNTA)-promoted RCC may be a useful experimental model, but it is not well characterized. In this study, histological alterations and oxidative stress markers were analyzed at different times throughout RCC development, histological subtype was re-evaluated in the light of current classification, and a tamarind seed extract (TSE) effect was examined. Male Wistar rats experimental groups were control, TSE, DEN, DEN+FeNTA, and TSE+DEN+FeNTA. TSE was given 2 weeks before DEN administration (200 mg/kg) and throughout the experiment. Fourteen days after DEN treatment, two FeNTA doses (9 mg Fe/kg) for acute nephrotoxicity study, and increasing FeNTA doses (3-9 mg Fe/kg) twice a week for 16 weeks for carcinogenesis protocol, were administered. In acute study, necrosis and renal failure were observed and TSE ameliorated them. Throughout carcinogenesis protocol, preneoplastic lesions were observed since 1 month of FeNTA treatment, which were more evident at 2 months, when also renal cysts and RCC were already detected. RCC tumors were obtained without changes in renal function, and clear cell histological subtype was identified in all cases. 4-Hydroxy-2-nonenal and 3-nitro-L: -tyrosine levels increased progressively throughout protocol. TSE decreased both oxidative stress markers and, although there was no statistical difference, it delayed RCC progress and decreased its incidence (21 %). This study brings an insight of the time course events in this carcinogenesis model, identifies clear cell subtype and establishes TSE renoprotective effects.

  18. Contrast-induced nephrotoxicity: possible synergistic effect of stress hyperglycemia.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Oxidative stress on the renal tubules has been implicated as a mechanism of injury in both stress hyperglycemia and contrast-induced nephrotoxicity. The purpose of this study was to determine whether the combination of these effects has a synergistic effect on accentuating renal tubular apoptosis and therefore increasing the risk of contrast-induced nephrotoxicity.

  19. The role of glutathione and cysteine conjugates in the nephrotoxicity of o-xylene in rats

    Energy Technology Data Exchange (ETDEWEB)

    Morel, G.; Bonnet, P.; Cossec, B.; Morel, S.; Cour, C.; Lambert, A.M.; Roure, M.B.; Brondeau, M.T. [Institut National de Recherche et de Securite, 54 - Vandoeuvre (France)

    1998-09-01

    Moderate nephrotoxicity was induced in male and female rats exposed to o-xylene for 4 h at atmospheric concentrations of {proportional_to}3000 ppm. The xylene in vivo nephrotoxicity resulted in low enzyme leakage from the kidney into the urine. This low leakage was confirmed in 24-h urine by an increase in {gamma}-glutamyltranspeptidase ({gamma}GT), N-acetyl-{beta}-d-glucosaminidase (NAG) and alkaline phosphatase (ALP) activities. Compared to the control, both the 24-h urine output and the glucose excretion increased in male and female rats. These increases were probably a result of damage to the renal proximal tubules. The role of the metabolic pathway of glutathione in the emergence of the renal damage observed with o-xylene was investigated in rats. Recent studies indicate that the metabolic pathway of glutathione may be a bioactivation pathway, which is responsible for nephrotoxic effects with several drugs or chemicals. The renal toxicity of three synthesized o-xylene thio-conjugates was investigated in several groups of female rats. Administration of S-(o-methylbenzyl)glutathione (i.p., 1 mmol/kg), S-(o-methylbenzyl)cysteine (per os, 1 mmol/kg) or N-acetyl-S-(o-methylbenzyl)cysteine (i.p., 0.75 mmol/kg) to female rats did not induce renal toxicity, as monitored by urinary biochemical parameters ({gamma}GT, NAG, ALP, glucose). The data obtained suggest that the glutathione pathway would appear to be only detoxication, and probably does not contribute to the renal toxicity of o-xylene in female rats. Thus, either another metabolic pathway or other intermediate metabolites are probably involved in the nephrotoxic action of o-xylene. (orig.) (orig.) With 2 figs., 1 tab., 23 refs.

  20. The role of glutathione and cysteine conjugates in the nephrotoxicity of o-xylene in rats.

    Science.gov (United States)

    Morel, G; Bonnet, P; Cossec, B; Morel, S; Cour, C; Lambert, A M; Roure, M B; Brondeau, M T

    1998-09-01

    Moderate nephrotoxicity was induced in male and female rats exposed to o-xylene for 4 h at atmospheric concentrations of approximately 3000 ppm. The xylene in vivo nephrotoxicity resulted in low enzyme leakage from the kidney into the urine. This low leakage was confirmed in 24-h urine by an increase in gamma-glutamyltranspeptidase (gammaGT), N-acetyl-beta-D-glucosaminidase (NAG) and alkaline phosphatase (ALP) activities. Compared to the control, both the 24-h urine output and the glucose excretion increased in male and female rats. These increases were probably a result of damage to the renal proximal tubules. The role of the metabolic pathway of glutathione in the emergence of the renal damage observed with o-xylene was investigated in rats. Recent studies indicate that the metabolic pathway of glutathione may be a bioactivation pathway, which is responsible for nephrotoxic effects with several drugs or chemicals. The renal toxicity of three synthesized o-xylene thio-conjugates was investigated in several groups of female rats. Administration of S-(o-methylbenzyl)glutathione (i.p., 1 mmol/kg), S-(o-methylbenzyl)cysteine (per os, 1 mmol/kg) or N-acetyl-S-(o-methylbenzyl)cysteine (i.p., 0.75 mmol/kg) to female rats did not induce renal toxicity, as monitored by urinary biochemical parameters (gammaGT, NAG, ALP, glucose). The data obtained suggest that the glutathione pathway would appear to be only detoxication, and probably does not contribute to the renal toxicity of o-xylene in female rats. Thus, either another metabolic pathway or other intermediate metabolites are probably involved in the nephrotoxic action of o-xylene.

  1. In Vivo Renal Clearance, Biodistribution, Toxicity of Gold nanoclusters

    CERN Document Server

    Zhang, Xiao-Dong; Shen, Xiu; Liu, Pei-Xun; Fan, Fei-Yue; Fan, Sai-Jun; 10.1016/j.biomaterials.2012.03.020

    2012-01-01

    Gold nanoparticles have shown great prospective in cancer diagnosis and therapy, but they can not be metabolized and prefer to accumulate in liver and spleen due to their large size. The gold nanoclusters with small size can penetrate kidney tissue and have promise to decrease in vivo toxicity by renal clearance. In this work, we explore the in vivo renal clearance, biodistribution, and toxicity responses of the BSA- and GSH-protected gold nanoclusters for 24 hours and 28 days. The BSA-protected gold nanoclusters have low-efficient renal clearance and only 1% of gold can be cleared, but the GSH-protected gold nanoclusters have high-efficient renal clearance and 36 % of gold can be cleared after 24 hours. The biodistribution further reveals that 94% of gold can be metabolized for the GSH-protected nanoclusters, but only less than 5% of gold can be metabolized for the BSA-protected nanoclusters after 28 days. Both of the GSH- and BSA-protected gold nanoclusters cause acute infection, inflammation, and kidney fu...

  2. Effect of hyperbaric oxygen on cyclosporine-induced nephrotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ay, Hakan; Uzun, Gunalp; Onem, Yalcin; Aydinoz, Secil; Yildiz, Senol; Bilgi, Oguz; Topal, Turgut; Atasoyu, Enes Murat

    2007-01-01

    Reactive oxygen species have been suggested to be involved in cyclosporine nephrotoxicity. Hyperbaric oxygen is known to induce the generation of reactive oxygen species in tissues. The aim of this study was to investigate whether the use of hyperbaric oxygen concurrently with cyclosporine potentiates cyclosporine nephrotoxicity by inducing oxidative stress in kidneys. The study consisted of four groups of rats: a control group, a cyclosporine group (15 mg/kg/day intraperitoneally for 14 days), a hyperbaric oxygen group (60 min. every day for five days at 2.5 atmosphere absolute), and a cyclosporine + hyperbaric oxygen group (cyclosporine 15 mg/kg/day intraperitoneally for 14 days + hyperbaric oxygen for 60 min at 2.5 atmosphere absolute every day for five days on the last five days of cyclosporine treatment). Oxidative stress was determined by measuring renal thiobarbituric acid-reactive substances content, renal superoxide dismutase, and glutathione peroxidase activities. Cyclosporine increased serum urea and creatinine levels, indicating the development of nephrotoxicity, and induced significant oxidative stress in rat kidneys. Hyperbaric oxygen alone did not alter any of the biochemical and oxidative stress parameters compared to the control group. When used concurrently with cyclosporine, hyperbaric oxygen significantly reduced cyclosporine-induced oxidative stress, but it neither attenuated nor aggravated cyclosporine-induced nephrotoxicity. These results suggest that reactive oxygen species are involved in cyclosporine nephrotoxicity, but are not the direct cause of the toxicity. Although concurrent use of cyclosporine and hyperbaric oxygen did not exacerbate cyclosporine nephrotoxicity in this model, we recommend that the renal functions of patients be monitored periodically when these treatments are used concurrently.

  3. Protective effects of alpha lipoic acid versus N-acetylcysteine on ifosfamide-induced nephrotoxicity.

    Science.gov (United States)

    El-Sisi, Alaa El-Din E; El-Syaad, Magda E; El-Desoky, Karima I; Moussa, Ethar A

    2015-02-01

    Ifosfamide (IFO) is a highly effective chemotherapeutic agent for treating a variety of pediatric solid tumors. However, its use is limited due to its serious side effect on kidneys. The side-chain oxidation of IFO in renal tubular cells produces a reactive toxic metabolite that is believed to be responsible for its nephrotoxic effect. Therefore, this study was carried out to investigate the possible underlying mechanisms that may be involved in IFO-induced nephrotoxicity, including free radical generation and the possible role of alpha lipoic acid (ALA) versus N-acetylcysteine (NAC) in protection against this toxicity. Male albino rats were injected intraperitoneally with saline, IFO (50 mg/kg daily for 5 days), IFO + ALA (100 mg/kg daily for 8 days) and IFO + NAC (200 mg/kg daily for 8 days). Kidney malondialdehyde, nitric oxide and glutathione contents and serum biochemical parameters and histopathological analysis were determined. Both ALA and NAC markedly reduced the severity of renal dysfunction induced by IFO. NAC was more nephroprotective than ALA. This study suggests that oxidative stress is possibly involved in the IFO-induced nephrotoxicity in rats. The study also suggests the potential therapeutic role for ALA and NAC against IFO-induced nephrotoxicity.

  4. Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity.

    Science.gov (United States)

    Homma-Takeda, Shino; Kitahara, Keisuke; Suzuki, Kyoko; Blyth, Benjamin J; Suya, Noriyoshi; Konishi, Teruaki; Terada, Yasuko; Shimada, Yoshiya

    2015-12-01

    Renal toxicity is a hallmark of uranium exposure, with uranium accumulating specifically in the S3 segment of the proximal tubules causing tubular damage. As the distribution, concentration and dynamics of accumulated uranium at the cellular level is not well understood, here, we report on high-resolution quantitative in situ measurements by high-energy synchrotron radiation X-ray fluorescence analysis in renal sections from a rat model of uranium-induced acute renal toxicity. One day after subcutaneous administration of uranium acetate to male Wistar rats at a dose of 0.5 mg uranium kg(-1) body weight, uranium concentration in the S3 segment of the proximal tubules was 64.9 ± 18.2 µg g(-1) , sevenfold higher than the mean renal uranium concentration (9.7 ± 2.4 µg g(-1) ). Uranium distributed into the epithelium of the S3 segment of the proximal tubules and highly concentrated uranium (50-fold above mean renal concentration) in micro-regions was found near the nuclei. These uranium levels were maintained up to 8 days post-administration, despite more rapid reductions in mean renal concentration. Two weeks after uranium administration, damaged areas were filled with regenerating tubules and morphological signs of tissue recovery, but areas of high uranium concentration (100-fold above mean renal concentration) were still found in the epithelium of regenerating tubules. These data indicate that site-specific accumulation of uranium in micro-regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney.

  5. [The acute renal and cerebral toxicity of lithium: a cerebro-renal syndrome? A case report].

    Science.gov (United States)

    Prencipe, M; Cicchella, A; Del Giudice, A; Di Giorgio, A; Scarlatella, A; Vergura, M; Aucella, F

    2013-01-01

    This descriptive report describes the case of a 50 year-old woman with bipolar disorder, whose maintenance therapy comprised risperidone, sodium valproato and lithium carbonate without any past occurrence of toxicity. Her past medical history was significant for hypertension, cardiopathy and obesity. She presented with a 1-week history of fever, increasing confusion and slurred speech. At presentation, the patient was somnolent. Laboratory investigations revealed a serum creatinine of 3,6 mg/dl, BUN 45 mg/dl serum lithium 3,0 mEq/L with polyuria defined as more than 3 litres a day. EEG and ECG were abnormal. CT brain scanning and lumbar puncture were negative for brain haemorrage or infection. Lithium toxicity causes impairment of renal concentration and encephalopathy due to lithium recirculation, a mechanism responsible for the so-called cerebro-renal syndrome, where dialysis plays an important role in treatment.The patient was treated with continous veno-venous haemodiafiltration (CVVHDF) over 35 hours with gradual improvement of her general condition and efficacy of renal concentration. Our case highlights a few important points. Lithium nefrotoxicity and neurotoxicity can cause a cerebro-renal syndrome even when serum lithium levels are not particularly raised (2,5-3,5 mEq/L). Haemodialysis is the treatment of choice to reduce the molecular mechanisms of lithium-related changes in urinary concentration and reinstate dopaminergic activity in the brain.

  6. Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Shreesh Ojha

    2016-01-01

    Full Text Available Cisplatin (CSP is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage.

  7. The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

    Science.gov (United States)

    2013-01-01

    Background Chronic cyclosporine-(CsA)-mediated loss of kidney function is a major clinical problem in organ transplantation. We hypothesized that the mineralocorticoid receptor antagonist eplerenone (EPL) prevents chronic CsA-induced renal interstitial volume increase, tubule loss, and functional impairment in a rat model. Methods Sprague–Dawley rats received CsA alone (15 mg/kg/d p.o.), CsA and EPL (approximately 100 mg/kg/day p.o.) or vehicle (control) for 12 weeks. At 11 weeks, chronic indwelling arterial and venous catheters were implanted for continuous measurements of arterial blood pressure (BP) and GFR (inulin clearance) in conscious, freely moving animals. Plasma was sampled for analysis and kidney tissue was fixed for quantitative stereological analyses. Results Compared to controls, CsA-treatment reduced relative tubular volume (0.73±0.03 vs. 0.85±0.01, pcyclosporine rat nephropathy model, EPL reduces renal tissue injury, hypofiltration, hypertension, and growth impairment. MR antagonists should be tested for their renoprotective potential in patients treated with calcineurin inhibitors. PMID:23425330

  8. Pentavalent antimonial nephrotoxicity in the rat Disfunção tubular renal em ratos tratados com antimoniais pentavalentes

    Directory of Open Access Journals (Sweden)

    Joel Paulo R. Veiga

    1990-08-01

    Full Text Available Aspects of the renal function were assessed in rats treated with the pentavalent antimonials Glucantime (Meglumine Antimoniate, Rhodia or Pentostam (Sodium Stibogluconate, Wellcome. In dose of 30 mg of Sb v (Glucantime or Pentostam by 100 mg of weight by day for 30 days, renal functional changes were observed consisting of disturbances in urine concentrating capacity. Such disturbances were expressed by significantly low values of urine osmolality as compared to the basal values previous to the drugs. The decrease in urine osmolality was associated to a significant increase in urinary flow and in negative free-water clearance. There was no alteration in osmolar clearance and in fractional excretion of sodium. These observations suggest an interference of the drugs in the action of the antidiuretic hormone. The disturbance in urine concentration was reversible after a seven days period without the drugs administration. No significant histopathological alterations were observed in the kidneys of the rats treated with the drugs. On the other hand, the rats treated with a high dose of Pentostam (200 mg/100 grams of weight/day showed the functional and the histopathological alterations of the acute tubular necrosis.Estudou-se a função renal de ratos tratados com Glucantime (Antimoniato de Meglumine, Rhodia e Pentostam (Estibogluconato de Sódio, Wellcome na dose de 30 mg de Sb v por 100 g de peso por dia, durante 30 dias. Observou-se um distúrio na concentração urinária, que foi reversível 7 dias após cessada a administração das drogas. O estudo histopatológico do rim, por meio da microscopia óptica, não evidenciou alterações significativas. Por outro lado, ratos tratados com altas doses dos antimoniais (200 mg de Sb v por 100 g de peso por dia mostraram alterações funcionais e histopatológicas renais compatíveis com necrose tubular aguda.

  9. FISIOPATOLOGÍA DE LA INSUFICIENCIA RENAL AGUDA POR CISPLATINO

    Directory of Open Access Journals (Sweden)

    Rodriguez Macías EL

    2013-09-01

    Full Text Available Cisplatin is one of the major antineoplastic used for treatment of tumors such as testicular, ovarian, cervical, lung, bladder and head, among others. It has been described various types of toxicities induced by cisplatin, but the renal is the main one. This toxicity consist sof an acute reduction in renal plasma flow and a decline in glomerular filtration and installation of a tubular necrosis, with predominant involvement of the distal tubules and accumulation of cellular debris (lumen obstruction. Other mechanisms involved in renal injury are microangiopathy and pro-inflammatory mediators. We conclude that the nephrotoxicity caused by cisplatin can induce renal failure in which tubular structural damage predominates.

  10. Human renal tubular cells contain CD24/CD133 progenitor cell populations: Implications for tubular regeneration after toxicant induced damage using cadmium as a model.

    Science.gov (United States)

    Shrestha, Swojani; Somji, Seema; Sens, Donald A; Slusser-Nore, Andrea; Patel, Divyen H; Savage, Evan; Garrett, Scott H

    2017-09-15

    The proximal tubules of the kidney are target sites of injury by various toxicants. Cadmium (Cd(+2)), an environmental nephrotoxicant can cause adverse effects and overt renal damage. To decipher the mechanisms involved in nephrotoxicity, an in vitro model system is required. Mortal cultures of human proximal tubule (HPT) cells have served, as models but are difficult to acquire and do not lend themselves to stable transfection. The immortalized human proximal tubule cell line HK-2, has served as a model but it lacks vectorial active transport and shows signs of lost epithelial features. Recently a new proximal tubule cell line was developed, the RPTEC/TERT1, and the goal of this study was to determine if this cell line could serve as a model to study nephrotoxicity. Global gene expression analysis of this cell line in comparison to the HK-2 and HPT cells showed that the RPTEC/TERT1 cells had gene expression patterns similar to HPT cells when compared to the HK-2 cells. The HPT and the RPTEC/TERT1 cell line had an increased population of stem/progenitor cells co-expressing CD24 and CD133 when compared to the HK-2 cells. The level of expression of cadherins, claudins and occludin molecules was also similar between the RPTEC/TERT1 and the HPT cells. Acute exposure to Cd(+2) resulted in necrosis of the RPTEC/TERT1 cells when compared to the HK-2 cells which died by apoptosis. Thus, the RPTEC/TERT1 cells are similar to HPT cells and can serve as a good model system to study mechanisms involved in toxicant induced renal damage. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Integrated transcriptomic and proteomic evaluation of gentamicin nephrotoxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Com, Emmanuelle, E-mail: emmanuelle.com@univ-rennes1.fr [sanofi-aventis R and D, Disposition Safety and Animal Research, Vitry-sur-Seine (France); INSERM U625, Proteomics Core Facility Biogenouest, Rennes (France); Boitier, Eric; Marchandeau, Jean-Pierre [sanofi-aventis R and D, Disposition Safety and Animal Research, Vitry-sur-Seine (France); Brandenburg, Arnd [Genedata AG, Basel (Switzerland); Schroeder, Susanne [Nycomed GmbH, Barsbüttel (Germany); Hoffmann, Dana; Mally, Angela [University of Würzburg, Department of Toxicology, University of Würzburg, Würzburg (Germany); Gautier, Jean-Charles [sanofi-aventis R and D, Disposition Safety and Animal Research, Vitry-sur-Seine (France)

    2012-01-01

    Gentamicin is an aminoglycoside antibiotic, which induces renal tubular necrosis in rats. In the context of the European InnoMed PredTox project, transcriptomic and proteomic studies were performed to provide new insights into the molecular mechanisms of gentamicin-induced nephrotoxicity. Male Wistar rats were treated with 25 and 75 mg/kg/day subcutaneously for 1, 3 and 14 days. Histopathology observations showed mild tubular degeneration/necrosis and regeneration and moderate mononuclear cell infiltrate after long-term treatment. Transcriptomic data indicated a strong treatment-related gene expression modulation in kidney and blood cells at the high dose after 14 days of treatment, with the regulation of 463 and 3241 genes, respectively. Of note, the induction of NF-kappa B pathway via the p38 MAPK cascade in the kidney, together with the activation of T-cell receptor signaling in blood cells were suggestive of inflammatory processes in relation with the recruitment of mononuclear cells in the kidney. Proteomic results showed a regulation of 163 proteins in kidney at the high dose after 14 days of treatment. These protein modulations were suggestive of a mitochondrial dysfunction with impairment of cellular energy production, induction of oxidative stress, an effect on protein biosynthesis and on cellular assembly and organization. Proteomic results also provided clues for potential nephrotoxicity biomarkers such as AGAT and PRBP4 which were strongly modulated in the kidney. Transcriptomic and proteomic data turned out to be complementary and their integration gave a more comprehensive insight into the putative mode of nephrotoxicity of gentamicin which was in accordance with histopathological findings. -- Highlights: ► Gentamicin induces renal tubular necrosis in rats. ► The mechanisms of gentamicin nephrotoxicity remain still elusive. ► Transcriptomic and proteomic analyses were performed to study this toxicity in rats. ► Transcriptomic and proteomic

  12. Evaluation of biochemical effects of Casuarina equisetifolia extract on gentamicin-induced nephrotoxicity and oxidative stress in rats. Phytochemical analysis.

    Science.gov (United States)

    El-Tantawy, Walid Hamdy; Mohamed, Shaza Abdel-Halim; Abd Al Haleem, Ekram Nemr

    2013-11-01

    Nephrotoxicity is defined as renal dysfunction that arises as result of exposure to external agents such as drugs and environmental chemicals. The present work was undertaken to carry out the phytochemical study and nephroprotective activity of methanolic extract of Casuarina equisetifolia leaves in gentamicin-induced nephrotoxicity in Wistar rats. Flavonoids and phenolic acids were identified and quantified using high performance liquid chromatography. Subcutaneous injection of rats with gentamicin (80 mg/kg body weight/day) for six consecutive days induced marked acute renal toxicity, manifested by a significant increase in serum urea, creatinine and uric acid levels, along with a significant depletion of serum potassium level, compared to normal controls. Also oxidative stress was noticed in renal tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Administration of plant extract at a dose of 300 mg/kg once daily for 4 weeks restored normal renal functions and attenuated oxidative stress. In conclusion, Casuarina equisetifolia leaves extract ameliorates gentamicin-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing lipid peroxidation and improving intracellular antioxidant defense, thus extract may be used as nephroprotective agent.

  13. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Amel M. Soliman

    2016-05-01

    Full Text Available Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight, and a group that received both cisplatin and OMEE (500 mg/kg body weight for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy.

  14. Renal cadmium overload without nephrotoxicity.

    OpenAIRE

    1981-01-01

    A redundant nickel/cadmium battery worker was investigated for non-specific fatigue after completing five years in the industry. Sensitive techniques for in-vivo organ cadmium measurement showed a moderate accumulation in the liver but a very large concentration in the kidneys. Despite this, overall glomerular and tubular function were not impaired. It was concluded that the mechanism of proteinuria observed in some cadmium workers is obscure and not clearly related to the degree of kidney sa...

  15. Phlorizin pretreatment reduces acute renal toxicity in a mouse model for diabetic nephropathy.

    Science.gov (United States)

    Brouwers, Bas; Pruniau, Vincent P E G; Cauwelier, Elisa J G; Schuit, Frans; Lerut, Evelyne; Ectors, Nadine; Declercq, Jeroen; Creemers, John W M

    2013-09-20

    Streptozotocin (STZ) is widely used as diabetogenic agent in animal models for diabetic nephropathy (DN). However, it is also directly cytotoxic to kidneys, making it difficult to distinguish between DN-related and STZ-induced nephropathy. Therefore, an improved protocol to generate mice for DN studies, with a quick and robust achievement of the diabetic state, without direct kidney toxicity is required. To investigate the mechanism leading to STZ-induced nephropathy, kidney damage was induced with a high dose of STZ. This resulted in delayed gastric emptying, at least partially caused by impaired desacyl ghrelin clearance. STZ uptake in the kidneys is to a large extent mediated by the sodium/glucose cotransporters (Sglts) because the Sglt inhibitor phlorizin could reduce STZ uptake in the kidneys. Consequently, the direct toxic effects in the kidney and the gastric dilatation were resolved without interfering with the β-cell toxicity. Furthermore, pancreatic STZ uptake was increased, hereby decreasing the threshold for β-cell toxicity, allowing for single low non-nephrotoxic STZ doses (70 mg/kg). In conclusion, this study provides novel insights into the mechanism of STZ toxicity in kidneys and suggests a more efficient regime to induce DN with little or no toxic side effects.

  16. Effect of nettle (Urtica dioica) extract on gentamicin induced nephrotoxicity in male rabbits

    Institute of Scientific and Technical Information of China (English)

    Nadia Abdulkarim Salih

    2015-01-01

    To investigate the antioxidant effect of an orally administered ethanol extract of nettle (Urtica dioica) and its protective role in preventing or ameliorating oxidative stress as a major factor in gentamicin-induced nephrotoxicity in male rabbits. Methods: Twenty rabbits were divided into 4 equal groups: (G1) control group, (G2) gentamicin treated group (100 mg/kg), (G3) nettle treated group (100 mg/kg), (G4) combination treated group with both gentamicin (100 mg/kg) and nettle (100 mg/kg) for 10 days. The antioxidant properties of nettle were evaluated using different antioxidant tests, such as determination of glutathione and malondialdehyde levels and total phenolic content analysis. Results: Biochemical and histopathological study revealed that gentamicin caused nephrotoxicity observed clearly in the histopathological section of the kidney in the gentamicin treated group. Serum creatinine and blood urea nitrogen were biochemical indicators for nephrotoxicity which increased significantly in gentamicin treated group; other groups have no significant change in these two parameters. Nettle extract protected the rabbits from alteration in the level of blood urea nitrogen and serum creatinine when given after inducing of gentamicin nephrotoxicity. The nettle treated group showed a great effect as an antioxidant factor by increasing the glutathione level and reducing malondialdehyde level. No significant changes in biochemical parameters and no renal histopathological changes observed in the groups treated with nettle extract, which meant nettle had powerful antioxidant activity. Conclusions: Therefore, it can be assumed that the nephroprotective effect shown by nettle in gentamicin-induced nephrotoxicity can reserve intracellular levels of biological pathways and supportively enhance excretion of toxic levels of gentamicin.

  17. Effect of nettle(Urtica dioica) extract on gentamicin induced nephrotoxicity in male rabbits

    Institute of Scientific and Technical Information of China (English)

    Nadia; Abdulkarim; Salih

    2015-01-01

    Objective:To investigate the antioxidant ef ect of an orally administered ethanol extract of nettle(Urtica dioica) and its protective role in preventing or ameliorating oxidative stress as a major factor in gentamicin-induced nephrotoxicity in male rabbits. Methods: Twenty rabbits were divided into 4 equal groups:(G1) control group,(G2) gentamicin treated group(100 mg/kg),(G3) nettle treated group(100 mg/kg),(G4) combination treated group with both gentamicin(100 mg/kg) and nettle(100 mg/kg) for 10 days. The antioxidant properties of nettle were evaluated using dif erent antioxidant tests, such as determination of glutathione and malondialdehyde levels and total phenolic content analysis. Results: Biochemical and histopathological study revealed that gentamicin caused nephrotoxicity observed clearly in the histopathological section of the kidney in the gentamicin treated group. Serum creatinine and blood urea nitrogen were biochemical indicators for nephrotoxicity which increased signii cantly in gentamicin treated group; other groups have no signii cant change in these two parameters. Nettle extract protected the rabbits from alteration in the level of blood urea nitrogen and serum creatinine when given after inducing of gentamicin nephrotoxicity. The nettle treated group showed a great ef ect as an antioxidant factor by increasing the glutathione level and reducing malondialdehyde level. No signii cant changes in biochemical parameters and no renal histopathological changes observed in the groups treated with nettle extract, which meant nettle had powerful antioxidant activity. Conclusions: Therefore, it can be assumed that the nephroprotective ef ect shown by nettle in gentamicin-induced nephrotoxicity can reserve intracellular levels of biological pathways and supportively enhance excretion of toxic levels of gentamicin.

  18. Ciprofloxacin-Induced Renal Failure

    Directory of Open Access Journals (Sweden)

    Audra Fuller

    2015-10-01

    Full Text Available Acute renal failure (ARF is a common diagnosis in hospitalized patients, particularly in intensive care units (ICU. Determining the cause and contributing factors associated with ARF is crucial during treatment. The etiology is complex, and several factors often contribute to its development. Medications can cause acute tubular necrosis, acute interstitial nephritis, and crystal-induced or post-obstructive nephropathy. There have been several case reports of ARF secondary to fluoroquinolones. Here we report the development of acute renal failure within a few days of initiating oral ciprofloxacin therapy and briefly describe the different types of renal failure secondary to fluoroquinolone administration. Clinical studies demonstrate that using fluoroquinolones with other potentially nephrotoxic medications requires monitoring of renal function to limit the renal toxicity with these medications. Also, the risk-benefit profile of patients requiring fluoroquinolones should be considered.

  19. Cymbopogon citratus protects against the renal injury induced by toxic doses of aminoglycosides in rabbits

    Directory of Open Access Journals (Sweden)

    N Ullah

    2013-01-01

    Full Text Available Renal injury is the most common side-effect of aminoglycosides. These antimicrobial drugs are particularly effective against Gram-negative microorganisms. The present study was conducted to investigate the renal protective activity of Cymbopogon citratus in gentamicin-induced nephrotoxicity. Male rabbits were divided into four groups (n=6 including group 1 (0.9% saline treated, group 2 (80 mg/kg/day gentamicin-treated, group 3 (200 mg/kg/day Cymbopogon citratus treated and group 4 (80 mg/kg/day gentamicin and 200 mg/kg/day Cymbopogon citratus treated. Biochemical kidney functioning parameters, urinary enzymes and histopathological examination were performed. The results of the present study showed that simultaneous administration of Cymbopogon citrates and gentamicin significantly protected alteration in body weight, blood urea nitrogen, serum creatinine, creatinine clearance, serum uric acid, serum electrolytes, urinary volume, urinary protein, urinary lactate dehydrogenase and urinary alkaline phosphatase induced by gentamicin. Histological examination of the kidney also suggested the same. It is concluded from the current study that co-administration of Cymbopogon citratus with gentamicin for 3 weeks successfully prevented renal damage associated with aminoglycosides.

  20. Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin.

    Science.gov (United States)

    Yalcin, Suayib; Müftüoğlu, Sevda; Cetin, Eren; Sarer, Banu; Yildirim, Berna Akkuş; Zeybek, Dilara; Orhan, Bülent

    2003-01-01

    Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.

  1. Effect of platelet activating factor antagonist treatment on gentamicin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Barbero

    1992-01-01

    Full Text Available To assess whether PAF could be involved in the gentamicin-induced nephrotoxicity, we have studied the effect of PAF antagonist BN-52021 on renal function in rats after gentamicin (GENTA treatment. Experiments were completed in 21 Wistar rats divided into three groups: group GENTA was injected with gentamicin 100 mg kg−1 body wt/day s.c. for 6 days. Group GENTA + BN received gentamicin and BN-52021 i.p. 5 mg kg−1 body wt/day. A third group served as control. Rats were placed in meta-bolic cages and plasma creatinine and creatinine clearance were measured daily. GENTA group showed a progressive increase in plasma creatinine, a drop in creatinine clearance and an increase in urinary excretion of N-acetyl-β-D-glucosaminidase and alkaline phosphatase. GENTA + BN group showed a lesser change in plasma creatinine and a creatinine clearance, but no difference with GENTA group in urinary excretion of NAG and AP were observed. Histological examination revealed a massive cortical tubular necrosis in rats treated with gentamicin, whereas in BN-52021 injected animals tubular damage was markedly attenuated. The present results suggest a role for PAF in the gentamicininduced nephro-toxicity.

  2. Optimized conformal paraaortic lymph node irradiation is not associated with enhanced renal toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Nevinny-Stickel, M.; Forthuber, B.C.; Posch, A.; Beer, B.; Lukas, P.; Seppi, T. [Innsbruck Medical Univ. (Austria). Dept. of Therapeutic Radiology and Oncology; Poljanc, K. [Technische Univ. Vienna (Austria). Atomic Inst. of the Austrian Universities; Heute, D. [Innsbruck Medical Univ. (Austria). Dept. of Nuclear Medicine; Lechner, J. [Innsbruck Medical Univ. (Austria). Div. of Physiology

    2007-07-15

    Background and Purpose: For patients with gynecologic carcinomas, irradiation of paraaortic lymph nodes (PLNs) is a routine treatment concept. Planning target volumes (PTVs) individually optimized by radiation field delineations along the big vessels permit the inclusion of at least 97% of potentially involved PLNs. However, this novel treatment technique might increase radiation-induced nephrotoxicity. Therefore, the actual incidence of kidney damage after PLN irradiation has to be assessed in order to validate the safety of this treatment concept. Patients and Methods: 19 patients were treated with irradiation alone (50.4 Gy; 5 x 1.8 Gy/week) and monitored for up to 90 months. Functional renal parameters, namely renal plasma flow (RPF) and glomerular filtration rate (GFR), were assessed by dynamic renal scintigraphy. Additionally, patients were clinically observed (i.e., hypertension, proteinuria) and calculations of normal-tissue complication probability (NTCP) values for nonuniform kidney irradiation were performed using the Lyman-Wolbarst algorithm. Results: Two patients with anticipated moderate NTCP values (12.6% and 8.7%) showed slightly impaired RPF rates at 12, 24, and after 48 months of follow-up. Only one patient in the subgroup showing NTCP values > 50% (n = 9) developed a notable impairment of renal RPF. However, all patients including those with elevated complication probabilities exhibited neither impaired GFR nor clinically apparent symptoms related to a loss of functioning renal tissue from 12 to > 48 months post irradiation. Conclusion: Conformal irradiation of retroperitoneal lymph nodes with individual PTV delineation appears not to be associated with clinically relevant functional impairment of the kidneys. (orig.)

  3. A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity

    NARCIS (Netherlands)

    Nieskens, Tom T G; Peters, Janny G P; Schreurs, Marieke J; Smits, Niels; Woestenenk, Rob; Jansen, Katja; van der Made, Thom K; Röring, Melanie; Hilgendorf, Constanze; Wilmer, Martijn J; Masereeuw, Roos

    2016-01-01

    Drug-induced nephrotoxicity still hampers drug development, because current translation from in vitro or animal studies to human lacks high predictivity. Often, renal adverse effects are recognized only during clinical stages of drug development. The current study aimed to establish a robust and a m

  4. Effects of dietary sodium and magnesium on cyclosporin A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats.

    Science.gov (United States)

    Mervaala, E M; Pere, A K; Lindgren, L; Laakso, J; Teräväinen, T L; Karjala, K; Vapaatalo, H; Ahonen, J; Karppanen, H

    1997-03-01

    Arterial hypertension, nephrotoxicity, and magnesium loss are common side effects of the immunosuppressive agent cyclosporin A (CsA). In the present study, the effects of dietary sodium and magnesium on CsA toxicity were examined in spontaneously hypertensive rats. A 6-week treatment with CsA during a moderately low-sodium diet (Na 0.3%, Mg 0.2% of the dry weight of the chow) raised blood pressure only slightly, without evidence of nephrotoxicity. By contrast, CsA during a high-sodium diet (Na 2.6%) produced a pronounced rise in blood pressure as well as marked nephrotoxicity, comprising decreased creatinine clearance, increased levels of serum creatinine and urea, and increased urinary protein excretion. During the high-sodium diet, CsA decreased myocardial and bone magnesium concentration and increased myocardial and renal calcium concentration. Magnesium supplementation (Mg 0.6%) protected against the CsA-induced hypertension and nephrotoxicity during the high-sodium diet. Magnesium supplementation also completely prevented the CsA-induced myocardial magnesium depletion and calcium accumulation in the heart and kidney during the high-sodium diet. Our findings indicate a detrimental interaction between increased sodium intake and CsA treatment and a marked protection by concomitant oral magnesium supplementation.

  5. Proteomic approaches in understanding a detected relationship between chemotherapy-induced nephrotoxicity and cell respiration in HK-2 cells.

    Science.gov (United States)

    Perez, Juliana Dinéia; Colucci, Juliana Almada; Sakata, Maísa Mayumi; Cunha, Tatiana Sousa; Arita, Danielle Yuri; Casarini, Dulce Elena

    2011-01-01

    Nephrotoxicity is a prominent component of the profile of chemotherapeutic agents and to date proteomics has represented the main technique to identify protein profiles in response to xenobiotic exposure. We made use of two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight analysis to evaluate chemotoxicity effects of cisplatin (CPT) and carboplatin (CB) on proteins from human renal proximal tubule epithelial cells (HK-2). Tandem mass spectrometry analysis showed that ATP synthase subunit α and serine hydroxymethyltransferase were only expressed in HK-2 cells exposed to CPT. Since CPT causes damage in cellular respiration, we suggest that this might be a protective adaptation to CPT-induced nephrotoxicity. Thioredoxin-dependent peroxide reductase disappeared in the CPT group and was upregulated in the CB group, suggesting that CB exposure stimulates preventive apoptotic mechanisms. We suggest a relationship between chemotherapeutic agent-induced nephrotoxicity and cell respiration. The identification of proteins differentially expressed in HK-2 cells, when exposed to CPT and CB, not only supplies important information to understand the molecular action mechanisms, which are triggered by metal-based drugs in cell nephrotoxicity, but also can lead to the design of more effective anticancer drugs. These results provide important insights into the investigation of possible biomarker(s) of toxicity that could eventually reduce the side effects of chemotherapeutic agents. Copyright © 2011 S. Karger AG, Basel.

  6. An integrated view of cisplatin-induced nephrotoxicity and ototoxicity.

    Science.gov (United States)

    Karasawa, Takatoshi; Steyger, Peter S

    2015-09-17

    Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Resveratrol protects against arsenic trioxide-induced nephrotoxicity by facilitating arsenic metabolism and decreasing oxidative stress.

    Science.gov (United States)

    Yu, Meiling; Xue, Jiangdong; Li, Yijing; Zhang, Weiqian; Ma, Dexing; Liu, Lian; Zhang, Zhigang

    2013-06-01

    Arsenic trioxide (As(2)O(3)) is an environmental toxicant and a potent antineoplastic agent. Exposure to arsenic causes renal cancer. Resveratrol is a well-known polyphenolic compound that is reported to reduce As(2)O(3)-induced cardiotoxicity. The present study aimed to investigate the effect of resveratrol on As(2)O(3)-induced nephrotoxicity and arsenic metabolism. Chinese Dragon-Li cats were injected with 1 mg/kg As(2)O(3) on alternate days; resveratrol (3 mg/kg) was administered via the forearm vein 1 h before the As(2)O(3) treatment. On the sixth day, the cats were killed to determine the histological renal damage, renal function, the accumulation of arsenic, and antioxidant activities in the kidney. Urine samples were taken for arsenic speciation. In the resveratrol + As(2)O(3)-treated group, activities of glutathione peroxidase, catalase, and superoxide dismutase, the ratio of reduced glutathione to oxidized glutathione, the total arsenic concentrations, and the percentage of methylated arsenic in urine were significantly increased. The concentrations of renal malondialdehyde, reactive oxygen species, 8-hydroxydeoxyguanosine, serum creatinine, blood urea nitrogen, and renal arsenic accumulation were significantly decreased and reduced renal morphologic injury was observed compared with the As(2)O(3)-treated group. These results demonstrate that resveratrol could significantly scavenge reactive oxygen species, inhibit As(2)O(3)-induced oxidative damage, and significantly attenuate the accumulation of arsenic in renal tissues by facilitating As(2)O(3) metabolism. These data suggest that use of resveratrol as postremission therapy for acute promyelocytic leukemia as well as adjunctive therapy in patients with exposure to arsenic may decrease arsenic nephrotoxicity.

  8. Relationships between Serum Levels of Atazanavir and Renal Toxicity or Lithiasis

    OpenAIRE

    Marinescu, C. I.; Leyes, M.; M. A. Ribas; Peñaranda, M.; Murillas, J.; Campins, A. A.; Martin-Pena, L.; Barcelo, B.; Barceló-Campomar, C.; Grases, F.; Frontera, G; Melchor Riera Jaume

    2015-01-01

    The main aim of this study is to describe the relationship between serum levels of atazanavir, renal toxicity, and lithiasis. This is a prospective observational study of patients being treated with atazanavir (ATV) at Son Espases Teaching Hospital, Palma de Mallorca, between 2011 and 2013. The study includes 98 patients. Sixteen were found to have a history of urolithiasis. During a median monitoring period of 23 months, nine patients suffered renal colic, in three of whom ATV crystals were ...

  9. Hypertension and nephrotoxicity in the rate of decline in kidney function in diabetic nephropathy.

    Science.gov (United States)

    Aubia, J; Hojman, L; Chine, M; Lloveras, J; Masramon, J; Llorach, I; Cuevas, X; Puig, J M

    1987-01-01

    Serum creatinine levels were determined prospectively every 2 to 3 months in 40 patients with diabetic nephropathy for a global observation period of 864 months. The monthly creatinine increasing rate was significantly lower in normotensive periods, mean arterial pressure (MAP) less than 115 mmHg, when compared with hypertensive periods, MAP greater than 125 mmHg. No significant difference was shown in periods with borderline hypertension (MAP between 115-124 mmHg). The mean creatinine increases were of 0.036 mg/dl/month, 0.3 mg/dl/month and 0.046 mg/dl/month respectively. Normotension was associated with a slowing down of the rate of decline in renal function in this group of moderate kidney failure with an initial mean serum creatinine of 2.26 mg/dl. The exposure of patients to nephrotoxics (aminoglycosides, and possibly anesthesia) significantly accelerated the decline in renal function: 0.39 mg/dl/month and 0.17 mg/dl/month respectively according to the concomitance or not of toxics and hypertension. The reported protective effect of diabetes against aminoglycosides nephrotoxicity in experimental conditions was not reflected in our clinical results. On the contrary, we suggest a possible enhanced sensibility of the diabetic patient with diabetic nephropathy to aminoglycosides leading to an acceleration of the progression of renal failure.

  10. Cisplatin Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Seyed Seifollah Beladi Mousavi

    2014-02-01

    The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with the administration of full intravenous isotonic saline before and after cisplatin administration. Although a number of pharmacologic agents including sodium thiosulfate, N-acetylcysteine, theophylline and glycine have been evaluated for prevention of nephrotoxicity, none have proved to have an established role, thus, additional clinical studies will be required to confirm their probable effects.

  11. Antioxidant effect of Arabic gum against mercuric chloride-induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Gado AM

    2013-10-01

    Full Text Available Ali M Gado,1 Badr A Aldahmash21Forensic Medicine and Clinical Toxicology Department, College of Medicine, Tanta University, Tanta, Egypt; 2Medical Laboratory Department, College of Health Sciences, King Saud University, Riyadh, Saudi ArabiaAbstract: The effects of Arabic gum (AG against nephrotoxicity of mercury (Hg, an oxidative-stress inducing substance, in rats were investigated. A single dose of mercuric chloride (5 mg/kg intraperitoneal injection induced renal toxicity, manifested biochemically by a significant increase in serum creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite production in kidney tissues. In addition, reduced glutathione, glutathione peroxidase, and catalase enzymes in renal tissues were significantly decreased. Pretreatment of rats with AG (7.5 g/kg/day per oral administration, starting 5 days before mercuric chloride injection and continuing through the experimental period, resulted in a complete reversal of Hg-induced increase in creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite to control values. Histopathologic examination of kidney tissues confirmed the biochemical data; pretreatment of AG prevented Hg-induced degenerative changes of kidney tissues. These results indicate that AG is an efficient cytoprotective agent against Hg-induced nephrotoxicity by a mechanism related at least in part to its ability to decrease oxidative and nitrosative stress and preserve the activity of antioxidant enzymes in kidney tissues.Keywords: mercury, acacia gum, oxidative stress, lipid per oxidation, kidney toxicity

  12. Unexpected Nephrotoxicity in Male Ablactated Rats Induced by Cordyceps militaris: The Involvement of Oxidative Changes

    Directory of Open Access Journals (Sweden)

    Xiaowen Zhou

    2013-01-01

    Full Text Available Recently, many nutraceutical products containing the powdered or extracted parts of C. militaris have become available for health care. Due to the increased morbidity and mortality, poisonings associated with the use of herbs have raised the universal attention. Herein, we carried out the 28-day repeated toxicity test in male and female ablactated rats (three weeks old given C. militaris powder orally at 0 (control, 1, 2, and 3 g/kg per day. Noticeable increments of serum aspartate and alanine aminotransferase (ALT and AST levels were observed for both sexes, suggestive of weak hepatic toxicity. Nephrotoxicity characterized by tubular epithelium degeneration and necrosis was observed at the high dose, and the male rats were more susceptible to renal toxicity than female rats. In addition, the genes and protein expressions of novel markers of kidney toxicity, such as kidney injury molecule-1 (KIM-1 were enlarged in the renal cortex and the urine. Moreover, C. militaris treatment significantly decreased superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GPx activities. However, the ratio of glutathione oxidized form (GSSG/glutathione reduced form (GSH was increased by C. militaris treatment. We conclude that dietary contamination with C. militaris may have renal toxicity potentials, at least in part by causing oxidative damage to the kidney.

  13. Unexpected Nephrotoxicity in Male Ablactated Rats Induced by Cordyceps militaris: The Involvement of Oxidative Changes

    Science.gov (United States)

    2013-01-01

    Recently, many nutraceutical products containing the powdered or extracted parts of C. militaris have become available for health care. Due to the increased morbidity and mortality, poisonings associated with the use of herbs have raised the universal attention. Herein, we carried out the 28-day repeated toxicity test in male and female ablactated rats (three weeks old) given C. militaris powder orally at 0 (control), 1, 2, and 3 g/kg per day. Noticeable increments of serum aspartate and alanine aminotransferase (ALT and AST) levels were observed for both sexes, suggestive of weak hepatic toxicity. Nephrotoxicity characterized by tubular epithelium degeneration and necrosis was observed at the high dose, and the male rats were more susceptible to renal toxicity than female rats. In addition, the genes and protein expressions of novel markers of kidney toxicity, such as kidney injury molecule-1 (KIM-1) were enlarged in the renal cortex and the urine. Moreover, C. militaris treatment significantly decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities. However, the ratio of glutathione oxidized form (GSSG)/glutathione reduced form (GSH) was increased by C. militaris treatment. We conclude that dietary contamination with C. militaris may have renal toxicity potentials, at least in part by causing oxidative damage to the kidney. PMID:23533520

  14. Low serum zinc is associated with elevated risk of cadmium nephrotoxicity

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    Lin, Yu-Sheng, E-mail: Lin.Yu-Sheng@epa.gov [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC (United States); Ho, Wen-Chao [Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan (China); Caffrey, James L. [Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, TX (United States); Sonawane, Babasaheb [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC (United States)

    2014-10-15

    Background: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available. Objective: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans. Methods: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011–2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m{sup 2} and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5 mg/mmol in women. Results: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 μg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09–4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13–3.69) than their low cadmium (<0.18 μg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39–8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01). Conclusions: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity. - Highlights: • Blood cadmium was associated with increased risk of nephrotoxicity. • Low serum zinc may exacerbate risk of cadmium-mediated renal dysfunction. • Both zinc deficiency and elevated cadmium exposure are global public health issues.

  15. Relationships between Serum Levels of Atazanavir and Renal Toxicity or Lithiasis

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    C. I. Marinescu

    2015-01-01

    Full Text Available The main aim of this study is to describe the relationship between serum levels of atazanavir, renal toxicity, and lithiasis. This is a prospective observational study of patients being treated with atazanavir (ATV at Son Espases Teaching Hospital, Palma de Mallorca, between 2011 and 2013. The study includes 98 patients. Sixteen were found to have a history of urolithiasis. During a median monitoring period of 23 months, nine patients suffered renal colic, in three of whom ATV crystals were evidenced in urine. Cumulative incidence of renal colic was 9.2 per 100 patients. The variables related to having renal colic were the presence of alkaline urine pH and lower basal creatinine clearance. The mean serum level of ATV was slightly higher in patients with renal colic—1,303 μg/L versus 1,161 μg/L—but did not reach statistical significance. Neither were any significant differences detected by analysing the levels according to the timetable for ATV dosage. Cumulative incidence of renal colic was high in patients being treated with ATV, in 33% of whom the presence of ATV crystals was evidenced in urine. We were unable to demonstrate a relationship between ATV serum levels and renal colic or progression towards renal failure.

  16. Relationships between Serum Levels of Atazanavir and Renal Toxicity or Lithiasis.

    Science.gov (United States)

    Marinescu, C I; Leyes, M; Ribas, M A; Peñaranda, M; Murillas, J; Campins, A A; Martin-Pena, L; Barcelo, B; Barceló-Campomar, C; Grases, F; Frontera, G; Riera Jaume, Melchor

    2015-01-01

    The main aim of this study is to describe the relationship between serum levels of atazanavir, renal toxicity, and lithiasis. This is a prospective observational study of patients being treated with atazanavir (ATV) at Son Espases Teaching Hospital, Palma de Mallorca, between 2011 and 2013. The study includes 98 patients. Sixteen were found to have a history of urolithiasis. During a median monitoring period of 23 months, nine patients suffered renal colic, in three of whom ATV crystals were evidenced in urine. Cumulative incidence of renal colic was 9.2 per 100 patients. The variables related to having renal colic were the presence of alkaline urine pH and lower basal creatinine clearance. The mean serum level of ATV was slightly higher in patients with renal colic-1,303 μg/L versus 1,161 μg/L-but did not reach statistical significance. Neither were any significant differences detected by analysing the levels according to the timetable for ATV dosage. Cumulative incidence of renal colic was high in patients being treated with ATV, in 33% of whom the presence of ATV crystals was evidenced in urine. We were unable to demonstrate a relationship between ATV serum levels and renal colic or progression towards renal failure.

  17. Protective Effects of Zinc Supplementation on Renal Toxicity in Rats Exposed to Cadmium

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    Morshedi

    2014-07-01

    Full Text Available Background Cadmium (Cd is a nonessential element with many industrial applications and is one of the most toxic pollutants in the environment. The ultimate goal of occupational health is prevention of health hazards on workplace; hence, is as a hazardous chemical contaminant in the workplace, Cd needs special attention. Objectives The object of this study was to determine the effect of ZnCl2 on Cd-induced nephrotoxicity in rats. Materials and Methods Adult male rats were given CdCl2 at doses of 0, 1, 2, and 3 mg/kg. Another series of rats were pretreated with 4 mg/kg of ZnCl2 30 minutes prior to administration of various doses of CdCl2. The experiment was repeated for seven consecutive days. Twenty-four hours after administering the latest dose, animals were sacrificed. Blood samples were analyzed for blood urea nitrogen (BUN and creatinine levels. Kidney tissues were excised for measuring malondialdehyde (MDA concentration. Results In contrast to the animals that received ZnCl2, CdCl2 induced a dose-dependent elevation in BUN, creatinine, and MDA in those without ZnCl2 pretreatment. Zinc chloride had significantly decreased all biochemical parameters and protected kidney cells against Cd-induced toxicity. Conclusions The results of this study supported the potential protective effects of ZnCl2 on rat kidney tissues against CdCl2 toxicity.

  18. Anti-nephrotoxic activity of some medicinal plants from tribal rich pockets of Odisha

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    Satyaranjan Mishra

    2014-01-01

    Full Text Available Background: Gentamicin, a strong cationic drug accumulated at biological membranes causes net increase in oxidative stress and lipid peroxidation leading to necrotic changes in renal tubles and consequently precipitates acute nephrotoxicity. Several phytoconstituents and plants extracts demonstrated significant anti-oxidant and cyto-protective activities. Vitex negundo Linn. (VN, Oroxylum indicum Vent. (OI and Barringtonia acutangula Linn. (BA are widely found throughout the Asian sub-continent including India, used extensively in different forms of Indian traditional medicine like Ayurveda and Unani. Objective: Nephroprotective activity of extracts of VN roots, OI whole plant and BA leaves were investigated against experimentally induced acute nephrotoxicity [Gentamicin (i.p; 80mg/kg for 7 days] in Wistar rats as test animals. Materials and Methods: The rats were treated with Cystone (5 mL/kg; p.o taken as positive control and methanol-dichloromethane (1:1 extracts of VN, OI and BA (200 mg/kg; p.o as test drugs for 7 days. Following the said treatments, biochemical parameters of urine (volume, creatinine and lactate dehydrogenase (LDH and serum (urea, creatinine, albumin and total protein were estimated. Renal anti-oxidant markers viz., superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GPx and lipid peroxidation (LPO in renal tissue were assayed. Tissue sections of kidneys from different groups were made and histopathological features were observed. Result: The extracts of VN, OI and BA significantly attenuated the nephrotoxicity by elevation of body weight, CAT, GPx and SOD or lowering urine LDH and creatinine, serum urea; serum creatinine and LPO respectively. Histopathological score of VN, OI and BA treated groups were 1+, 2+ and 2+ respectively against 4+ of the toxic group. Conclusion: The findings suggested the significant nephroprotection of VN roots followed by OI whole plant and BA leaves.

  19. Chitosan Prevents Gentamicin-Induced Nephrotoxicity via a Carbonyl Stress-Dependent Pathway

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    Chu-Kung Chou

    2015-01-01

    Full Text Available Aminoglycosides are widely used to treat infections; however, their applications are limited by nephrotoxicity. With the increase of antibiotic resistance, the use of aminoglycosides is inevitable. Low-molecular-weight chitosan (LMWC has shown renal protective effects in dialysis patients. However, no study has evaluated LMWC for preventing aminoglycoside-induced nephrotoxicity or determined the mechanisms underlying the renal protective effects. In this study, LMWC (165 or 825 mg/kg/day or metformin (100 mg/kg/day was orally administered for 13 days to rats with nephropathy induced by gentamicin (GM, a kind of aminoglycoside (150 mg/kg/day i.p. for 6 days. Both LMCW doses improved renal function. Serum creatinine levels improved in rats treated with 165 and 825 mg/kg/day LMWC (from 2.14 ± 0.74 mg/dL to 1.26 ± 0.46 mg/dL and 0.69 ± 0.12 mg/dL, resp., P < 0.05. Blood urea nitrogen levels were also improved in these rats (from 73.73 ± 21.13 mg/dL to 58.70 ± 22.71 mg/dL and 28.82 ± 3.84 mg/dL, resp., P < 0.05. Additionally, renal tissue morphology improved after LMWC treatment, and accumulation of renal methylglyoxal, a damage factor associated with carbonyl stress, was reversed. These results show that LMWC prevents GM-induced renal toxicity via a carbonyl stress-dependent pathway.

  20. Investigation of cadmium toxicity on renal epithelial cells using nuclear microprobe analysis

    Energy Technology Data Exchange (ETDEWEB)

    Khodja, Hicham E-mail: khodja@drecam.cea.fr; Avoscan, Laure; Carriere, Marie; Carrot, Francine; Gouget, Barbara

    2003-09-01

    Cadmium is a highly toxic metal that causes well-known severe renal damages. Its toxicity is frequently investigated in vitro using numerous epithelial models. The accumulation and transport of cadmium in cultured renal epithelial cells has been studied by means of nuclear microscopy (micro-PIXE coupled with micro-RBS) for cell monolayer analyses, and by ICP-MS for culture medium analyses. Cell viability, measured by biochemical tests, was used as toxicity indicator. Dependence on cadmium concentration (1-100 {mu}M) and exposure time (1-24 h) was found. Micro-PIXE reveals a strong anti-correlation of intra-cellular cadmium concentration with zinc concentration, a biological metal, suggesting substitution mechanism of both metals.

  1. Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies

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    Sharma Alok

    2010-10-01

    Full Text Available Background: Calcineurin inhibitors (cyclosporine and tacrolimus are important constituents of post renal transplant immunosuppression. However, renal toxicity limits their utility. Histological features of calcineurin inhibitor toxicity (CNIT have been the subject of few studies using protocol biopsy samples, and consensus on diagnostic criteria is still evolving. Aims: To analyze the spectrum of histological changes in protocol renal allograft biopsies with evidence of CNIT and identify additional features that are likely to help the pathologist in arriving at a diagnosis. Materials and Methods: One hundred and forty protocol allograft biopsies performed at 1, 6 and 12 months post renal transplant were studied. The defining features of CNIT included: isometric vacuolization of proximal tubular cells, arteriolar hyalinosis with medial/peripheral nodules and striped pattern of tubular atrophy/interstitial fibrosis. Other features such as global glomerulosclerosis, vacuolization of smooth muscle cells of arterioles, tubular microcalcinosis, ischemic shrinkage of glomeruli and hyperplasia of juxtaglomerular apparatus (JGA were also analyzed and graded semiquantitatively. Results: CNIT was seen in 17/140 protocol biopsies (12.1%. In addition to the diagnostic criteria, arteriolar hyalinosis, smooth muscle cell vacuolization of arterioles and hyperplasia of JGA were found to be useful indicators of CNIT. Conclusions: There is a relatively high incidence of CNIT in protocol allograft biopsies. A critical analysis of renal biopsy in adequate number of serial step sections to identify these features is mandatory, as many of these features are subtle and are likely to be missed if not specifically sought.

  2. Protective Effect of Morocco Carob Honey Against Lead-Induced Anemia and Hepato-Renal Toxicity

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    Aicha Fassi Fihri

    2016-06-01

    Full Text Available Background/Aims: Natural honey has many biological activities including protective effect against toxic materials. The aim of this study was to evaluate the protective effect of carob honey against lead-induced hepato-renal toxicity and lead-induced anemia in rabbits. Methods: Twenty four male rabbits were allocated into four groups six rabbits each; group 1: control group, received distilled water (0.1 ml / kg.b.wt /daily; group 2: received oral lead acetate (2 g/kg.b.wt/daily; group 3: treated with oral honey (1g /kg.b.wt/daily and oral lead (2 g/kg.b.wt/daily, and group 4: received oral honey (1 g/kg.b.wt/daily. Honey and lead were given daily during 24 days of experimentation. Laboratory tests and histopathological evaluations of kidneys were done. Results: Oral administration of lead induced hepatic and kidney injury and caused anemia during three weeks of the exposure. Treatment with honey prevented hepato-renal lead toxicity and ameliorated lead-induced anemia when honey was given to animals during lead exposure. Conclusion: It might be concluded that honey has a protective effect against lead-induced blood, hepatic and renal toxic effects.

  3. Evaluation of “Dream Herb,” Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells

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    Miriam E. Mossoba

    2016-01-01

    Full Text Available A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. “Dream herb,” Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening of C. zacatechichi for safety especially important. We exposed human proximal tubule HK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects of C. zacatechichi relative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement.

  4. Evaluation of “Dream Herb,” Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells

    Science.gov (United States)

    Flynn, Thomas J.; Vohra, Sanah; Wiesenfeld, Paddy; Sprando, Robert L.

    2016-01-01

    A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. “Dream herb,” Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening of C. zacatechichi for safety especially important. We exposed human proximal tubule HK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects of C. zacatechichi relative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement. PMID:27703475

  5. Ultrasensitive techniques for measurement of uranium in biological samples and the nephrotoxicity of uranium: Proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Kathren, R.L.; Weber, J.R. (eds.)

    1988-04-01

    Edited transcripts are provided of two public meetings sponsored by the Division of Radiation Programs and Earth Sciences of the Nuclear Regulatory Commission, Occupational Radiation Protection Branch. The first meeting, held on December 3, 1985, included nine presentations covering ultrasensitive techniques for measurement of uranium in biological specimens. Topics included laser-spectrometric techniques for uranium bioassay, correlation of urinary uranium samples with air sampling results in industrial settings, delayed neutron counting, laser-kinetic phosphometry, isotope dilution mass spectrometry, resonance ionization spectroscopy, fission track analysis, laser-induced fluorescence, and costs of sampling and processing. The nine presentations of the second meeting dealt with the nephrotoxicity of uranium. Among the topics presented were the physiology of the kidney, the effects of heavy metals on the kidney, animal studies in uranium nephrotoxicity, comparisons of kidney histology in nine humans, renal effects in uranium mill workers, renal damage from different uranium isotopes, and Canadian studies on uranium toxicity. Discussions following the presentations are included in the edited transcripts. 30 refs., 9 figs., 9 tabs.

  6. Role of biomarkers of nephrotoxic acute kidney injury in deliberate poisoning and envenomation in less developed countries.

    Science.gov (United States)

    Mohamed, Fahim; Endre, Zoltan H; Buckley, Nicholas A

    2015-07-01

    Acute kidney injury (AKI) has diverse causes and is associated with increased mortality and morbidity. In less developed countries (LDC), nephrotoxic AKI (ToxAKI) is common and mainly due to deliberate ingestion of nephrotoxic pesticides, toxic plants or to snake envenomation. ToxAKI shares some pathophysiological pathways with the much more intensively studied ischaemic AKI, but in contrast to ischaemic AKI, most victims are young, previously healthy adults. Diagnosis of AKI is currently based on a rise in serum creatinine. However this may delay diagnosis because of the kinetics of creatinine. Baseline creatinine values are also rarely available in LDC. Novel renal injury biomarkers offer a way forward because they usually increase more rapidly in AKI and are normally regarded as absent or very low in concentration, thereby reducing the need for a baseline estimate. This should increase sensitivity and speed of diagnosis. Specificity should also be increased for urine biomarkers since many originate from the renal tubular epithelium. Earlier diagnosis of ToxAKI should allow earlier initiation of appropriate therapy. However, translation of novel biomarkers of ToxAKI into clinical practice requires better understanding of non-renal factors in poisoning that alter biomarkers and the influence of dose of nephrotoxin on biomarker performance. Further issues are establishing LDC population-based normal ranges and assessing sampling and analytical parameters for low resource settings. The potential role of renal biomarkers in exploring ToxAKI aetiologies for chronic kidney disease of unknown origin (CKDu) is a high research priority in LDC. Therefore, developing more sensitive biomarkers for early diagnosis of nephrotoxicity is a critical step to making progress against AKI and CKDu in the developing world. © 2015 The British Pharmacological Society.

  7. Nefrotoxicidade por lítio Lithium nephrotoxicity

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    Jobson Lopes de Oliveira

    2010-01-01

    Full Text Available O lítio é amplamente empregado na terapia do transtorno bipolar. Sua toxicidade renal inclui distúrbio na capacidade de concentração urinária e natriurese, acidose tubular renal, nefrite túbulo-intersticial evoluindo para doença renal crônica e hipercalcemia. O efeito adverso mais comum é o diabetes insipidus nefrogênico, que acomete de 20%-40% dos pacientes semanas após o início do tratamento. A nefropatia crônica correlaciona-se com a duração do uso de lítio. A detecção precoce de disfunção renal deve ser feita através de monitoração rigorosa dos pacientes e colaboração entre o psiquiatra e o nefrologista. Recentes trabalhos experimentais e clínicos começam a esclarecer os mecanismos pelos quais o lítio induz alteração da função renal. No presente trabalho, objetivamos revisar a patogênese, a apresentação clínica, os aspectos histopatológicos e o tratamento da nefrotoxicidade induzida pelo lítio.Lithium is widely used in the therapy of bipolar disorder. Its toxicity includes urinary concentration deficit and natriuresis, renal tubular acidosis, tubulointerstitial nephritis which complicates with chronic kidney disease and hypercalcemia. The most common adverse effect is diabetes insipidus, which occurs in 20-40% of patients some weeks after initiation of treatment. Such chronic nephropathy correlates with duration of lithium use. Early detection of renal dysfunction should be achieved by rigorous monitoring of patients and collaboration between the psychiatrist and nephrologist. Recent experimental and clinical studies are now clarifying the mechanisms by which lithium induces renal abnormalities. The aim of this work is to review the pathogenesis, clinical presentation, histopathologic aspects and treatment of lithium nephrotoxicity.

  8. A comparison of toxicities in acute myeloid leukemia patients with and without renal impairment treated with decitabine.

    Science.gov (United States)

    Levine, Lauren B; Roddy, Julianna Vf; Kim, Miryoung; Li, Junan; Phillips, Gary; Walker, Alison R

    2017-01-01

    Purpose There are limited data regarding the clinical use of decitabine for the treatment of acute myeloid leukemia in patients with a serum creatinine of 2 mg/dL or greater. Methods We retrospectively evaluated 111 patients with acute myeloid leukemia who had been treated with decitabine and compared the development of toxicities during cycle 1 in those with normal renal function (creatinine clearance greater than or equal to 60 mL/min) to those with renal dysfunction (creatinine clearance less than 60 mL/min). Results Notable differences in the incidence of grade ≥3 cardiotoxicity (33% of renal dysfunction patients vs. 16% of normal renal function patients, p = 0.042) and respiratory toxicity (40% of renal dysfunction patients vs. 14% of normal renal function patients, p = 0.0037) were observed. The majority of heart failure, myocardial infarction, and atrial fibrillation cases occurred in the renal dysfunction group. The odds of developing grade ≥3 cardiotoxicity did not differ significantly between patients with and without baseline cardiac comorbidities (OR 1.43, p = 0.43). Conclusions This study noted a higher incidence of grade ≥3 cardiac and respiratory toxicities in decitabine-treated acute myeloid leukemia patients with renal dysfunction compared to normal renal function. This may prompt closer monitoring, regardless of baseline cardiac comorbidities. Further evaluation of decitabine in patients with renal dysfunction is needed.

  9. Evaluation of renoprotective effect of Aphanizomenon flos-aquae on cisplatin-induced renal dysfunction in rats.

    Science.gov (United States)

    Kuriakose, Gini C; Kurup, Muraleedhara G

    2008-01-01

    Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide array of both pediatric and adult malignancies. Dose-dependent and cumulative nephrotoxicity is the major toxicity of this compound, sometimes requiring a reduction in dose or discontinuation of treatment. Recent evidence has implicated oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Aphanizomenon flos-aquae (AFA), blue-green algae, is claimed to be a potential antioxidant. The present study was designed to explore the renoprotective potential of AFA against cisplatin-induced oxidative stress and renal dysfunction. The ethanolic extract of Aphanizomenon flos-aquae (EEAFA) (25, 50, 100 mg/kg(-1) p.o.) was administered two days before through three days after cisplatin challenge (5 mg/kg(-1) i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance, and serum nitrite levels. Renal oxidative stress was determined by renal TBARS levels, reduced glutathione levels, and enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (GST). A single dose of cisplatin produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic EEAFA treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the present study clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of AFA in cisplatin-induced nephrotoxicity.

  10. Nephrotoxicity of 2-bromo-(cystein-S-yl) hydroquinone and 2-bromo-(N-acetyl-L-cystein-S-yl) hydroquinone thioethers.

    Science.gov (United States)

    Monks, T J; Jones, T W; Hill, B A; Lau, S S

    1991-11-01

    The in vivo toxicity of isomeric cystein-S-yl and N-acetylcystein-S-yl conjugates of 2-bromohydroquinone was determined in male Sprague-Dawley rats. 2-Bromo-(dicystein-S-yl)hydroquinone [2-Br-(diCYS)HQ] and 2-bromo-(di-N-acetyl-L-cystein-S-yl)hydroquinone [2-Br-(diNAC)HQ] were considerably more nephrotoxic than their corresponding monosubstituted thioethers and 2-Br-(diCYS)HQ was more nephrotoxic than 2-Br-(diNAC)HQ. 2-Br-(diCYS)HQ caused elevations in blood urea nitrogen (BUN) concentrations and increases in the urinary excretion of glucose, lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (gamma-GT) at a dose of 25 mumol/kg (iv). In contrast, 2-Br-(diNAC)HQ caused significant elevations in BUN at 100 mumol/kg and glucosuria and enzymuria at 50 mumol/kg. 2-Br-3-(CYS)HQ and 2-Br-5&6-(CYS)HQ caused increases in the biochemical indices of nephrotoxicity at doses between 50 and 150 mumol/kg whereas 2-Br-5-(NAC)HQ and 2-Br-6-(NAC)HQ required doses of 150-200 mumol/kg to cause smaller, though significant increases in urinary glucose, gamma-GT, and LDH excretion. The histological alterations caused by each thioether were qualitatively similar; only differences in the extent of the renal proximal tubular damage were observed. The initial lesion appears to involve the cells of the medullary ray and the S3M within the outer stripe of the outer medulla. The in vivo nephrotoxicity of 2-Br-(DiCYS)HQ, 2-Br-(diNAC)HQ, and the most potent monosubstituted thioethers, 2-Br-5&6-(CYS)HQ and 2-Br-6-(NAC)HQ, was investigated further. Pretreatment of animals with aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase (beta-lyase), had no effect on the toxicity of 2-Br-(diCYS)HQ, partially inhibited the toxicity of 2-Br-5&6-(CYS)HQ, and almost completely protected against the toxicity of both 2-Br-6-(NAC)HQ and 2-Br-(diNAC)HQ. Thus, the nephrotoxicity of 2-Br-5&6-(CYS)HQ, 2-Br-6-(NAC)HQ, and 2-Br-(diNAC)HQ may be mediated, in part, via their processing by beta

  11. Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity.

    Science.gov (United States)

    Humanes, Blanca; Jado, Juan Carlos; Camaño, Sonia; López-Parra, Virginia; Torres, Ana María; Álvarez-Sala, Luís Antonio; Cercenado, Emilia; Tejedor, Alberto; Lázaro, Alberto

    2015-01-01

    Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.

  12. Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity

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    Blanca Humanes

    2015-01-01

    Full Text Available Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs. Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.

  13. Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation.

    Science.gov (United States)

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Nafees, Sana; Seth, Amlesh; Ali, Nemat; Rashid, Summya; Sultana, Sarwat

    2012-01-25

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.

  14. The effect of the carotenoid bixin and annatto seeds on hematological markers and nephrotoxicity in rats subjected to chronic treatment with cisplatin

    Directory of Open Access Journals (Sweden)

    Lucéia F. Souza

    Full Text Available ABSTRACT This study assessed the protective effect of the carotenoid bixin and annatto seeds against possible nephrotoxicity induced with a single peritoneal administration of pharmacological cisplatin in male Wistar rats. After 48 h, the blood cell differential count showed a significant reduction in neutrophil counts in rats that received a diet rich in bixin when compared to the group that received only cisplatin. The use of cisplatin led to an increase in kidney weight. The carotenoid bixin attenuated renal injury, characterized by increased polymorphonuclear infiltration. No protective effect was observed with respect to Annatto. These results demonstrate the role of toxic cisplatin and suggest that bixin affords a protective effect against cisplatin-induced nephrotoxicity in adult Wistar rats.

  15. The use of biomarkers for assessing HAART-associated renal toxicity in HIV-infected patients.

    Science.gov (United States)

    del Palacio, María; Romero, Sara; Casado, Jose L

    2012-09-01

    Renal toxicity has become an important issue in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Several biomarkers are available for monitoring renal function, although no consensus exists on how best to apply these tools in HIV infection. The best biomarker is the glomerular filtration rate (GFR), and several creatinine-based estimates equations of GFR are widely used in HIV infection, with clinical advantages for the equation developed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Although serum cystatin C has been proposed as a more sensitive marker of renal dysfunction in HIV infection, it may be affected by ongoing inflammation. Tubular dysfunction can be simple or complex, depending on whether the tubular transport of one or more substances is affected. Multiple renal tubular dysfunction or Fanconi syndrome is characterized by alterations in the reabsorption of glucose, amino acids, phosphate and often also bicarbonate. Therefore, Fanconi syndrome would be the tip of the iceberg, and the most unusual and severe manifestation. In the last years, several low molecular weight proteins as markers of tubular alteration, including retinol-binding protein, b2-microglobulin, and neutrophil gelatinase associated lipocalin have become available. Different studies have shown differences in urine concentrations of these proteins in patients receiving tenofovir, but again, no consistent data have shown their clinical usefulness in predicting the clinical consequences of tubular alteration. Thus, we review findings from recent studies performed in this area to describe the performance of new biomarkers for renal damage in HIV-infected patients.

  16. Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney

    Directory of Open Access Journals (Sweden)

    Ayodele Jacob Akinyemi

    2017-04-01

    Full Text Available In this study, the effect of enzymes involved in degradation of renal adenosine and l-arginine was investigated in rats exposed to cadmium (Cd and treated with curcumin, the principal active phytochemical in turmeric rhizome. Animals were divided into six groups (n = 6: saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. The results of this study revealed that the activities of renal adenosine deaminase and arginase were significantly increased in Cd-treated rats when compared with the control (p < 0.05. However, co-treatment with curcumin inhibits the activities of these enzymes compared with Cd-treated rats. Furthermore, Cd intoxication increased the levels of some renal biomarkers (serum urea, creatinine, and electrolytes and malondialdehyde level with a concomitant decrease in functional sulfhydryl group and nitric oxide (NO. However, co-treatment with curcumin at 12.5 mg/kg and 25 mg/kg, respectively, increases the nonenzymatic antioxidant status and NO in the kidney, with a concomitant decrease in the levels of malondialdehyde and renal biomarkers. Therefore, our results reinforce the importance of adenosine deaminase and arginase activities in Cd poisoning conditions and suggest some possible mechanisms of action by which curcumin prevent Cd-induced renal toxicity in rats.

  17. Protective effects of 6-hydroxy-1-methylindole-3-acetonitrile on cisplatin-induced oxidative nephrotoxicity via Nrf2 inactivation.

    Science.gov (United States)

    Moon, Ji Hee; Shin, Ji-Sun; Kim, Jong-Bin; Baek, Nam-In; Cho, Young-Wuk; Lee, Yong Sup; Kay, Hee Yeon; Kim, Soo-dong; Lee, Kyung-Tae

    2013-12-01

    We previously demonstrated the ethanol extract of the roots of Brassica rapa protects against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Here, we investigated the nephroprotective effects of 6-hydroxy-1-methylindole-3-acetonitrile (6-HMA), which was isolated from the roots of B. rapa, on cisplatin-induced toxicity in renal epithelial LLC-PK1 cells and in rats with acute renal injury. Pretreatment of LLC-PK1 cells with 6-HMA ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased levels of glutathione (GSH). In addition, 6-HMA inhibited cisplatin-induced heme oxygenase-1 (HO-1) expression, possibly due to the suppression of the nuclear translocation and binding activity of NF-E2-related factor 2 (Nrf2). Furthermore, 6-HMA administered rats showed lower levels of blood urea nitrogen (BUN), creatinine, and urinary lactate dehydrogenase (LDH) than cisplatin alone-treated rats in cisplatin-induced renal injury model. Moreover, 6-HMA inhibited the cisplatin-induced formation of MDA and GSH depletion and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). Taken together, these findings indicate 6-HMA is a major active constituent from the roots of B. rapa to have a protective effect against cisplatin-induced nephrotoxicity by attenuating oxidative stress.

  18. Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation

    Science.gov (United States)

    Estrela, Gabriel R.; Wasinski, Frederick; Batista, Rogério O.; Hiyane, Meire I.; Felizardo, Raphael J. F.; Cunha, Flavia; de Almeida, Danilo C.; Malheiros, Denise M. A. C.; Câmara, Niels O. S.; Barros, Carlos C.; Bader, Michael; Araujo, Ronaldo C.

    2017-01-01

    The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1β and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation. PMID:28303105

  19. A renal-targeted triptolide aminoglycoside (TPAG) conjugate for lowering systemic toxicities of triptolide.

    Science.gov (United States)

    Qi, Bowen; Wang, Xinyi; Zhou, Yangyang; Han, Qiao; He, Ling; Gong, Tao; Sun, Xun; Fu, Yao; Zhang, Zhirong

    2015-06-01

    Triptolide (TP), a naturally derived compound, is proven effective in the treatment of nephritis and chronic allograft nephropathy. However, the severe multiorgan toxicity greatly limited it from further clinic use. 2-Glucosamine was demonstrated as a potential targeting ligand that could specifically interact with megalin receptors highly expressed in renal proximal tubules. In this study, 2-glucosamine was employed as a glycosyl donor while triptolide the acceptor to afford a nonhydrolyzable triptolide derivative-triptolide aminoglycoside (TPAG). The kidney-targeting efficiency, pharmacodynamic properties and safety of TPAG were thus evaluated. TPAG displayed 6.94-fold of AUC(0-t, kidney) and 13.96-fold of MRT(0-t, kidney) compared to TP. Additionally, TPAG presented improved protective effect against renal ischemia/reperfusion injury. Compared to TP's multiorgan toxicity, TPAG showed minimum toxicity toward the kidney and genital systems, and greatly lowered toxicity in the liver and immune systems. In sum, our study presented an alternative structure modification of triptolide with improved safety and efficacy profiles.

  20. p-Methoxyl-diphenyl diselenide protects against cisplatin-induced renal toxicity in mice.

    Science.gov (United States)

    Wilhelm, Ethel A; Bortolatto, Cristiani F; Nogueira, Cristina W

    2012-05-01

    The present study was designed to investigate the effects of p-methoxyl-diphenyl diselenide (OMePhSe)(2) on oxidative stress and renal damage parameters of mice exposed to cisplatin. (OMePhSe)(2) (50 and 100 mg/kg/day) was orally administered to mice for six consecutive days. On the third day after the beginning of (OMePhSe)(2) treatment, the renal toxicity was induced by injecting cisplatin (10 mg/kg intraperitoneal) in mice. (OMePhSe)(2) treatment (50 mg/kg) partially reduced plasma urea and creatinine levels increased by cisplatin. Histopathological examination of kidneys showed that (OMePhSe)(2) ameliorated renal injury caused by cisplatin. (OMePhSe)(2) attenuated the decrease in reduced glutathione (GSH) and ascorbic acid (AA) levels, the inhibition of glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and catalase (CAT) activities caused by cisplatin in kidney. (OMePhSe)(2) treatment partially protected against the inhibition of renal δ-aminolevulinic dehydratase (δ-ALA-D) activity caused by cisplatin. No alteration in renal lipid peroxidation levels was found in cisplatin and/or (OMePhSe)(2) groups. (OMePhSe)(2) was effective against the increase in reactive species (RS) levels caused by the cisplatin exposure. Based on the renoprotective and antioxidant actions of (OMePhSe)(2) we suggest that this organoselenium compound could be considered a feasible candidate to protect against toxicity commonly encountered in cisplatin exposure.

  1. Flavocoxid attenuates gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    El-Kashef, Dalia H; El-Kenawi, Asmaa E; Suddek, Ghada M; Salem, Hatem A

    2015-12-01

    Gentamicin is a widely used antibiotic against serious and life-threatening infections; however, its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine whether flavocoxid has a protective effect against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of flavocoxid on gentamicin induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was determined. Twenty-four male Wistar albino rats were randomly divided into three groups, namely control, gentamicin (100 mg/kg, i.p.) and gentamicin plus flavocoxid (20 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood, urine samples and kidneys were collected for further analysis. Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated renal somatic index (RSI), serum creatinine, blood urea nitrogen, serum lactate dehydrogenase, and protein in urine with a concomitant reduction in serum albumin and normalized creatinine clearance value as compared with the controls. Moreover, a significant increase in renal contents of malondialdehyde, myeloperoxidase, and tumor necrosis factor-alpha with a significant decrease in renal reduced glutathione and superoxide dismutase activities was detected upon gentamicin administration together with increasing the sensitivity of isolated urinary bladder rings to ACh. Exposure to gentamicin induced necrosis of renal tubular epithelial cells. Flavocoxid protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by gentamicin treatment. In addition, flavocoxid significantly reduced the responses of isolated bladder rings to ACh. The results from our study indicate that flavocoxid supplement attenuates gentamicin-induced renal injury via the amelioration of

  2. Prevention of cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Hayati Fatemeh

    2016-01-01

    Full Text Available Cisplatin has a well-established role in the treatment of broad spectrum of malignancies; however its use is limited because of cisplatin-induced nephrotoxicity (CIN which can be progressive in more than 50% of cases. The most important risk factors for CIN include higher doses of cisplatin, previous cisplatin chemotherapy, underlying kidney damage and concurrent treatment with other potential nephrotoxin agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media. Different strategies have been offered to diminish or prevent nephrotoxicity of cisplatin. The standard approach for prevention of CIN is the administration of lower doses of cisplatin in combination with full intravenous hydration prior and after cisplatin administration. Cisplatin-induced oxidative stress in the kidney may be prevented by natural antioxidant compounds. The results of this review show that many strategies for prevention of CIN exist, however, attention to the administration of these agent for CIN is necessary.

  3. Pycnogenol prevents potassium dichromate K2Cr2O7-induced oxidative damage and nephrotoxicity in rats.

    Science.gov (United States)

    Parveen, Kehkashan; Khan, Mohd Rashid; Siddiqui, Waseem A

    2009-10-30

    Environmental and occupational exposure to chromium compounds, especially hexavalent chromium [Cr(VI)], is widely recognized as a potential nephrotoxic in humans and animals. Its toxicity is associated with overproduction of free radicals, which induces oxidative damage. Recent evidence indicates that Pycnogenol (PYC), French maritime pine bark extract, exhibits antioxidant potential and protects against various oxidative stressors. The aim of the present study was to examine the modulating impacts of PYC on potassium dichromate K2Cr2O7-induced oxidative damage and nephrotoxicity in rats. Male Wistar rats were divided into four groups. The first group was control, the second group was control plus pre-treated with PYC (10 mg/kg, body weight; in saline; intraperitoneally; once daily for 3 weeks) as drug control and the third group was saline pre-treated plus treated with a single injection of K2Cr2O7 (15 mg/kg, body weight; in saline; intraperitoneally) as toxicant group. The fourth group was PYC pre-treated plus K2Cr2O7 injected. Forty-eight hours after K2Cr2O7-treatment, blood was drawn for estimation of renal injury markers in serum. Rats were then sacrificed, and their kidneys were dissected for biochemical and histopathological assays. K2Cr2O7-treated rats showed significant increases in markers of renal injury in serum, including blood urea nitrogen (BUN), serum creatinine (Scr), and alkaline phosphatase (ALP), which were significantly (P rats with PYC significantly (P rats. These results were also supported and confirmed with histopathological findings. The study suggests that PYC is effective in preventing K2Cr2O7-induced oxidative mediated nephrotoxicity, but more studies are needed to confirm the effects of PYC as a nephroprotective agent.

  4. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy.

    Science.gov (United States)

    Markowitz, G S; Radhakrishnan, J; Kambham, N; Valeri, A M; Hines, W H; D'Agati, V D

    2000-08-01

    This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine 2.5 mg/dl at biopsy (P = 0. 008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized

  5. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway

    Science.gov (United States)

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-sung

    2016-01-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy-induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292] PMID:26728272

  6. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

    Science.gov (United States)

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-Sung

    2016-05-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

  7. Progress in treatment and study of renal toxicity by mercury poisoning%汞的肾毒性及治疗研究进展

    Institute of Scientific and Technical Information of China (English)

    陈子安; 聂志勇; 李万华; 胡鹏遥; 隋昕; 邱泽武; 王永安

    2016-01-01

    Mercury is one of the common heavy-metal toxins,which can cause damage throughout the body in a variety of ways. Cases of renal toxicity of mercury poisoning are increasing clinically. However,little is known about nephrotoxicity mechanisms,and treatment remains unsatisfactory. The mechanism of mercury toxic nephropathy is reviewed in this paper,including the direct toxic effect on the kidney,the injury to the biomembrane system,generation of Hg-metallothionein,imbalance of intra⁃cellular calciumion,oxidative damage,induced apoptosis,and immune injury. Besides,the mechanism and limitation of common therapies,potential developments of the field are discussed. This review will facilitate further investigations therapies about both the mechanism and treatment of mercury toxic nephropathy.%汞是常见的重金属毒物,多种原因导致的急慢性汞中毒可对人体多个脏器产生严重损害。临床上因汞中毒导致的肾病逐年增多,其损伤机制尚不明确,治疗手段有限。本文就汞的肾毒性作用机制研究进展进行综述,包括汞对肾的直接毒性作用,生物膜系统受损,汞-金属硫蛋白复合物形成,胞内Ca2+平衡失调,氧化损伤,诱导细胞凋亡,免疫性损伤等。归纳总结了临床上常见治疗方法的机理及局限,并对几种当前研究的热点问题和发展方向进行了介绍,在此基础之上探究汞对肾造成损害的疾病模型,旨在为临床上慢性汞中毒导致的肾病的治疗方法提供相关支持。

  8. Phytopreventative effects of Gynostemma pentaphyllum against acute Indomethacin-induced gastrointestinal and renal toxicity in rats.

    Science.gov (United States)

    Hesse, Cristina; Razmovski-Naumovski, Valentina; Duke, Colin C; Davies, Neal M; Roufogalis, Basil D

    2007-06-01

    In the present study, the phytoprotective effects of gypenosides from Gynostemma pentaphyllum throughout the gastrointestinal tract and kidney were examined in indomethacin-treated rats. Indomethacin induced gastric and intestinal damage as well as renal toxicity after a single toxicological dose (10 mg/kg) in rats. Acute oral administration of the gypenoside extract (200 mg/kg) significantly reduced gastric and intestinal toxicity induced by indomethacin as measured by ulceration, caecal haemoglobin and plasma haptoglobin. A significant decrease in small intestinal lactose fermenting enterobacteria was evident in animals treated with indomethacin and those pre-treated with G. pentaphyllum then indomethacin. In the renal system, kidney toxicity was evident after indomethacin and in animals pre-treated with indomethacin plus G. pentaphyllum with an increase in urinary N-acetyl-beta-glucosaminidase and a decrease in urinary sodium and chloride electrolyte output. However, a significant increase in urinary microprotein in indomethacin-treated animals was not present in indomethacin plus G. pentaphyllum-treated animals. These studies demonstrate the efficacy of Gynostemma pentaphyllum in lowering gastrointestinal damage induced by indomethacin. The results suggest further investigations of Gynostemma gypenosides are warranted to examine the mechanisms of this phytoprotective activity. (c) 2007 John Wiley & Sons, Ltd.

  9. The Usefulness of Determining Neutrophil Gelatinase-Associated Lipocalin Concentration Excreted in the Urine in the Evaluation of Cyclosporine A Nephrotoxicity in Children with Nephrotic Syndrome

    Directory of Open Access Journals (Sweden)

    Ewa Gacka

    2016-01-01

    Full Text Available Introduction. The use of cyclosporine (CsA in the treatment of nephrotic syndrome (NS contributed to a significant reduction in the amount of corticosteroids used in therapy and its cumulative side effects. One of the major drawbacks of CsA therapy is its nephrotoxicity. Prolonged CsA treatment protocols require sensitive, easily available, and simple to measure biomarkers of nephrotoxicity. NGAL is an antibacterial peptide, excreted by cells of renal tubules in response to their toxic or inflammatory damage. Aim of the Study. The aim of this study was to assess the suitability of the NGAL concentration in the urine as a potential biomarker of the CsA nephrotoxicity. Material and Methods. The study was performed on a group of 31 children with NS treated with CsA. The control group consisted of 23 children diagnosed with monosyptomatic enuresis. The relationship between NGAL excreted in urine and the time of CsA treatment, concentration of CsA in blood serum, and other biochemical parameters was assessed. Results. The study showed a statistically significant positive correlation between urine NGAL concentration and serum triglycerides concentration and no correlation between C0 CsA concentration and other observed parameters of NS. The duration of treatment had a statistically significant influence on the NGAL to creatinine ratio. Conclusions. NGAL cannot be used alone as a simple CsA nephrotoxicity marker during NS therapy. Statistically significant correlation between NGAL urine concentration and the time of CsA therapy indicates potential benefits of using this biomarker in the monitoring of nephrotoxicity in case of prolonged CsA therapy.

  10. Synergistic protective role of ceftriaxone and ascorbic acid against subacute diazinon-induced nephrotoxicity in rats.

    Science.gov (United States)

    Abdel-Daim, Mohamed M

    2016-03-01

    Diazinon (DZN) is a synthetic organophosphrus acaricide and insecticide widely used for veterinary and agricultural purposes. However, its animal and human exposure leads to nephrotoxicity. Our experimental objective was to evaluate protective effects of ceftriaxone and/or ascorbic acid-vitamin C against DZN-induced renal injury in male Wistar albino rats. DZN-treated animals revealed significant elevation in serum biochemical parameters related to renal injury: urea, uric acid and creatinine. DZN intoxication significantly increased renal lipid peroxidation, and significant inhibition in antioxidant biomarkers including, reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase and total antioxidant capacity. In addition, DZN significantly reduced serum acetylcholinestrase level. Moreover, It induced serum and kidney tumor necrosis factor-α level. Both ceftriaxone and vitamin C protect against DZN-induced serum as well as renal tissue biochemical parameters when used alone or in combination along with DZN-intoxication. Furthermore, both ceftriaxone and vitamin C produced synergetic nephroprotective and antioxidant effects. Therefore, it could be concluded that ceftriaxone and/or vitamin C administration are able to minimize the toxic effects of DZN by its free radical-scavenging and potent antioxidant activity.

  11. Synergistic protective effects of ceftriaxone and ascorbic acid against subacute deltamethrin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Abdel-Daim, Mohamed M; El-Ghoneimy, Ashraf

    2015-03-01

    Deltamethrin (DLM) is a synthetic class II pyrethroid acaricide and insecticide widely used for veterinary and agricultural purposes. However, its animal and human exposure leads to nephrotoxicity. Our experimental objective was to evaluate protective effects of ceftriaxone and/or ascorbic acid against DLM-induced renal injury in male Wistar albino rats. DLM-treated animals revealed significant alterations in serum biochemical parameters related to renal injury; urea, uric acid and creatinine. There was a significant increase in renal lipid peroxidation and a significant inhibition in antioxidant biomarkers. Moreover, DLM significantly reduced serum acetylcholinesterase (AChE) activity. In addition, It induced serum and kidney tumor necrosis factor-α (TNF-α). Both ceftriaxone and ascorbic acid protect against DLM-induced biochemical alterations in serum and renal tissue when used alone or in combination along with DLM-intoxication. Furthermore, both ceftriaxone and ascorbic acid produced synergetic nephroprotective and antioxidant effects. Therefore, it could be concluded that ceftriaxone and/or ascorbic acid administration able to minimize the toxic effects of DLM through their free radical-scavenging and potent antioxidant activity.

  12. Nephrotoxic mechanisms of drugs and environmental toxins

    Energy Technology Data Exchange (ETDEWEB)

    Porter, G.A. (ed.)

    1982-01-01

    This book contains 39 contributions divided into five sections each with its own editor and introductory chapter. The first section of nine chapters is concerned with the pathophysiology of acute renal failure. The second section is concerned with the growing problem of renal failure due to the use of antimicrobial agents such as the aminoglycosides. The various causes of tubulointerstitial nephropathy, notably analgesic drugs and environmental toxins such as mycotoxins and lead, are covered in the third section. Environmental and industrial nephrotoxins, such as cadmium, and halogenated aliphatic hydrocarbons, such as chloroform, are the subject of the fourth section. The last section of nine chapters is concerned mainly with a relatively new area of research into immunological mechanisms of nephrotoxicity and the evidence that drugs and other environmental chemicals can serve as antigens for immune complex formation.

  13. Ameliorative effect of Apodytes dimidiata on cisplatin-induced nephrotoxicity in Wistar rats.

    Science.gov (United States)

    Divya, Menon Kunnathully; Lincy, Lawrence; Raghavamenon, Achuthan Chathrattil; Babu, Thekkekara Devassy

    2016-10-01

    Context Nutraceuticals possessing antioxidant potential have been used to alleviate side effects exerted by many chemotherapeutics, including cisplatin. Since Apodytes dimidiata E. Mey. Ex Arn. (Icacinaceae) shows antioxidant potential, it may possess significant chemoprotective effects. Objectives The study investigated whether A. dimidiata could attenuate cisplatin-induced renal damage. Materials and methods Nephrotoxicity was induced by cisplatin (single i.p., 16 mg/kg b wt.) in Wistar rats. Methanolic leaf extract of A. dimidiata (AMF) was administered at a dose of 250 mg/kg b. wt. orally for 5 consecutive days before/after cisplatin administration. Blood and renal parameters were analysed. Total phenolic and flavonoid content in AMF and its NO scavenging effect was determined. Results Significant protective effect of AMF on cisplatin-induced nephrotoxicity was observed in pre-treated animals. The reduction of urea, creatinine and lipid peroxidation was 58.31%, 42.19% and 60%, respectively, and the increase in haemoglobin and leucocyte count was 28.25% and 42.91%, respectively. The increase calculated for GSH, GPx, SOD and catalase was 35.64%, 18.14%, 74.42% and 35.46%, respectively. Tissue architecture of kidney was almost normal in AMF treated animals. The results were comparable to the standard drug, silymarin. AMF contained high level of polyphenols and flavonoids and was found to scavenge NO radicals (IC50 121.8 μg/mL). Discussion and conclusion AMF can effectively counteract cisplatin mediated renal acute toxicity possibly by scavenging reactive oxygen and nitrogen species. Accordingly, the study suggests that AMF can ameliorate free radical-induced damage associated with chemotherapeutic drugs.

  14. Amylase-creatinine clearance ratio. A simple test to predict gentamicin nephrotoxicity.

    Science.gov (United States)

    Aderka, D; Tene, M; Graff, E; Levo, Y

    1988-05-01

    The initial target of aminoglycoside nephrotoxicity is the proximal tubule. Yet, no simple test is available to predict such toxicity. Taking advantage of the fact that amylase is filtered in the glomerulus and reabsorbed by the proximal tubules, we prospectively examined in 23 patients if changes in renal amylase creatinine clearance ratio (ACCR) can predict gentamicin nephrotoxicity. Eighteen of these patients had an initial creatinine clearance (rCcr) above 30 mL/min. Eleven of them (group A) had an ACCR above 3.5% (control 3% +/- 1.03%) and all exhibited an average reduction of 32.2% +/- 11.6% in rCcr following one week of gentamicin therapy. In contrast, only one of seven patients (group B) with an initial ACCR below 3.5% had a reduction, albeit transient, in rCcr. During gentamicin therapy, group A patients had a further increase in ACCR which was proportional to the reduction observed in rCcr (r = -.54). Our preliminary data suggest that ACCR may prove a simple and possibly a reliable predictor of kidney function deterioration during gentamicin therapy in patients with rCcr above 30 mL/min: patients with pretherapy ACCR above 3.5% may exhibit a deterioration in the creatinine clearance during the first week of therapy. For patients with pretherapy renal failure (rCcr less than 30 mL/min) the creatinine levels (but not the ACCR) seem to retain their significance in predicting and monitoring further renal function deterioration during aminoglycoside therapy.

  15. Efficacy and Toxicity of Mammalian Target Rapamycin Inhibitors in Patients with Metastatic Renal Cell Carcinoma with Renal Insufficiency: The Korean Cancer Study Group GU 14-08

    Science.gov (United States)

    Kim, Ki Hyang; Kim, Joo Hoon; Lee, Ji Young; Kim, Hyo Song; Heo, Su Jin; Kim, Ji Hyung; Kim, Ho Young; Rha, Sun Young

    2016-01-01

    Purpose We evaluated the efficacy and toxicity of mammalian target rapamycin inhibitors in Korean patients with metastatic renal cell carcinoma (mRCC) with chronic renal insufficiency not requiring dialysis. Materials and Methods Korean patients with mRCC and chronic renal insufficiency not requiring dialysis treated with everolimus or temsirolimus between January 2008 and December 2014 were included. Patient characteristics, clinical outcomes, and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) durations were evaluated according to the degree of renal impairment. Results Eighteen patients were considered eligible for the study (median age, 59 years). The median glomerular filtration rate was 51.5 mL/min/1.73 m2. The best response was partial response in six patients and stable disease in 11 patients. The median PFS and OS durations were 8 months (95% confidence interval [CI], 0 to 20.4) and 32 months (95% CI, 27.5 to 36.5), respectively. The most common non-hematologic and grade 3/4 adverse events included stomatitis, fatigue, flu-like symptoms, and anorexia as well as elevated creatinine level. Conclusion Mammalian target rapamycin inhibitors were efficacious and did not increase toxicity in Korean patients with mRCC and chronic renal insufficiency not requiring dialysis. PMID:26875195

  16. Adverse Renal Effects of Novel Molecular Oncologic Targeted Therapies: A Narrative Review

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    Kenar D. Jhaveri

    2017-01-01

    Full Text Available Novel targeted anti-cancer therapies have resulted in improvement in patient survival compared to standard chemotherapy. Renal toxicities of targeted agents are increasingly being recognized. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here we review the adverse renal effects associated with a selection of currently approved targeted cancer therapies, directed to EGFR, HER2, BRAF, MEK, ALK, PD1/PDL1, CTLA-4, and novel agents targeted to VEGF/R and TKIs. In summary, electrolyte disorders, renal impairment and hypertension are the most commonly reported events. Of the novel targeted agents, ipilumumab and cetuximab have the most nephrotoxic events reported. The early diagnosis and prompt recognition of these renal adverse events are essential for the general nephrologist taking care of these patients.

  17. Exposure to Hyperbaric Oxygen Intensified Vancomycin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Sabler, Itay M; Berkovitch, Matitiahu; Sandbank, Judith; Kozer, Eran; Dagan, Zahi; Goldman, Michael; Bahat, Hilla; Stav, Kobi; Zisman, Amnon; Klin, Baruch; Abu-Kishk, Ibrahim

    2016-01-01

    It has been suggested that oxidative stress is a potential mechanism for vancomycin-induced nephrotoxicity and hyperbaric oxygen therapy (HBO) has been shown to be effective in treating renal toxicity that has been pharmacologically induced in animal models. The aim of this study was to investigate the effect of HBO therapy on vancomycin-induced nephrotoxicity in rats. The study group comprised 36 Sprague Dawley male rats. We treated 30 with 500 mg/kg of intraperitoneal vancomycin once a day for 7 days. Half of these rats received a daily 1-hour treatment with HBO at 2 Atmospheres (ATM) on the same 7 days and formed the HBO+ group. The other 15 subjects received no HBO treatment (HBO- group). The remaining six rats served as the control group, three received HBO treatments alone and no treatment was administered to the other three rats. Laboratory results were obtained on day 8 and the intervention and control groups were compared. Rats in the HBO+ group gained less weight than the HBO- group (11.6 grams vs 22.6 grams; P = 0,008) and had significantly higher serum blood urea nitrogen (99.6 vs 52.6 mg/dL; Pvancomycin blood levels were also higher in the HBO+ group (27.8 vs 6.7 μg/mL; P = 0.078). There were no pathological kidney changes in the control group. All the kidneys from the treated groups (vancomycin +HBO and vancomycin HBO-) showed moderate to severe histopathological changes with no statistical significance between them. This study demonstrated that exposure to hyperbaric oxygen intensified vancomycin-induced nephrotoxicity in rats.

  18. Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip.

    Science.gov (United States)

    Kim, Sejoong; LesherPerez, Sasha Cai; Kim, Byoung Choul C; Yamanishi, Cameron; Labuz, Joseph M; Leung, Brendan; Takayama, Shuichi

    2016-03-24

    Nephrotoxicity is often underestimated because renal clearance in animals is higher compared to in humans. This paper aims to illustrate the potential to fill in such pharmacokinetic gaps between animals and humans using a microfluidic kidney model. As an initial demonstration, we compare nephrotoxicity of a drug, administered at the same total dosage, but using different pharmacokinetic regimens. Kidney epithelial cell, cultured under physiological shear stress conditions, are exposed to gentamicin using regimens that mimic the pharmacokinetics of bolus injection or continuous infusion in humans. The perfusion culture utilized is important both for controlling drug exposure and for providing cells with physiological shear stress (1.0 dyn cm(-2)). Compared to static cultures, perfusion culture improves epithelial barrier function. We tested two drug treatment regimens that give the same gentamycin dose over a 24 h period. In one regimen, we mimicked drug clearance profiles for human bolus injection by starting cell exposure at 19.2 mM of gentamicin and reducing the dosage level by half every 2 h over a 24 h period. In the other regimen, we continuously infused gentamicin (3 mM for 24 h). Although junctional protein immunoreactivity was decreased with both regimens, ZO-1 and occludin fluorescence decreased less with the bolus injection mimicking regimen. The bolus injection mimicking regimen also led to less cytotoxicity and allowed the epithelium to maintain low permeability, while continuous infusion led to an increase in cytotoxicity and permeability. These data show that gentamicin disrupts cell-cell junctions, increases membrane permeability, and decreases cell viability particularly with prolonged low-level exposure. Importantly a bolus injection mimicking regimen alleviates much of the nephrotoxicity compared to the continuous infused regimen. In addition to potential relevance to clinical gentamicin administration regimens, the results are important in

  19. Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa.

    Science.gov (United States)

    Karwasra, Ritu; Kalra, Prerna; Nag, T C; Gupta, Y K; Singh, Surender; Panwar, Anuj

    2016-11-01

    Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concentrations of reduced glutathione and superoxide dismutase, elevation in TNF-α level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boerhaavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg.

  20. Renal impairment and late toxicity in germ-cell cancer survivors

    DEFF Research Database (Denmark)

    Lauritsen, J.; Mortensen, M. S.; Kier, M. G. G.

    2015-01-01

    Background Treatment with bleomycin–etoposide–cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large...... cohort of germ-cell cancer survivors. Patients and methods BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow......-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. Results GFR changed (ΔGFR) −11.3%, −15...

  1. Protective Effect of Cleistocalyx nervosum var. paniala Fruit Extract against Oxidative Renal Damage Caused by Cadmium

    Directory of Open Access Journals (Sweden)

    Warut Poontawee

    2016-01-01

    Full Text Available Cadmium nephrotoxicity is a serious environmental health problem as it will eventually end up with end stage renal disease. The pathobiochemical mechanism of this toxic heavy metal is related to oxidative stress. This study investigated whether Cleistocalyx nervosum var. paniala fruit extract (CNFE could protect the kidney against oxidative injury caused by cadmium. Initial analysis of the extract revealed antioxidant abilities and high levels of polyphenols, particularly catechin. Its potential renal benefits was further explored in rats treated with vehicle, CNFE, cadmium (2 mg/kg, and cadmium plus CNFE (0.5, 1, 2 g/kg for four weeks. Oxidative renal injury was developed after cadmium exposure as evidenced by blood urea nitrogen and creatinine retention, glomerular filtration reduction, renal structural damage, together with increased nitric oxide and malondialdehyde, but decreased antioxidant thiols, superoxide dismutase, and catalase in renal tissues. Cadmium-induced nephrotoxicity was diminished in rats supplemented with CNFE, particularly at the doses of 1 and 2 g/kg. It is concluded that CNFE is able to protect against the progression of cadmium nephrotoxicity, mostly via its antioxidant power. The results also point towards a promising role for this naturally-occurring antioxidant to combat other human disorders elicited by disruption of redox homeostasis.

  2. Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities.

    Science.gov (United States)

    Kollmannsberger, Christian; Bjarnason, Georg; Burnett, Patrick; Creel, Patricia; Davis, Mellar; Dawson, Nancy; Feldman, Darren; George, Suzanne; Hershman, Jerome; Lechner, Thomas; Potter, Amy; Raymond, Eric; Treister, Nathaniel; Wood, Laura; Wu, Shenhong; Bukowski, Ronald

    2011-01-01

    The multitargeted tyrosine-kinase inhibitor sunitinib has emerged as one of the standards of care for good- and intermediate-risk metastatic renal cell carcinoma. Although generally associated with acceptable toxicity, sunitinib exhibits a novel and distinct toxicity profile that requires monitoring and management. Fatigue, diarrhea, anorexia, oral changes, hand-foot syndrome and other skin toxicity, thyroid dysfunction, myelotoxicity, and hypertension seem to be the most common and clinically relevant toxicities of sunitinib. Drug dosing and treatment duration are correlated with response to treatment and survival. Treatment recommendations for hypertension have been published but, currently, no standard guidelines exist for the management of noncardiovascular side effects. To discuss the optimal management of noncardiovascular side effects, an international, interdisciplinary panel of experts gathered in November 2009. Existing literature on incidence, severity, and underlying mechanisms of side effects as well as on potential treatment options were carefully reviewed and discussed. On the basis of these proceedings and the thorough review of the existing literature, recommendations were made for the monitoring, prevention, and treatment of the most common noncardiovascular side effects and are summarized in this review. The proactive assessment and consistent and timely management of sunitinib-related side effects are critical to ensure optimal treatment benefit by allowing appropriate drug dosing and prolonged treatment periods.

  3. Amla as an antihyperglycemic and hepato-renal protective agent in fluoride induced toxicity

    Directory of Open Access Journals (Sweden)

    Rupal A Vasant

    2012-01-01

    Full Text Available Purpose of the study was to examine the antihyperglycemic and hepato-renal protective effects of Emblica officinalis (Eo fruit as a food supplement in fluoride induced toxicity. Eo fruit powder was incorporated into the diet (2.5, 5 and 10 gm % of fluoride exposed animals for a duration of 30 days. Fluoride exposure caused significant elevation in plasma glucose, serum glutamate oxaloacetate transaminase (SGOT, serum glutamate pyruvate transaminase (SGPT, acid phosphatase (ACP, alkaline phosphatase (ALP activities, hepatic glucose-6-phosphatase (G-6-Pase and decreased hepatic glycogen content, hexokinase activity and antioxidant profiles (hepatic and renal. An inclusion of Eo fruit powder significantly reduced plasma glucose levels, SGOT, SGPT, ACP and ALP activities, hepatic G-6-Pase activity and increased hepatic glycogen content and hexokinase activity. Hepatic and renal antioxidant status of fluoride exposed animals improved upon feeding Eo fruit powder. We, therefore, conclude that E. officinalis fruit could be useful in regulating hyperglycemia and enhances antioxidant status of fluoride exposed animals.

  4. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice.

    Directory of Open Access Journals (Sweden)

    Emil Schüler

    Full Text Available The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity.C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys. At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a global transcriptional variations in kidney tissues, (b morphological changes in the kidneys, (c changes in white and red blood cell count as well as blood levels of urea, and (d changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy.In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months.Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these

  5. Renal Toxicity of Mercuric Chloride at Different Time Intervals in Rats

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    W.A. Al-Madani

    2009-01-01

    Full Text Available This study was undertaken to study the renal toxicity of mercuric chloride in rats at different periods of time. The following groups of rats were studied: i control, ii placebo, iii rats injected with a single ip dose of 100 mg/kg body weight of 2, 3 dimercapto- 1-propanesulfonic acid, iv rats injected with a single ip dose of 100 mg/kg body weight of 2, 3 dimercapto-1-propanesulfonic acid (DMPS followed by a single dose ip of 2.0 mg HgCl2/kg body weight one hour after DMPS injection v rats injected with a single ip dose of 2.0 mg HgCl2/kg body weight. Results indicate that mercuric chloride was more toxic after 48 hours of its administration when compared to 24 hours. Mercuric chloride administration caused an impairment of renal function which was evident from a significant decrease in urine volume, urinary excretion of urea, creatinine and glomerular filteration rate (P < 0.001 when compared to other treated groups. There was an increased excretion of protein, albumin and γ—glutamyltransferase in the urine of mercuric chloride treated rats. Administration of 2, 3 dimercapto-1-propanesulfonic acid before mercuric chloride treatment caused the altered indices to return to near normal levels.

  6. Long-term renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT)

    Energy Technology Data Exchange (ETDEWEB)

    Gerstein, Johanna; Meyer, Andreas; Fruehauf, Joerg; Karstens, Johann H.; Bremer, Michael [Dept. of Radiation Oncology, Medical School Hannover (Germany); Sykora, Karl-Walter [Dept. of Pediatric Hematology and Oncology, Medical School Hannover (Germany)

    2009-11-15

    Purpose: to retrospectively assess the incidence and time course of renal dysfunction in children ({<=} 16 years) following total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT). Patients and methods: between 1986 and 2003, 92 children (median age, 11 years; range, 3-16 years) underwent TBI before allogeneic SCT. 43 of them had a minimum follow-up of 12 months (median, 51 months; range, 12-186 months) and were included into this analysis. Conditioning regimen included chemotherapy and fractionated TBI with 12 Gy (n = 26) or 11.1 Gy (n = 17). In one patient, renal dose was limited to 10 Gy by customized renal shielding due to known nephropathy prior to SCt. Renal dysfunction was defined as an increase of serum creatinine > 1.25 times the upper limit of age-dependent normal. Results: twelve children (28%) experienced an episode of renal dysfunction after a median of 2 months (range, 1-10 months) following SCT. In all but one patient renal dysfunction was transient and resolved after a median of 8 months (range, 3-16 months). One single patient developed persistent renal dysfunction with onset at 10 months after SCT. None of these patients required dialysis. The actuarial 3-year freedom from persistent renal toxicity for children surviving > 12 months after SCt was 97.3%. Conclusion: the incidence of persistent renal dysfunction after fractionated TBI with total doses {<=} 12 Gy was very low in this analysis. (orig.)

  7. Renal function affects absorbed dose to the kidneys and haematological toxicity during {sup 177}Lu-DOTATATE treatment

    Energy Technology Data Exchange (ETDEWEB)

    Svensson, Johanna; Berg, Gertrud [Sahlgrenska University Hospital, Department of Oncology, Goeteborg (Sweden); Waengberg, Bo [Sahlgrenska University Hospital, Department of Surgery, Goeteborg (Sweden); Larsson, Maria [University of Gothenburg, Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, Goeteborg (Sweden); Forssell-Aronsson, Eva; Bernhardt, Peter [University of Gothenburg, Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, Goeteborg (Sweden); Sahlgrenska University Hospital, Department of Medical Physics and Medical Bioengineering, Goeteborg (Sweden)

    2015-05-01

    Peptide receptor radionuclide therapy (PRRT) has become an important treatment option in the management of advanced neuroendocrine tumours. Long-lasting responses are reported for a majority of treated patients, with good tolerability and a favourable impact on quality of life. The treatment is usually limited by the cumulative absorbed dose to the kidneys, where the radiopharmaceutical is reabsorbed and retained, or by evident haematological toxicity. The aim of this study was to evaluate how renal function affects (1) absorbed dose to the kidneys, and (2) the development of haematological toxicity during PRRT treatment. The study included 51 patients with an advanced neuroendocrine tumour who received {sup 177}Lu-DOTATATE treatment during 2006 - 2011 at Sahlgrenska University Hospital in Gothenburg. An average activity of 7.5 GBq (3.5 - 8.2 GBq) was given at intervals of 6 - 8 weeks on one to five occasions. Patient baseline characteristics according to renal and bone marrow function, tumour burden and medical history including prior treatment were recorded. Renal and bone marrow function were then monitored during treatment. Renal dosimetry was performed according to the conjugate view method, and the residence time for the radiopharmaceutical in the whole body was calculated. A significant correlation between inferior renal function before treatment and higher received renal absorbed dose per administered activity was found (p < 0.01). Patients with inferior renal function also experienced a higher grade of haematological toxicity during treatment (p = 0.01). The residence time of {sup 177}Lu in the whole body (range 0.89 - 3.0 days) was correlated with grade of haematological toxicity (p = 0.04) but not with renal absorbed dose (p = 0.53). Patients with inferior renal function were exposed to higher renal absorbed dose per administered activity and developed a higher grade of haematological toxicity during {sup 177}Lu-DOTATATE treatment. The study confirms the

  8. Nephrotoxic effects of aminoglycosides on the developing kidney

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    Samira Samiee-Zafarghandy

    2013-06-01

    Full Text Available Aminoglycosides are the most commonly used antibiotics in infants hospitalized in neonatal intensive care units. Despite their outstanding efficacy profile, aminoglycosides remain relatively toxic with a narrow therapeutic index and a potential to cause nephrotoxicity and/or ototoxicity. Although aminoglycoside-induced nephrotoxicity has been the subject of multiple studies, the short- and long-term effect of aminoglycosides administration on the developing kidney of the fetus or premature newborn has not yet been determined. In this review the currently available evidence about the effects of aminoglycosides on the developing kidney and the mechanisms involved in aminoglycoside-induced nephrotoxicity are presented. Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge research

  9. [Renal risks of dietary complements: a forgotten cause].

    Science.gov (United States)

    Dori, Olympia; Humbert, Antoine; Burnier, Michel; Teta, Daniel

    2014-02-26

    The use of dietary complements like vitamins, minerals, trace elements, proteins, aminoacids and plant-derived agents is prevalent in the general population, in order to promote health and treat diseases. Dietary complements are considered as safe natural products and are easily available without prescription. However, these can lead to severe renal toxicity, especially in cases of unknown pre-existing chronic kidney disease (CKD). In particular, Chinese herbs including aristolochic acid, high doses of vitamine C, creatine and protein complements may lead to acute and chronic renal failure, sometimes irreversible. Dietary complement toxicity should be suspected in any case of unexplained renal impairement. In the case of pre-existing CKD, the use of potentially nephrotoxic dietary complements should be screened for.

  10. Hydrogen sulfide : A novel nephroprotectant against cisplatin-induced renal toxicity

    NARCIS (Netherlands)

    Dugbartey, George J.; Bouma, Hjalmar R.; Lobb, Ian; Sener, Alp

    2016-01-01

    Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links,

  11. Modulator effects of meloxicam against doxorubicin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Hassan, Memy H; Ghobara, Mohamed; Abd-Allah, Gamil M

    2014-08-01

    Doxorubicin-induced renal toxicity overshadows its anticancer effectiveness. This study is aimed at assessing the possible modulator effects of meloxicam, a cyclooxigenase-2 inhibitor, on doxorubicin-induced nephrotoxicity in mice and exploring some of the modulator mechanisms. Forty male mice were divided for treatment, for 2 weeks, with saline, meloxicam (daily), doxorubicin (twice/week), or both meloxicam and doxorubicin. Doxorubicin induced a significant increase in relative kidney weight to body weight, kidney lipid perooxidation, plasma levels of interleukin-6 and tumor necrosis factor-α, kidney caspase-3 activity, and kidney prostaglandin E2 (PGE2) content. Doxorubicin disturbed kidney histology, abrogated renal function tests (serum creatinine, uric acid, and blood urea nitrogen), induced a significant decrease in antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and catalase) and reduced glutathione (GSH) content. The administration of meloxicam with doxorubicin mitigated all doxorubicin-disturbed parameters. Meloxicam ameliorated doxorubicin-induced renal injury via inhibition of inflammatory PGE2, inflammatory cytokines, caspase-3 activity, antioxidant effect, and free radical scavenging activity.

  12. Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice

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    Hyojung Lee

    2013-01-01

    Full Text Available Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug. In the present study, we examined whether paeonol, a major compound of Moutan Cortex, has protective effects on cisplatin-induced acute renal failure in mice. To accomplish this, Balb/c mice (6 to 8 wk of age, weighing 20 to 25 g were administered, Moutan Cortex (300 mg/kg or paeonol (20 mg/kg once a day. At day 4, mice received cisplatin (30, 20, or 10 mg/kg intraperitoneally. The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of proinflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin.

  13. Amelioration of cisplatin induced nephrotoxicity in Swiss albino mice by Rubia cordifolia extract

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    Joy Jisha

    2008-01-01

    Full Text Available Background: Cisplatin is one of the most effective chemotherapeutics against a wide range of cancers including head, neck, ovarian and lung cancers. But its usefulness is limited by its toxicity to normal tissues, including cells of the kidney proximal tubule. The purpose of the present study is to investigate whether the hydro-alcoholic extract of Rubia cordifolia could decrease the intensity of toxicity in Swiss albino mice. Materials and Methods: Cisplatin at a dose of 12 mg/kg body wt was administered intraperitoneally to Swiss albino mice. Another set of animals was given hydro-alcoholic extract of Rubia cordifolia at different doses along with cisplatin treatment. The antioxidant levels, serum creatinine, serum urea etc. were analyzed. Results: The extract could significantly decrease the cisplatin induced nephrotoxicity as inferred from the tissue antioxidant status in the drug administered animals. Remarkable change was observed in serum creatinine and urea levels. Lipid peroxidation in the kidney and liver tissues was also considerably reduced in Rubia cordifolia extract treated animals. Conclusion: Hydro-alcoholic extracts of Rubia cordifolia are effective in reducing the renal damage caused by the cancer chemotherapeutic drug cisplatin. Since Rubia cordifolia has been in use as an important ingredient in the traditional Ayurvedic system of medicine, it could be safe and beneficial to use this herbal extract as an adjuvant to ameliorate renal damage in patients undergoing cancer chemotherapy with cisplatin.

  14. Effect of Coenzyme-Q10 on Doxorubicin-Induced Nephrotoxicity in Rats

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    Azza A. K. El-Sheikh

    2012-01-01

    Full Text Available Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10 on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100 mg/kg of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15 mg/kg at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology. Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox-induced nephrotoxicity with a precaution to dosage adjustment.

  15. A SILAC-Based Approach Elicits the Proteomic Responses to Vancomycin-Associated Nephrotoxicity in Human Proximal Tubule Epithelial HK-2 Cells.

    Science.gov (United States)

    Li, Zhi-Ling; Zhou, Shu-Feng

    2016-01-29

    Vancomycin, a widely used antibiotic, often induces nephrotoxicity, however, the molecular targets and underlying mechanisms of this side effect remain unclear. The present study aimed to examine molecular interactome and analyze the signaling pathways related to the vancomycin-induced nephrotoxicity in human proximal tubule epithelial HK-2 cells using the stable isotope labeling by amino acids in cell culture (SILAC) approach. The quantitative proteomic study revealed that there were at least 492 proteins interacting with vancomycin and there were 290 signaling pathways and cellular functions potentially regulated by vancomycin in HK-2 cells. These proteins and pathways played a critical role in the regulation of cell cycle, apoptosis, autophagy, EMT, and ROS generation. These findings suggest that vancomycin-induced proteomic responses in HK-2 cells involvefunctional proteins and pathways that regulate cell cycle, apoptosis, autophagy, and redox homeostasis. This is the first systemic study revealed the networks of signaling pathways and proteomic responses to vancomycin treatment in HK-2 cells, and the data may be used to discriminate the molecular and clinical subtypes and to identify new targets and biomarkers for vancomycin-induced nephrotoxic effect. Further studies are warranted to explore the potential of quantitative proteomic analysis in the identification of new targets and biomarkers for drug-induced renal toxicity.

  16. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng.

    Science.gov (United States)

    Yousef, Mokhtar I; Hussien, Hend M

    2015-04-01

    Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage, including DNA fragmentation, upregulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidant enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes.

  17. Drug-induced renal injury

    African Journals Online (AJOL)

    Drugs can cause acute renal failure by causing pre-renal, intrinsic or post-renal toxicity. Pre-renal ... incidence of drug dose adjustment in renal impairment in the SAMJ. ... Fever, haemolytic anaemia, thrombocytopenia, renal impairment and.

  18. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

    Directory of Open Access Journals (Sweden)

    Kilic Ulkan

    2013-01-01

    Full Text Available Abstract Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days, cisplatin treatment (7 mg/kg b.w., i.p. and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin

  19. Protective potential of Tamarindus indica against gentamicin-induced nephrotoxicity.

    Science.gov (United States)

    Ullah, Naveed; Azam Khan, Mir; Khan, Taous; Ahmad, Waqar

    2014-01-13

    Abstract Context: Gentamicin is an antibiotic that is effective against Gram-negative microorganisms. However, its clinical applications are often limited due to nephrotoxic effects. Objective: This study investigated the protective effects of aqueous-ethanol extract of Tamarindus indica L. (Leguminosae) fruits against gentamicin-induced renal toxicity. Materials and methods: A daily dose of 200 mg/kg of 70% aqueous-ethanol extract derived from T. indica was employed in male rabbits as a co-therapy with gentamicin (80 mg/kg) for a period of three weeks. Serum and urinary renal function parameters and histological assessments were carried out and compared with one way analysis of variance (Graphpad prism version 5.00, Graphpad Software, San Diego, CA). Results: The results showed that gentamicin-treated animals had significantly elevated blood urea nitrogen (54.1 ± 2.6 mg/dl), serum creatinine (4.0 ± 0.1 mg/dl), serum uric acid (2.3 ± 0.1 mg/dl) and urinary protein excretion (3.8 ± 0.3 mg/dl) with a fall in body weight (10 ± 1%), creatinine clearance (0.7 ± 0.09 ml/min), serum potassium (3.4 ± 0.1 mEq/l), serum calcium (7.6 ± 0.2 mg/dl), urinary volume (126 ± 9 ml/24 h) and urinary lactate dehydrogenase secretion (103.1 ± 4.2 U/l). However, animals treated by co-therapy with gentamicin and T. indica had significantly improved renal structure and function. Discussion and conclusion: Co-therapy of 200 mg/kg/d of T. indica for a period of three weeks successfully prevented functional and morphological derangements caused by gentamicin as assessed by different renal function parameters and histological examinations.

  20. Effects of Sodium Selenite on Formaldehyde Induced Renal Toxicity in Mice

    Directory of Open Access Journals (Sweden)

    Shabnam Mohammadi 1,2 * , Maryam Moghimian 3, Hanieh Torabzadeh 4, Mahla Langari 4, Roghayeh Nazeri 4, Zahra Karimi 4, Elham Sangari 4, Najmeh Jagarmi 5, Alireza Mohammad Zadeh 3, Mehdi Karimi 7, Kamyar Tavakkoli 8, Ali Delshad 9, Fatemeh Mohammadzadeh 3, Majid Ghayour-Mobarhan 10

    2016-12-01

    Full Text Available Background: Formaldehyde is widely used for industrial applications. Renal injury is an adverse effect associated with formaldehyde. Few studies have explored the potential benefits of protective factors on formaldehyde induced renal toxicity. This study evaluated the dose dependent effects of sodium selenite on the biochemical and histopathological effects of formaldehyde on murine kidney. Methods: Forty eight adult Balb/c male mice were randomized into six groups: a control group, a formaldehyde group and experimental III-VI groups. Formaldehyde group was injected with 10 mg/kg formaldehyde and groups III-VI received intraperitoneally doses of 0.1, 0.2, 0.4, 0.8 mg/kg selenium. After two weeks, a stereological study was done in accordance with the principle of Cavalieri and serum concentrations of urea and creatinine were measured. Data were analyzed using ANOVA and SPSS software. Results: Glomerosclerosis, necrosis and vacuolization were observed in the convoluted tubules of animals treated with formaldehyde. The biochemical markers, volume and count of glomeruli in the group treated with formaldehyde was significantly difference compared to the control group (P<0.05. The volume of the glomeruli in the group treated with 0.2 and 0.4 mg selenium and urea level in the group treated with 0.4 and 0.1 mg/kg selenium was significantly difference compared to the control group (P <0.05. The count of glomeruli and creatinine level in the selenium group was significantly difference compared to the control group (P ≤ 0.0001. Conclusions: A dose of 0.2 mg/kg of sodium selenite caused partial protective effect on the renal tissue and function in exposed to formaldehyde.

  1. Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models

    Energy Technology Data Exchange (ETDEWEB)

    Van der Hauwaert, Cynthia; Savary, Grégoire [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Buob, David [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Leroy, Xavier; Aubert, Sébastien [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); Flamand, Vincent [Service d' Urologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Hennino, Marie-Flore [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Perrais, Michaël [Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); and others

    2014-09-15

    Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. - Highlights: • Renal proximal tubular (PT) cells are highly sensitive to xenobiotics. • Expression of genes involved in xenobiotic disposition was measured. • PT cells exhibited the highest similarities with renal tissue.

  2. A case of sodium chlorite toxicity managed with concurrent renal replacement therapy and red cell exchange.

    Science.gov (United States)

    Romanovsky, Adam; Djogovic, Dennis; Chin, Dat

    2013-03-01

    Sodium chlorite is a powerful oxidizing agent with multiple commercial applications. We report the presentation and management of a single case of human toxicity of sodium chlorite. A 65-year-old man presented to hospital after accidentally ingesting a small amount of a sodium chlorite solution. His principal manifestations were mild methemoglobinemia, severe oxidative hemolysis, disseminated intravascular coagulation, and anuric acute kidney injury. He was managed with intermittent hemodialysis, followed by continuous venovenous hemofiltration for management of acute kidney injury and in an effort to remove free plasma chlorite. Concurrently, he underwent two red cell exchanges, as well as a plasma exchange, to reduce the burden of red cells affected by chlorite. These interventions resulted in the cessation of hemolysis with stabilization of serum hemoglobin and platelets. The patient survived and subsequently recovered normal renal function. This is only the second case of sodium chlorite intoxication reported in the medical literature and the first to report the use of renal replacement therapy in combination with red cell exchange in its management.

  3. An integrative view of cisplatin-induced renal and cardiac toxicities : Molecular mechanisms, current treatment challenges and potential protective measures

    NARCIS (Netherlands)

    Dugbartey, George J; Peppone, Luke J; de Graaf, Inge A M

    2016-01-01

    Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies

  4. Hydrogen sulfide ameliorates the kidney dysfunction and damage in cisplatin-induced nephrotoxicity in rat

    Directory of Open Access Journals (Sweden)

    Akram Ahangarpour

    2014-06-01

    Full Text Available Hydrogen Sulfide (H2S prevents and treats a variety of disorders via its cytoprotective effects. However, the effects of H2S on rats with cisplatin (CP nephrotoxicity are unclear. The aim was to study the effects of H2S on rats with CP nephrotoxicity. Thirty male Sprague-Dawley rats were divided into three groups: control group, nephrotoxic group received single dose of CP (6 mg kg-1 and nephrotoxic groups that received single dose 100 µmol kg-1 NaHS. On fifth day after injection, urine of each rat was collected over a 24-hr period. Animals were sacrificed 6 days after CP (or vehicle treatment, and blood, urine, and kidneys were obtained, prepared for light microscopy evaluation, lipid peroxidation content and laboratory analysis. The results showed that plasma urea (226%, creatinine (271%, renal lipid peroxidation content (151%, Na and K fractional excretion, urine protein, volume and kidney weight in CP nephrotoxic rats were significantly higher and urine osmolarity and creatinine clearance lower than in controls. Increases of the proximal tubular cells apoptosis and mesangial matrix in CP nephrotoxicity group rats were observed. Hydrogen sulfide reversed the CP-induced changes in the experimental rats H2S prevented the progression of CP nephrotoxicity in rats possibly through its cytoprotective effects such as antioxidant properties.

  5. Risk factors for nephrotoxicity onset associated with polymyxin B therapy.

    Science.gov (United States)

    Dubrovskaya, Yanina; Prasad, Nishant; Lee, Yuman; Esaian, Diana; Figueroa, Deborah A; Tam, Vincent H

    2015-01-01

    Polymyxin B is an active agent against many MDR Gram-negative bacteria, but nephrotoxicity is a major hindrance to its widespread use. To guide its optimal use, we determined the risk factors for nephrotoxicity onset associated with polymyxin B. In a multicentre, retrospective, cohort study, we evaluated adult patients with normal renal function who received ≥72 h of polymyxin B therapy. Pertinent information was retrieved from medical records; patients were followed for up to 30 days after therapy was started. The primary endpoint of this study was the onset of nephrotoxicity. A Cox proportional hazards model was used for analysis. A total of 192 patients (52.1% male, 67.7% Caucasian) were evaluated. The mean ± SD age, actual body weight (ABW) and daily dose by ABW were 68.3 ± 17.2 years, 71.5 ± 20.4 kg and 1.5 ± 0.5 mg/kg, respectively. The median duration of therapy was 9.5 days. The overall prevalence rate of nephrotoxicity was 45.8% and the median onset of nephrotoxicity was 9 days. Independent risk factors for the onset of nephrotoxicity included daily dose by ABW (HR = 1.73; P = 0.022), concurrent use of vancomycin (HR = 1.89; P = 0.005) and contrast media (HR = 1.79; P = 0.009). Nephrotoxicity was seen earlier in the high-risk group (P = 0.003). Risk factors for nephrotoxicity onset associated with polymyxin B were identified. In conjunction with susceptibility and other pharmacokinetic/pharmacodynamic data, our results can be used to optimize treatment for MDR Gram-negative infections. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Possible role of cysteine-S-conjugate β-lyase in species differences in cisplatin nephrotoxicity.

    Science.gov (United States)

    Katayama, Rieko; Nagata, Saori; Iida, Hiroko; Yamagishi, Norio; Yamashita, Tetsuro; Furuhama, Kazuhisa

    2011-09-01

    To better understand species differences in cisplatin nephrotoxicity, we focused on renal cysteine-S-conjugate β-lyase (C-S lyase), which may play a crucial role in the metabolism of platinum (Pt)-cysteine conjugates. Aminooxyacetic acid hemihydrochloride (AOAA), an inhibitor of C-S lyase, reduced renal injuries due to cisplatin in rats, suggesting involvement of C-S lyase. On day 5 following a bolus cisplatin injection, three species showed in vivo nephrotoxic potentials in the order of rats>mice=rabbits (the highest to lowest), based on body surface. The levels of renal Pt residue at the nephrotoxic dose were in order of rabbits>rats>mice. Meanwhile, the activity of endogenous (basal) mitochondrial aspartate aminotransferase (AST), one of the C-S lyases, in the renal cortex of naive animals was rats>mice=rabbits. In a qualitative Western blot analysis, expression of mitochondrial C-S lyase in the kidney was observed at approximately 37kDa in all five species used. In in vitro studies, the cytotoxicity of cisplatin was dependent on the expression level of C-S lyase mRNA in the respective renal cells. These results demonstrate that species differences in cisplatin nephrotoxicity are attributable to an interaction of renal Pt transition with C-S lyase activity.

  7. Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats.

    Science.gov (United States)

    Lakhera, Abhijeet; Ganeshpurkar, Aditya; Bansal, Divya; Dubey, Nazneen

    2015-06-01

    Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies. Acute toxicity in Wistar rats was determined by the OECD Guideline (423). Animals were divided into four groups. The first group served as positive control, while the second group was toxic control (gentamicin treated). The third and fourth group were treated with the extract (200 and 400 mg/kg gentamicin). After 8 days, the animals were sacrificed and biochemical and histopathological studies were carried out. Phytochemical screening of the extract demonstrated Coriandrum sativum to be rich in flavonoids, polyphenolics and alkaloids. Results of acute toxicity suggested the use of 200 mg/kg and 400 mg/kg for Coriandrum sativum in the study. Coriandrum sativum extract at the dose of 400 mg/kg significantly (pCoriandrum sativum extract ameliorated renal histological lesions. It is concluded that Coriandrum sativum is a potential source of nephroprotective phytochemical activity, with flavonoids and polyphenols as the major components.

  8. Salicylic Acid Attenuates Gentamicin-Induced Nephrotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Pavle Randjelovic

    2012-01-01

    Full Text Available Gentamicin (GM is a widely used antibiotic against serious and life-threatening infections, but its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine the protective effect of salicylic acid (SA in gentamicin-induced nephrotoxicity in rats. Quantitative evaluation of gentamicin-induced structural alterations and degree of functional alterations in the kidneys were performed by histopathological and biochemical analyses in order to determine potential beneficial effects of SA coadministration with gentamicin. Gentamicin was observed to cause a severe nephrotoxicity which was evidenced by an elevation of serum urea and creatinine levels. The significant increases in malondialdehyde (MDA levels and protein carbonyl groups indicated that GM-induced tissue injury was mediated through oxidative reactions. On the other hand, simultaneous SA administration protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by GM treatment. Exposure to GM caused necrosis of tubular epithelial cells. Necrosis of tubules was found to be prevented by SA pretreatment. The results from our study indicate that SA supplement attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation in gentamicin-treated rats.

  9. Salicylic acid attenuates gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Randjelovic, Pavle; Veljkovic, Slavimir; Stojiljkovic, Nenad; Jankovic-Velickovic, Ljubinka; Sokolovic, Dusan; Stoiljkovic, Milan; Ilic, Ivan

    2012-01-01

    Gentamicin (GM) is a widely used antibiotic against serious and life-threatening infections, but its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine the protective effect of salicylic acid (SA) in gentamicin-induced nephrotoxicity in rats. Quantitative evaluation of gentamicin-induced structural alterations and degree of functional alterations in the kidneys were performed by histopathological and biochemical analyses in order to determine potential beneficial effects of SA coadministration with gentamicin. Gentamicin was observed to cause a severe nephrotoxicity which was evidenced by an elevation of serum urea and creatinine levels. The significant increases in malondialdehyde (MDA) levels and protein carbonyl groups indicated that GM-induced tissue injury was mediated through oxidative reactions. On the other hand, simultaneous SA administration protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by GM treatment. Exposure to GM caused necrosis of tubular epithelial cells. Necrosis of tubules was found to be prevented by SA pretreatment. The results from our study indicate that SA supplement attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation in gentamicin-treated rats.

  10. Modifying cyclosporine associated renal allograft dysfunction

    Directory of Open Access Journals (Sweden)

    Mohapatra N

    2009-01-01

    Full Text Available Transplantation is accepted therapy for chronic kidney disease. However the essential immuno-suppressive agents for graft survival have their own side-effects. Renal biopsy is a reliable tool for diagnosing cyclosporine (CsA nephrotoxicity. To present our observations on CsA toxicity in renal allograft biopsies, we studied prospectively 207 renal allograft biopsies performed for graft dysfunction as per Ahmedabad Tole-rance Induction Protocol (ATIP and compared them to 50 controls from January to October 2007. The ATIP comprised donor specific leucocyte infusions, low dose target specific irradiation; non-myeloablative condi-tioning with Anti-T ± B cell antibodies followed by intraportal administration of cultured donor bone marrow (BM ± adipose tissue derived mesenchymal stem cells. Renal transplantation was performed following nega-tive lymphocytotoxicity cross-matching. The post-transplant immunosuppressive agents included CsA 2.5 ± 0.5 mg/kg BW/day and prednisone 0.2 mg/kg BW/day. The controls were transplanted using standard triple immunosuppressive agents including CsA 5 ± 1 mg/Kg BW/day, prednisone 0.6 mg/kg BW/day, and MMF/ Azathioprine. The Institutional Review Board approved the ATIP. The biopsies were categorized into 2 groups; group A (N=97: performed < 6 months, group B (N= 160, > 6 months posttransplant. Acute CsA toxicity was observed in group A: 2.5% ATIP and 11.1% controls; group B: 16.2% ATIP and 8.8% controls. Chronic CsA toxicity was observed in group B: 10.8 % ATIP and 17.6 % controls. Acute toxicity was more in the ATIP, while chronic toxicity was more in the controls. CsA doses were reduced post-biopsy and resulted in improved graft function evaluated by serum creatinine. We conclude that CsA nephrotoxicity evaluated by allograft biopsy resulted in allograft function recovery by decreasing the cyclosporine dose, and the ATIP decreased the incidence of CsA nephrotoxicity.

  11. NEPHROPROTECTIVE ACTIVITY OF CYANOTIS FASCICULATA VAR., FASCICULATA AGAINST CISPLATIN INDUCED NEPHROTOXICITY

    Directory of Open Access Journals (Sweden)

    Murthy R.L.N

    2011-09-01

    Full Text Available Cisplatin is quite effective against various neoplastic diseases, but its potential nephrotoxicity leads to increased morbidity, complications and hospitalization costs. Prevention of nephrotoxicity may allow clinicians to administer higher doses for added therapeutic benefits. So, the present investigation was designed to evaluate the ability of the 70% hydro-alcoholic extract of Cyanotis fasciculata Var., fasciculata (CFEE to combat Cisplatin induced nephrotoxicity. Where, CFEE demonstrated dose dependent decrement of elevated biochemical markers of nephrotoxicity along with significant restoration of protective-GSH levels and suppression of LPO levels in tissues. Further, the remarkable renal-cellular rejuvenation found in histopathological studies also enunciated the organ protective activity of CFEE. It was concluded that, in addition to polyphenolics, some of the phyto-fragments found during GC-MS analysis might also contributed to the protection offered by CFEE.

  12. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Sarró, Eduard, E-mail: eduard.sarro@vhir.org [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Jacobs-Cachá, Conxita, E-mail: conxita.jacobs@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Itarte, Emilio, E-mail: emili.itarte@uab.es [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Meseguer, Anna, E-mail: ana.meseguer@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain)

    2012-01-15

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  13. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress

    OpenAIRE

    Amel M. Soliman; Shreen Desouky; Mohamed Marzouk; Sayed, Amany A.

    2016-01-01

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3...

  14. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    Energy Technology Data Exchange (ETDEWEB)

    Aburto, Andrés [Program of M.Sc., Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Barría, Agustín [School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Cárdenas, Areli [Ph.D. Program, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Carpio, Daniel; Figueroa, Carlos D. [Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia (Chile); Burgos, Maria E. [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Ardiles, Leopoldo, E-mail: leopoldoardiles@gmail.com [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile)

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  15. Tephrosia purpurea ameliorates N-diethylnitrosamine and potassium bromate-mediated renal oxidative stress and toxicity in Wistar rats.

    Science.gov (United States)

    Khan, N; Sharma, S; Alam, A; Saleem, M; Sultana, S

    2001-06-01

    In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide-induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T purpurea against N-diethylnitrosamine-initiated and potassium bromate-mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N-diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO3 (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione-S-transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N-diethylnitrosamine-initiated and KBrO3 promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate-induced lipid peroxidation and xanthine oxidase activities were significantly reduced (Ppurpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N-diethylnitrosamine and KBrO3.

  16. Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells.

    Science.gov (United States)

    Li, Min; Balamuthusamy, Saravanan; Simon, Eric E; Batuman, Vecihi

    2008-07-01

    Using target-specific short interfering (si) RNAs, we silenced the tandem endocytic receptors megalin and cubilin genes in cultured human renal proximal tubule epithelial cells. Transfection by siRNA resulted in up to 90% suppression of both megalin and cubilin protein and mRNA expression. In HK-2 cells exposed to kappa-light chain for up to 24 h, light chain endocytosis was reduced in either megalin- or cubilin-silenced cells markedly but incompletely. Simultaneous silencing of both the cubilin and megalin genes, however, resulted in near-complete inhibition of light chain endocytosis, as determined by measuring kappa-light chain protein concentration in cell cytoplasm and by flow cytometry using FITC-labeled kappa-light chain. In these cells, light chain-induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial-to-mesenchymal transition as well as the associated cellular and morphological alterations were also markedly suppressed. The results demonstrate that light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor and identify endocytosis as a key step in light chain cytotoxicity. Blocking light chain endocytosis prevents its nephrotoxic effects on human kidney proximal tubule cells.

  17. Rapid blood clearance and lack of long-term renal toxicity of {sup 177}Lu-DOTATATE enables shortening of renoprotective amino acid infusion

    Energy Technology Data Exchange (ETDEWEB)

    Kashyap, Raghava; Eu, Peter [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne (Australia); Jackson, Price [Peter MacCallum Cancer Centre, Department of Physical Sciences, Melbourne (Australia); Hofman, Michael S.; Hicks, Rodney J. [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne (Australia); The University of Melbourne, Departments of Medicine and Radiology, Melbourne (Australia); Beauregard, Jean-Mathieu [Universite Laval, Department of Radiology, Quebec City (Canada); Zannino, Diana [Peter MacCallum Cancer Centre, Department of Biostatistics and Clinical Trials, Melbourne (Australia)

    2013-12-15

    The aim of the study was to investigate the feasibility of shortening the recommended 4-h renoprotective amino acid infusion in patients receiving peptide receptor chemoradionuclide therapy (PRCRT) using radiosensitizing 5-fluorouracil. We evaluated the clearance of radiopeptide from the blood, long-term nephrotoxicity in patients undergoing PRCRT with the conventional 4-h amino acid infusion and renal uptake in patients receiving an abbreviated infusion. The whole-blood clearance of {sup 177}Lu-DOTA-octreotate (LuTate) was measured in 13 patients receiving PRCRT. A retrospective analysis of short-term and long-term changes in glomerular filtration rate (GFR) in 96 consecutive patients receiving a 4-h infusion was performed. Renal LuTate retention estimated using quantitative SPECT/CT in 22 cycles delivered with a 2.5-h amino acid infusion was compared with that in 72 cycles with the 4-h infusion. LuTate demonstrated biexponential blood clearance with an initial clearance half-time of 21 min. Approximately 88 % of blood activity was cleared within 2 h. With the 4-h protocol, there was no significant change in GFR (1.2 ml/min mean increase from baseline; 95 % CI -6.9 to 4.4 ml/min) and no grade 3 or 4 nephrotoxicity at the end of induction PRCRT. The long-term decline in GFR after a median follow up of 22 months was 2.2 ml/min per year. There was no significant difference in the renal LuTate retention measured in patients receiving a 2.5-h amino acid infusion compared to those who had a 4-h infusion. The greatest renal exposure to circulating radiopeptide occurs in the first 1 - 2 h after injection. This, combined with the safety of LuTate PRCRT, allows consideration of an abbreviated amino acid infusion, increasing patient convenience and reducing human resource allocation. (orig.)

  18. Protective Effects of Houttuynia cordata Thunb. on Gentamicin-induced Oxidative Stress and Nephrotoxicity in Rats.

    Science.gov (United States)

    Kang, Changgeun; Lee, Hyungkyoung; Hah, Do-Yun; Heo, Jung Ho; Kim, Chung Hui; Kim, Euikyung; Kim, Jong Shu

    2013-03-01

    Development of a therapy providing protection from, or reversing gentamicin-sulfate (GS)-induced oxidative stress and nephrotoxicity would be of great clinical significance. The present study was designed to investigate the protective effects of Houttuynia cordata Thunb. (HC) against gentamicin sulfate-induced renal damage in rats. Twenty-eight Sprague-Dawley rats were divided into 4 equal groups as follows: group 1, control; group 2, GS 100 mg/kg/d, intraperitoneal (i.p.) injection; group 3, GS 100 mg/kg/d, i.p. + HC 500 mg/kg/d, oral; and group 4, GS 100 mg/kg/d i.p. + HC 1000 mg/kg/d, oral administration). Treatments were administered once daily for 12 d. After 12 d, biochemical and histopathological analyses were conducted to evaluate oxidative stress and renal nephrotoxicity. Serum levels of creatinine, malondialdehyde (MDA), and blood urea nitrogen (BUN), together with renal levels of MDA, glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were quantified to evaluate antioxidant activity. Animals treated with GS alone showed a significant increase in serum levels of creatinine, BUN, and MDA, with decreased renal levels of GSH, SOD, and CAT. Treatment of rats with HC showed significant improvement in renal function, presumably as a result of decreased biochemical indices and oxidative stress parameters associated with GS-induced nephrotoxicity. Histopathological examination of the rat kidneys confirmed these observations. Therefore, the novel natural antioxidant HC may protect against GSinduced nephrotoxicity and oxidative stress in rats.

  19. Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity.

    Directory of Open Access Journals (Sweden)

    Ping Jia

    Full Text Available Aminoglycoside antibiotics, especially gentamicin, are widely used to treat Gram-negative infections due to their efficacy and low cost. Nevertheless the use of gentamicin is limited by its major side effect, nephrotoxicity. Xenon (Xe provided substantial organoprotective effects in acute injury of the brain and the heart and protected against renal ischemic-reperfusion injury. In this study, we investigated whether xenon could protect against gentamicin-induced nephrotoxicity. Male Wistar rats were intermittently exposed to either 70% xenon or 70% nitrogen (N2 balanced with 30% oxygen before and during gentamicin administration at a dose of 100 mg/kg for 7 days to model gentamicin-induced kidney injury. We observed that intermittent exposure to Xe provided morphological and functional renoprotection, which was characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress, but not a reduction in inflammation. We also found that Xe pretreatment upregulated hypoxia-inducible factor 2α (HIF-2α and its downstream effector vascular endothelial growth factor, but not HIF-1α. With regard to the three HIF prolyl hydroxylases, Xe pretreatment upregulated prolyl hydroxylase domain-containing protein-2 (PHD2, suppressed PHD1, and had no influence on PHD3 in the rat kidneys. Pretreatment with Xe also increased the expression of miR-21, a microRNA known to have anti-apoptotic effects. These results support Xe renoprotection against gentamicin-induced nephrotoxicity.

  20. A metabolic profiling analysis of the nephrotoxicity of acyclovir in rats using ultra performance liquid chromatography/mass spectrometry.

    Science.gov (United States)

    Xing, Wenmin; Gu, Lili; Zhang, Xinyue; Xu, Jiadong; Lu, Hong

    2016-09-01

    Acyclovir (ACV) exposure is a common cause of acute kidney injury (AKI). The toxicity mechanism of ACV has always been a matter of debate. The present study investigated into the time-effect relationship and dose-effect relationship of ACV-induced nephrotoxicity in rats using metabonomics. Twenty-four rats were randomly divided into four groups: a 0.9% NaCl solution group, and 100, 300, and 600mg/kg ACV-treated groups; the ACV or vehicle solution was administered with a single intravenous injection. Urine was collected at different time periods (12h before administration, and 0-6h, 7-12h, and 13-24h after administration). Routine urinalysis was conducted by a urine automatic analyzer. Renal markers, including urine urea nitrogen, urine creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG) activity, were determined using established protocols. Urinary metabolites were evaluated using ultra performance liquid chromatography/mass spectrometry (UPLC/MS). In the ACV-treated rats, increased levels of protein (PRO), occult blood (BLD), white blood cell (WBC), and NAG activity in urine were observed, while the urine creatinine and urea nitrogen levels showed a decrease compared with the control. Moreover, urine metabolites significantly changed after the treatment with ACV, and all the effects induced by ACV were dose-time dependent. Finally, 4 metabolites (guanine, 4-guanidinobutyric acid, creatinine, and urea) were identified, which can be used for further research on the mechanism of ACV-induced nephrotoxicity.

  1. Allium sativum aqueous extract prevents potassium dichromate-induced nephrotoxicity and lipid oxidation in rats

    Directory of Open Access Journals (Sweden)

    Sergio L. Becerra-Torres

    2014-04-01

    Full Text Available Context: The potassium dichromate (K2Cr2O7 induces nephrotoxicity by oxidative stress mechanisms. Aims: To study the potential protection of an aqueous extract of Allium sativum against the K2Cr2O7-induced nephrotoxicity and lipid oxidation in rats. Methods: Twenty four hours after treatment, biomarkers such as proteinuria, creatinine clearance, malondialdehyde production, specific enzyme activity of gamma glutamyl transpeptidase and alanine aminopeptidase, and renal clearance of para-aminohippuric acid and inulin were measured. Results: The K2Cr2O7 caused significant renal dysfunction, but A. sativum extract prevented this condition by improving all measured biomarkers. Conclusions: A single injection of K2Cr2O7 induced nephrotoxicity in rats, but the supply of an Allium sativum aqueous extract prevented the disorders caused by this metal.

  2. Biochemical, liver and renal toxicities of Melissa officinals hydroalcoholic extract on balb/C mice

    Directory of Open Access Journals (Sweden)

    Namjoo Abdolrasool

    2013-04-01

    Full Text Available Introduction: Melissa officinalis is usually used as antispasmodic, antiaxiety and antibacterial agent. However, its toxicity has not been evaluated, yet. In this study biochemical, liver and renal toxicities of Melissa officinals hydroalcoholic extract were evaluated in balb/C mice. Methods: In an experimental study, 21 balb/C male mice were randomly designated to three equal groups. Group I was treated with normal saline and groups II and III were respectively treated with 0.450 and 1.350 g/kg, hydroalcoholic extract of Melissa officinals daily for two weeks, intraperitoneally. Then on 15th day of the experiment, blood samples were obtained from the heart. The blood was centrifuged and then the sera were evaluated for alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, urea and creatinine, using autoanalyzer and commercial kits. The liver and kidney tissues were also hystopathologically evaluated. The data were analyzed by one-way ANOVA, Tukey’s post hoc test, and Kruskal-Wallis at a significance level of p<0.05. Results: Melissa officinals dose dependently caused a significant reduction in alkaline phosphatase and alanine aminotransferase levels compared to the control group. Furthermore, Melissa officinals extract had no effect on the amount of urea and creatinine compared to the control group. The liver and kidney histopathological changes in the groups that received different doses of the extract showed mild, moderate, and severe tissue injuries. Conclusion: The biochemical analysis in this study indicates that the extract of Melissa officinals causes liver tissue damage in mice; therefore, its consumption in high doses should be avoided.

  3. Evaluation of biochemical effects of Casuarina equisetifolia extract on gentamicin-induced nephrotoxicity and oxidative stress in rats. Phytochemical analysis

    OpenAIRE

    El-Tantawy, Walid Hamdy; Mohamed, Shaza Abdel-Halim; Abd Al Haleem, Ekram Nemr

    2013-01-01

    Nephrotoxicity is defined as renal dysfunction that arises as result of exposure to external agents such as drugs and environmental chemicals. The present work was undertaken to carry out the phytochemical study and nephroprotective activity of methanolic extract of Casuarina equisetifolia leaves in gentamicin-induced nephrotoxicity in Wistar rats. Flavonoids and phenolic acids were identified and quantified using high performance liquid chromatography. Subcutaneous injection of rats with gen...

  4. Hemin Attenuates Cisplatin-Induced Acute Renal Injury in Male Rats

    Directory of Open Access Journals (Sweden)

    Mohamed A. Al-Kahtani

    2014-01-01

    Full Text Available Background. The aim of this study is to investigate the protective effects of hemin (the heme oxygenase-1 [OH-1] inducer against nephrotoxic effects induced by cisplatin [cis-diamminedichloroplatinum II (CP] in male rats. Methods. The evaluation was performed through monitoring renal redox parameters: lipid peroxidation (LPO, glutathione peroxidase (GPx, superoxide dismutase (SOD, glutathione reductase (GR, and reduced glutathione (GSH. The work also examined renal function tests (urea and creatinine, tissue proinflammatory mediator like nitric oxide (NO, and kidney cytopathology. Results. A single intraperitoneal dose of CP (10 mg/kg b.w. caused significant elevation of blood urea, serum creatinine, and renal LPO and NO, along with significant decline of the activities of GPx and GR, but renal SOD activity and GSH level were statistically insignificant as compared to control group. Subcutaneous injection of hemin (40 µmol/kg b.w. partially ameliorated CP-induced renal damage, based on suppression of blood urea, serum creatinine, the renal MDA and NO levels, and increased antioxidant capacity in CP-treated rats. The results of histopathological and ultrastructural investigations supported the renoprotective effect of hemin against CP-induced acute toxicity. Conclusion. The induction of HO-1 by hemin is a promising approach in the treatment of CP-induced nephrotoxicity. However, further preclinical studies are warranted to test effectiveness of CP/hemin on the outcome of tumor chemotherapy.

  5. Tropisetron attenuates cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Zirak, Mohammad Reza; Rahimian, Reza; Ghazi-Khansari, Mahmoud; Abbasi, Ata; Razmi, Ali; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem; Dehpour, Ahmad Reza

    2014-09-05

    Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.

  6. Nephrotoxicity of 4-cycloocten-1-carbaldehyde.

    Science.gov (United States)

    Messinger, Horst; Kleber, Marcus; Aulmann, Walter

    2004-12-01

    Natural and synthetic chemicals are often used in the fragrance industry. A toxicological profile of the synthetic fragrance booster, 4-cycloocten-1-carbaldehyde, was generated using a test program including the following methods: acute oral toxicity, acute dermal toxicity, acute skin and eye irritation, skin sensitization, subchronic toxicity, and mutagenicity. The substance was strongly irritating to the skin but only weakly irritating to the eye. It gave a clear indication of having skin-sensitizing properties. Based on the comprehensive data from a mutagenicity test battery, 4-cycloocten-1-carbaldehyde was assessed to be nonmutagenic. Although its acute toxicological profile shows no toxicity after oral or dermal application, 4-cycloocten-1-carbaldehyde displays a complex toxicological response after repeated dosing over 13 weeks. 4-Cycloocten-1-carbaldehyde or its metabolites show clear nephrotoxic properties focusing on tubular cells of the kidney. In view of these data no no-effect level can be derived from this study with 4-cycloocten-1-carbaldehyde. A broad interaction of the test substance with various tissue types and cell parameters together with severe and irreversible organic defects even at low doses leads to the conclusion that 4-cycloocten-1-carbaldehyde is unsuitable for the intended use in industrial fragrance formulations.

  7. Body composition by computed tomography as a predictor of toxicity in patients with renal cell carcinoma treated with sunitinib.

    LENUS (Irish Health Repository)

    Cushen, Samantha J

    2014-04-21

    Sunitinib is a standard first-line option for metastatic renal cell carcinoma (mRCC). Body composition is a prognostic factor in cancer patients and patients with loss of skeletal muscle mass and fat-free mass (FFM) are prone to dose-limiting toxicity (DLT) during targeted drug therapy. We investigated whether body composition by computed tomography predicted DLT from sunitinib in mRCC.

  8. Comparative effects of chelating agents on distribution, excretion, and renal toxicity of gold sodium thiomalate in rats.

    Science.gov (United States)

    Takahashi, Y; Funakoshi, T; Shimada, H; Kojima, S

    1994-05-31

    The effects of various chelating agents, such as (2S)-1-(3-mercaptopropionyl)-L-proline (captopril), N-(2-mercaptopropionyl)-glycine (tiopronin), L-cysteine (L-Cys), D-cysteine (D-Cys), N-acetyl-L-cysteine (L-NAC), N-benzyl-D-glucamine dithiocarbamate (BGD), and ethylenediaminetetraacetate (EDTA), on the distribution, excretion, and renal toxicity of gold sodium thiomalate (AuTM) in rats were investigated. Rats were intraperitoneally injected with the chelating agents (1.2 mmol/kg each) immediately after intravenous injection of AuTM (0.026 mmol/kg). Treatment with captopril or tiopronin significantly prevented increases in the urinary excretion of protein, aspartate aminotransferase (AST), and glucose and the blood urea nitrogen (BUN) level after AuTM injection. L-NAC and D-Cys significantly prevented increases in the urinary excretion of protein, AST, and glucose after AuTM injection, but did not reduce to control levels. Treatment with BGD, EDTA, or L-Cys did not prevent AuTM-induced increases in the urinary excretion of protein, AST, and glucose and BUN level. Tiopronin significantly increased the urinary excretion of gold. Captopril slightly promoted both the urinary and fecal excretion of gold, resulting in the significant increase in the total excretion of the metal. Tiopronin and captopril significantly decreased the gold concentration in the kidney and liver. L-Cys, D-Cys, L-NAC, BGD, and EDTA had no significant effect on the excretion or distribution of gold at 7 days after AuTM injection. These results indicate that tiopronin and captopril can ameliorate the renal toxicity induced by AuTM. In addition, the comparative effects of 2,3-dimercaptopropane sulfonate (DMPS), N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine), captopril, and tiopronin at various dose levels (1.2, 0.4 or 0.2 mmol/kg) on the distribution and renal toxicity of gold were studied. DMPS was effective in removing gold from the kidney and in protecting against the renal toxicity

  9. Evaluation of Risk Factors for Intravenous Colistin Use-related Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Iftihar Koksal

    2016-07-01

    Full Text Available Objectives: We investigated the incidence of and risk factors for nephrotoxicity in patients using intravenous colistin. Methods: This retrospective, observational study was conducted at Karadeniz Technical University, Faculty of Medicine, clinics and intensive care unit between 1 January 2009 and 1 January 2013. Intravenous colistin was administered to 133 patients at a dose of 2.5−5.0 mg/kg/day. Results: The patients mean age was 54.3±19.1 years and the mean duration of treatment was 13.5±3.6 days. Nephrotoxicity developed in 5.0±2.8 days in 38 (28.6% patients. Based on RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease criteria, 15 (39.5% patients were class 1, 17 (44.7% were class 2, six (15.8% were class 3, and none were class 4. The mean duration of development of nephrotoxicity was 5.0±2.8 days. Hemodialysis requirement was observed in two (5.2% of the 38 patients who developed nephrotoxicity. In these cases, colistin therapy was not discontinued. Nephrotoxicity was correlated with advanced age, high pretreatment serum creatinine levels, diabetes mellitus, and chronic obstructive pulmonary disease. Conclusions: The use of colistin is relatively safe for patients that have normal renal functions. However, better standardization of the definition of nephrotoxicity in those patients with the use of scoring systems and close monitoring are necessary.

  10. Nonpreventive role of aerobic exercise against cisplatin-induced nephrotoxicity in female rats

    Directory of Open Access Journals (Sweden)

    Jalaledin Noroozi

    2015-01-01

    Conclusions: Aerobic exercise cannot reduce CP-induced nephrotoxicity in female rats. Increasing the damage in female rats may be related to female sex hormone estrogen or gender differences in renal hemodynamic and renin-angiotensin system activity in the presence of exercise. In general, it is recommended that the females under CP chemotherapy avoid exercising during treatment.

  11. Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

    DEFF Research Database (Denmark)

    Nielsen, Finn Thomsen; Jensen, Boye L; Marcussen, Niels

    2008-01-01

    BACKGROUND: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. METHODS...

  12. Effect of n-Hexane extract of Nigella sativa on gentamicin-induced nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Nasim A Begum

    2006-03-01

    Full Text Available The present study investigated whether the administration of the n-hexane extract of the Nigella sativa Linn. (kalajira ameliorates gentamicin-induced nephrotoxicity in rats. Gentamicin (100 mg/kg/day for 7 days was administered and nephrotoxicity was evaluated biochemically (significantly decreased reduced glutathione in renal cortex and significantly increased serum creatinine and serum urea and histologically (moderate degree of proximal tubular damage. The n-hexane extract of N. sativa (5 ml/kg/day was administered as pre-, post- and concomitant treatment for 7 days in the nephrotoxic rats. Statistically significant amelioration in all the biochemical parameters supported by significantly improved renal cortical histology was observed in the n-hexane extract of N. sativa treated nephrotoxic rats, which was more evident in the post-treatment group than the pre- treatment and the concomitantly-treated group. It is suggested that some ingredients contained in the n-hexane extract of N. sativa effected in ameliorating the signs of nephrotoxicity and that the specific active principle of the n-hexane extract of N. sativa responsible for this amelioration if obtained, would be more useful.

  13. Possible Protective Effect of Diacerein on Doxorubicin-Induced Nephrotoxicity in Rats

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    Marwa M. M. Refaie

    2016-01-01

    Full Text Available Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX. Interleukin 1 has major role in DOX-induced nephrotoxicity, so we investigated the effect of interleukin 1 receptor antagonist diacerein (DIA on DOX-induced nephrotoxicity. DIA (25 and 50 mg/kg/day was administered orally to rats for 15 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of DOX (15 mg/kg at the 11th day. We measured levels of serum urea, creatinine, renal reduced glutathione (GSH, malondialdehyde (MDA, total nitrites (NOx, catalase, and superoxide dismutase (SOD. In addition, caspase-3, tumor necrosis factor alpha (TNFα, nuclear factor kappa B (NFκB expressions, and renal histopathology were assessed. Our results showed that DOX-induced nephrotoxicity was ameliorated or reduced by both doses of DIA, but diacerein high dose (DHD showed more improvement than diacerein low dose (DLD. This protective effect was manifested by significant improvement in all measured parameters compared to DOX treated group by using DHD. DLD showed significant improvement of creatinine, MDA, NOx, GSH, histopathology, and immunohistochemical parameters compared to DOX treated group.

  14. The tacrolimus metabolism rate influences renal function after kidney transplantation.

    Directory of Open Access Journals (Sweden)

    Gerold Thölking

    Full Text Available The effective calcineurin inhibitor (CNI tacrolimus (Tac is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx. However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006 which revealed a higher incidence of CNI nephrotoxicity (p = 0.015 and BK nephropathy (p = 0.024 in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient's risk management strategies.

  15. Protective role of Ipomoea obscura (L.) on cyclophosphamide-induced uro- and nephrotoxicities by modulating antioxidant status and pro-inflammatory cytokine levels.

    Science.gov (United States)

    Hamsa, T P; Kuttan, Girija

    2011-06-01

    Cyclophosphamide (CP) is widely used, alone or in combination with other chemotherapeutic agents, for the treatment of neoplastic diseases. Its urotoxicity may cause dose-limiting side-effects, for example haemorrhagic cystitis. This urotoxicity may lead to nephrotoxicity. In the present study, we investigated the protective role of Ipomoea obscura against CP-induced uro- and nephrotoxicities in animal models. Swiss albino mice were treated with an acute dose of CP (1.5 mmol/kg body wt ip) in the presence and absence of alcoholic extract of I. obscura (10 mg/kg, body wt, ip) for 5 days. The toxicities caused by CP were reversed by the extract administration as evident from the decrease in BUN, serum creatinine levels as well as an increase in body weight. A significant increase in kidney antioxidant system such as, GSH, SOD, CAT, and GPx was also observed in extract-treated animals. Histopathological analysis of urinary bladder and kidney indicated that CP-induced tissue damage was significantly reduced in animals treated with I. obscura. The lowered levels of cytokines IFN-γ and IL-2, after CP treatment were found to be increased in treated animals. At the same time the level of proinflammatory cytokine TNF-α, which was elevated during CP administration, was significantly reduced by extract administration. This study clearly demonstrates that I. obscura can ameliorate CP-induced bladder and renal toxicities by modulating antioxidant status and proinflammatory cytokine levels.

  16. Arsenic-mediated nephrotoxicity.

    Science.gov (United States)

    Robles-Osorio, Ma Ludivina; Sabath-Silva, Elizabeth; Sabath, Ernesto

    2015-05-01

    Chronic kidney disease (CKD) is an important global health problem that affects 8-15% of the population according to epidemiological studies done in different countries. Essential to prevention is the knowledge of the environmental factors associated with this disease, and heavy metals such as lead and cadmium are clearly associated with kidney injury and CKD progression. Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease, and the evidence linking urinary arsenic excretion with CKD, higher urinary excretion of low molecular proteins, albuminuria or other markers of renal in injury is still limited, and more studies are necessary to characterize the role of arsenic on renal injury and CKD progression. Global efforts to reduce arsenic exposure remain important and research is also needed to determine whether specific therapies are beneficial in susceptible populations.

  17. Protective effect of dietary flaxseed oil on arsenic-induced nephrotoxicity and oxidative damage in rat kidney.

    Science.gov (United States)

    Rizwan, Sana; Naqshbandi, Ashreeb; Farooqui, Zeba; Khan, Aijaz Ahmed; Khan, Farah

    2014-06-01

    Arsenic, a naturally occurring metalloid, is capable of causing acute renal failure as well as chronic renal insufficiency. Arsenic is known to exert its toxicity through oxidative stress by generating reactive oxygen species (ROS). Flaxseed, richest plant based dietary source of ω-3 polyunsaturated fatty acids (PUFAs) and lignans have shown numerous health benefits. Present study investigates the protective effect of flaxseed oil (FXO) on sodium arsenate (NaAs) induced renal damage. Rats prefed with experimental diets (Normal/FXO diet) for 14days, were administered NaAs (20mg/kg body weight i.p.) once daily for 4days while still on the experimental diets. NaAs nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. Administration of NaAs led to a significant decline in the specific activities of brush border membrane (BBM) enzymes both in kidney tissue homogenates and in the isolated membrane vesicles. Lipid peroxidation and total sulfhydryl groups were altered upon NaAs treatment, indicating the generation of oxidative stress. NaAs also decreased the activities of metabolic enzymes and antioxidant defence system. Histopathological studies supported the biochemical findings showing extensive damage to the kidney by NaAs. In contrast, dietary supplementation of FXO prior to and alongwith NaAs treatment significantly attenuated the NaAs-induced changes.

  18. P glycoprotein: a new mechanism to control drug-induced nephrotoxicity.

    Science.gov (United States)

    del Moral, R G; Olmo, A; Aguilar, M; O'Valle, F

    1998-01-01

    The role of P glycoprotein (P-gp) in kidney is now being explored, and under physiological conditions, this protein is thought to be an excretory pump of cationic xenobiotics and metabolites. Functionally, two different types of P-gp have been described, but only the class I has been related to drug transport, and its overexpression confers the multidrug resistance phenotype in tumoral cells. It has been proposed that P-gp is involved in the energy-dependent transport of substrates through the cell membrane (toxic metabolites, toxins, nutrients, ions, peptides, etc.)--like a 'hydrophobic molecule vacuum cleaner'. Several physiological functions have been attributed to P-gp: defense against xenobiotic aggression and transmembrane transport of prenylcysteine methyl esters, removing these cytotoxic metabolites from cells. A variety of substrates ranging from chemotherapeutics to steroid hormones, antibiotics, and calcium channel blockers can be transported by P-gp, suggesting the possible involvement of this protein in other unknown functions. Results from our group and others have suggested that overexpression of P-gp in renal tubular and mesangial cells prevents pharmacological nephrotoxicity by cyclosporin A (CsA). On the other hand CsA, a substrate of the pump, could act as a blocker in tubular cells by competitive inhibition. One relevant aspect in kidney is the possible relationship between P-gp and protein kinase C. Several reports suggest that protein kinase C may play a role in inducing the P-gp overexpression in cells under xenobiotic pressure, through activation of the ras oncoprotein family. This could be mediated directly by angiotensin II as a ras activator. This way, the detoxicant function of P-gp against products of the ras catabolism could mediate their accumulation when the 'vacuum cleaner' function is blocked by CsA or tacrolimus, contributing to the initial development of fibroblastic activation that leads to interstitial fibrosis associated with

  19. Perillyl Alcohol Protects against Fe-NTA-Induced Nephrotoxicity and Early Tumor Promotional Events in Rat Experimental Model

    Directory of Open Access Journals (Sweden)

    Tamanna Jahangir

    2007-01-01

    Full Text Available Plants have been widely used as protective agents against a wide variety of processes and compounds that damage tissues via free radical mechanisms. Perillyl alcohol (PA is a naturally occurring monoterpene found in the essential oils of numerous species of plants including mints, cherries and celery seeds. This monocyclic monoterpene has shown antioxidant and therapeutic activity in various studies against various xenobiotics. In this study, we have analyzed the effects of PA against single intraperitoneal dose of ferric nitrilotriacetate (Fe-NTA (9 mg iron per kg body weight-induced nephrotoxicity and early tumor promotional events. The pretreatment of Fe-NTA-treated rats with 0.5% per kg body weight dose and 1% per kg body weight dose of PA for seven consecutive days significantly reversed the Fe-NTA-induced malondialdehyde formation, xanthine oxidase activity (P < 0.001, ornithine decarboxylase activity (P < 0.001 and 3[H]thymidine incorporation in renal DNA (P < 0.001 with simultaneous significant depletion in serum toxicity markers blood urea nitrogen and creatinine (P < 0.001. Significant restoration at both the doses was recorded in depleted renal glutathione content, and its dependent enzymes with prophylactic treatment of PA. Present results suggest that PA potentially attenuates against Fe-NTA-induced oxidative damage and tumor promotional events that preclude its development as a future drug to avert the free radical-induced toxicity.

  20. Protective effect of CV247 against cisplatin nephrotoxicity in rats.

    Science.gov (United States)

    Máthé, C; Szénási, G; Sebestény, A; Blázovics, A; Szentmihályi, K; Hamar, P; Albert, M

    2014-08-01

    CV247 (CV), an aqueous mixture of copper (Cu) and manganese (Mn) gluconates, vitamin C and sodium salicylate increased the antitumour effects of cisplatin (CDPP; cis-diamminedichloroplatinum) in vitro. We hypothesized that the antioxidant and cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2) inhibitory components of CV can protect the kidneys from CDPP nephrotoxicity in rats. CDPP (6.5 mg/kg, intraperitoneally) slightly elevated serum creatinine (Crea) and blood urea nitrogen (BUN) 12 days after treatment. Kidney histology demonstrated extensive tubular epithelial damage and COX-2 immunoreactivity increased 14 days after treatment. A large amount of platinum (Pt) accumulated in the kidney of CDPP-treated rats. Furthermore, CDPP decreased renal iron (Fe), molybdenum (Mo), zinc (Zn), Cu and Mn concentrations and increased plasma Fe and Cu concentrations. CDPP elevated plasma free radical concentration. Treatment with CV alone for 14 days (twice 3 ml/kg/day orally) did not influence these parameters. Chronic CV administration after CDPP reduced renal histological damage and slightly decreased COX-2 immunoreactivity, while failed to prevent the increase in Crea and BUN levels. Blood free radical concentration was reduced, that is, CV improved redox homeostasis. CV restored plasma Fe and renal Fe, Mo and Zn, while decreased Pt and elevated Cu and Mn concentrations in the kidney. Besides the known synergistic antitumour effects with CDPP, CV partially protected the kidneys from CDPP nephrotoxicity probably through its antioxidant effect.

  1. Drug absorption related nephrotoxicity assessment on an intestine-kidney chip.

    Science.gov (United States)

    Li, Zhongyu; Su, Wentao; Zhu, Yujuan; Tao, Tingting; Li, Dong; Peng, Xiaojun; Qin, Jianhua

    2017-05-01

    Drug absorption in the intestine is tightly related to drug-induced nephrotoxicity, which is a relatively common side effect in clinical practice. It highlights a great need to develop predictive models with high accuracy in the early stage during new drug discovery and development. Herein, we presented a novel intestine-kidney chip, which recapitulated drug absorption in the intestine and its resultant drug toxicity on the kidney. This work aims to provide an integrated tool for accurate assessment of drug absorption-related nephrotoxicity in vitro. A microfluidic device with multi-interfaces was designed, which facilitated the co-culture of the intestinal and glomerular endothelial cells in compartmentalized micro-chambers. Thus, drug absorption and following nephrotoxicity could be explored in a single assay based on the formation of the intact intestine function on the chip. Specifically, we adopt digoxin (DIG) as a model drug combined with colestyramine (COL) or Verapamil (VER), which significantly influence DIG absorption in the intestine. Different degrees of nephrotoxicity under drug combinations were further observed on the chip, including cell apoptosis, cell viability, and lactate dehydrogenase leakage. These features were consistent with the variance of DIG absorption by the intestinal cells. In agreement with clinical observations, our data demonstrated that DIG-induced nephrotoxicity was enhanced combined with VER but weakened with COL. All of these findings suggest that the established microdevice might provide a useful and cost-effective platform in vitro for testing drug absorption and nephrotoxicity in preclinical trials during new drug development.

  2. Efficacy of safranal to cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Karafakıoğlu, Yasemin Sunucu; Bozkurt, Mehmet Fatih; Hazman, Ömer; Fıdan, A Fatih

    2017-03-20

    The aim of the present study was to investigate the effects of safranal on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague-Dawley rats were randomly divided into five groups. The control group received physiological saline; animals in Group 2 received only safranal and in Group 3 received only cisplatin; 5 days of safranal treatment was performed following administration of cisplatin for the animals in Group 4; 5 days of safranal pretreatment was applied to the animals in Group 5 before administration of cisplatin. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and safranal (200 mg/kg) was administered by gavage. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. The concentrations of creatinine and urea in plasma and levels of malondialdehyde (MDA) and glutathione (GSH) as well as total antioxidant status (TAS) and total oxidant status (TOS) were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. MDA and TOS levels of rats that received cisplatin alone were not significantly different compared with those of the control group, but GSH and TAS levels in the only cisplatin-administered group were significantly decreased. Safranal administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared with the only cisplatin-administered group, pretreatment with safranal being more effective. As a result, safranal treatment might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat.

  3. The protective effect of theophyline in cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Seyed Seifollah Beladi Mousavi

    2014-01-01

    Full Text Available Cisplatin is a potent and a major anti-neoplastic drug in the treatment of a broad spectrum of malignancies. However, its clinical use is limited by renal tubular dysfunction that occurs in a significant percent of patients. The aim of the present study was to evaluate the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity. The trial design was prospective, randomized, double-blinded and placebo controlled. Chemotherapeutic patients who received cisplatin at a dosage of at least 50 mg/m 2 alone or in combination with other chemotherapy agent(s were included in the study. There were a total of 76 patients who were randomly divided into two groups. In group 1 (n = 38, placebo was advised; in group 2 (n = 38, patients received 4 mg/kg aminophyline as an intravenous loading dose, followed by theophyline in a dose of 200 mg three times daily orally for four consecutive days. The placebo group had 22 males and 16 females and the theophyline group had 26 males and 12 females. The mean age was 51 ± 17.6 years and the mean dose of cisplatin was 86.71 ± 43.18 mg. The prevalence of cisplatin nephrotoxicity in groups 1 and 2 was 7.9 and 5.3%, respectively, and the difference was not significant (P = 1. In addition, there was no significant association of cisplatin nephrotoxicity with age (P = 0.1, gender (P = 0.64 and mean dose of cisplatin (P = 0.8. These results indicate that prophy-lactic application of aminophyline and theophyline does not have a protective effect against cisplatin nephrotoxicity.

  4. Matricaria chamomilla attenuates cisplatin nephrotoxicity.

    Science.gov (United States)

    Salama, Ragaa H M

    2012-07-01

    Matricaria chamomilla is extensively consumed as a tea or tonic. Despite its widespread use as a home remedy, relatively few trials evaluated its benefits in nephro protection. Hence, this study evaluates the protective role of M. chamomilla in cisplatin nephrotoxicity rat model. The study was conducted on 32 rats divided into four groups. The first group (G1) was injected with saline intra-peritoneally (IP); G2 was injected with 5 mg/kg cisplatin on day 0 of the experiment and repeated four times, with five days free interval. G3 and G4 were injected daily with M. chamomilla (50 mg/kg) IP, starting five days before the experiment (-5 day); in addition, G4 was injected with cisplatin. On day 16, animals were scarified and serum and/or kidney tissue was used to determine: (a) kidney function tests (serum urea, creatinine, gamma glutamyl transferase (GGT), NAG, β-gal), (b) oxidative stress indices (NO, LPO), (c) antioxidant activities (SOD, GSH, total thiols), (d) apoptotic indices (Cathepsin D, DNA fragmentation) and (e) mineral (calcium). M. chamomilla significantly increased the body weight, normalized the kidney functions, improved the apoptotic markers, reduced the oxidative stress markers and corrected the hypo-calcemia that resulted from cisplatin nephrotoxicity. M. chamomilla is a promising nephro-protective compound reducing cisplatin nephrotoxicity most probably by its antioxidant activities and inhibition of gamma glutamyl transferase activity.

  5. Matricaria chamomilla attenuates cisplatin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Ragaa H.M. Salama

    2012-01-01

    Full Text Available Matricaria chamomilla is extensively consumed as a tea or tonic. Despite its widespread use as a home remedy, relatively few trials evaluated its benefits in nephro protection. Hence, this study evaluates the protective role of M. chamomilla in cisplatin nephrotoxicity rat model. The study was conducted on 32 rats divided into four groups. The first group (G1 was injected with saline intra-peritoneally (IP; G2 was injected with 5 mg/kg cisplatin on day 0 of the experiment and repeated four times, with five days free interval. G3 and G4 were injected daily with M. chamomilla (50 mg/kg IP, starting five days before the experiment (-5 day; in addition, G4 was injected with cisplatin. On day 16, animals were scarified and serum and/or kidney tissue was used to determine: (a kidney function tests (serum urea, creatinine, gamma glutamyl transferase (GGT, NAG, β-gal, (b oxidative stress indices (NO, LPO, (c antioxidant activities (SOD, GSH, total thiols, (d apoptotic indices (Cathepsin D, DNA fragmentation and (e mineral (calcium. M. chamomilla significantly increased the body weight, normalized the kidney functions, improved the apoptotic markers, reduced the oxidative stress markers and corrected the hypo-calcemia that resulted from cisplatin nephrotoxicity. M. chamomilla is a promising nephro-protective compound reducing cisplatin nephrotoxicity most probably by its antioxidant activities and inhibition of gamma glutamyl transferase activity.

  6. Renal tubule cell repair following acute renal injury.

    Science.gov (United States)

    Humes, H D; Lake, E W; Liu, S

    1995-01-01

    Experimental data suggests the recovery of renal function after ischemic or nephrotoxic acute renal failure is due to a replicative repair process dependent upon predominantly paracrine release of growth factors. These growth factors promote renal proximal tubule cell proliferation and a differentiation phase dependent on the interaction between tubule cells and basement membrane. These insights identify the molecular basis of renal repair and ischemic and nephrotoxic acute renal failure, and may lead to potential therapeutic modalities that accelerate renal repair and lessen the morbidity and mortality associated with these renal disease processes. In this regard, there is a prominent vasoconstrictor response of the renal vasculature during the postischemic period of developing acute renal failure. The intravenous administration of pharmacologic doses of atrial natriuretic factor (ANF) in the postischemic period have proven efficacious by altering renal vascular resistance, so that renal blood flow and glomerular filtration rate improve. ANF also appears to protect renal tubular epithelial integrity and holds significant promise as a therapeutic agent in acute renal failure. Of equal or greater promise are the therapeutic interventions targeting the proliferative reparative zone during the postischemic period. The exogenous administration of epidermal growth factor or insulin-like growth factor-1 in the postischemic period have effectively decreased the degree of renal insufficiency as measured by the peak serum creatinine and has hastened renal recovery as measured by the duration of time required to return the baseline serum creatinine values. A similarly efficacious role for hepatocyte growth factor has also been recently demonstrated.

  7. (Toxic hepatitis and acute renal failure after inhalation of chloride solvents: report of one case (author's transl))

    Energy Technology Data Exchange (ETDEWEB)

    Teixido Planas, J.; Martinez-Castelao, A.; Romero Gonzalez, R.; Grino Boira, J.; Gonzalez Segura, C.; Caralps Riera, A.

    1981-06-25

    Due to a combination of ingested ethanol and inhaled trichloroethylene (Tri) a 28 year old man developed toxic hepatitis and acute oliguric renal failure, both of which had a favorable evolution. Tri has been described as a cause of hepatic disfunction and acute renal failure due to acute tubular necrosis, although some of the cases described are controversial, because Tri was either contaminated by other dissolvents or could not be proven pure, with the exception of one case. In many there was ethanol ingestion. The Tri inhaled by our patient was found to contain less than 1% of carbon tetrachloride (C-Tchl). This would suggest the C-Tchl to be responsible for the clinical picture although the combination Tri/ethanol cannot be discarded as the causal agent, due to the small amount of contaminant present.

  8. Fatal group A streptococcal necrotizing fasciitis and toxic shock syndrome in a patient with psoriasis and chronic renal impairment.

    Science.gov (United States)

    Chong, Alvin H; Burrows, Nigel P

    2002-08-01

    A 78-year-old woman presented with rapid onset of skin pain which evolved into oedema, discoloration and infarction. She was diagnosed with group A beta-haemolytic streptococcus (Streptococcus pyogenes) necrotizing fasciitis and streptococcal toxic shock syndrome. The patient had a past history of psoriasis and end-stage renal impairment. Despite treatment with multiple antibiotics in an intensive care unit, the skin infarction involving the upper trunk continued to expand and the patient died within 24 hours of hospital admission. Group A streptococcus and Staphylococcus aureus were cultured from a tissue biopsy. Renal failure and compromised skin barrier function are known to predispose to invasive streptococcal infections, but necrotizing fasciitis has only rarely been reported in association with psoriasis. This case illustrates the fulminant nature of the infection.

  9. Evaluation of nephrotoxic effect of lead exposure among automobile repairers in Nnewi Metropolis

    Directory of Open Access Journals (Sweden)

    Ubuo K. Amah

    2014-06-01

    Full Text Available Background: Lead toxicity is one of the most common occupational hazards that affect several organs of the body, kidney inclusive. Auto repairers are exposed to lead in petrol, radiator, leaded battery, lead soldering wire, and spray paints, thus this study was designed to evaluate lead-induced nephrotoxic effect among automobile repairers. Methods: A total of 80 male subjects within the age range of 20 and 65 years were recruited for this study. 50 subjects were occupationally exposed automobile repairers, of which 15 were electricians, 21 mechanics and 14 panel beaters/spray painters, whereas 30 were non-exposed students and staff from Nnamdi Azikiwe University, Nnewi campus. Blood sample was collected from these individuals and their blood lead levels were determined alongside creatinine, urea, uric acid, sodium, potassium, chloride and bicarbonate. Results: The results showed that the mean levels of blood lead is significantly higher in automobile repairers than in control group (P 0.05. The evaluation of the renal function markers show that, there were significant increases in the mean serum concentration of creatinine, urea, and uric acid in the study group compare to the control subjects (P 0.05. Conclusion: Findings from this study show that blood lead level is high among automobile repairers above CDC recommended level for adults. This high blood lead level among automobile repairers may be responsible for raised levels of renal markers which may eventually lead to their renal damage. [Int J Res Med Sci 2014; 2(3.000: 1107-1111

  10. Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs.

    Science.gov (United States)

    Dobson, Roy L M; Motlagh, Safa; Quijano, Mike; Cambron, R Thomas; Baker, Timothy R; Pullen, Aletha M; Regg, Brian T; Bigalow-Kern, Adrienne S; Vennard, Thomas; Fix, Andrew; Reimschuessel, Renate; Overmann, Gary; Shan, Yuching; Daston, George P

    2008-11-01

    This paper describes research relating to the major recall of pet food that occurred in Spring 2007 in North America. Clinical observations of acute renal failure in cats and dogs were associated with consumption of wet pet food produced by a contract manufacturer producing for a large number of companies. The affected lots of food had been formulated with wheat gluten originating from China. Pet food and gluten were analyzed for contaminants using several configurations of high-performance liquid chromatography (HPLC) and mass spectrometry (MS), which revealed a number of simple triazine compounds, principally melamine and cyanuric acid, with lower concentrations of ammeline, ammelide, ureidomelamine, and N-methylmelamine. Melamine and cyanuric acid, have been tested and do not produce acute renal toxicity. Some of the triazines have poor solubility, as does the compound melamine cyanurate. Pathological evaluation of cats and dogs that had died from the acute renal failure indicated the presence of crystals in kidney tubules. We hypothesized that these crystals were composed of the poorly soluble triazines, a melamine-cyanuric acid complex, or a combination. Sprague dawley rats were given up to 100 mg/kg ammeline or ammelide alone, a mixture of melamine and cyanuric acid (400/400 mg/kg/day), or a mixture of all four compounds (400 mg/kg/day melamine, 40 mg/kg/day of the others). Neither ammeline nor ammelide alone produced any renal effects, but the mixtures produced significant renal damage and crystals in nephrons. HPLC-MS/MS confirmed the presence of melamine and cyanuric acid in the kidney. Infrared microspectroscopy on individual crystals from rat or cat (donated material from a veterinary clinic) kidneys confirmed that they were melamine-cyanuric acid cocrystals. Crystals from contaminated gluten produced comparable spectra. These results establish the causal link between the contaminated gluten and the adverse effects and provide a mechanistic explanation

  11. Decursin Mediated Protection on Cisplatin-induced Nephrotoxicity in SD Rats and BDF1 Mice

    Institute of Scientific and Technical Information of China (English)

    Jiang Cheng-zhe; Han Ilhyun; Choung Seyoung

    2012-01-01

    Tisplatin is one of the valuable icancer agents against several types of neoplasm. However, nephrotoxicity is the major adverse effect representing in cisplatin therapy. In this study, the animal tests detecting protective effects of a natural compound, Decursin, on cisplatin-induced nephrotoxicity were examined by using in vivo model. Pretreatment Decursin 10, 20 and 40 mg · kg^-1 at 48, 24 and 6 h, and administration of a single dose of Cisplatin 5.2 mg · kg^-1. Nephrotoxicity was evaluated by serum BUN and creatinine examination. There was significant difference in body weights, serum BUN and creatinine levels of the normal group. Based on the new understanding of the protective mechanisms of cisplatin-induced nephrotocivity, new strategies can be developed to prevent renal injury or to enhance recovery after cisplatin treatment.

  12. Urine proteomic profiling of uranium nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Malard, V.; Gaillard, J.C.; Sage, N. [CEA, DSV, IBEB, SBTN, Laboratoire de Biochimie des Systemes Perturbes (LBSP), Bagnols-sur-Ceze, F-30207 (France); Berenguer, F. [CEA, DSV, IBEB, SBTN, Laboratoire d' Etude des Proteines Cibles (LEPC), Bagnols-sur-Ceze, F-30207 (France); Quemeneur, E. [CEA, DSV, IBEB, SBTN, Bagnols-sur-Ceze, F-30207 (France)

    2009-07-01

    Uranium is used in many chemical forms in civilian and military industries and is a known nephro-toxicant. A key issue in monitoring occupational exposure is to be able to evaluate the potential damage to the body, particularly the kidney. In this study we used innovative proteomic techniques to analyse urinary protein modulation associated with acute uranium exposure in rats. Given that the rat urinary proteome has rarely been studied, we first identified 102 different proteins in normal urine, expanding the current proteome data set for this central animal in toxicology. Rats were exposed intravenously to uranyl nitrate at 2.5 and 5 mg/kg and samples were collected 24 h later. Using two complementary proteomic methods, a classic 2-DE approach and semi-quantitative SDS-PAGE-LC-MS/MS, 14 modulated proteins (7 with increased levels and 7 with decreased levels) were identified in urine after uranium exposure. Modulation of three of them was confirmed by western blot. Some of the modulated proteins corresponded to proteins already described in case of nephrotoxicity, and indicated a loss of glomerular permeability (albumin, alpha-1-anti-proteinase, sero-transferrin). Others revealed tubular damage, such as EGF and vitamin D-binding protein. A third category included proteins never described in urine as being associated with metal stress, such as ceruloplasmin. Urinary proteomics is thus a valuable tool to profile uranium toxicity non-invasively and could be very useful in follow-up in case of accidental exposure to uranium. (authors)

  13. Synthesis, Characterization and renal toxicity of ZnO and polyethylene glycol Coated ZnO nanoparticles

    Directory of Open Access Journals (Sweden)

    Banafsheh Raisi Dehkourdi

    2017-01-01

    Full Text Available Objective(s: The wide scale use of Zinc oxide nanoparticles (ZnO NPs in the consumer market world makes human beings more prone to the exposure to ZnO nanoparticles and its adverse effects. Therefore, the aim of the present study is to assess renal toxicity potential of ZnO and Polyethylene glycol Coated ZnO Nanoparticles in rat.Materials and Methods: Co-precipitation chemical method was used in order to synthesize ZnO nanoparticles. The synthesized nanoparticles were coated with PEG (Polyethylene glycol and the coating interactions were investigated by FTIR (Fourier Transform Infrared Spectroscopy. Structural properties of ZnO NPs were evaluated by TEM (Transmission Electron Microscope and XRD (X Ray Diffraction. Toxicity assessment of ZnO and PEG coated ZnO nanoparticles were studied in rat by intra peritoneal injections during a one-month. Renal factors (Creatinine, Uric acid and Blood Urea Nitrogen were measured 15 and 30 days post injection.Results: The synthesized nanoparticles were single phase and have spinel structure. Their size distribution was around 18 nm. Some kidney factors were changed due to the injection of both uncoated and coated nanoparticles (especially in groups received concentrations of more than 100 mg per kg of body weight. Renal factors changes were more considerable in groups received ZnO NPs in comparison with those received PEG coated ZnO NPs. Chemical toxicity studies showed that there was no irreversible effect in the groups received  concentrations less than 200 mg/kg (mg per kg of body weight.Conclusion: The results indicated that renal factors were changed during 15 days post injection, especially in groups received high doses (200 mg/kg. The results of measurements 30 days post injection showed less change in comparison with the control and this indicates that there was no irreversible effect on kidney. Moreover, PEG coated nanoparticles were less toxic in comparison with Uncoated ZnO NPs.

  14. Reduction of renal uptake of radiolabeled octreotate by amifostine coadministration

    NARCIS (Netherlands)

    M.L. Melis (Marleen); R. Valkema (Roelf); E.P. Krenning (Eric); M. de Jong (Marcel)

    2012-01-01

    textabstractMegalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PRRT with 177Lu-DOTA,Tyr3-octreotate. This study de

  15. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qing [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Guo, Dong [Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Dong, Zhongqi [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Zhang, Wei [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Zhang, Lei; Huang, Shiew-Mei [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD (United States); Polli, James E. [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Shu, Yan, E-mail: yshu@rx.umaryland.edu [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)

    2013-11-15

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic

  16. [Cyclosporin, toxicity and efficacy in rejection of liver allografts in the rat].

    Science.gov (United States)

    Settaf, A; Gugenheim, J; Lahlou, M K; Gigou, M; Capron-Laudereau, M; Charpentier, B; Reynes, M; Lokiec, F; Bismuth, H

    1989-01-01

    52 orthotopic liver transplants were performed in DA to lewis rat strain combination, in order to appreciate cyclosporine toxicity, and efficacy at doses of 10 mg/kg day (G II) and 20 mg/kg/day (GIII) compared to liver allografts in DA/lewis rats. The first signs of cyclosporine hepatotoxicity are biological (increased plasma level of bilirubine and transaminase) that were noticed at the dose of 20 mg/kg/day. Histological signs (cells inclusion, hepatocytic necrosis) appeared late and were less constant as well as difficult to assert creatinine plasma level was the best reflect of cyclosporine nephrotoxicity. Renal toxicity was practically constant at the dose of 20 mg/kg/day. In spite of renal and hepatic toxicity, cyclosporin by itself, allows the abolition of the acute rejection of liver allografts in the rat.

  17. Abrogation of cisplatin-induced nephrotoxicity by emodin in rats.

    Science.gov (United States)

    Ali, Badreldin H; Al-Salam, Suhail; Al Husseini, Isehaq S; Al-Lawati, Intisar; Waly, Mostafa; Yasin, Javed; Fahim, Mohamed; Nemmar, Abderrahim

    2013-04-01

    Nephrotoxicity of the anticancer drug cisplatin (CP) involves the generation of reactive oxygen species in renal cortex, and emodin (a rhubarb anthraquinone) has strong antioxidant and anticancer actions. Therefore, we tested here the possible ameliorative effect of emodin on CP nephrotoxicity in rats. Emodin was given orally (10 mg/kg/day for nine consecutive days), and on day 4, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Five days after CP treatment, rats were killed, and blood and urine samples, and kidneys were collected for the assessment of histopathological renal damage and apoptosis, and for biochemical estimation of creatinine and urea concentrations in plasma and urine, several cytosolic antioxidant enzyme activities in kidneys, and urinalyses. CP significantly increased the concentrations of urea and creatinine, and decreased creatinine clearance. It also significantly reduced cortical glutathione concentration and the activity of superoxide dismutase. CP treatment significantly increased urine volume and N-acetyl-β-D-glucosaminidase activity and significantly decreased osmolarity and protein concentrations. Emodin treatment markedly and significantly mitigated all these effects. Sections from saline- and emodin-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with emodin. The concentration of CP in the cortical tissues was not significantly altered by emodin treatment. The results suggested that emodin had ameliorated CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies emodin may be considered a potentially useful nephroprotective agent.

  18. Prevention of cisplatin induced nephrotoxicity by terpenes isolated from Ganoderma lucidum occurring in Southern Parts of India.

    Science.gov (United States)

    Pillai, Thulasi G; John, Mathew; Sara Thomas, Gifty

    2011-01-01

    Investigations were carried out to determine the protective effect of terpenes isolated from the fruiting bodies of Ganoderma lucidum (Fr) P.Karst against nephrotoxicity caused by the cisplatin, in mice. Intraperitoneal administration of cisplatin (16 mg/kg body wt) resulted in significant nephrotoxicity in mice. Serum urea, creatinine and ALP levels were drastically elevated indicating severe nephrotoxicity . The renal antioxidant defense system such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and concentration of reduced glutathione (GSH) were depleted by cisplatin injection. The oral administration of terpenes at a dose of 100mg/kg body weight prevented increase in urea, creatinine levels and ALP activity and also maintained the renal antioxidant defense. The Ganoderma terpenes also imparted protection against cisplatin induced renal tissue lipid peroxidation. The results indicated that the total terpenes isolated from G. lucidum possessed significant in vivo antioxidant activity and rendered protection against cisplatin induced nephrotoxicity. The results suggest the potential therapeutic use of Ganoderma terpenes to prevent nephrotoxicity caused during chemotherapy using cisplatin.

  19. The efficacy and nephrotoxicity associated with colistin use in an intensive care unit in Vietnam: Use of colistin in a population of lower body weight

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    Nguyen Gia Binh

    2015-06-01

    Conclusion: A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort.

  20. Potentiation of cadmium nephrotoxicity by acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Bernard, A.M.; Russis, R. de; Ouled Amor, A.; Lauwerys, R.R.

    1988-10-01

    The possible interactions between acetaminophen and cadmium (Cd) on the kidney were investigated in female Sprague-Dawley rats. Acetaminophen was administered in the food at an average dose of 900 mg/kg and Cd in drinking water at the concentration of 200 ppm. The treatment with acetaminophen and Cd lasted 2 and 10 months, respectively. No interaction between Cd and acetaminophen was observed during the period of their concomitant administration: the increase in albuminuria caused by Cd and acetaminophen was additive, while the tubular impairment caused by acetaminophen (increased ..beta../sub 2/-microglobulinuria and decreased kidney concentrating ability) was not exacerbated by Cd. None of these treatments affected the glomerular filtration rate. Four months after the end of acetaminophen treatment, the renal changes had almost completely disappeared in the rats which had received the analgesic alone. Those continously exposed to Cd had developed slight tubular damage, as evidenced by an increased urinary excretion of ..beta../sub 2/-microglobulin and ..beta..-N-acetylglucosaminidase. By contrast, rats pretreated with acetaminophen for 2 months and exposed to Cd showed a marked increase in urinary excretion of albumin and ..beta../sub 2/-microglobulin, suggesting an interaction between both treatments. At the end of the study, only the interaction with ..beta../sub 2/-microglobulin excretion was still evident; that with the urinary excretion of ..beta..-N-acetylglucosaminidase and albumin having been masked by the chronic progessive nephrosis affecting most animals at that stage. As acetaminophen had no effect on the renal accumulation of Cd, it may be concluded that pretreatment with this analygesic at a dose causing slight tubular dysfunction renders rat kidney more sensitive to the nephrotoxic action of Cd. This observation may be of clinical relevance for population groups occupationally or environmentally exposed to Cd.

  1. Flavonoids, the emerging dietary supplement against cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Athira, K V; Madhana, Rajaram Mohanrao; Lahkar, Mangala

    2016-03-25

    The letter illustrates the emerging potential of flavonoids as dietary supplement to ameliorate cisplatin-induced nephrotoxicity and refers to the recent article on ''Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat'' by Chtourou et al. They demonstrated that supplementation of naringin, a flavanone glycoside, found in grape and citrus fruit species, can attenuate cisplatin-induced renal dysfunction via restoration of redox balance and suppression of inflammation, NF-κB activation and apoptosis. The chemotherapeutic efficacy of cisplatin has always compelled the researchers to find solution to ameliorate its side effects. In recent years, numerous candidates have been evaluated for their protective potential against cisplatin-induced nephrotoxicity and flavonoids have come up with promising results. The future prospects might be promising with a proper refinement and collective integration of the preclinical and clinical research in the field of flavonoid supplementation to cisplatin therapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Nephrotoxicity of cefepime: A new cephalosporin antibiotic in rats

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    Mossad Gamaleddin Ahmed Elsayed

    2014-01-01

    Full Text Available Objectives: To investigate the nephrotoxic effect and biochemical alterations induced by cefepime in rats. Materials and Methods: Cefepime was administered intramuscularly at doses of 45, 90 and 180 mg/kg b.wt. once daily for 5 consecutive days. The serum and urine samples were used for quantitative determination of urea, creatinine, glucose, total protein, calcium, sodium and potassium. The histopathological examination of kidney tissues was performed 1, 4 and 8 days after the last dose of cefepime administration. Results: Cefepime induced a significant increase in the total amount of urine per day, urea and creatinine concentration in the serum and urine and significant decrease in their clearance. Cefepime also caused a significant gluocosuria and proteinuria and significant decrease in their serum concentrations. The effect of cefepime on serum and urine concentrations of calcium, sodium and potassium were also determined. Cefepime injection in the three tested doses caused renal tubular, glomerular and vascular changes. The severity of these changes was dose dependent. In conclusion, these results suggest a possible contribution of cefepime in the nephrotoxicity and biochemical alterations, especially at high doses. Therefore, the renal functions should be monitored during the cefepime therapy.

  3. Azadirachta indica Attenuates Cisplatin-Induced Nephrotoxicity and Oxidative Stress

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    Ahmed E. Abdel Moneim

    2014-01-01

    Full Text Available We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt on cisplatin- (CP- induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i as histopathological damage of the renal tissue, (ii as increases in serum uric acid, urea, and creatinine, (iii as increases in malondialdehyde (MDA and nitric oxide (NO, (iv as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  4. Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity.

    Science.gov (United States)

    Bulacio, Romina Paula; Anzai, Naohiko; Ouchi, Motoshi; Torres, Adriana Mónica

    2015-08-17

    Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.

  5. 中药毒性的代谢组学研究(Ⅱ):吡咯里西啶类生物碱的肝肾毒性%Metabonomic Study on the Toxicity of Chinese Medicine (Ⅱ) : Hepato-nephrotoxicity of Pyrrolizidine Alkaloids

    Institute of Scientific and Technical Information of China (English)

    祁乃喜; 刘玉梅; 何翠翠; 华嘉; 李建新

    2012-01-01

    目的 分析经中药千里光中吡咯里西啶类生物碱染毒后大鼠尿液内源性代谢产物的变化,研究该类生物碱的肝肾毒性,为中药毒性评价提供简单可靠的方法.方法 利用生物核磁共振技术分析对照组,吡咯里西啶类生物碱口服给药组的大鼠7d的尿液、结合模式识别技术和主成分分析法评价吡咯里西啶类生物碱对大鼠尿液内源性代谢物的影响,探讨吡咯里西啶类生物碱的肝肾毒性.结果 与对照组相比,口服吡咯里西啶类生物碱引起大鼠尿中牛磺酸,氧化三甲胺以及二甲基甘氨酸含量的持续增高,说明对肝脏及肾脏造成了损伤,提示吡咯里西啶类生物碱存在肝肾毒性.结论 从代谢组学的角度可以诠释中药千里光的肝肾毒性,提示代谢组学方法可为传统中药毒性研究提供新的手段.%OBJECTIVE To study the hepato-nephrotoxicity of pyrrolizidine alkaloids isolated from Herba Senecionis Scan-dentis via analyzing changes of endogenous metabolites in rat urines after administration of the alkaloids,and provide a simple and reliable method for toxicity evaluation of traditional Chinese medicine(TCM). METHODS The hepato-nephrotoxicity of the alkaloids was explored through analyzing urines collected from rats in both the control and pyrrolizidine alkaloids orally administrated groups in 7 days by bio-nuclear magnetic resonance(bio-NMR),and evaluating pyrrolizidine alkaloids' influences on endogenous metabolites in urine by pattern recognition technique and principal component analysis(PCA). RESULTS Compared with the control group,the continuous increase of taurine,trimethylamine-N-oxide(TMAO)and dimethylglycine(DMG)in urines of pyrrolizidine alkaloids orally administrated group proved that alkaloids had caused damages to the liver and kidney,which indicated the hepato-nephrotoxicity of pyrrolizidine alkaloids.CONCLUSION The hepato-nephrotoxicity of Herba Senecionis Scandentis could be

  6. Methods of reduction of cisplatin nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Walker, E.M. Jr.; Gale, G.R.

    Cisplatin, an agent widely used in the chemotherapy of a variety of human malignancies, is often dose-limited owing to its nephrotoxicity. Some of the approaches under consideration, regarding the reduction of cisplatin nephrotoxicity, include the use of hydration and osmotic diuresis, pharmacological diuretics, chelating agents or agents which otherwise react with cisplatin or reverse cisplatin-induced deoxyribonucleic acid cross-links, and antioxidants to destroy free radicals, especially superoxide radicals, produced by cisplatin. The effects of each of these and other interventions on cisplatin-induced nephrotoxicity are delineated, along with their proposed mechanisms and effects on therapeutic efficacy. The current status of development of organoplatinum analogs yielding congeners with less nephrotoxicity and greater efficacy is discussed briefly. Finally, a possible role of endogenous and/or exogenous prostaglandins in protecting against or reversing heavy metal nephrotoxicity is suggested.

  7. Characterization of the chemical reactivity and nephrotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide, a potential reactive metabolite of trichloroethylene.

    Science.gov (United States)

    Irving, Roy M; Pinkerton, Marie E; Elfarra, Adnan A

    2013-02-15

    N-Acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NA-DCVC) has been detected in the urine of humans exposed to trichloroethylene and its related sulfoxide, N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (NA-DCVCS), has been detected as hemoglobin adducts in blood of rats dosed with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) or S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS). Because the in vivo nephrotoxicity of NA-DCVCS was unknown, in this study, male Sprague-Dawley rats were dosed (i.p.) with 230 μmol/kg b.w. NA-DCVCS or its potential precursors, DCVCS or NA-DCVC. At 24 h post treatment, rats given NA-DCVC or NA-DCVCS exhibited kidney lesions and effects on renal function distinct from those caused by DCVCS. NA-DCVC and NA-DCVCS primarily affected the cortico-medullary proximal tubules (S(2)-S(3) segments) while DCVCS primarily affected the outer cortical proximal tubules (S(1)-S(2) segments). When NA-DCVCS or DCVCS was incubated with GSH in phosphate buffer pH 7.4 at 37°C, the corresponding glutathione conjugates were detected, but NA-DCVC was not reactive with GSH. Because NA-DCVCS exhibited a longer half-life than DCVCS and addition of rat liver cytosol enhanced GSH conjugate formation, catalysis of GSH conjugate formation by the liver could explain the lower toxicity of NA-DCVCS in comparison with DCVCS. Collectively, these results provide clear evidence that NA-DCVCS formation could play a significant role in DCVC, NA-DCVC, and trichloroethylene nephrotoxicity. They also suggest a role for hepatic metabolism in the mechanism of NA-DCVC nephrotoxicity.

  8. Protective Effects of Intralipid and Caffeic Acid Phenethyl Ester on Nephrotoxicity Caused by Dichlorvos in Rats

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    Muhammet Murat Celik

    2015-01-01

    Full Text Available The protective effects of Caffeic Acid Phenethyl Ester (CAPE and intralipid (IL on nephrotoxicity caused by acute Dichlorvos (D toxicity were investigated in this study. Forty-eight Wistar Albino rats were divided into 7 groups as follows: Control, D, CAPE, intralipid, D + CAPE, D + IL, and D + CAPE + IL. When compared to D group, the oxidative stress index (OSI values were significantly lower in Control, CAPE, and D + IL + CAPE groups. When compared to D + IL + CAPE group, the TOS and OSI values were significantly higher in D group (P<0.05. When mitotic cell counts were assessed in the renal tissues, it was found that mitotic cell count was significantly higher in the D group while it was lower in the D + CAPE, D + IL, and D + IL + CAPE groups when compared to the control group (P<0.05. Also, immune reactivity showed increased apoptosis in D group and low profile of apoptosis in the D + CAPE group when compared to the Control group. The apoptosis level was significantly lower in D + IL + CAPE compared to D group (P<0.05 in the kidneys. As a result, we concluded that Dichlorvos can be used either alone or in combination with CAPE and IL as supportive therapy or as facilitator for the therapeutic effect of the routine treatment in the patients presenting with pesticide poisoning.

  9. Evaluation of nephroprotective, diuretic, and antioxidant activities of plectranthus amboinicus on acetaminophen-induced nephrotoxic rats.

    Science.gov (United States)

    Palani, S; Raja, S; Naresh, R; Kumar, B Senthil

    2010-05-01

    Plectranthus amboinicus (PA), commonly known as country borage, is a folkoric medicinal plant. Juice from its leaves is commonly used for illnesses including liver and renal conditions in the Asian sub-continent. Acetaminophen (APAP), used as an analgesic, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective, diuretic, and antioxidant activities of the ethanol extract of PA at two doses of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. This study shows that APAP significantly increases the levels of serum urea (UR), hemoglobin (Hb), total leukocyte count, creatinine, raised body weight, and reduced levels of neutrophils, granulocytes, uric acid, and platelet concentration. Ethanol extract of PA rescued these phenotypes by increasing anti-oxidative responses as assessed by biochemistry and histopathology. In addition, the ethanol extract of PA at two doses showed a significant diuretic activity by increased levels of total urine output and urinary elerolytes such as sodium and potassium. In conclusion, these data suggest that the ethanol extract of PA possess nephroprotective and antioxidant effects against APAP-induced nephrotoxicity and strong diuretics effect in rats.

  10. Does intraperitoneal medical ozone preconditioning and treatment ameliorate the methotrexate induced nephrotoxicity in rats?

    Science.gov (United States)

    Aslaner, Arif; Çakır, Tuğrul; Çelik, Betül; Doğan, Uğur; Mayir, Burhan; Akyüz, Cebrail; Polat, Cemal; Baştürk, Ahmet; Soyer, Vural; Koç, Süleyman; Şehirli, Ahmet Özer

    2015-01-01

    Methotrexate is a chemotherapeutic agent used for many cancer treatments. It leads to toxicity with its oxidative injury. The purpose of our study is investigating the medical ozone preconditioning and treatment has any effect on the methotrexate-induced kidneys by activating antioxidant enzymes in rats. Eighteen rats were divided into three equal groups; control, Mtx without and with medical ozone. Nephrotoxicity was performed with a single dose of 20 mg/kg Mtx intraperitoneally at the fifteenth day of experiment on groups 2 and 3. Medical ozone preconditioning was performed at a dose of 25 mcg/ml (5 ml) intraperitoneally everyday in the group 3 and treated with medical ozone for five more days while group 2 was received only 5 ml of saline everyday for twenty days. All rats were sacrificed at the end of third week and the blood and kidney tissue samples were obtained to measure the levels of TNF-α, IL-1β, malondialdehyde, glutathione and myeloperoxidase. Kidney injury score was evaluated histolopatologically. Medical ozone preconditioning and treatment ameliorated the biochemical parameters and kidney injury induced by Mtx. There was significant increase in tissue MDA, MPO activity, TNF-α and IL-1β (Pnephrotoxicity induced by Mtx in rats by activating antioxidant enzymes and prevented renal tissue.

  11. PROTECTIVE EFFECT OF AQUEOUS AND METHANOLIC EXTRACTS OF LAGENARIA SICERARIA SEEDS IN GENTAMICIN INDUCED NEPHROTOXICITY

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    Mahurkar N.

    2012-06-01

    Full Text Available The aim of present study was to carry out the preliminary phytochemical studies and nephroprotective activity of metahanolic and aqueous extracts of Lagenaria siceraria seeds, family cucurbitaceae. These studies revealed the presence of flavonoids, tannins (ellagitannins, saponins, polyphenols, triterpenes, lagenin (protein in the extracts. The extract was found to be potent diuretic which causes excretion of sodium and potassium. Gentamicin is an extensively used aminolgycoside antibiotic. It has been reported to produce nephrotoxicity even at normal therapeutic dose level. Gentamicin was administrated intraperitonealy at a dose of 80mg/kg body weight for 9 days. The biochemical parameters viz. serum createnine, blood urea nitrogen (BUN and serum uric acid was found to be significantly increased whereas serum total protein was decreased. Histopathological sections showed marked glomerular, peritubular and blood vessel congestion. These increased levels of biochemical parameters and extent of renal damage were decreased by the methanolic and aqueous extracts of Lagenaria siceraria seeds at a dose of 250mg/kg, Cystone tab. (500mg/kg was used as reference standard to compare with the toxicant and test group animals.

  12. Renal Cortical Lactate Dehydrogenase: A Useful, Accurate, Quantitative Marker of In Vivo Tubular Injury and Acute Renal Failure.

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    Richard A Zager

    Full Text Available Studies of experimental acute kidney injury (AKI are critically dependent on having precise methods for assessing the extent of tubular cell death. However, the most widely used techniques either provide indirect assessments (e.g., BUN, creatinine, suffer from the need for semi-quantitative grading (renal histology, or reflect the status of residual viable, not the number of lost, renal tubular cells (e.g., NGAL content. Lactate dehydrogenase (LDH release is a highly reliable test for assessing degrees of in vitro cell death. However, its utility as an in vivo AKI marker has not been defined. Towards this end, CD-1 mice were subjected to graded renal ischemia (0, 15, 22, 30, 40, or 60 min or to nephrotoxic (glycerol; maleate AKI. Sham operated mice, or mice with AKI in the absence of acute tubular necrosis (ureteral obstruction; endotoxemia, served as negative controls. Renal cortical LDH or NGAL levels were assayed 2 or 24 hrs later. Ischemic, glycerol, and maleate-induced AKI were each associated with striking, steep, inverse correlations (r, -0.89 between renal injury severity and renal LDH content. With severe AKI, >65% LDH declines were observed. Corresponding prompt plasma and urinary LDH increases were observed. These observations, coupled with the maintenance of normal cortical LDH mRNA levels, indicated the renal LDH efflux, not decreased LDH synthesis, caused the falling cortical LDH levels. Renal LDH content was well maintained with sham surgery, ureteral obstruction or endotoxemic AKI. In contrast to LDH, renal cortical NGAL levels did not correlate with AKI severity. In sum, the above results indicate that renal cortical LDH assay is a highly accurate quantitative technique for gauging the extent of experimental acute ischemic and toxic renal injury. That it avoids the limitations of more traditional AKI markers implies great potential utility in experimental studies that require precise quantitation of tubule cell death.

  13. A Case of Severe Hydroxychloroquine-Induced Retinal Toxicity in a Patient with Recent Onset of Renal Impairment: A Review of the Literature on the Use of Hydroxychloroquine in Renal Impairment

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    Rajen Tailor

    2012-01-01

    Full Text Available We present a case of a 67-year-old female who presented with a twelve-month history of progressive blurred vision in both eyes. The patient was on hydroxychloroquine 200 mg twice a day for eight years for the treatment of scarring alopecia. Two years prior to presenting, the patient was found to have chronic kidney disease stage 3 secondary to hypertension. Examination revealed bilateral reduced visual acuities with attenuated arterioles and pigmentary changes on retinal assessment. Goldmann visual fields showed grossly constricted fields in both eyes. The patient was diagnosed with retinal toxicity secondary to hydroxychloroquine probably potentiated by renal impairment. Risk factors for retinal toxicity secondary to hydroxychloroquine can be broadly divided into dose-related and patient-related factors. Our patient developed severe retinal toxicity despite being on the recommended daily dose (400 mg per day. Although retinal toxicity at this dose has been documented, the development of renal impairment without dose adjustment or close monitoring of visual function is likely to have potentiated retinal toxicity. This case highlights the need to monitor renal function in patients on hydroxychloroquine. Should renal impairment develop, either the drug should be stopped or the dose reduced with close monitoring of visual function by an ophthalmologist.

  14. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

    Science.gov (United States)

    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  15. Minimal renal toxicity after Rituximab DHAP with a modified cisplatin application scheme in patients with relapsed or refractory diffuse large B-cell lymphoma

    OpenAIRE

    Lisenko, Katherina; McClanahan, F.; Schöning, Tilman; Schwarzbich, Mark Alexander; Cremer, Martin; Dittrich, Tobias; Ho, Anthony D; Witzens-Harig, Mathias

    2016-01-01

    Background: Rituximab (R) in combination with DHAP is a widely accepted salvage regimen for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). A common adverse effect of this protocol is renal toxicity which may result in treatment discontinuation. Assuming that a lower single dose of cisplatin over several days would reduce renal toxicity, our institution has chosen to administer cisplatin in a dosage of 25 mg/m2 per day as a 3-h infusion over 4 consecutive days. M...

  16. The Protective Roles of Zinc and Magnesium in Cadmium-Induced Renal Toxicity in Male Wistar Rats

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    Nasim Babaknejad

    2014-12-01

    Full Text Available Background: Cadmium (Cd is a heavy metal that has widespread use. It enters the food chain in different ways, including soil and water. Cadmium can cause dysfunction of different body organs. Zinc (Zn and magnesium (Mg supplementation can have protective effects against cadmium toxicity due to their antagonistic and antioxidants properties. This study examines the influence of supplemental Zn and Mg on Cd renal toxicity. Methods: Young male Wistar rats were divided into six groups of five. The Cd group received 1 mg Cd/kg and the control group received 0.5 mg/kg normal saline (i.p.. The other four groups were administered 1 mg/kg Cd+0.5 mg/kg Zn, 1 mg/kg Cd+1.5 mg/kg Zn, 1 mg/kg Cd+ 0.5 mg/kg Mg, and 1 mg/kg Cd+ 1.5 mg/kg Mg (i.p. for 21 days. Then, serum sodium, potassium, urea, creatinine, and protein levels were measured. Results: The results indicated that creatinine and protein levels decreased while urea, sodium, and potassium levels increased as a result of Cd exposure. Co-administered Cd and Zn and Mg decreased urea and increased sodium serum level in comparison to the cadmium group. Treatment by Mg, contrary to co-administered Cd and Zn, reduced serum protein level compared to the cadmium group. Compared to the cadmium treated group, Zn and Mg treatment enhanced serum creatinine level and reduced serum potassium level. Conclusion: The findings seem to suggest that zinc and magnesium compounds, due to their antagonistic and antioxidant activities, can protect Cd renal toxic effects in a dose-dependent manner.

  17. PROTECTIVE ROLE OF SYLIMARIN ON METHOTREXATE INDUCED HEPATO-NEPHROTOXICITY IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

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    Adel Abd Elhaleim Hagag

    2016-09-01

    Background:ALL is the most common childhood malignancy. ALL are treated with methotrexate (MTX based chemotherapy protocols. MTX can cause unpredictable serious hepato-renal side effects. Sylimarin has antioxidant and anti-inflammatory activities, membrane stabilizing effect,stimulate tissue regeneration and inhibit deposition of collagen fibers.This study aims to evaluate the protective effects of Sylimarin on MTX induced hepato-nephrotoxicity in children with ALL. Patients and Methods: 80 children with newly diagnosed ALL were included in the study. They were divided randomly into: Group I that included 40 children with ALL with their ages ranging from 4-13 years and mean age of 6.85± 2.89 years who received Sylimarin 420 mg/day in 3 divided doses for one week after each MTX dose and Group II that included 40 children with ALL with their ages ranging from 4-12 years and mean age value of 7.30±2.6 years who received placebo for one week after MTX therapy.For all patients liver functions including serum bilirubin, serum protein and its fractions albumin, globulin and albumin globulin ratio, alkaline phosphatase, ALT and AST, prothrombin time and activityand renal functions including blood urea and serum creatinine, serum cystatin C and urinary N-acetyl-beta-D-glucosaminidase were doneto assess hepatic and renal toxicity before and after chemotherapy. Results: There were significant differences in ALT, AST and alkaline phosphatase levels and Prothrombin time and activity between group I and II after chemotherapy, with higher level of ALT and AST (P value = 0.000, alkaline phosphatase (P value= 0.017, and lower Prothrombin activity (P value= 0.020 and prolonged prothrombin time (P value= 0.001 in group II compared with group I. There were no significant differences as regard total bilirubin (P. value=0.563, serum protein and albumin levels between group I and II. There were no significant differences between studied groups as regard kidney functions before

  18. P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yuanyuan; Yuan, Fahuan; Cao, Xuejiao [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Zhai, Zhifang [Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Gang Huang [Department of Medical Genetics, Third Military Medical University, Chongqing 430038 (China); Du, Xiang; Wang, Yiqin; Zhang, Jingbo; Huang, Yunjian; Zhao, Jinghong [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Hou, Weiping, E-mail: hwp0518@aliyun.com [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China)

    2014-11-15

    Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease. - Highlights: • The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity. • P2X7R blockade significantly attenuated the cisplatin-induced renal injury. • P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue. • P2X7R blockade

  19. Strain-specific renal toxicity of heterologous antilymphocyte [gamma]-globulin in mice7

    NARCIS (Netherlands)

    Cohen, B.J.; Vries, M.J. de; Noord, M.J. van; Lubbe, F.H.

    1970-01-01

    Severe glomerulonephritis followed one to five weekly i.p. injections in TLFM mice of rabbit antimouse lymphocyte [gamma]-globulin (ALG). Glomerulonephritis did not occur in C57BL mice subjected to the same regimen. Administration of normal rabbit [gamma]-globulin (NRG) to RFM mice also caused renal

  20. Strain-specific renal toxicity of heterologous antilymphocyte [gamma]-globulin in mice7

    NARCIS (Netherlands)

    Cohen, B.J.; Vries, M.J. de; Noord, M.J. van; Lubbe, F.H.

    1970-01-01

    Severe glomerulonephritis followed one to five weekly i.p. injections in TLFM mice of rabbit antimouse lymphocyte [gamma]-globulin (ALG). Glomerulonephritis did not occur in C57BL mice subjected to the same regimen. Administration of normal rabbit [gamma]-globulin (NRG) to RFM mice also caused renal

  1. Deferasirox nephrotoxicity-the knowns and unknowns.

    Science.gov (United States)

    Díaz-García, Juan Daniel; Gallegos-Villalobos, Angel; Gonzalez-Espinoza, Liliana; Sanchez-Niño, Maria D; Villarrubia, Jesus; Ortiz, Alberto

    2014-10-01

    In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

  2. Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin) in mouse xenografts.

    Science.gov (United States)

    Boulikas, Teni

    2004-07-01

    Cisplatin has been one of the most widely used and most effective cytotoxic agents in the treatment of malignancies but causes severe adverse reactions including nausea/vomiting, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, asthenia, and ototoxicity. A liposomal formulation of cisplatin, Lipoplatin, was developed in order to reduce the systemic toxicity of cisplatin. A single treatment of rats with 30 mg/kg Lipoplatin resulted in no toxicity whereas 2 or 3 weekly administrations at 30 mg/kg to rats gave neutropenia but no nephrotoxicity. On the contrary, a single injection to rats of 5 mg/kg cisplatin resulted in severe nephrotoxicity. Thus, Lipoplatin is less toxic than cisplatin in rats. Intraperitoneal or intravenous injection of Lipoplatin to SCID (severe combined immunodeficient) mice with subcutaneous breast MCF-7 or prostate LNCaP human tumors resulted in size reduction of the tumors; histological examination of the treated tumors in xenografts was consistent with apoptosis in tumor cells; thus, Lipoplatin appears to exert its cytotoxic effects to tumors in a mechanism similar to that of cisplatin. The preclinical studies reported here set the foundation for the clinical use of Lipoplatin as an exciting new drug with lower toxicity than cisplatin, endowed with proapoptotic properties.

  3. Age-related differences in susceptibility to cisplatin-induced renal toxicity†

    Science.gov (United States)

    Espandiari, P.; Rosenzweig, B.; Zhang, J.; Zhou, Y.; Schnackenberg, L.; Vaidya, V. S.; Goering, P. L.; Brown, R. P.; Bonventre, J. V.; Mahjoob, K.; Holland, R. D.; Beger, R. D.; Thompson, K.; Hanig, J.; Sadrieh, N.

    2009-01-01

    Limited experimental models exist to assess drug toxicity in pediatric populations. We recently reported how a multi-age rat model could be used for pre-clinical studies of comparative drug toxicity in pediatric populations. The objective of this study was to expand the utility of this animal model, which previously demonstrated an age-dependent sensitivity to the classic nephrotoxic compound, gentamicin, to another nephrotoxicant, namely cisplatin (Cis). Sprague-Dawley rats (10, 25, 40 and 80 days old) were injected with a single dose of Cis (0, 1, 3 or 6 mg kg−1 i.p.). Urine samples were collected prior and up to 72 h after treatment in animals that were ≥25 days old. Several serum, urinary and `omic' injury biomarkers as well as renal histopathology lesions were evaluated. Statistically significant changes were noted with different injury biomarkers in different age groups. The order of age-related Cis-induced nephrotoxicity was different than our previous study with gentamicin: 80 > 40 > 10 > 25 day-old vs 10 ≥ 80 > 40 > 25-day-old rats, respectively. The increased levels of kidney injury molecule-1 (Kim-1: urinary protein/tissue mRNA) provided evidence of early Cis-induced nephrotoxicity in the most sensitive age group (80 days old). Levels of Kim-1 tissue mRNA and urinary protein were significantly correlated to each other and to the severity of renal histopathology lesions. These data indicate that the multi-age rat model can be used to demonstrate different age-related sensitivities to renal injury using mechanistically distinct nephrotoxicants, which is reflected in measurements of a variety of metabolite, gene transcript and protein biomarkers. PMID:19839026

  4. In vitro effects of platinum compounds on renal cellular respiration in mice.

    Science.gov (United States)

    Almarzooqi, Saeeda-S; Alfazari, Ali-S; Abdul-Kader, Hidaya-M; Saraswathiamma, Dhanya; Albawardi, Alia-S; Souid, Abdul-Kader

    2015-01-01

    Cisplatin, carboplatin and oxaliplatin are structurally-related compounds, which are commonly used in cancer therapy. Cisplatin (Platinol(®)) has Boxed Warning stating: "Cumulative renal toxicity associated with PLATINOL is severe", while carboplatin and oxaliplatin are less nephrotoxic. These drugs form platinum adducts with cellular DNA. Their bindings to cellular thiols (e.g., glutathione and metallothionein) are known to contribute to drug resistance while thiol depletion augments platinum toxicity. Using phosphorescence oxygen analyzer, this study investigated the effects of platinum drugs on renal cellular respiration (mitochondrial O2 consumption) in the presence and absence of the thiol blocking agent N-ethylmaleimide (used here as a model for thiol depletion). Renal cellular ATP was also determined. Kidney fragments from C57BL/6 mice were incubated at 37 °C in Krebs-Henseleit buffer (gassed with 95% O2:5% CO2) with and without 100 μM platinum drug in the presence and absence of 100 μM N-ethylmaleimide for ≤ 6 h. Platinum drugs alone had no effects on cellular respiration (P ≥ 0.143) or ATP (P ≥ 0.161). N-ethylmaleimide lowered cellular respiration (P ≤ 0.114) and ATP (P = 0.008). The combination of platinum drug and N-ethylmaleimide significantly lowered both cellular respiration (P ≤ 0.006) and ATP (P ≤ 0.003). Incubations with N-ethylmaleimide alone were associated with moderate-to-severe tubular necrosis. Incubations with cisplatin+N-ethylmaleimide vs. cisplatin alone produced similar severities of tubular necrosis. Tubular derangements were more prominent in carboplatin+N-ethylmaleimide vs. carboplatin alone and in oxaliplatin+N-ethylmaleimide vs. oxaliplatin alone. These results demonstrate the adverse events of thiol depletion on platinum-induced nephrotoxicities. The results suggest cellular bioenergetics is a useful surrogate biomarker for assessing drug-induced nephrotoxicities.

  5. JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin.

    Science.gov (United States)

    Qiu, Mingning; Ke, Longzhi; Zhang, Sai; Zeng, Xin; Fang, Zesong; Liu, Jianjun

    2017-08-01

    Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells. The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species. We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production. JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

  6. Detection of sub-clinical lead toxicity in monocasters

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, B.D.; Krishnaswamy, K. [Food and Drug Toxicology Research Centre National Institute of Nutrition, Jamai Osmania (India)

    1995-06-01

    Lead poisoning has been documented since antiquity but occupational lead intoxication still continues to occur. Now there is a growing consensus that low levels of lead exposure often do not result in the manifestation of toxic symptoms, but may have subclinical toxicity on haemopoitic and renal system. Such toxicities are reported even at blood lead concentrations which were thought to be safe (60-80 {mu}g/dl) a decade ago. One of the several effects of lead, is inhibition of erythrocyte delta-aminolevulinic acid dehydratase (d-ALAD), rate limiting enzyme of the heme synthesis. Similar effect on d-ALAD has been reported even at the blood lead concentrations of 20-30 {mu}g/dl which are much below the toxic limits of 60 {mu}g/dl. Occupational lead nephropathy has been reported from several countries. Ultrastructural alteration in renal tubules, due to chronic exposure of lead, are seen in both animals and human renal biopsy samples. However, detecting early renal damage is a difficult task, since the routine renal function tests like creatine clearance, Insulin clearance (GFR) etc. are altered only after severe kidney damage. Recently increased urinary excretion of lysomal enzyme N-acetyl-B-D-glucosaminidase, a marker of early nephrotoxicity has been reported in the workers exposed to various chemicals including lead. The present study has therefore been undertaken to evaluate the subclinical lead toxicity on haemopoetic and renal system using non invassive techniques in monocasters, who are occupationally exposed to lead fumes while preparing the type set letter blocks. 23 refs., 3 figs.

  7. Aminoglycosides in septic shock: an overview, with specific consideration given to their nephrotoxic risk.

    Science.gov (United States)

    Boyer, Alexandre; Gruson, Didier; Bouchet, Stéphane; Clouzeau, Benjamin; Hoang-Nam, Bui; Vargas, Frédéric; Gilles, Hilbert; Molimard, Mathieu; Rogues, Anne-Marie; Moore, Nicholas

    2013-04-01

    Aminoglycoside nephrotoxicity has been reported in patients with sepsis, and several risk factors have been described. Once-daily dosing and shorter treatment have reduced nephrotoxicity risk, and simplified aminoglycoside monitoring. This review focuses on nephrotoxicity associated with aminoglycosides in the subset of patients with septic shock or severe sepsis. These patients are radically different from those with less severe sepsis. They may have, for instance, renal impairment due to the shock per se, sepsis-related acute kidney injury, frequent association with pre-existing risk factors for renal failure such as diabetes, dehydration and other nephrotoxic treatments. In this category of patients, these risk factors might modify substantially the benefit-risk ratio of aminoglycosides. In addition, aminoglycoside administration in critically ill patients with sepsis is complicated by an extreme inter- and intra-individual variability in drug pharmacokinetic/pharmacodynamic characteristics: the volume of distribution (Vd) is frequently increased while the elimination constant can be either increased or decreased. Consequently, and although its effect on nephrotoxicity has not been explored, a different administration schedule, i.e. a high-dose once daily (HDOD), and several therapeutic drug monitoring (TDM) options have been proposed in these patients. This review describes the historical perspective of these different options, including those applying to subsets of patients in which aminoglycoside administration is even more complex (obese intensive care unit [ICU] patients, patients needing continuous or discontinuous renal replacement therapy [CRRT/DRRT]). A simple linear dose adjustment according to aminoglycoside serum concentration can be classified as low-intensity TDM. Nomograms have also been proposed, based on the maximum (peak) plasma concentration (Cmax) objectives, weight and creatinine clearance. The Sawchuk and Zaske method (based on the

  8. Nephroprotective effect of vanillic acid against cisplatin induced nephrotoxicity in wistar rats: a biochemical and molecular study.

    Science.gov (United States)

    Sindhu, Ganapathy; Nishanthi, Emayavaramban; Sharmila, Ramalingam

    2015-01-01

    Cisplatin is one of the extensively used anticancer drugs against various cancers. Dosage dependent nephrotoxicity is the major problem in cisplatin chemotherapy. Cisplatin induced nephrotoxicity results in the depletion of renal antioxidant defence system. Our present study is aimed to investigate the nephroprotective effect of vanilic acid to against cisplatin induced nephrotoxicity in male wistar rats. Elevated levels of serum creatinine, blood urea nitrogen, serum uric acid and reduced antioxidant status were observed as indicatives of nephrotoxicity in cisplatin (7mg/kg bw) alone administered rats. Animals which are pre-treated with vanillic acid (50mg/kg and 100mg/kg) restored the elevated levels of renal function markers and reduced antioxidant status to near normalcy when compared to cisplatin alone treated animals. Cisplatin induced lipid peroxidation was markedly reduced by oral administration of vanillic acid at a high dose. The findings in the present study suggest that vanillic acid is a potential antioxidant that reduce cisplatin nephrotoxicity and can be as a combinatorial regimen in cancer chemotherapy.

  9. Influence of cyclosporine on the occurrence of nephrotoxicity after allogeneic hematopoietic stem cell transplantation: a systematic review

    Directory of Open Access Journals (Sweden)

    Juliana Bastoni da Silva

    2014-10-01

    Full Text Available Cyclosporine, a drug used in immunosuppression protocols for hematopoietic stem cell transplantation that has a narrow therapeutic index, may cause various adverse reactions, including nephrotoxicity. This has a direct clinical impact on the patient. This study aims to summarize available evidence in the scientific literature on the use of cyclosporine in respect to its risk factor for the development of nephrotoxicity in patients submitted to hematopoietic stem cell transplantation. A systematic review was made with the following electronic databases: PubMed, Web of Science, Embase, Scopus, CINAHL, LILACS, SciELO and Cochrane BVS. The keywords used were: "bone marrow transplantation" OR "stem cell transplantation" OR "grafting, bone marrow" AND cyclosporine OR cyclosporin OR "risk factors" AND "acute kidney injury" OR "acute kidney injuries" OR "acute renal failure" OR "acute renal failures" OR "nephrotoxicity". The level of scientific evidence of the studies was classified according to the Oxford Centre for Evidence Based Medicine. The final sample was composed of 19 studies, most of which (89.5% had an observational design, evidence level 2B and pointed to an incidence of nephrotoxicity above 30%. The available evidence, considered as good quality and appropriate for the analyzed event, indicates that cyclosporine represents a risk factor for the occurrence of nephrotoxicity, particularly when combined with amphotericin B or aminoglycosides, agents commonly used in hematopoietic stem cell transplantation recipients.

  10. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Khames, Ali; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

    2017-02-28

    Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin.

  11. Protective effects of hesperidin on oxidative stress, dyslipidaemia and histological changes in iron-induced hepatic and renal toxicity in rats

    Directory of Open Access Journals (Sweden)

    Leelavinothan Pari

    2015-01-01

    Full Text Available The present study was to evaluate the protective role of hesperidin (HDN against iron-induced hepatic and renal toxicity in rats. Administration of iron (30 mg/kg body weight intraperitoneally for 10 days, the levels of serum hepatic markers, renal functional markers, lipid profile, lipid peroxidation markers and iron concentration in blood were significantly (p < 0.05 increased. The toxic effect of iron was also indicated by significant (p < 0.05 decrease in the levels of plasma, liver and kidney of enzymatic and non-enzymatic antioxidants. Administration of hesperidin at different doses (20, 40 and 80 mg/kg body weight significantly (p < 0.05 reversed the levels of serum hepatic markers, renal functional markers, lipid profile, lipid peroxidation markers, restored the levels of hepatic, renal enzymatic antioxidants and non-enzymatic antioxidants with decrease in iron concentration in blood. Hesperidin at a dose of 80 mg/kg body weight exhibits significant protection on hepatic and renal when compared with other two doses (20 and 40 mg/kg body weight. All these changes were corroborating by histological observations of liver and kidney. This study demonstrated the protective role of hesperidin in reducing toxic effects of iron in experimental rats.

  12. Once-daily oral administration of cyclosporine in a lung transplant patient with a history of renal toxicity of calcineurin inhibitors.

    Science.gov (United States)

    Matsuda, Yuya; Chen, Fengshi; Miyata, Hitomi; Date, Hiroshi

    2014-07-01

    Cyclosporine is usually administered orally in two divided doses every 12 h in transplant patients. However, some patients have difficulty in achieving therapeutic levels after transplantation. In fact, cyclosporine is reportedly administered once daily in renal and liver transplantation cases, but not in lung transplantation cases. We report a patient with a history of calcineurin inhibitor-induced renal toxicity who successfully underwent living-donor lobar lung transplantation (LDLLT) with the novel immunosuppressive strategy of once-daily administration of cyclosporine. An 18-year old man with progressive respiratory insufficiency after bone marrow transplantation was referred to our hospital for lung transplantation. He had a history of renal toxicity due to calcineurin inhibitors. Based on his history of tacrolimus- and cyclosporine-induced renal toxicity, we decided to initiate basiliximab as induction therapy, followed by once-daily cyclosporine administration to obtain high enough blood cyclosporine concentrations at 2 h post-dose (C2) and lowered trough blood concentrations (C0) for protection of renal function as maintenance therapy. LDLLT was successfully performed, and the postoperative course was uneventful and free of rejection episodes. Cyclosporine dosing was adjusted with intensive therapeutic drug monitoring of blood cyclosporine levels. One year after LDLLT, the patient is alive and well with no problems with daily life activities. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  13. A comparative study on renal biopsy before and after long-term calcineurin inhibitors therapy: an insight for pathogenesis of its toxicity.

    Science.gov (United States)

    Singh, Lavleen; Singh, Geetika; Sharma, Alok; Sinha, Aditi; Bagga, Arvind; Dinda, A K

    2015-01-01

    Calcineurin inhibitors (CNIs) are effective immunosuppressive agents for the successful treatment of childhood steroid-resistant nephrotic syndrome (SRNS). Because these patients require long-term treatment, the identification of early markers of CNI-induced nephrotoxicity (CNIN) is imperative. The monitoring of CNI trough levels, serum creatinine, and glomerular filtration rate is not an accurate marker of CNIN. The present study has been undertaken to identify early markers of CNIN in SRNS patients. Twenty-four pediatric SRNS patients were included with paired renal biopsies, before initiation (time zero biopsy) and at least 1 year after CNI therapy (protocol renal biopsy) with standard dosage. Semiquantitative morphologic grading of the histologic features was done for assessing CNIN. Immunohistochemical markers for oxidative stress (nitrotyrosine [NT]), fibrogenic cytokine (transforming growth factor β1 [TGF-β1]), and endothelial injury (endothelial nitric oxide synthase [eNOS]) were evaluated. In addition, ultrastructural study was done to assess mitochondrial injury in endothelial and tubular epithelial cells. The protocol renal biopsies in comparison with time zero biopsies showed significant increase in glomerulosclerosis, juxtaglomerular apparatus hyperplasia, tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and smooth muscle vacuolization (P biopsies. Mean mitochondrial injury grade among post-CNI cases in endothelial cells and proximal tubular cells was 2.28 and 1.4, whereas in pre-CNI, it was 0.28 and 0.27, respectively. We propose that immunohistochemical overexpression of NT, eNOS, and TGF-β1 is an early marker of CNIN. Endothelial and proximal tubular mitochondrial injury may play an important role in the pathogenesis of CNIN.

  14. Protective Effects of Houttuynia cordata Thunb. on Gentamicin-induced Oxidative Stress and Nephrotoxicity in Rats

    OpenAIRE

    Kang, Changgeun; Lee, Hyungkyoung; Hah, Do-Yun; Heo, Jung Ho; Kim, Chung Hui; Kim, Euikyung; Kim, Jong Shu

    2013-01-01

    Development of a therapy providing protection from, or reversing gentamicin-sulfate (GS)-induced oxidative stress and nephrotoxicity would be of great clinical significance. The present study was designed to investigate the protective effects of Houttuynia cordata Thunb. (HC) against gentamicin sulfate-induced renal damage in rats. Twenty-eight Sprague-Dawley rats were divided into 4 equal groups as follows: group 1, control; group 2, GS 100 mg/kg/d, intraperitoneal (i.p.) injection; group 3,...

  15. Effect of caraway on gentamicin-induced oxidative stress, inflammation and nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Hoda Erjaee

    2015-07-01

    Full Text Available Different potentially therapeutic approaches to prevent or attenuate gentamicin (GEM induced nephrotoxicity have been proposed. The aim of the present study was to investigate the possible protective effects of caraway seed oil against GEM-induced nephrotoxicity in rats. Rats (24 were randomly assigned into four equal groups: i normal control group, ii treated with GEM, iii pretreated with orally caraway seed oil 10 (mg kg−1 plus GEM and iv treated with GEM and caraway seed oil 10 mg kg−1. Biochemical examinations were utilized for evaluation of the oxidative stress and renal nephrotoxicity. Creatinine, blood urea nitrogen (BUN, plasma malondialdehyde (MDA levels, catalase (CAT, superoxide dismutase (SOD and glutathione peroxidase (GSH-Px activities were determined. Administration of gentamicin to rats induced a marked renal failure, characterized by a significant increase in plasma creatinine and BUN concentrations. The animals treated with gentamicin alone showed a significantly higher plasma MDA level andlower SOD, GSH-Px and CAT activities when compared with the control group. Treatment and simultaneous treatment with caraway seed oil produced amelioration in MDA and increased the activity of antioxidant enzymes SOD, GSH-Px and CAT when compared with the gentamicin treated group. In addition, GEM nephrotoxicity increased renal inflammatory cytokines (TNF-α, IL-6 and IFN-γ. Pro-inflammatory cytokines were significantly decreased (P<0.05 in the test groups administered caraway seed oil. These findings suggest that caraway seed oil treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress and inflammation in rats.

  16. 10-DHGD ameliorates cisplatin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Elseweidy, Mohamed M; Zaghloul, Mohamed S; Younis, Nahla N

    2016-10-01

    Organs subjected to chronic injuries may develop tissue fibrosis. Several factors contribute to the combat injurious stimuli to repair, heal and alleviate any disturbance. Secretion of chemokines, migration of inflammatory cells to the affected site and activation of fibroblast for production of extracellular matrix (ECM) are examples. Recently, few studies have delt with 10-dehydrogingerdione (10-DHGD), one of the active constituent of ginger extracts that has been published. This constituent proved to be potent antioxidant, anti-inflammatory, cholesterol ester transfer protein (CETP) inhibitor, indeed, a hypolipemic agent. It has been selected in the present study as a natural anti-inflammatory agent to combat inflammation, nephrotoxicity and renal fibrosis-induced by cisplatin. Renal fibrosis state demonstrated a significant increase in creatinine, urea, nuclear factor kappa (NF-kB), insulin like growth factor I (IGF-I), fibroblast growth factor-23 (FGF-23) along with a significant decrease of hepatocytes growth factor (HGF), renal glutathione (GSH) and in confirm to histopathological examination of kidney tissue. Administration of 10-DHGD orally daily for 4 weeks resulted in a significant improvement of both the biomarkers studied in addition to the histopathological profile of the renal tissues.

  17. Prevention of contrast media nephrotoxicity--the story so far

    Energy Technology Data Exchange (ETDEWEB)

    Morcos, S.K. E-mail: sameh.morcos@sth.nhs.uk

    2004-05-01

    Contrast media nephrotoxicity (CMN) in patients with pre-existing renal impairment remains a clinically significant problem. The first step to reduce the chance of CMN is to identify patients at risk through the use of screening questionnaires and renal function measurement. Patients at risk requiring injection of contrast medium (CM) because of important clinical indications should receive a small dose of either non-ionic iso-osmolar dimeric or non-ionic low osmolar monomeric CM and hydration. Intravenous infusion (1 ml/kg body weight/h) of 0.9% saline starting 4 h before CM injection and continuing for at least 12 h afterwards is effective in reducing the incidence of CMN. Prophylactic haemodialysis does not lower the risk of this complication. The value of pharmacological manipulation with renal vasodilators (calcium channel blockers, dopamine, atrial natriuretic peptide, fenoldopam (selective dopamine-1 receptor agonist), prostaglandin E{sub 1}, non-selective adenosine receptors antagonist (theophylline), non-selective endothelin receptor antagonist or the antioxidant acetylcysteine has not been fully proven. However, haemofiltration for several hours before and after contrast medium injection offers good protection against CMN in patients with advanced renal disease.

  18. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats.

    Science.gov (United States)

    Hafez, Heba M; Ibrahim, Mohamed A; Ibrahim, Salwa A; Amin, Entesar F; Goma, Wafaey; Abdelrahman, Aly M

    2015-12-05

    Methotrexate (MTX), a chemotherapeutic and immunosuppressant drug, is generally well-tolerated by most patients. However, its cytotoxic nature contributes to life-threatening side effects including hepatotoxicity and nephrotoxicity. The present study investigated the possible role of tumor necrosis factor-alpha (TNF-α) inhibitor, etanercept and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine, on MTX-induced hepatotoxicity and nephrotoxicity in rats. Rats were divided into 7 groups: control group, etanercept group, aminoguanidine group, MTX group, MTX+etanercept group, MTX+aminoguanidine group, and MTX+etanercept+aminoguanidine group. MTX caused hepatotoxicity and nephrotoxicity as evidenced biochemically by significant increase in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine, respectively as well as by histopathological changes. Such effects were associated with significant changes in oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase, and glutathione (GSH)) as well as by upregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. Etanercept and aminoguanidine significantly attenuated MTX-hepatotoxicity and nephrotoxicity. The protective effect of either agent was associated with significant improvement in oxidative stress parameters as well as by downregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. The study suggested that inhibitors of either TNF-α and/or iNOS have protective effect in MTX-induced hepatotoxicity and nephrotoxicity. The protective effect of either agent relies, at least partially, on their antioxidant effects and decreased TNF-α, iNOS, and caspase-3 expressions.

  19. Contrast-media-induced nephrotoxicity: a consensus report

    Energy Technology Data Exchange (ETDEWEB)

    Morcos, S.K.; Thomsen, H.S.; Webb, J.A.W. [Department of Diagnostic Imaging, Northern General Hospital NHS Trust, Sheffield (United Kingdom)

    1999-10-01

    The purpose of this study was, using consensus methodology, to document current understanding of contrast media nephrotoxicity (CMN) and to identify areas where there is disagreement or confusion. To draw up guidelines for avoiding CMN based on the current understanding of the condition established by the survey. One hundred sixty-four statements were mailed to 148 members of the European Society of Urogenital Radiology (ESUR) and to 48 experts in the field of CMN. They were asked about the definition, clinical features, predisposing factors and pathophysiology of CMN and about prophylactic measures. The importance of the statements was rated on a scale from 1 to 10 (1 least important, 10 most important). Fifty-three members (38 %) and 23 experts (48 %) responded. Both groups considered that an increase in serum creatinine that peaks within 3-4 days and a decrease in creatinine clearance are the most important (rating > 7) features of CMN. Enzymuria was not considered important (rating < 6). Pre-existing renal insufficiency, diabetic nephropathy, dehydration, congestive heart failure, concurrent administration of nephrotoxic drugs and the dose and type of contrast media were considered to be risk factors. Reduction in renal perfusion and damage to tubular cells were considered the main factors in the pathophysiology of CMN (rating > 6). Hydration and the use of low osmolar contrast media were thought to minimize the incidence of CMN (rating > 6). The majority of the responders (84.6 % of members and 95.5 % of experts) believe that the incidence of CMN in patients with normal renal function is less than 5 %. Of the members, 62.5 %, and 35.3 % of experts, believe that the incidence of CMN is 20-30 % in the presence of risk factors. There was disagreement about the definition of CMN, the threshold dose of contrast media above which renal complications may develop, the safe period between repeat injections, the relevance of contrast media renal retention shown on CT

  20. A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Mi Liu

    2016-01-01

    Full Text Available Accumulating evidence demonstrated that hydrogen sulfide (H2S is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

  1. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    Science.gov (United States)

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  2. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone

    Directory of Open Access Journals (Sweden)

    Atefeh Aminian

    2016-07-01

    Full Text Available Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg, animals received intraperitoneal injections of morphine (5 mg/kg/day and/or naltrexone (20 mg/kg/day, an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy.

  3. Large animal hepatotoxic and nephrotoxic plants.

    Science.gov (United States)

    Oladosu, L A; Case, A A

    1979-10-01

    The hepatotoxic and nephrotoxic plants of large domestic animals have been reviewed. The most important ones are those widely distributed as weeds over pastures, negelcted forests and grasslands, those used as ornamentals, the nitrate concentrating forage crops, and the cyanophoric plants. Crotolaria spp, the ragwort (Senecia jacobaea), the lantana spp. and heliotopum are common hepatoxic plants. Amaranthus retroflexus, Datura stramonium, Solanum rostratum, and the castor oil plant (Ricinus communis) are nephrotoxic plants.

  4. Effect of cyclooxygenase inhibitors on gentamicin-induced nephrotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Hosaka E.M.

    2004-01-01

    Full Text Available The frequent use of nonsteroidal anti-inflammatory drugs (NSAID in combination with gentamicin poses the additional risk of nephrotoxic renal failure. Cyclooxygenase-1 (COX-1 is the main enzyme responsible for the synthesis of renal vasodilator prostaglandins, while COX-2 participates predominantly in the inflammatory process. Both are inhibited by non-selective NSAID such as indomethacin. Selective COX-2 inhibitors such as rofecoxib seem to have fewer renal side effects than non-selective inhibitors. The objective of the present study was to determine whether the combined use of rofecoxib and gentamicin can prevent the increased renal injury caused by gentamicin and indomethacin. Male Wistar rats (250-300 g were treated with gentamicin (100 mg/kg body weight, ip, N = 7, indomethacin (5 mg/kg, orally, N = 7, rofecoxib (1.4 mg/kg, orally, N = 7, gentamicin + rofecoxib (100 and 1.4 mg/kg, respectively or gentamicin + indomethacin (100 and 5 mg/kg, respectively, N = 8 for 5 days. Creatinine clearance and alpha-glutathione-S-transferase concentrations were used as markers of renal injury. Animals were anesthetized with ether and sacrificed for blood collection. The use of gentamicin plus indomethacin led to worsened renal function (0.199 ± 0.019 ml/min, as opposed to the absence of a nephrotoxic effect of rofecoxib when gentamicin plus rofexicob was used (0.242 ± 0.011 ml/min. These results indicate that COX-2-selective inhibitors can be used as an alternative treatment to conventional NSAID, especially in situations in which risk factors for nephrotoxicity are present.

  5. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Yuhui; Huang, Jiawei; Gu, Ying; Liu, Cong; Li, Hong; Liu, Jing; Ren, Jiong; Yang, Zhangyou [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China); Peng, Shuangqing [Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Science, 20 Dongdajie Street, Fengtai District, Beijing 100071 (China); Wang, Weidong, E-mail: wwdwyl@sina.com [Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Li, Rong, E-mail: yuhui_hao@126.com [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China)

    2015-09-15

    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT −/−) and corresponding wild-type (MT +/+) mice was investigated to determine any associations with MT. Each MT −/− or MT +/+ mouse was pretreated with a single dose of DU (10 mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4 days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT −/− mice significantly increased than in MT +/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT −/− mice. The apoptosis rate in MT −/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT −/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT −/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. - Highlights: • MT −/− and MT +/+ mice were used to evaluate nephrotoxicity of DU. • Renal damage was more evident in the MT −/− mice after exposure to DU. • Exogenous MT also protects against DU-induced nephrotoxicity. • MT deficiency induced more ROS and apoptosis after exposure to

  6. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with {sup 177}Lu-octreotate

    Energy Technology Data Exchange (ETDEWEB)

    Sabet, Amir; Ezziddin, Khaled; Reichman, Karl; Haslerud, Torjan; Ahmadzadehfar, Hojjat; Biersack, Hans-Juergen; Ezziddin, Samer [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Pape, Ulrich-Frank [Charite, University Medicine Berlin, Campus Virchow Clinic, Department of Hepatology and Gastroenterology, Berlin (Germany); Nagarajah, James [University Hospital, Department of Nuclear Medicine, Essen (Germany)

    2014-03-15

    Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine - allowing only approximate estimates of GFR - the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using {sup 99m}Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with {sup 177}Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by {sup 99m}Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m{sup 2} per year, relative yearly reduction -1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2-10 ml/min/m{sup 2} per year) and 16 patients (22 %) a significant (>10 ml/min/m{sup 2} per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m{sup 2} per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of

  7. The Flavonoid Apigenin Ameliorates Cisplatin-Induced Nephrotoxicity through Reduction of p53 Activation and Promotion of PI3K/Akt Pathway in Human Renal Proximal Tubular Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Sung Min Ju

    2015-01-01

    Full Text Available Apigenin is a member of the flavone subclass of flavonoids present in fruits and vegetables. Apigenin has long been considered to have various biological activities, such as antioxidant, anti-inflammatory, and antitumorigenic properties, in various cell types. Cisplatin was known to exhibit cytotoxic effect to renal cells by inducing apoptosis through activation of p53. The present study investigated the antiapoptotic effects of apigenin on the cisplatin-treated human renal proximal tubular epithelial (HK-2 cells. HK-2 cells were pretreated with apigenin (5, 10, 20 μM for 1 h and then treated with 40 μM cisplatin for various times. Apigenin inhibited the cisplatin-induced apoptosis of HK-2 cells. Interestingly, apigenin itself exerted cytostatic activity because of its ability to induce cell cycle arrest. Apigenin inhibited caspase-3 activity and PARP cleavage in cisplatin-treated cells. Apigenin reduced cisplatin-induced phosphorylation and expression of p53, with no significant influence on production of ROS that is known to induce p53 activation. Furthermore, apigenin promoted cisplatin-induced Akt phosphorylation, suggesting that enhanced Akt activation may be involved in cytoprotection. Taken together, these results suggest that apigenin ameliorates cisplatin-induced apoptosis through reduction of p53 activation and promotion of PI3K/Akt pathway in HK-2 cells.

  8. Microsomal protein synthesis inhibition: an early manifestation of gentamicin nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, W.M.; Mela-Riker, L.M.; Houghton, D.C.; Gilbert, D.N.; Buss, W.C.

    1988-08-01

    Aminoglycoside antibiotics achieve bacterial killing by binding to bacterial ribosomes and inhibiting protein synthesis. To examine whether similar mechanisms could be present in renal tubular cells prior to the onset of overt proximal tubular necrosis due to these drugs, we isolated microsomes from Fischer rats given 20 mg/kg gentamicin every 12 h subcutaneously for 2 days and from vehicle-injected controls. Concomitant studies of renal structure, function, and mitochondrial respiration were carried out. (3H)leucine incorporation into renal microsomes of treated animals was reduced by 21.9% (P less than 0.01), whereas brain and liver microsomes from the same animals were unaffected. Gentamicin concentration in the renal microsomal preparation was 56 micrograms/ml, a value 7- to 10-fold above concentrations necessary to inhibit bacterial growth. Conventional renal function studies were normal (blood urea, serum creatinine, creatinine clearance). Treated animals showed only a mild reduction of inulin clearance, 0.71 compared with 0.93 ml.min-1.100 g-1 in controls (P less than 0.05), and an increase in urinary excretion of N-acetylglucosaminidase of 20 compared with 14.8 units/l (P less than 0.05). Renal slice transport of p-aminohippuric acid, tetraethylammonium, and the fractional excretion of sodium were well preserved. There was no evidence, as seen by light microscopy, of proximal tubular necrosis. Mitochondrial cytochrome concentrations were normal and respiratory activities only slightly reduced. Processes similar to those responsible for bacterial killing could be involved in experimental gentamicin nephrotoxicity before overt cellular necrosis.

  9. Studies on the protective effect of dietary fish oil on cisplatin induced nephrotoxicity in rats.

    Science.gov (United States)

    Naqshbandi, Ashreeb; Khan, Md Wasim; Rizwan, Sana; Rehman, Sayeed Ur; Khan, Farah

    2012-02-01

    Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, however, dose dependent nephrotoxicity remains the major concern for its long term use. Several agents/strategies were attempted to prevent CP nephrotoxicity but were not found suitable for clinical practice. Dietary fish oil (FO) enriched in ω-3 fatty acids has been shown to prevent/reduce the progression of certain types of cancers, cardiovascular and renal disorders. The present study was undertaken to see whether FO can prevent CP-induced nephrotoxic and other deleterious effects. Rats were prefed experimental diets for 10days and then received a single dose of CP (6mg/kg body weight) intraperitoneally while still on diet. Serum/urine parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM) and oxidative stress in rat kidney were analyzed. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP decreased the activities of metabolic enzymes, antioxidant defense system and BBM enzymes. In contrast, FO alone increased enzyme activities of carbohydrate metabolism and brush border membrane (BBM). FO feeding to CP treated rats markedly enhanced resistance to CP-elicited deleterious effects. Dietary FO supplementation ameliorated CP induced specific metabolic alterations and oxidative damage due to its intrinsic biochemical antioxidant properties.

  10. Pomegranate flower extract does not prevent cisplatin-induced nephrotoxicity in female rats

    Directory of Open Access Journals (Sweden)

    Sima Jilanchi

    2014-01-01

    Full Text Available Background: Nephrotoxicity is the major side-effect of cisplatin (CDDP, and it is reported to be gender-related. We evaluated the effects of pomegranate flower extract (PFE as an antioxidant on CDDP-induced nephrotoxicity in female rats. Methods: Twenty-three adult female rats in four groups treated as following. Groups 1 and 2 received PFE at doses of 25 and 50 (mg/kg/day, respectively, for 9 days, and from day 3 on, they also received cisplatin (CDDP (2.5 mg/kg daily. Group 3 was treated as group 1 expects saline instead of PFE, and group 4 received PFE (25 mg/kg/day alone. Results: Cisplatin alone increased the serum levels of blood urea nitrogen, creatinine, and nitrite; and kidney tissue damage score and kidney weight. However, PFE not only did not ameliorate the induced nephrotoxicity, but also aggravated renal tissue damage. Conclusions: Pomegranate extract as an antioxidant did not ameliorate CDDP-induced nephrotoxicity in female rats.

  11. Encephalopathy and Hypotonia due to Baclofen Toxicity in a Patient with End-Stage Renal Disease

    OpenAIRE

    Ijaz, Mohsin; Tariq, Hassan; KASHIF,MUHAMMAD; Marquez, Jose Gomez

    2015-01-01

    Patient: Female, 57 Final Diagnosis: Baclofen toxicity Symptoms: Encephalopathy • hypotonia Medication: Baclofen Clinical Procedure: Hemodialysis Specialty: Critical Care Objective: Unusual or unexpected effect of treatment Background: Baclofen is a centrally acting gamma-aminobutyric acid agonist used for the symptomatic relief of skeletal muscle spasm and spasticity in traumatic spinal cord lesions, multiple sclerosis, cerebral palsy, and stroke. It is also used in the treatment of chronic ...

  12. A Case of Sodium Chlorite Toxicity Managed with Concurrent Renal Replacement Therapy and Red Cell Exchange

    OpenAIRE

    Romanovsky, Adam; Djogovic, Dennis; Chin, Dat

    2012-01-01

    Introduction Sodium chlorite is a powerful oxidizing agent with multiple commercial applications. We report the presentation and management of a single case of human toxicity of sodium chlorite. Case report A 65-year-old man presented to hospital after accidentally ingesting a small amount of a sodium chlorite solution. His principal manifestations were mild methemoglobinemia, severe oxidative hemolysis, disseminated intravascular coagulation, and anuric acute kidney injury. He was managed wi...

  13. DNA damage response in nephrotoxic and ischemic kidney injury.

    Science.gov (United States)

    Yan, Mingjuan; Tang, Chengyuan; Ma, Zhengwei; Huang, Shuang; Dong, Zheng

    2016-10-27

    DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore relies on a thorough elucidation of the DDR pathways in various forms of AKI.

  14. Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

    DEFF Research Database (Denmark)

    Lankhorst, Stephanie; Baelde, Hans J; Kappers, Mariëtte H W

    2015-01-01

    of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only...... histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner. We conclude that the sunitinib-induced rise in blood pressure requires......Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency...

  15. Developmental nephrotoxicity of aristolochic acid in a zebrafish model

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Yu-Ju; Chen, Yau-Hung, E-mail: yauhung@mail.tku.edu.tw

    2012-05-15

    Aristolochic acid (AA) is a component of Aristolochia plant extracts which is used as a treatment for different pathologies and their toxicological effects have not been sufficiently studied. The aim of this study was to evaluate AA-induced nephrotoxicity in zebrafish embryos. After soaking zebrafish embryos in AA, the embryos displayed malformed kidney phenotypes, such as curved, cystic pronephric tubes, pronephric ducts, and cases of atrophic glomeruli. The percentages of embryos with malformed kidney phenotypes increased as the exposure dosages of AA increased. Furthermore, AA-treated embryos exhibited significantly reduced glomerular filtration rates (GFRs) in comparison with mock-control littermates (mock-control: 100 ± 2.24% vs. 10 ppm AA treatment for 3–5 h: 71.48 ± 18.84% ∼ 39.41 ± 15.88%), indicating that AA treatment not only caused morphological kidney changes but also induced renal failure. In addition to kidney malformations, AA-treated zebrafish embryos also exhibited deformed hearts, swollen pericardiums, impaired blood circulation and the accumulation(s) of red blood cells. Whole-mount in situ hybridization studies using cmlc2 and wt1b as riboprobes indicated that the kidney is more sensitive than the heart to AA damage. Real-time PCR showed that AA can up-regulate the expression of proinflammatory genes like TNFα, cox2 and mpo. These results support the following conclusions: (1) AA-induced renal failure is mediated by inflammation, which causes circulation dysfunction followed by serious heart malformation; and (2) the kidney is more sensitive than the heart to AA injury. -- Highlights: ► Zebrafish were used to evaluate aristolochic acid (AA)-induced nephrotoxicity. ► AA-treated zebrafish embryos exhibited deformed heart as well as malformed kidney. ► Kidney is more sensitive to AA injury than the heart.

  16. Paricalcitol may improve oxidative DNA damage on experimental amikacin-induced nephrotoxicity model.

    Science.gov (United States)

    Bulut, Gulay; Basbugan, Yildiray; Ari, Elif; Erten, Remzi; Bektas, Havva; Alp, Hamit Hakan; Bayram, Irfan

    2016-06-01

    This study aimed to investigate the possible protective effect of paricalcitol on experimental amikacin-induced nephrotoxicity model in rats. Wistar albino rats (n = 32) were allocated into four equal groups of eight each, the control (Group C), paricalcitol (Group P), amikacin-induced nephrotoxicity (Group A), and paricalcitol-treated amikacin-induced nephrotoxicity (Group A + P) groups. Paricalcitol was given intra-peritoneally at a dose of 0.4 μg/kg/d for 5 consecutive days prior to induction of amikacin-induced nephrotoxicity. Intra-peritoneal amikacin (1.2 g/kg) was used to induce nephrotoxicity at day 4. Renal function parameters, oxidative stress biomarkers, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio), kidney histology, and vascular endothelial growth factor (VEGF) immunoexpression were determined. Group A + P had lower mean fractional sodium excretion (p < 0.001) as well as higher creatinine clearance (p = 0.026) than the amikacin group (Group A). Renal tissue malondialdehyde levels (p = 0.035) and serum 8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio) (p < 0.001) were significantly lower; superoxide dismutase (p = 0.024) and glutathione peroxidase (p = 0.007) activities of renal tissue were significantly higher in group A + P than in group A. The mean scores of tubular necrosis (p = 0.024), proteinaceous casts (p = 0.038), medullary congestion (p = 0.035), and VEGF immunoexpression (p = 0.018) were also lower in group A + P when compared with group A. This study demonstrates the protective effect of paricalcitol in the prevention of amikacin-induced nephrotoxicity in an experimental model. Furthermore, it is the first study to demonstrate that paricalcitol improves oxidative DNA damage in an experimental acute kidney injury model.

  17. An Extract of Rhodobacter sphaeroides Reduces Cisplatin-Induced Nephrotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Wen-Wei Chang

    2013-11-01

    Full Text Available Cisplatin is used as a treatment for various types of solid tumors. Renal injury severely limits the use of cisplatin. Renal cell apoptosis, oxidative stress, and inflammation contribute to cisplatin-induced nephrotoxicity. Previously, we found that an extract of Rhodobacter sphaeroides (Lycogen™ inhibited proinflammatory cytokines and the production of nitric oxide in activated macrophages in a dextran sodium sulfate (DSS-induced colitis model. Here, we evaluated the effect of Lycogen™, a potent anti-inflammatory agent, in mice with cisplatin-induced renal injury. We found that attenuated renal injury correlated with decreased apoptosis due to a reduction in caspase-3 expression in renal cells. Oral administration of Lycogen™ significantly reduced the expression of tumor necrosis factor-α and interleukin-1β in mice with renal injury. Lycogen™ reduces renal dysfunction in mice with cisplatin-induced renal injury. The protective effects of the treatment included blockage of the cisplatin-induced elevation in serum urea nitrogen and creatinine. Meanwhile, Lycogen™ attenuated body weight loss and significantly prolonged the survival of mice with renal injury. We propose that Lycogen™ exerts anti-inflammatory activities that represent a promising strategy for the treatment of cisplatin-induced renal injury.

  18. Sulforaphane Attenuates Gentamicin-Induced Nephrotoxicity: Role of Mitochondrial Protection

    Science.gov (United States)

    Huerta-Yepez, Sara; Medina-Campos, Omar Noel; Zatarain-Barrón, Zyanya Lucía; Hernández-Pando, Rogelio; Torres, Ismael; Tapia, Edilia; Pedraza-Chaverri, José

    2013-01-01

    Sulforaphane (SFN), an isothiocyanate naturally occurring in Cruciferae, induces cytoprotection in several tissues. Its protective effect has been associated with its ability to induce cytoprotective enzymes through an Nrf2-dependent pathway. Gentamicin (GM) is a widely used antibiotic; nephrotoxicity is the main side effect of this compound. In this study, it was investigated if SFN is able to induce protection against GM-induced nephropathy both in renal epithelial LLC-PK1 cells in culture and in rats. SFN prevented GM-induced death and loss of mitochondrial membrane potential in LLC-PK1 cells. In addition, it attenuated GM-induced renal injury (proteinuria, increases in serum creatinine, in blood urea nitrogen, and in urinary excretion on N-acetyl-β-D-glucosaminidase, and decrease in creatinine clearance and in plasma glutathione peroxidase activity) and necrosis and apoptosis in rats. The apoptotic death was associated with enhanced active caspase-9. Caspase-8 was unchanged in all the studied groups. In addition, SFN was able to prevent GM-induced protein nitration and decrease in the activity of antioxidant enzymes catalase and glutathione peroxidase in renal cortex. In conclusion, the protective effect of SFN against GM-induced acute kidney injury could be associated with the preservation in mitochondrial function that would prevent the intrinsic apoptosis and nitrosative stress. PMID:23662110

  19. Sulforaphane Attenuates Gentamicin-Induced Nephrotoxicity: Role of Mitochondrial Protection

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    Mario Negrette-Guzmán

    2013-01-01

    Full Text Available Sulforaphane (SFN, an isothiocyanate naturally occurring in Cruciferae, induces cytoprotection in several tissues. Its protective effect has been associated with its ability to induce cytoprotective enzymes through an Nrf2-dependent pathway. Gentamicin (GM is a widely used antibiotic; nephrotoxicity is the main side effect of this compound. In this study, it was investigated if SFN is able to induce protection against GM-induced nephropathy both in renal epithelial LLC-PK1 cells in culture and in rats. SFN prevented GM-induced death and loss of mitochondrial membrane potential in LLC-PK1 cells. In addition, it attenuated GM-induced renal injury (proteinuria, increases in serum creatinine, in blood urea nitrogen, and in urinary excretion on N-acetyl-β-D-glucosaminidase, and decrease in creatinine clearance and in plasma glutathione peroxidase activity and necrosis and apoptosis in rats. The apoptotic death was associated with enhanced active caspase-9. Caspase-8 was unchanged in all the studied groups. In addition, SFN was able to prevent GM-induced protein nitration and decrease in the activity of antioxidant enzymes catalase and glutathione peroxidase in renal cortex. In conclusion, the protective effect of SFN against GM-induced acute kidney injury could be associated with the preservation in mitochondrial function that would prevent the intrinsic apoptosis and nitrosative stress.

  20. Nonparallel nephrotoxicity dose-response curves of aminoglycosides.

    OpenAIRE

    1981-01-01

    Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Some high-dose studies in rats have also suggested that the slope of the nephrotoxicity dose-response curve of netilmicin was less steep than the slopes of other aminoglycosides. Therefore, the slopes of the nephrotoxicity dose-response curves of ...

  1. Interferência do intervalo de administração da droga sobre a nefrotoxicidade da gentamicina em ratos Influence of the dose regimen on the gentamicin nephrotoxicity in rats

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    Verônica Cunha Rodrigues Oliveira

    2001-06-01

    Full Text Available A insuficiência renal aguda (IRA que apresenta índice de mortalidade em torno de 50%, pode ser definida como um abrupto declínio da filtração glomerular, resultante de isquemia ou toxicidade. A nefrotoxicidade por drogas é uma das etiologias mais freqüentes (27% e sugere-se que o intervalo de administração da droga pode interferir neste efeito colateral, entretanto o melhor regime de administração ainda não está bem estabelecido. Este conhecimento proporcionaria uma atuação mais direcionada de enfermagem na prevenção desta IRA hospitalar. Os resultados obtidos nesta pesquisa, indicam que a infusão única de gentamicina determina menor nefrotoxicidade, provavelmente devido à redução da sua concentração plasmática nas 24hs, diminuindo o acúmulo intracelular deste fármaco, um dos principais mecanismos celulares deste tipo de lesão. Este regime de tratamento mostra portanto vantagens quanto ao custo, efeito nefrotóxico e segurança quanto à eficácia terapêutica.The acute renal failure (ARF, that still presents a righ mortality rate (50% can be defined as an abrupt decline of the glomerular filtration, resultant of isquemic or toxicity event. The drugs nephrotoxicity is one of the most frequent cause (27% of ARF and it is suggested that the interval of administration of the drug can interfere in this side effect, however the best administration regimen is not very well established. This study evaluated the renal function of rats that received gentamicin (100mg/kg in one dose or in two doses (2x 50mg/kg,by intraperitoneal infusion. The results obtained in this research, indicated that the single infusion of gentamicin determined smaller nephrotoxicity by the reduction of serum concentration of this drug in 24 hours, decreasing the intracelular accumulation of this gentamicin, which is one of the main cellular mechanisms of this renal injury. The single dose treatment regime, otherwise, showes advantages not only related

  2. Cell-metal interactions: A comparison of natural uranium to other common metals in renal cells and bone osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Milgram, S. [Laboratoire Pierre Suee, CEA-CNRS UMR 9956, CEA/Saclay, 91191 Gif-sur-Yvette (France); Carriere, M. [Laboratoire Pierre Suee, CEA-CNRS UMR 9956, CEA/Saclay, 91191 Gif-sur-Yvette (France); Thiebault, C. [Laboratoire Pierre Suee, CEA-CNRS UMR 9956, CEA/Saclay, 91191 Gif-sur-Yvette (France); Berger, P. [Laboratoire Pierre Suee, CEA-CNRS UMR 9956, CEA/Saclay, 91191 Gif-sur-Yvette (France); Khodja, H. [Laboratoire Pierre Suee, CEA-CNRS UMR 9956, CEA/Saclay, 91191 Gif-sur-Yvette (France); Gouget, B. [Laboratoire Pierre Suee, CEA-CNRS UMR 9956, CEA/Saclay, 91191 Gif-sur-Yvette (France)]. E-mail: barbara.gouget@cea.fr

    2007-07-15

    Uranium acute intoxication has been documented to induce nephrotoxicity. Kidneys are the main target organs after short term exposures to high concentrations of the toxic, while chronic exposures lead to its accumulation in the skeleton. In this paper, chemical toxicity of uranium is investigated for rat osteoblastic bone cells and compared to results previously obtained on renal cells. We show that bone cells are less sensitive to uranium than renal cells. The influence of the chemical form on U cytotoxicity is demonstrated. For both cell types, a comparison of uranium toxicity with other metals or metalloids toxicities (Mn, Ni, Co, Cu, Zn, Se and Cd) permits classification of Cd, Zn, Se{sup IV} and Cu as the most toxic and Ni, Se{sup VI}, Mn and U as the least toxic. Chemical toxicity of natural uranium proves to be far less than that of cadmium. To try to explain the differences in sensitivities observed between metals and different cell types, cellular accumulations in cell monolayers are quantified by inductively coupled plasma-mass spectroscopy (ICP-MS), function of time or function of dose: lethal doses which simulate acute intoxications and sub-lethal doses which are more realistic with regard to environmentally metals concentrations. In addition to being more resistant, bone cells accumulated much more uranium than did renal cells. Moreover, for both cell models, Mn, U-citrate and U-bicarbonate are strongly accumulated whereas Cu, Zn and Ni are weakly accumulated. On the other hand, a strong difference in Cd behaviour between the two cell types is shown: whereas Cd is very weakly accumulated in bone cells, it is very strongly accumulated in renal cells. Finally, elemental distribution of the toxics is determined on a cellular scale using nuclear microprobe analysis. For both renal and osteoblastic cells, uranium was accumulated in as intracellular precipitates similar to those observed previously by SEM/EDS.

  3. Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis.

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    Malik, Salma; Suchal, Kapil; Gamad, Nanda; Dinda, Amit Kumar; Arya, Dharamvir Singh; Bhatia, Jagriti

    2015-02-05

    Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant-antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. The protective effect of trimetazidine against cisplatin-induced nephrotoxicity in rats.

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    El-Sherbeeny, Nagla A; Attia, Ghalia M

    2016-07-01

    Nephrotoxicity is a dose-limiting side effect of cisplatin (CSP). The study investigated the possible protective role of trimetazidine (TMZ) against CSP-induced nephrotoxicity in rats. Rats were divided into four groups; control, TMZ, CSP, and CSP + TMZ. The CSP group showed significant deterioration in kidney function with structural changes in the form of interstitial hemorrhage, glomeruli shrinkage and peritublar capillary congestion, tubular cells vacuolation, pyknosis, shedding and necrosis, and inflammatory cell infiltrates, all indicating renal damage. CSP also caused a significant increase in the lipid peroxidation marker malondialdehyde (MDA) levels, renal nuclear factor kappa B (NF-κB) DNA-binding activity and protein expression, and tumor necrosis factor alpha (TNF-α) and IL-6 levels. Treatment with TMZ before and after CSP injection produced significant improvement of kidney function and histopathology. TMZ treatment also significantly attenuated CSP-induced oxidative stress and suppressed elevated levels of TNF-α and IL-6 and NF-κB expression and its DNA-binding activity caused by CSP administration. TMZ has a protective effect against CSP-induced nephrotoxicity mediated by reduction of oxidative stress and attenuation of CSP-induced inflammation.

  5. Effect of Camel's Milk on Cisplatin-Induced Nephrotoxicity in Swiss Albino Mice

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    Mohamed M.E. Afifi

    2010-01-01

    Full Text Available Problem statement: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Camel's milk has good nutritive value, antigenotoxic and anticytotoxic effects. The aim of the present study was to assess the protective effect of camel's milk against Cisplatin-induced renal oxidative stress in mice. Approach: Forty mal Swiss albino mice were randomly divided into four groups (n = 10. Group I, control group. Group II was received cisplatin (12 mg kg-1 for 5 alternate days. Group III was received camel's milk (33 mL kg-1 for consecutive 30 days. Group IV was received camel's milk (33 mL kg-1 for consecutive 30 days before administration of Cisplatin. Results: Cisplatin-induced oxidative stress was indicated by increased level of tissue Malondialdehyde (MDA, serum creatinine and urea, decreased the concentration of reduced Glutathione (GSH, Vitamin C (Vit. C and Vitamin E (Vit. E and decreased both activities and gene expression of Superoxid Dismutase (SOD, Catalase (CAT, Glutathione Raductase (GR and Glutathione Peroxidase (GPx. Camel's milk reduced these biochemical changes and counteracted the deleterious effects of cisplatin Conclusion: The present study demonstrated the renoprotective potential of camel's milk against cisplatin-induced oxidative stress and renal dysfunction in mice. Hence, camel's milk has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.

  6. Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy.

    Science.gov (United States)

    Prins, J M; Weverling, G J; de Blok, K; van Ketel, R J; Speelman, P

    1996-11-01

    There is no established dosing schedule for once-daily aminoglycoside dosing regimens, and accepted guidelines for monitoring therapy are lacking. We derived a simplified schedule from the Hull and Sarubbi (J. H. Hull and F. A. Sarubbi, Ann. Intern. Med. 85:183-189, 1976) nomogram, for which efficacy and safety in a once-daily dosing regimen were previously demonstrated, and prospectively followed serum aminoglycoside levels in patients. The standard treatment was gentamicin or tobramycin at 4 mg/kg of body weight given intravenously once daily. When the renal function was decreased, the daily dose was reduced, as follows: for an estimated creatinine clearance of between 50 and 80 ml/min, the daily dose was 3.25 mg/kg, for an estimated creatinine clearance of between 30 and 50 ml/min, the daily dose was 2.5 mg/kg, and for an estimated creatinine clearance of below 30 ml/min, the daily dose was 2 mg/kg. A total of 221 patients were studied (184 received gentamicin and 37 received tobramycin). First trough levels above 2 mg/liter were recorded in 11% of the patients, and they all had a baseline creatinine clearance below 50 ml/min, or a substantial decrease in clearance between enrollment and the day that the trough level was obtained. A peak level below 6 mg/liter was recorded in 6% of the patients, and half of them received the lowest daily dose. Twenty-five of the 179 evaluable patients (14%; 95% confidence interval, 9 to 19%) fulfilled the criteria for nephrotoxicity. In a multiple regression analysis, the duration of treatment and the use of other nephrotoxic antibiotics or high-dose furosemide, but not trough levels, were significant risk factors. Since the meaning of low peak levels is unclear and since most studies with multiple daily regimens confirm the lack of an association between trough levels and toxicity, we believe that monitoring of serum drug levels can be restricted to monitoring of trough levels in patients with a creatinine clearance below 50 ml

  7. Antioxidant-rich date palm fruit extract inhibits oxidative stress and nephrotoxicity induced by dimethoate in rat.

    Science.gov (United States)

    Saafi-Ben Salah, Emna Behija; El Arem, Amira; Louedi, Mouna; Saoudi, Mongi; Elfeki, Abdelfattah; Zakhama, Abdelfattah; Najjar, Mohamed Fadhel; Hammami, Mohamed; Achour, Lotfi

    2012-03-01

    Recent investigations have proved the crucial role of nutritional antioxidants to prevent the damage caused by toxic compounds. In this study, the antioxidant effect of date palm fruit extract on dimethoate-induced oxidative stress and nephrotoxicity in rat is investigated and compared with the effect of the well-known antioxidant vitamin C. Male Wistar rats were randomly divided into six groups of ten each: a control group (C), a group that received dimethoate (20 mg/kg body weight) (D), a group given Deglet Nour extract (DNE), a group treated with DNE 30 min before the administration of dimethoate (DNE + D), a group which received VitC (100 mg/kg body weight) plus dimethoate (Vit C + D), and a group given dimethoate for the first month and DNE 30 min after administration of dimethoate, during the second month (D + DNE). These components were daily administered by gavage for 2 months. After completing the treatment period, blood samples from rats were collected under inhaled diethyl ether anesthesia for serum urea, uric acid, and creatinine levels, while the rat kidneys were obtained for enzyme assays and histology. Oral administration of dimethoate in rats induced a marked renal failure characterized by a significant increase in serum creatinine and urea levels (p < 0.01) in addition to a significant decrease in serum uric acid (p < 0.05). Interestingly, these drastic modifications were accompanied by a marked enhancement of lipid peroxidation in kidney, indicating a significant induction of oxidative damage (p < 0.01) and dysfunctions of enzymatic antioxidant defenses. These biochemical alterations were also accompanied by histological changes in kidney revealed by a narrowed Bowman's space, tubular degeneration, tubular cell desquamation, and tubular dilatation of proximal tubules. Treatment with date palm fruit extract (Deglet Nour) and also with vitamin C significantly (p < 0.05) reversed the serum renal markers to their near-normal levels

  8. Protective effect of quercetin against gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Abdel-Raheem, Ihab Talat; Abdel-Ghany, Ahmed Ali; Mohamed, Gamal Abdallah

    2009-01-01

    Gentamicin (GM) is an antibiotic widely used in treating severe gram-negative infections. However, its clinical use is limited by its nephrotoxicity. Several lines of evidence indicate that free radicals are important mediators of gentamicin nephrotoxicity. Therefore, the aim of this work was to investigate the possible protective effect of the flavonoid quercetin, an antioxidant, on gentamicin-induced nephrotoxicity. For this purpose, rats were divided into four groups. First group served as a control and injected with the normal saline, second group was injected with quercetin (50 mg/kg/d, per os) for 7 d, third group was injected with gentamicin (80 mg/kg/d, intraperitoneally) for 7 d and the fourth group of animals was injected with quercetin plus gentamicin simultaneously for 7 d. Total protein levels were estimated in 24-h urine samples to assess kidney dysfunction. The rats were sacrificed on the seventh day and kidneys were collected for histopathological studies. Blood urea nitrogen (BUN) and creatinine levels were measured in the blood. Moreover, glutathione (GSH), lipid peroxide (TBARS) levels, superoxide dismutase (SOD) and catalase (CAT) activities were determined in renal tissues. GM-treated rats showed early kidney dysfunction as urinary total protein, BUN and serum creatinine levels were significantly increased. The significant decrease in GSH levels, SOD, CAT activities and increase in TBARS levels, indicated that GM-induced nephrotoxicity was mediated through oxidative stress reactions. Histopathological examination of GM-treated rats revealed degenerative changes in glomeruli and tubules. On the other hand, simultaneous administration of quercetin plus gentamicin protected kidney tissues against nephrotoxic effects of gentamicin as evidenced from amelioration of histopathological changes and normalization of kidney biochemical parameters.

  9. Complete remission with sunitinib in a poor-risk patient with metastatic renal cell carcinoma: the fine balance between toxicity and efficacy.

    Science.gov (United States)

    Massari, Francesco; Ciccarese, Chiara; Bimbatti, Davide; Fantinel, Emanuela; Modena, Alessandra; Simbolo, Michele; Brunelli, Matteo; Artibani, Walter; Martignoni, Guido; Scarpa, Aldo; Tortora, Giampaolo

    2015-04-01

    Sunitinib represents a reasonable therapeutic option for first-line treatment of poor-risk metastatic renal cell carcinoma and the treatment should aim at the delicate balance between managing side effects to improve the toxicity profile and patient compliance to treatment while maintaining anticancer efficacy. Achievement of a complete response, although rare, is possible, even in poor-risk patients. Treatment discontinuation represents a viable alternative for both tumour biology and patients' quality of life. To date, no molecular markers have been identified with prognostic and/or predictive value for guiding therapeutic decisions. Further research should aim at gaining in-depth knowledge of renal cell carcinoma biology for a tailored personalized therapy. We report a case of poor-risk metastatic renal cell carcinoma, with Von Hippel-Lindau loss of function, which achieved and maintained a complete remission after first-line therapy with sunitinib by using a reduced dosage and a modified schedule of treatment.

  10. Hypercalcemia and renal function impairment associated with vitamin D toxicity: case report

    Directory of Open Access Journals (Sweden)

    Vanessa Guerra

    Full Text Available Abstract Nowadays vitamin D (25-OHD deficiency is supposed to be a global epidemic condition. Expectedly, vitamin D measurement and intake exponentially increased in Brazil in this decade. Although the benefit of vitamin D to general health is still in debate, its indiscriminate use potentially may lead to enhance the incidence of vitamin D intoxication, which is considered a rare disorder. We report a case of a 70 year old diabetic male with chronic renal disease (blood creatinine of 1.6 mg/dL who progressed suddenly to acute kidney injury (blood creatinine of 5.7 mg/dL associated with hypercalcemia and high blood levels of vitamin D. Vitamin D and calcitriol were discontinued and hypercalcemia was managed by hydration followed by furosemide. Thereafter, disodium pamidronate was administered and the patient did not undergo on dialysis. It took approximately 14 months to normalize 25-OHD levels and blood creatinine returned to basal levels only after 24 months. The indicated labeling dosage was 2000 IU, but most likely the vitamin D manipulated preparation was higher as the vitamin D blood levels were very high. Although rare, vitamin D intoxication is becoming more frequent as the patients use frequently manipulated preparations that could be subject to errors in the manufacturing and labeling of the tablets or capsules. The present report alerts to the potential increase in the incidence of severe vitamin D intoxication due to the frequent use of this secosteroid as a nutritional supplement. At the same time, it is necessary to improve regulation on the nutrient supplement market.

  11. Hypercalcemia and renal function impairment associated with vitamin D toxicity: case report.

    Science.gov (United States)

    Guerra, Vanessa; Vieira Neto, Osvaldo Merege; Laurindo, Alan Fernandes; Paula, Francisco Jose Albuquerque de; Moysés Neto, Miguel

    2016-12-01

    Nowadays vitamin D (25-OHD) deficiency is supposed to be a global epidemic condition. Expectedly, vitamin D measurement and intake exponentially increased in Brazil in this decade. Although the benefit of vitamin D to general health is still in debate, its indiscriminate use potentially may lead to enhance the incidence of vitamin D intoxication, which is considered a rare disorder. We report a case of a 70 year old diabetic male with chronic renal disease (blood creatinine of 1.6 mg/dL) who progressed suddenly to acute kidney injury (blood creatinine of 5.7 mg/dL) associated with hypercalcemia and high blood levels of vitamin D. Vitamin D and calcitriol were discontinued and hypercalcemia was managed by hydration followed by furosemide. Thereafter, disodium pamidronate was administered and the patient did not undergo on dialysis. It took approximately 14 months to normalize 25-OHD levels and blood creatinine returned to basal levels only after 24 months. The indicated labeling dosage was 2000 IU, but most likely the vitamin D manipulated preparation was higher as the vitamin D blood levels were very high. Although rare, vitamin D intoxication is becoming more frequent as the patients use frequently manipulated preparations that could be subject to errors in the manufacturing and labeling of the tablets or capsules. The present report alerts to the potential increase in the incidence of severe vitamin D intoxication due to the frequent use of this secosteroid as a nutritional supplement. At the same time, it is necessary to improve regulation on the nutrient supplement market.

  12. Protective effect of lycopene on gentamicin-induced oxidative stress and nephrotoxicity in rats.

    Science.gov (United States)

    Karahan, I; Ateşşahin, A; Yilmaz, S; Ceribaşi, A O; Sakin, F

    2005-11-15

    A potential therapeutic approach to protect or reverse gentamicin-induced oxidative stress and nephrotoxicity would have more importance for clinical consequences. Therefore, the present study was designed to investigate the possible protective effects of lycopene against gentamicin-induced renal damage in rats. Male Sprague-Dawley rats were divided into four groups of six rats in each one; first group served as control. The other groups were treated intraperitoneally with gentamicin alone (100 mg kg(-1) per day) for six successive days, gentamicin for 6 days following 10 days of orally lycopene (4 mg kg(-1) per day) pre-treatment and 6-days of simultaneous lycopene and gentamicin. Biochemical and histopathological examinations were utilized for evaluation of the oxidative stress and renal nephrotoxicity. Creatinine, urea, Na(+) and K(+) levels in plasma and malondialdehyde (MDA), reduced glutathione (GSH) levels and glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined in kidney tissue. Administration of gentamicin to rats induced a marked renal failure, characterized by a significant increase in plasma creatinine and urea concentrations. The animals treated with gentamicin alone showed a significantly higher kidney MDA and lower GSH-Px and CAT activities but unaffected GSH concentrations when compared with the control group. Pre-treatment with lycopene produced amelioration in biochemical indices of nephrotoxicity in plasma. However, little changes were observed in the kidney MDA and GSH levels and GSH-Px and CAT activities when compared with the gentamicin treated group. The histological structures of the renal proximal tubules showed similar patterns. On the other hand, administration of simultaneous lycopene to rats produced amelioration in MDA and GSH levels and GSH-Px and CAT activities when compared with gentamicin group. In addition, simultaneous lycopene was found to reduce the degree of kidney tissue damage in histopathological

  13. Urinary tubular protein-based biomarkers in the rodent model of cisplatin nephrotoxicity: a comparative analysis of serum creatinine, renal histology, and urinary KIM-1, NGAL, and NAG in the initiation, maintenance, and recovery phases of acute kidney injury.

    Science.gov (United States)

    Sinha, Vikash; Vence, Luis M; Salahudeen, Abdulla K

    2013-03-01

    Several biomarkers are becoming available for the early detection of acute kidney injury (AKI), but few have been directly compared. To compare urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl glucosaminidase (NAG) against serum creatinine and renal histological score in the initiation, maintenance, and recovery phases of cisplatin (CP)-induced AKI. Sprague-Dawley rats (300-350 g) were injected once through their tail veins with CP (CP group) at 5.5 mg/kg or with same volume of normal saline vehicle (Control group). Rats were euthanized at 2, 4, 6, 12, and 24 hours, and on days 2, 3, 6, and 10 (n = 12 in the CP group and n = 6 in the Control group at each time point), and urine, blood, and kidney samples were analyzed. A significant increase in serum creatinine was noted by day 3 in the CP group versus Control group [1.46 (0.12) vs 0.28 (0.03) mg/dL; mean (SE); P CP group. Urinary kidney injury molecule-1 levels were significantly higher at 24 hours in the CP group than in the Control group [48.26 (13.13) vs 8.21 (3.31) pg/mg creatinine; P CP than in the Control group [NAG, 8.19 (0.82) vs 3.48 (0.40) pg/mg creatinine, P G 0.05; NGAL, 2911.80 (368.10) vs 1412.60 (250.20) pg/mg creatinine, P CP to discern the time course and pattern of expression.

  14. The role of magnesium supplementation in cisplatin-induced nephrotoxicity in a rat model: No nephroprotectant effect

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    Farzaneh Ashrafi

    2012-01-01

    Results: All CP-treated animals lost weight, and the percentage of weight loss in Group 1 (low dose Mg sulfate treated was significantly higher compared with the positive control group (Group 4, P < 0.05. The increase in blood urea nitrogen (BUN and creatinine (Cr levels in serum in Group 1 were more than those in other groups ( P < 0.05. No statistical differences were observed in serum magnesium, nitrite, and total protein levels among the groups. The kidney tissue damage in Groups 1-3 was not significantly different when compared with Group 4. Moreover, the kidney and testis weights in Group 1 were significantly greater than those in the positive control group (P < 0.05. Conclusion: Regarding the BUN and Cr levels in the serum, kidneys weight, and the histopathological study, the low dose of Mg supplementation intensifies kidney toxicity and renal dysfunction in CP-induced nephrotoxicity in the rat model. However, the protective role of Mg with moderate and high doses is not certain.

  15. Angiography for renal artery stenosis: no additional impairment of renal function by angioplasty

    Energy Technology Data Exchange (ETDEWEB)

    Lufft, Volkmar; Fels, Lueder M.; Egbeyong-Baiyee, Daniel; Olbricht, Christoph J. [Abteilung Nephrologie, Medizinische Hochschule Hannover (Germany); Hoogestraat-Lufft, Linda; Galanski, Michael [Abteilung Diagnostische Radiologie, Medizinische Hochschule Hannover (Germany)

    2002-04-01

    The aim of this study was to compare renal function between patients with renal angiography and patients with renal angiography and angioplasty (AP) for renal artery stenosis (RAS). Forty-seven patients with suspected RAS were prospectively investigated by digital subtraction angiography (DSA) using non-ionic low osmolar contrast media (CM). In 22 patients RAS was detected and in 16 cases an angioplasty was performed in the same session. The following parameters were determined 1 day prior to and after the DSA, respectively: serum creatinine (S-Crea, {mu}mol/l) and single-shot inulin clearance (In-Cl, ml/min) for the evaluation of renal function; and urine alpha 1-microglobuline (AMG, {mu}g/g Crea) and beta-N-acetyl-glucoseaminidase (beta-NAG, U/g Crea) as markers of tubular toxicity. Serum creatinine was measured additionally 2 days after CM had been injected. In both groups with and without AP 174{+-}65 and 104{+-}56 ml of CM (p<0.0005) were used, respectively. There were no differences with regard to renal function or risk factors for CM nephrotoxicity between both groups. In the group with AP S-Crea and In-Cl (each: mean{+-}SD) did not change significantly (before DSA: 171{+-}158 and 61{+-}24, after DSA: 189{+-}177 and 61{+-}25, respectively), beta-NAG (median) rose from 4 to 14 (p<0.05) and AMG from 8 to 55 (n.s., because of high SD). In the group without AP S-Crea increased from 134{+-}109 to 141{+-}113 (p<0.01), In-Cl dropped from 65{+-}26 to 62{+-}26 (p<0,01), beta NAG (median) rose from 4 to 8 (p=0.01), and AMG from 7 to 10 (n.s.). A rise in baseline S-Crea by more than 25% or 44 {mu}mol/l occurred in 4 and 2 patients in the group with and without AP, respectively. Creatinine increase was reversible in all cases within 7 days. In this study using sensitive methods to detect changes of renal function and tubular toxicity no additional renal function impairment in DSA with angioplasty for RAS compared with DSA alone could be demonstrated. Our data suggest

  16. Preventive Effect of Dihydromyricetin against Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo

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    Fei Wu

    2016-01-01

    Full Text Available Nephrotoxicity is a frequent severe side effect of cisplatin chemotherapy, limiting its clinical use despite being one of the most potent chemotherapy drugs. Dihydromyricetin is a highly abundant compound purified from the leaves of Ampelopsis grossedentata. Previous studies have demonstrated the anti-inflammatory and antioxidative effects of Dihydromyricetin both in vitro and in vivo, but little is known about the effects of Dihydromyricetin on cisplatin-induced nephrotoxicity and its underlying mechanisms. In the present study, we investigated its potential renoprotective effect and found that Dihydromyricetin ameliorated the renal functional impairment and structural damage caused by cisplatin. Moreover, Dihydromyricetin markedly attenuated cisplatin-induced oxidative stress, as well as protecting against cisplatin-induced inflammation and apoptotic cell death in mouse kidney tissues. These results collectively highlight the potential of DMY as a rational renoprotective agent against cisplatin.

  17. Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration.

    Science.gov (United States)

    Groseclose, M Reid; Laffan, Susan B; Frazier, Kendall S; Hughes-Earle, Angela; Castellino, Stephen

    2015-06-01

    As part of an investigative nephrotoxicity study, kidney tissues from juvenile rats orally administered dabrafenib at different age intervals between postnatal day (PND) 7 to 35 were investigated by MALDI and LDI imaging mass spectrometry (IMS) to determine the chemical composition of tubular deposits. In the youngest age group (PND 7-13), MALDI IMS demonstrated that a dabrafenib carboxylic acid metabolite was diffusely localized to the regions of tubular deposits (medulla and corticomedullary junction); however, no dabrafenib-related material was detected directly from the deposits. Rather, the LDI IMS analysis determined that the deposits were composed primarily of calcium phosphate. Based on these data, the dabrafenib associated nephrotoxicity, including the formation of tubular deposits, was determined to be age dependent. Furthermore, immature renal function was hypothesized to be responsible for the susceptibility of the youngest pups.

  18. Ultrastructural evaluation of the effect of N-acetylcysteine on methotrexate nephrotoxicity in rats.

    Science.gov (United States)

    Çağlar, Yildiz; Özgür, Hülya; Matur, Irem; Yenilmez, Ebru Dündar; Tuli, Abdullah; Gönlüşen, Gülfiliz; Polat, Sait

    2013-07-01

    The aim of this study is to investigate the possible protective effect of N-Acetylcysteine (NAC) against the likely methotrexate (MTX) toxicity on the kidney using ultrastructural together with biochemical data. Moreover, the immunohistochemical detection of Ki67 nuclear antigen is to be evaluated. Fifteen male Wistar albino rats, weighing 240-290 g, were divided into three equal groups: Rats receiving MTX alone, rats receiving MTX plus NAC treatment, and rats comprising the control group. MTX (18 mg/kg/day, body weight) in dissolved physiologic saline was administered intraperitoneally to rats during 3 days. For the MTX plus NAC group, N-Acetylcysteine (300 mg/kg/day, body weight) was administered together with MTX. At the end of the third day, all the rats were killed with cervical dislocation to obtain blood and tissue samples. Application of MTX principally induced prominent large vacuolization in the proximal convoluted tubule cells, and focal thickening in the glomerular basal lamina of some glomeruli. A decrease in tissue SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase), and an increase in serum urea nitrogen and creatinine and in tissue MDA (malondialdehyde) levels were also seen in the MTX group. These changes were significantly reversed in the MTX-plus-NAC-treated group. Most of the vacuoles in the proximal convoluted tubule cells disappeared. Furthermore, an increase in antioxidant enzyme activities, a decrease in serum urea nitrogen and creatinine, and tissue MDA levels were all significant. Additionally, an increase in the number of Ki67 positive-stained cells in proximal tubules was also noted. In conclusion, NAC may be a promising substance against MTX-induced renal damage. It might be useful to use NAC supplementally to minimize MTX-induced nephrotoxicity.

  19. Amelioration of cisplatin-induced nephrotoxicity in rats by tetramethylpyrazine, a major constituent of the Chinese herb Ligusticum wallichi.

    Science.gov (United States)

    Ali, B H; Al-Moundhri, M; Eldin, M Tag; Nemmar, A; Al-Siyabi, S; Annamalai, K

    2008-07-01

    Nephrotoxicity of the anticancer drug, cisplatin (CP) involves enhanced renal generation of reactive oxygen metabolites and lipid peroxidation caused by decreased levels of antioxidants and antioxidant enzymes. Tetramethylpyrazine (TMP) is known to act as a strong antioxidant. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of TMP on CP nephrotoxicity in rats. TMP was given orally at a dose of 80 mg . kg(- 1) . day(- 1) for 7 days. Some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg on Day 6 of treatment. Animals were sacrificed 6 days after CP (or vehicle) treatment, and blood, urine, and kidneys were obtained. Nephrotoxicity was assessed biochemically by measuring creatinine and urea in serum, reduced glutathione (GSH) concentration in renal cortex, by urinalysis, and histopathologically by light microscopy. CP significantly increased the concentration of urea and creatinine (P rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly reduced when CP was given after pretreatment with TMP. CP cortical concentration was not significantly altered by TMP treatment. The results suggest that TMP ameliorated the histological, physiological, and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, TMP may potentially be useful as a nephroprotective agent.

  20. Late concentration-controlled calcineurin inhibitor withdrawal with mycophenolate mofetil in renal transplant recipients

    NARCIS (Netherlands)

    Mourer, Jacqueline Sarah

    2014-01-01

    Calcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about acute rejection. Therapeutic drug monitoring (TD

  1. Effects of Breviscapine on Renal Cell Apoptosis and Expression of Apoptosis-related Proteins in Mice with Cisplatin-induced Nephrotoxicity%灯盏花素对肾损害小鼠肾组织细胞凋亡及相关蛋白的影响

    Institute of Scientific and Technical Information of China (English)

    徐华; 常陆林; 马天江; 娄晓宇; 任亮

    2013-01-01

    目的:观察灯盏花素对顺铂致小鼠肾损害肾组织细胞凋亡及相关蛋白的影响.方法:将昆明种小鼠随机分为对照组、模型组、灯盏花素25,50 mg· kg-组.除对照组外,其余各组腹腔注射顺铂8 mg·kg-1制备小鼠肾损害模型,灯盏花素组分别灌胃给药,连续7d.给药结束后收集小鼠尿液进行尿蛋白(Upr)/尿肌酐(Ucr)及N-乙酰-β-D-氨基葡萄糖苷酶(NAG-U)测定.原位末端标记法(TUNEL)检测小鼠肾脏细胞凋亡状况,免疫组化法检测肾脏相关凋亡蛋白Bax和Bcl-2的表达.结果:模型组小鼠Upr/Ucr及NAG-U较对照组明显升高,肾组织的凋亡指数增加,肾组织细胞凋亡蛋白Bax及Bcl-2表达增强,Bax/Bcl-2比值升高(P<0.05,P<0.01),而2个灯盏花素实验组Upr/Ucr、NAG-U较模型组明显降低(P <0.05,P<0.01),其中灯盏花素50 mg· kg-小鼠较模型组肾组织细胞凋亡指数、Bax表达、Bax/Bcl-2减少,Bcl-2的表达增强(P<0.05,P<0.01).结论:Upr/Ucr与NAG-U可作为顺铂肾损害的评估指标.灯盏花素减轻顺铂肾损害的机制可能与增强凋亡相关蛋白Bcl-2的表达,降低Bax表达及Bax/Bcl-2的比值有关.%Objective: To observe the effects of breviscapine on renal cell apoptosis and expression of apoptosis-related proteins in mice with cisplatin-induced nephrotoxicity. Method: Kunming mice were randomly divided into four groups: control group, model group, breviscapine experimental groups by 25 mg·kg-1 or 50 mg· kg-1 . Three groups were given a single injection of cis-platinum complexes (CDDP) to establish the model of renal injury (8 mg·kg-1 , ip) except the control group, then the mice in two breviscapine experimental groups were given different dose (25, 50 mg·kg-1, ig) once a day for seven days. The urine samples were collect for measuring Urine protein ( Upr) /Urine creatinine (Ucr) and Ⅳ-aletyl-beta-D-glucosaminidase ( NAG-U ). Apoptosis of the renal cells were determined by TUNEL method, also the

  2. The risk factors of colistin methanesulfonate associated nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Elif Tükenmez Tigen

    2016-01-01

    Full Text Available Purpose: The risk factors of colistin methanesulfonate (CMS associated nephrotoxicity are important. Our study attempts look into the prevalence of CMS-associated nephrotoxicity in Intensive Care Units (ICUs, and related risk factors. Materials and Methods: The study was conducted between September 2010 and April 2012 on 55 patients who underwent CMS treatment. Nephrotoxicity risk was defined based on the Risk Injury Failure Loss End-stage kidney disease criteria. Results: Fifty-five patients included in the study. A total of 22 (40% patients developed nephrotoxicity. The correlation was detected between nephrotoxicity and patients over 65 with a high Acute Physiologic Assessment and Chronic Health Evaluation (APACHE II score. APACHE II score was revealed an independent risk factor for nephrotoxicity. Conclusion: Advanced age and a high APACHE II score are significant risk factors in the development of nephrotoxicity at ICUs following CMS use. Patient selection and close monitoring are critical when starting CMS treatment.

  3. Renal histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol administered in drinking water to F344 rats: a pathology working group review and re-evaluation.

    Science.gov (United States)

    Hard, Gordon C; Bruner, Richard H; Cohen, Samuel M; Pletcher, John M; Regan, Karen S

    2011-04-01

    An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert-butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u)-globulin (α(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the α(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both α(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk.

  4. Prevention of nephrotoxicity of ochratoxin A, a food contaminant.

    Science.gov (United States)

    Creppy, E E; Baudrimont, I; Betbeder, A M

    1995-12-01

    Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, mainly by Aspergillus ochraceus and also by Penicilium verrucosum. It was found all over the world in feed and human food and blood as well as in animal blood and tissues. The most threatening effects of OTA are its nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotoxic to all animal species studied so far and is increasingly involved in the Balkan endemic nephropathy (BEN), a human chronic interstitial nephropathy which is most of the time associated to urinary tract tumours. Since it seems impossible to avoid contamination of foodstuffs by toxigenic fungi, detoxification and detoxication for OTA are needed. To reduce or abolish the OTA-induced toxic effects, several mechanisms were investigated. The results of these investigations showed that some of the potential antidotes were efficient in preventing the main OTA toxic effects whereas some others were not. Promising compounds are structural analogues of OTA, and/or compounds having a high binding affinity for plasma proteins such as piroxicam, a non-steroidal anti-inflammatory drug (NSAID). Some enzymes such as superoxide dismutase (SOD) and catalase, radical scavengers, vitamins, prostaglandin (PG) synthesis inhibitors, (such as piroxicam), pH modificators, adsorbant resin such as cholestyramine etc. are efficient in vivo. Some of the results obtained in vivo were already confirmed in vitro and gave useful information on how to safely use these antidotes. The most generally acting compound seems to be A19 (Aspartame), a structural analogue of OTA and phenylalanine. When given to rats A19 (25 mg/kg/48 h) combined to OTA (289 micrograms/kg/48 h) for several weeks largely prevented OTA nephrotoxicity and genotoxicity. When given after intoxication of animals with OTA it washes out the toxin efficiently from the body. In vitro, A19 (10 micrograms/ml) prevents OTA (20-500 micrograms/ml) binding to plasma proteins. Its general

  5. Effects of lysine-induced acute renal failure in dogs.

    Science.gov (United States)

    Asanuma, Kentaro; Adachi, Kenji; Sugimoto, Tetsuro; Chiba, Shuichi

    2006-05-01

    This study investigates the effects of lysine-induced acute renal failure. Female dogs received a lysine hydrochloride (lysine) of 4500 mg/kg/day (3.75 ml/kg/hr) for 3 consecutive days. The dogs were observed for clinical signs. Body weights were recorded, food consumption and water consumption calculated, and urinalysis and blood biochemistry were performed daily. Plasma samples for amino acid determinations were obtained from all dogs, which were necropsied on Day 3. Histopathological examinations were done on all test animals. Compound-related findings include the following. Blood biochemistry results showed increases in ammonia, blood urea nitrogen, blood urea nitrogen/creatinine ratio, and creatinine. Urinary changes consisted of increases in urine volume, total protein, albumin, gamma-glutamyl transpeptidase, and N-acetyl-beta-D-glucosaminidase. In addition, macroscopic findings consisted of pale, congested capsule; microscopic findings consisted of hypertrophy of proximal convoluted tubule (mainly S1 segment), and degeneration/desquamation of urinary tubule (mainly S3 segment with hyaline casts) in the kidney. From these findings, it can be concluded that lysine is nephrotoxic in dogs. Nephrotoxicity of lysine may relate to direct tubular toxicity and to tubular obstruction.

  6. Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

    Science.gov (United States)

    Kaymakcalan, Marina D; Xie, Wanling; Albiges, Laurence; North, Scott A; Kollmannsberger, Christian K; Smoragiewicz, Martin; Kroeger, Nils; Wells, J Connor; Rha, Sun-Young; Lee, Jae Lyun; McKay, Rana R; Fay, André P; De Velasco, Guillermo; Heng, Daniel Y C; Choueiri, Toni K

    2016-02-01

    Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies. The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks. Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age ≥60 years, a glomerular filtration rate (GFR) factors to predict the risk of TrTD. In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice. © 2015 American Cancer Society.

  7. Gentamicin-induced ototoxicity and nephrotoxicity vary with circadian time of treatment and entail separate mechanisms.

    Science.gov (United States)

    Blunston, Mary A; Yonovitz, Al; Woodahl, Erica L; Smolensky, Michael H

    2015-01-01

    The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or interdependent phenomena. Two groups of 9 female Sprague-Dawley rats (200-250 g), each housed separately and entrained to a 12 h light (06:00-18:00 h) - 12 h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 Hours After Lights On (HALO), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged by both body weight loss relative to the pre-treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in auditory brainstem response (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-β-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240 min post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (first two weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during the treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p ototoxicity. The mean urinary NAG/CR ratio peaked after the first week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38-fold greater than baseline for the 14 HALO-treated ones. Ratio values declined

  8. Protective effects of glutathione on bromodichloromethane in vivo toxicity and in vitro macromolecular binding in Fischer 344 rats.

    Science.gov (United States)

    Gao, P; Thornton-Manning, J R; Pegram, R A

    1996-10-11

    Bromodichloromethane (BDCM), a carcinogenic water disinfection by-product, has been shown to be metabolized to intermediates that covalently bind to lipids and proteins, and this binding has been associated with trihalomethane-induced renal and hepatic toxicity. In this study, the effects of glutathione (GSH) on in vivo BDCM toxicity and in vitro BDCM macromolecular binding were evaluated. The in vivo toxicity of BDCM in animals pretreated with buthionine sulfoximine (BSO, a glutathione synthesis inhibitor) and in untreated male Fischer 344 rats was investigated. In another experiment, covalent binding to protein and lipid was quantified after [14C]BDCM was incubated with hepatic microsomal and S9 fractions and renal microsomes from F344 rats, under aerobic and anaerobic conditions, with and without added GSH. After oral dosing with BDCM, the BSO-pretreated animals had greatly increased levels of serum indicators of hepatotoxicity and serum and urinary indicators of nephrotoxicity compared to those in animals dosed solely with BDCM. Histopathological examination revealed that hepatic necrosis was more severe than renal necrosis in the BSO-treated rats. When GSH was added to an aerobic incubation, protein binding was decreased in hepatic microsomal and S9 fractions by 92 and 83%, respectively. GSH also decreased lipid binding by 55% in hepatic microsomal incubations carried out under anaerobic conditions. Addition of GSH decreased renal microsomal protein (aerobic) and lipid binding (anaerobic) by 20 and 43%, respectively. These data indicate that GSH is an important protective factor in the toxicity associated with BDCM.

  9. Mefenamic Acid Induced Nephrotoxicity: An Animal Model

    Directory of Open Access Journals (Sweden)

    Muhammad Nazrul Somchit

    2014-12-01

    Full Text Available Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs are used for the treatment of many joint disorders, inflammation and to control pain. Numerous reports have indicated that NSAIDs are capable of producing nephrotoxicity in human. Therefore, the objective of this study was to evaluate mefenamic acid, a NSAID nephrotoxicity in an animal model. Methods: Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day. Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN and creatinine activities were measured. Results: Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine. Conclusion: Results from this study suggest that mefenamic acid as with other NSAIDs capable of producing nephrotoxicity. Therefore, the study of the exact mechanism of mefenamic acid induced severe nephrotoxicity can be done in this animal model.

  10. [Nephrotoxicity and long-term treatment with lithium].

    Science.gov (United States)

    Gahr, Maximilian; Freudenmann, Roland W; Connemann, Bernhard J; Keller, Frieder; Schönfeldt-Lecuona, Carlos

    2014-01-01

    With particular focus on clinical, pathophysiologic and epidemiologic aspects this systematic review article presents the available data on nephrotoxic effects of a long-term treatment with lithium. Lithium may lead to tubular dysfunction (LITD = nephrogenic diabetes insipidus, hyperchloremic metabolic acidosis, increased natriuresis) and lithium-induced nephropathy (LIN) with reduced glomerular filtration rate (GFR). The histopathologic finding of LIN is chronic tubulo-interstitial nephritis. LITD frequently presents with polydipsia/-uria and reduced urine osmolality, while LIN features a wide clinical spectrum ranging from clinically asymptomatic presentations with reduced GFR to end-stage renal failure. LIN seems to feature slow progression and is significantly less frequent than LITD. Regular monitoring of renal function is indispensable for patients treated with lithium. Patients with reduced GFR under treatment with lithium should always be presented to a nephrologist. Currently, there are no guidelines for the handling of patients with LIN and ongoing treatment with lithium. Thus, regarding continuation of lithium-treatment an individual benefit/risk assessment is necessary.

  11. Investigation of ifosfamide and chloroacetaldehyde renal toxicity through integration of in vitro liver-kidney microfluidic data and pharmacokinetic-system biology models.

    Science.gov (United States)

    Leclerc, Eric; Hamon, Jeremy; Bois, Frederic Yves

    2016-02-01

    We have integrated in vitro and in silico data to describe the toxicity of chloroacetaldehyde (CAA) on renal cells via its production from the metabolism of ifosfamide (IFO) by hepatic cells. A pharmacokinetic (PK) model described the production of CAA by the hepatocytes and its transport to the renal cells. A system biology model was coupled to the PK model to describe the production of reactive oxygen species (ROS) induced by CAA in the renal cells. In response to the ROS production, the metabolism of glutathione (GSH) and its depletion were modeled by the action of an NFE2L2 gene-dependent pathway. The model parameters were estimated in a Bayesian context via Markov Chain Monte Carlo (MCMC) simulations based on microfluidic experiments and literature in vitro data. Hepatic IFO and CAA in vitro intrinsic clearances were estimated to be 1.85 x 10(-9) μL s(-1) cell(-1) and 0.185 x 10(-9) μL s(-1) cell(-1) ,respectively (corresponding to an in vivo intrinsic IFO clearance estimate of 1.23 l h(-1) , to be compared to IFO published values ranging from 3 to 10 l h(-1) ). After model calibration, simulations made at therapeutic doses of IFO showed CAA renal intracellular concentrations ranging from 11 to 131 μM. Intracellular CAA concentrations above 70 μM induced intense ROS production and GSH depletion. Those responses were time and dose dependent, showing transient and non-linear kinetics. Those results are in agreement with literature data reporting that intracellular CAA toxic concentrations range from 35 to 320 μM, after therapeutic ifosfamide dosing. The results were also consistent with in vitro CAA renal cytotoxicity data.

  12. Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Zhenzhou, E-mail: jiangcpu@yahoo.com.cn; Bao, Qingli, E-mail: bao_ql@126.com; Sun, Lixin, E-mail: slxcpu@126.com; Huang, Xin, E-mail: huangxinhx66@sohu.com; Wang, Tao, E-mail: wangtao1331@126.com; Zhang, Shuang, E-mail: cat921@sina.com; Li, Han, E-mail: hapo1101@163.com; Zhang, Luyong, E-mail: lyzhang@cpu.edu.cn

    2013-01-15

    This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague–Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans. -- Highlights: ► AAI-induced acute renal failure in rats and the proximal tubule was the target. ► Tubular mitochondria were morphologically aberrant in ultrastructural examination. ► AAI impair mitochondrial bioenergetic function and mtDNA replication.

  13. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study.

    Science.gov (United States)

    Garcia-Donas, Jesus; Esteban, Emilio; Leandro-García, Luis Javier; Castellano, Daniel E; del Alba, Aranzazu González; Climent, Miguel Angel; Arranz, José Angel; Gallardo, Enrique; Puente, Javier; Bellmunt, Joaquim; Mellado, Begoña; Martínez, Esther; Moreno, Fernando; Font, Albert; Robledo, Mercedes; Rodríguez-Antona, Cristina

    2011-11-01

    Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. In our observational, prospective study we enrolled previously untreated adults (≥ 18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75-7·30; p(unadjusted)=0·00049, p(adjusted)=0·0079) and rs307821 (3·31, 1·64-6·68; p(unadjusted)=0·00085, p(adjusted)=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67-8·41; p(unadjusted)=0·0014, p

  14. Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Sahu, Bidya Dhar [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Tatireddy, Srujana [National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037 (India); Koneru, Meghana [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Borkar, Roshan M. [National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Kumar, Jerald Mahesh [CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500 007 (India); Kuncha, Madhusudana [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Srinivas, R. [National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Shyam Sunder, R. [Faculty of Pharmacy, Osmania University, Hyderabad 500 007 (India); Sistla, Ramakrishna, E-mail: sistla@iict.res.in [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India)

    2014-05-15

    Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100 mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in

  15. Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection.

    Science.gov (United States)

    Sahu, Bidya Dhar; Tatireddy, Srujana; Koneru, Meghana; Borkar, Roshan M; Kumar, Jerald Mahesh; Kuncha, Madhusudana; Srinivas, R; Shyam Sunder, R; Sistla, Ramakrishna

    2014-05-15

    Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in

  16. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

    Directory of Open Access Journals (Sweden)

    Wei Li

    2016-09-01

    Full Text Available Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE and blood urea nitrogen (BUN levels. In addition, cisplatin increased the level of malondialdehyde (MDA and 4-hydroxynonenal (4-HNE, the makers of lipid peroxidation, and depleted glutathione (GSH content and superoxide dismutase (SOD activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1, 4-hydroxynonenal (4-HNE, tumor necrosis factor (TNF-α, interleukin (IL-1β, nuclear factor-kappa B (NF-κB p65, and cyclooxygenase-2 (COX-2 in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

  17. Nephroprotective effects of Zingiber zerumbet Smith ethyl acetate extract against paracetamol-induced nephrotoxicity and oxidative stress in rats

    Institute of Scientific and Technical Information of China (English)

    Zariyantey ABDUL HAMID; Siti Balkis BUDIN; Ng WEN JIE; Asmah HAMID; Khairana HUSAIN; Jamaludin MOHAMED

    2012-01-01

    Paracetamol (PCM) overdose can cause nephrotoxicity with oxidative stress as one of the possible mechanisms mediating the event.In this study,the effects of ethyl acetate extract of Zingiber zerunbet rhizome [200 mg per kg of body weight (mg/kg) and 400 mg/kg] on PCM-induced nephrotoxicity were examined.Rats were divided into five groups containing 10 rats each.The control group received distilled water while other groups were treated with extract alone (400 mg/kg),PCM alone (750 mg/kg),750 mg/kg PCM+200 mg/kg extract (PCM+200-extract),and 750 mg/kg PCM+400 mg/kg extract (PCM+400-extract),respectively,for seven consecutive days.The Z.zerumbet extract was given intraperitoneally concurrent with oral administration of PCM.Treatment with Z.zerumbet extract at doses of 200 and 400 mg/kg prevented the PCM-induced nephrotoxicity and oxidative impairments of the kidney,as evidenced by a significantly reduced (P<0.05) level of plasma creatinine,plasma and renal malondialdehyde (MDA),plasma protein carbonyl,and renal advanced oxidation protein product (AOPP).Furthermore both doses were also able to induce a significant increment (P<0.05) of plasma and renal levels of glutathione (GSH) and plasma superoxide dismutase (SOD) activity.The nephreprotective effects of Z.zerumbet extract were confirmed by a reduced intensity of renal cellular damage,as evidenced by histological findings.Moreover,Z.zerumbet extract administered at 400 mg/kg was found to show greater protective effects than that at 200 mg/kg.In conclusion,ethyl acetate extract of Z.zerumbet rhizome has a protective role against PCM-induced nephrotoxicity and the process is probably mediated through its antioxidant properties.

  18. Evaluation of Short-Term Bioassays to Predict Functional Impairment. Selected Short-Term Renal Toxicity Tests.

    Science.gov (United States)

    1980-10-01

    Axelsson and Piscator , 1966). In human clinical studies (Peterson et al., 1969; Hall, 1973), a low molecular weight beta 2-globulin (beta 2...glycerol-induced myohemoglobinuric acute renal fail- ure in the rat." Circulation Research 29:128-135. Axelsson, B. and M. Piscator , 1966. "Renal damage

  19. Protective effect of allicin against gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    El-Kashef, Dalia H; El-Kenawi, Asmaa E; Suddek, Ghada M; Salem, Hatem A

    2015-12-01

    In this study, the modulator effect of allicin on the oxidative nephrotoxicity of gentamicin in the kidneys of rats was investigated by determining indices of lipid peroxidation and the activities of antioxidant enzymes, as well as by histological analyses. Furthermore, the effect of allicin on gentamicin induced hypersensitivity of urinary bladder rings to ACh was estimated. Twenty-four male Wistar albino rats were randomly divided into three groups, control, gentamicin (100mg/kg, i.p.) and gentamicin+allicin (50mg/kg, orally). At the end of the study, all rats were sacrificed and then urine, blood samples and kidneys were taken. Gentamicin administration caused a severe nephrotoxicity as evidenced by an elevated kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), serum lactate dehydrogenase (LDH) and proteinuria with a reduction in serum albumin and creatinine clearance as compared with control group. In addition, a significant increase in renal contents of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx) and tumor necrosis factor-alpha (TNF-α) concomitantly with a significant decrease in renal reduced glutathione (GSH) and superoxide dismutase (SOD) activities was detected upon gentamicin injection. Exposure to gentamicin increased the sensitivity of isolated urinary bladder rings to ACh and induced acute renal tubular epithelial cells necrosis. Administration of allicin significantly decreased kidney/body weight ratio, serum creatinine, LDH, renal MDA, MPO, NOx and TNF-α while it significantly increased creatinine clearance, renal GSH content and renal SOD activity when compared to gentamicin-treated group. Additionally, allicin significantly reduced the responses of isolated bladder rings to ACh and ameliorated tissue morphology as evidenced by histological evaluation. Our study indicates that allicin exerted protection against structural and functional damage induced by gentamicin possibly due to its antioxidant, anti

  20. Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy.

    Science.gov (United States)

    Araya, Carlos E; Lew, Judy F; Fennell, Robert S; Neiberger, Richard E; Dharnidharka, Vikas R

    2008-11-01

    BKVAN has emerged as a major morbidity in kidney transplant recipients. Among treatment options is cidofovir, which can be nephrotoxic. We previously reported that intermediate dose cidofovir could be used without significant nephrotoxicity. We present extended results of the same treatment protocol in a larger cohort and with longer follow up. Diagnosis of BKVAN was based on detection of BK viral DNA from plasma and renal allograft biopsy tissue. All patients received cidofovir (0.25-1 mg/kg/dose) every 2-3 wk. Total number of cidofovir doses ranged from 1 to 18 (mean 8). This report includes eight patients, aged 5-21 yr, treated with intermediate dose cidofovir. Median follow-up was 11 months (range 4-32). Mean fall in reciprocal of serum creatinine (1/sCr) from baseline at BKVAN diagnosis was 64% (range 28-120%). A time-series plot of plasma BK virus PCR and 1/sCr showed marked reduction in viral loads without significant deterioration in 1/sCr from the initial value at BKVAN diagnosis. In this larger series with extended follow up, intermediate dose cidofovir without probenecid for the treatment of BKVAN continues to show stabilization of renal function without progression to renal failure.

  1. Nephrotoxicity in mice after repeated imaging using 111In- labeled peptides

    NARCIS (Netherlands)

    M.L. Melis (Marleen); E. Vegt (Erik); M.W. Konijnenberg (Mark); M. de Visser (Monique); M. Bijster (Magda); M. Vermeij (Marcel); E.P. Krenning (Eric); O.C. Boerman (Otto); M. de Jong (Marion)

    2010-01-01

    textabstractWe determined the renal radiation dose of a series of111Inlabeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. Methods: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention a

  2. Nephrotoxicity in mice after repeated imaging using 111In-labeled peptides.

    NARCIS (Netherlands)

    Melis, M.; Vegt, E.; Konijnenberg, M.W.; Visser, M. de; Bijster, M.; Vermeij, M.; Krenning, E.P.; Boerman, O.C.; Jong, M. de

    2010-01-01

    We determined the renal radiation dose of a series of (111)In-labeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. METHODS: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention after inj

  3. Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal

    Institute of Scientific and Technical Information of China (English)

    Can LI; Byung-kee BANG; Chul-woo YANG; Sun-woo LIM; Bo-kyung SUN; Bum-soon CHOI; Sylvia GLOWACKA; Alison J COX; Darren J KELLY; Yong-soo KIM; Jin KIM

    2004-01-01

    AIM: To examine whether the reversibility of chronic cyclosporine A (CsA) nephrotoxicity is associated with apoptotic cell death and its regulatory factors. METHODS: Chronic CsA nephrotoxicity was induced in SpragueDawley rats by administering CsA (15 mg/kg, sc) for 5 weeks, and then withdrawing it for 5 or 10 weeks. The effect of CsA withdrawal on apoptotic cell death was evaluated by an in situ TdT-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay and the expression of pro-apoptotic [(transforming growth factorbetal (TGF-31) and Fas] and anti-apoptotic [epidermal growth factors (EGF) and Bcl-2] factors. RESULTS:Discontinuation of CsA induced significant decreases in TUNEL-positive cells in a time-dependent manner and the reduction in TUNEL-positive cells was correlated with the tubulointerstitial fibrosis score (r=0.919, P<0.01).Upregulation of TGF-βI and Fas expression in CsA-treated rat kidneys was decreased significantly after withdrawal of CsA. In contrast, downregulated EGF and Bcl-2 expression returned to normal or supernormal levels.CONCLUSION: CsA withdrawal is associated with a decrease in apoptotic cell death and with changes in the expression of pro-apoptotic and anti-apoptotic molecules involved in renal wound repair. This may constitute one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity.

  4. Protective effect of L-propionylcarnitine in chronic cyclosporine-a induced nephrotoxicity.

    Science.gov (United States)

    Origlia, Nicola; Migliori, Massimiliano; Panichi, Vincenzo; Filippi, Cristina; Bertelli, Aldo; Carpi, Angelo; Giovannini, Luca

    2006-02-01

    Cyclosporine (CyA) is an immunosuppressive agent used after solid organ transplantation, but its clinical use is limited by side effects, the most important of which is nephrotoxicity. In a previous work we demonstrated that L-propionylcarnitine (L-PC), a propionyl ester of L-carnitine, is able to prevent CyA-induced acute nephrotoxicity reducing lipid peroxidation in the isolated and perfused rat kidney. CyA administration was associated with a dose dependent increase in renovascular resistance prevented by a pretreatment with L-PC. The aim of the present study was to confirm L-PC protective effect, previously described in vitro, in an in vivo rat model. Chronic nephrotoxicity study was carried out for 28 days. L-PC was administered (i.p. 25 mg/kg b.w.) since the first day, while CyA treatment was performed for the last 21 days (by oral administration 25 mg/kg b.w.). We demonstrate that L-PC was able to significantly lower blood pressure in CyA treated animals and to prevent CyA induced decrease in creatinine clearance. Moreover renal tissue analysis revealed that L-PC was able to reduce lipid hydroperoxide content and morphological abnormalities associated to chronic CyA administration. In conclusion our study demonstrated for the first time in vivo that L-PC protects against functional and tissue damage associated to chronic CyA administration.

  5. The potential protective role of taurine against 5-fluorouracil-induced nephrotoxicity in adult male rats.

    Science.gov (United States)

    Yousef, Hany N; Aboelwafa, Hanaa R

    2017-02-08

    Nephrotoxicity is common with the use of the chemotherapeutic agent 5-Fluorouracil (5-FU). The current study aimed to investigate the probable protective effect of taurine (TAU) against 5-FU-induced nephrotoxicity in rats using biochemical, histological and ultrastructural approaches. Twenty-four rats were equally divided into control, TAU, 5-FU and 5-FU+TAU groups. 5-FU significantly elevated levels of blood urea nitrogen (BUN), creatinine, and uric acid; while it reduced activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Also, 5-FU induced significant elevation in malondialdehyde (MDA) levels accompanied with marked decline in γ-glutamyltranspeptidase (GGT) and alkaline phosphatase (AP) levels in kidney tissues. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal renal structure, in addition to ultrastructural alterations represented by thickened and irregular glomerular basement membranes, congested glomerular capillaries, damaged lining fenestrated endothelium, mesangial cells hyperplasia with expanded mesangial matrix, and distorted podocyte's processes. Also, the proximal (PCT) and distal (DCT) convoluted tubules showed thickened basement membranes, destructed apical microvilli and loss of basal infoldings of their epithelial cells. Administration of TAU to 5-FU-treated rats reversed most of the biochemical, histological, and ultrastructural alterations. These results indicate that TAU has a protective effect against 5-FU-induced nephrotoxicity.

  6. The impact of alpha-lipoic acid on amikacin-induced nephrotoxicity.

    Science.gov (United States)

    Asci, Halil; Saygin, Mustafa; Cankara, Fatma Nihan; Bayram, Dilek; Yesilot, Sukriye; Candan, Ibrahim Aydin; Ilhan, Ilter

    2015-02-01

    Amikacin (AK) is an antibacterial drug, but it has remarkable nephrotoxic and ototoxic side effects due to increase in reactive oxygen radicals. This study was established to determine the possible protective effects of alpha-lipoic acid (ALA), a powerful antioxidant, on AK-induced nephrotoxicity. Three different groups of rats (n = 6) were administered saline (control), AK (1.2 g/kg, intraperitoneally), ALA (100 mg/kg, p.o.) and AK combination (ALA one day before the AK for five days). Renal function, oxidative stress markers and histological changes were evaluated at the end of the experiment. Malondialdehyde was increased as an indicator of free radical formation in AK-induced group and decreased with ALA treatment. While catalase activity was increased significantly, superoxide dismutase and glutathione peroxidase activities were not statistically significant increased with ALA treatment. The result showed that AK enhanced levels of urea, creatinine and blood urea nitrogen in serum significantly. Administration of ALA reduced these levels of biochemical markers. Histopathological observations were confirmed by biochemical findings. In conclusion, ALA is suggested to be a potential candidate to ameliorate AK-induced nephrotoxicity.

  7. Protective Role of Aerobic Exercise Against Cisplatin-Induced Nephrotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Zeynali

    2015-09-01

    Full Text Available Background Cisplatin (CP is a chemotherapy drug and nephrotoxicity is considered as its major side effect. Aerobic exercise is well known as an approach to reduce the side effects of many drugs. Objectives This study was designed to determine the protective role of aerobic exercise against CP-induced nephrotoxicity. Materials and Methods Thirty male Wistar rats were randomly divided into four groups. Group I had aerobic exercise on a treadmill one hour per day and five days per week for eight weeks. Then, the exercise protocol was continued for another week, but during this week, the animals also received CP (2.5 mg/kg/day; ip. Group II underwent the same protocol as group I without exercise in the last week during the CP therapy. Groups III and IV were assigned as positive and negative control groups, and were treated with CP and saline without exercise, respectively. Finally, the animals were sacrificed for the biochemical measurement and tissue histopathology investigation. Results CP alone without exercise increased serum levels of blood urea nitrogen (BUN, creatinine (Cr, and malondialdehyde (MDA; and kidney nitrite level, while treadmill exercise in group I significantly ameliorated these parameters (P < 0.05. Kidney and serum levels of MDA and nitrite did not alter significantly. Also, the severity of kidney tissue damage decreased significantly in groups I and II (P < 0.05. Conclusions Aerobic exercise may reduce CP-induced nephrotoxicity with a favorable effect on renal function by increasing activation of antioxidant system.

  8. Nordihydroguaiaretic acid attenuates potassium dichromate-induced oxidative stress and nephrotoxicity.

    Science.gov (United States)

    Yam-Canul, Paola; Chirino, Yolanda I; Sánchez-González, Dolores Javier; Martínez-Martínez, Claudia María; Cruz, Cristino; Villanueva, Cleva; Pedraza-Chaverri, José

    2008-03-01

    Larrea tridentata also known as Creosote bush, Larrea, chaparral, greasewood or gobernadora has been used in the folk medicine for the treatment of several illnesses. The primary product that is present at high concentrations in the leaves from this plant is nordihydroguaiaretic acid (NDGA) which is a powerful antioxidant. On the other hand, potassium dichromate (K(2)Cr(2)O(7))-induced nephrotoxicity is associated with oxidative stress. The aim of this work was to study the effect of NDGA on K(2)Cr(2)O(7)-induced nephrotoxicity and oxidative stress. Nephrotoxicity was induced by a single injection of K(2)Cr(2)O(7) (15 mg/Kg). A group of K(2)Cr(2)O(7)-treated rats was administered NDGA by mini osmotic pumps (17 mg/Kg/day). The results show that NDGA was able to ameliorate the structural and functional renal damage evaluated by histopathological analysis and by measuring proteinuria, urinary excretion of N-acetyl-beta-d-glucosaminidase, serum creatinine, and serum glutathione peroxidase activity. In addition, immunostaining of 4-hydroxy-2-nonenal and 3-nitrotyrosine, markers of oxidative and nitrosative stress, respectively, was ameliorated by the NDGA treatment. These data strongly suggest that the antioxidant properties of NDGA are involved in its renoprotective effect in K(2)Cr(2)O(7)-treated rats.

  9. Early diagnosis of kidney transplant rejection and cyclosporin nephrotoxicity by urine cytology.

    Science.gov (United States)

    Kyo, M; Gudat, F; Dalquen, P; Huser, B; Thiel, G; Fujimoto, N; Ichikawa, Y; Fukunishi, T; Nagano, S; Mihatsch, M J

    1992-01-01

    A total of 2000 urine samples from 53 kidney transplant recipients were studied to develop a routine method for the early diagnosis of rejection and cyclosporin (CSA) nephrotoxicity in urine. New-Sternheimer staining and an immunocytochemical technique were used together with classical Papanicolaou staining to differentiate cells in the urine. After cell count and differentiation of second morning urine samples with New-Sternheimer and Papanicolaou stains, immunocytochemistry was performed using antibodies against the following antigens: CD2, CD4, CD8, CD25, CD71 (transferrin receptor), HLA-DR and cytokeratin (Lu-5). Cell counts were obtained for the positively-reacting cells per millilitre of urine. By New-Sternheimer and Papanicolaou staining, CSA nephrotoxicity was characterized by the predominance of proximal tubular cells. During rejection episodes, increased numbers of mononuclear cells and renal epithelial cells were found. Immunocytochemical analysis showed a significant increase in CD2-, CD4-, CD8-, CD25-, CD71-, and HLA-DR-positive epithelial cells and in the ratio HLA-DR/cytokeratin-positive epithelial cells in rejection. CD25-positive cells had the highest sensitivity and specificity for the diagnosis of rejection. Our urine cytology technique proved to be a useful and non-invasive method for the early diagnosis of rejection and CSA nephrotoxicity.

  10. Evaluation of subchronic toxicity of pet food contaminated with melamine and cyanuric acid in rats.

    Science.gov (United States)

    Chen, Kun-Chao; Liao, Chen-Wei; Cheng, Fen-Pang; Chou, Chi-Chung; Chang, Shih-Chien; Wu, Jhaol-Huei; Zen, Jyh-Myng; Chen, Yng-Tay; Liao, Jiunn-Wang

    2009-12-01

    Outbreaks of food-associated renal failure in pets occurred in Asia and the United States of America in 2004 and 2007. They were related to the combined intoxication of cyanuric acid and melamine. Our aims were to investigate cyanuric acid and melamine contamination of pet food and to examine subchronic toxicity in rats. Levels of 10%, 20%, 50%, and 50%-100% (w/w) of contaminated pet food were fed to rats for three months. Analytical results revealed that the tainted food contained significant levels of cyanuric acid and melamine in a ratio of 1:6.8. Rats fed the diet of 50%-100% for three months exhibited elevated serum blood urea nitrogen and creatinine, as well as dose-dependent melamine/cyanuric acid crystal-induced nephrotoxicity. The melamine/cyanuric acid crystals of various sizes were mixed with necrotic cell debris and inflammatory cells, accompanied by tubular dilation and interstitial fibrosis. The immunohistochemistry index of proliferative cellular nuclear antigen and osteopontin in the kidney of the 50%-100% group were elevated, indicating regeneration of renal cells and the formation of crystals. In conclusion, the combination ratio of cyanuric acid to melamine and the acidic urine content were two factors that, upon repeated exposure, determined the severity of the nephrotoxicity.

  11. Nephro-protective effect of a novel formulation of unopened coconut inflorescence sap powder on gentamicin induced renal damage by modulating oxidative stress and inflammatory markers.

    Science.gov (United States)

    Jose, Svenia P; S, Asha; Im, Krishnakumar; M, Ratheesh; Santhosh, Savitha; S, Sandya; B, Girish Kumar; C, Pramod

    2017-01-01

    Fresh oyster white translucent sap obtained from the tender unopened inflorescence of coconut trees (Cocos nucifera) is identified to have great health benefits. Drug induced Nephrotoxicity is one of the major causes of renal damage in present generation. As a therapeutic agent, gentamicin imparts direct toxicity to kidney, resulting in acute tubular necrosis, glomerular and tubulointerstitial injury, haemodynamically mediated damage and obstructive nephropathy.There exists an increasing demand for safe and natural agents for the treatment and/or preventionofchronic nephrotoxicity and pathogenesis of kidney diseases. Our study shows the nephro protective/curing effect of a novel powder formulation of micronutrient enriched, unfermented coconut flower sap (CSP). The study was performed on adult male Wistar rats. The animals were grouped into three and treated separately with vehicle, gentamicin and gentamicin+CSP for 16days. Initially, gentamicin treatment significantly (pcoconut flower sap powder showed significant (p<0.05) reversal of all these biochemical parameters indicating an effective inhibition of the pathogenesis of nephrotoxicity and kidney disease.

  12. Protective effect of selenium on gentamicin-induced oxidative stress and nephrotoxicity in rats.

    Science.gov (United States)

    Randjelovic, Pavle; Veljkovic, Slavimir; Stojiljkovic, Nenad; Velickovic, Ljubinka; Sokolovic, Dusan; Stoiljkovic, Milan; Ilic, Ivan

    2012-04-01

    Gentamicin (GM) is a widely used antibiotic against serious, life-threatening infections, but its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine the protective effect of selenium (Se) in GM-induced nephrotoxicity in rats. Experiments were done on 32 adult Wistar rats divided into four groups of 8 animals each. The GM group received gentamicin (100 mg/kg), whereas the GM+Se group received the same dose of GM and selenium (1 mg/kg) by intraperitoneal (i.p.) injections on a daily basis. Animals in the Se group, serving as a positive control, received only selenium (1 mg/kg) and the control group received saline (1 mL/day), both given i.p. All groups were treated during 8 consecutive days. Quantitative evaluation of GM-induced structural alterations and degree of functional alterations in the kidneys were performed by histopathological and biochemical analyses in order to determine potential beneficial effects of selenium coadministration with GM. GM was observed to cause a severe nephrotoxicity, which was evidenced by an elevation of serum urea and creatinine levels. The significant increases in malondialdehyde levels and protein carbonyl groups indicated that GM-induced tissue injury was mediated through oxidative reactions. On the other hand, simultaneous selenium administration protected kidney tissue against oxidative damage and the nephrotoxic effect caused by GM treatment. Exposure to GM caused necrosis of tubular epithelial cells. Necrosis of tubules was found to be prevented by selenium pretreatment. The results from our study indicate that selenium supplementation attenuates oxidative-stress-associated renal injury by reducing oxygen free radicals and lipid peroxidation in GM-treated rats.

  13. Drug-induced renal disease.

    Science.gov (United States)

    Curtis, J R

    1979-11-01

    The clinical manifestations of drug-induced renal disease may include all the manifestations attributed to natural or spontaneous renal diseases such as acute renal failure, chronic renal failure, acute nephritic syndrome, renal colic, haematuria, selective tubular defects, obstructive nephropathy, etc. It is therefore vital in any patient with renal disease whatever the clinical manifestations might be, to obtain a meticulous drug and toxin inventory. Withdrawal of the offending drug may result in amelioration or cure of the renal disorder although in the case of severe renal failure it may be necessary to utilise haemodialysis or peritoneal dialysis to tide the patient over the period of acute renal failure. Analgesic nephropathy is an important cause of terminal chronic renal failure and it is therefore vital to make the diagnosis as early as possible. The pathogenesis of some drug-induced renal disorders appears to be immunologically mediated. There are many other pathogenetic mechanisms involved in drug-induced renal disorders and some drugs may under appropriate circumstances be responsible for a variety of different nephrotoxic effects. For example, the sulphonamides have been incriminated in examples of crystalluria, acute interstitial nephritis, acute tubular necrosis, generalised hypersensitivity reactions, polyarteritis nodosa and drug-induced lupus erythematosus.

  14. Protective effect of ω-3 polyunsaturated fatty acids on L-arginine-induced nephrotoxicity and oxidative damage in rat kidney.

    Science.gov (United States)

    Khan, M W; Priyamvada, S; Khan, S A; Khan, S; Naqshbandi, A; Yusufi, A N K

    2012-10-01

    L-Arginine (ARG), an essential amino acid, is the endogenous source of the deleterious nitric oxide. Dietary ω-3 polyunsaturated fatty acid (PUFA)-enriched fish oil (FO) has been shown to reduce the severity of certain types of cancers, cardiovascular disease, and renal disease. Present study examined whether feeding of FO/flaxseed oil (FXO) would have protective effect against ARG-induced nephrotoxicity. ARG-induced nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. ARG significantly altered the activities of metabolic and brush border membrane (BBM) enzymes. ARG caused significant imbalances in the antioxidant system. These alterations were associated with increased lipid peroxidation (LPO) and altered antioxidant enzyme activities. Feeding of FO and FXO with ARG ameliorated the changes in various parameters caused by ARG. Nephrotoxicity parameters lowered and enzyme activities of carbohydrate metabolism, BBM and inorganic phosphate (32Pi) transport were improved to near control values. ARG-induced LPO declined and antioxidant defense mechanism was strengthened by both FO and FXO alike. The results of the present study suggest that ω-3 PUFA-enriched FO and FXO from seafoods and plant sources, respectively, are similarly effective in reducing ARG-induced nephrotoxicity and oxidative damage. Thus, vegetarians who cannot consume FO can have similar health benefits from plant-derived ω-3 PUFA.

  15. Protective effects of the aqueous leaf extract of Aloe barbadensis on gentamicin and cisplatin-induced nephrotoxic rats

    Institute of Scientific and Technical Information of China (English)

    Paoulomi Chatterjee﹡; Aniruddha Mukherjee; Subhangkar Nandy

    2012-01-01

    Objective: To study the protective effects of the aqueous leaf extract of Aloe barbadensis (AEAB) on gentamicin and Cisplatin-induced nephrotoxic Wistar rats. Methods: In each model of nephrotoxicity, thirty adult male Wistar rats were evenly divided into 5 groups. Groups I and II served as untreated and model controls, respectively while groups III-V were the treatment groups which were pretreated with 100-200 mg/kg bodyweight per day of AEAB 1 h before each dose of the nephrotoxicants. On the 8th day(in case of gentamicin) and on 6th day(in case of Cisplatin), blood samples for serum urea, total protein and creatinine as well as some ions like sodium, potassium, chloride and uric acid while the rat kidneys for histology were obtained under inhaled diethyl ether anesthesia. Results: In the gentamicin nephrotoxic rats, 100-200 mg/kg bodyweight per day significantly attenuated elevations in the serum creatinine, total protein and blood urea nitrogen levels in dose related fashion and no treatment related effect on uric acid and ions, and attenuated the gentamicin-induced tubulonephrosis. Similar effects were also recorded in the Cisplatin model of acute renal injury. Conclusions:The nephroprotective effect of AEAB could be due to the inherent antioxidant and free-radical-scavenging principle(s) contained in the extract.In the near future, AEAB could constitute a lead to discovery of a novel drug for the treatment of drug-induced nephrotoxicity.

  16. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Energy Technology Data Exchange (ETDEWEB)

    Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  17. Long term streptomycin toxicity in the treatment of Buruli Ulcer: follow-up of participants in the BURULICO drug trial.

    Directory of Open Access Journals (Sweden)

    Sandor Klis

    2014-03-01

    Full Text Available BACKGROUND: Buruli Ulcer (BU is a tropical infectious skin disease that is currently treated with 8 weeks of intramuscular streptomycin and oral rifampicin. As prolonged streptomycin administration can cause both oto- and nephrotoxicity, we evaluated its long term toxicity by following-up former BU patients that had received either 4 or 8 weeks of streptomycin in addition to other drugs between 2006 and 2008, in the context of a randomized controlled trial. METHODS: Former patients were retrieved in 2012, and oto- and nephrotoxicity were determined by audiometry and serum creatinine levels. Data were compared with baseline and week 8 measurements during the drug trial. RESULTS: Of the total of 151 former patients, 127 (84% were retrieved. Ototoxicity was present in 29% of adults and 25% of children. Adults in the 8 week streptomycin group had significantly higher hearing thresholds in all frequencies at long term follow-up, and these differences were most prominent in the high frequencies. In children, no differences between the two treatment arms were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2.4% of patients at long term follow-up. CONCLUSIONS: Prolonged streptomycin administration in the adult study subjects caused significant persistent hearing loss, especially in the high frequency range. Nephrotoxicity was also present in both adults and children but appeared to be transient. Streptomycin should be given with caution especially in patients aged 16 or older, and in individuals with concurrent risks for renal dysfunction or hearing loss.

  18. Histological, ultrastructural and immunohistochemical studies on the protective effect of ginger extract against cisplatin-induced nephrotoxicity in male rats.

    Science.gov (United States)

    Ali, Doaa A; Abdeen, Ahmed M; Ismail, Mohammed F; Mostafa, Mai A

    2015-10-01

    Cisplatin (CP) is a widely used anticancer drug; however, it has several side effects such as nephrotoxicity. Ginger, the rhizome of Zingiber officinale, consumed since ancient times has numerous health benefits. The objective of this work was to evaluate the protective effect of ginger extract (GE) against CP-induced nephrotoxicity. CP group displayed a marked renal failure characterized by a significant increase in serum creatinine and blood urea nitrogen (BUN) levels in addition to severe histopathological and ultrastructural renal alterations. Also, CP group showed an increase in the immunohistochemical expression of Bax proapoptotic protein. In contrast, GE+CP group showed significant decrease in the elevated serum creatinine and BUN levels and an improvement in the histopathological and ultrastructural renal injury induced by CP. The overexpression of Bax proapoptotic protein was significantly decreased in the GE+CP group. Hence, the present results indicated that GE has a protective effect against CP-induced renal damage in rats. Thereby, such findings recommended the usage of GE to prevent and/or decrease the renal damage induced by CP chemotherapeutic treatment. © The Author(s) 2013.

  19. In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine.

    Science.gov (United States)

    Oktem, Faruk; Arslan, Meltem Koyuncu; Ozguner, Fehmi; Candir, Ozden; Yilmaz, H Ramazan; Ciris, Metin; Uz, Efkan

    2005-11-15

    The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels.

  20. Naringenin ameliorates daunorubicin induced nephrotoxicity by mitigating AT1R, ERK1/2-NFκB p65 mediated inflammation.

    Science.gov (United States)

    Karuppagounder, Vengadeshprabhu; Arumugam, Somasundaram; Thandavarayan, Rajarajan Amirthalingam; Pitchaimani, Vigneshwaran; Sreedhar, Remya; Afrin, Rejina; Harima, Meilei; Suzuki, Hiroshi; Suzuki, Kenji; Nakamura, Masahiko; Ueno, Kazuyuki; Watanabe, Kenichi

    2015-09-01

    Inflammation and oxidative stress play important roles in the progression of renal damage. The natural polyphenol naringenin is known to exert potent antioxidant and anti-inflammatory effects. In this study, we have investigated the effect of naringenin on kidney dysfunction, fibrosis, endoplasmic reticulum (ER) stress, angiotensin II type I receptor (AT1R) expression and inflammation in daunorubicin (DNR) induced nephrotoxicity model. Nephrotoxicity was induced in rats by intravenous injection of DNR at a cumulative dose of 9 mg/kg. After 1 week, naringenin (20mg/kg/day. p.o) was administered daily for 6 weeks. Biochemical studies were performed to evaluate renal function. Western blotting was performed to measure the protein levels of AT1R, endothelin (ET)1, ET receptor type A (ETAR), extracellular signal-regulated kinase (ERK)1/2, nuclear factor (NF)κB p65, peroxisome proliferator activated receptor (PPAR)γ, oxidative/ER stress, apoptosis, and inflammatory markers in the kidney of DNR treated rats. Histopathological analysis was done using hemotoxylin eosin and Masson trichrome stained renal sections to investigate the structural abnormalities and fibrosis. DNR treated rats suffered from nephrotoxicity as evidenced by worsened renal function, increased blood urea nitrogen, serum creatinine levels in renal tissues and histopathogical abnormalities. Treatment with naringenin mitigated these changes. Furthermore, naringenin up regulated PPARγ and down regulated AT1R, ET1, ETAR, p-ERK1/2, p-NFκB p65, ER stress, apoptosis, and inflammatory markers. Our results suggest that naringenin has an ability to improve renal function and attenuates AT1R, ERK1/2-NFκB p65 signaling pathway in DNR induced nephrotoxicity in rats.

  1. Switch to 1.5 grams MMF monotherapy for CNI-related toxicity in liver transplantation is safe and improves renal function, dyslipidemia, and hypertension.

    Science.gov (United States)

    Orlando, Giuseppe; Baiocchi, Leonardo; Cardillo, Andrea; Iaria, Giuseppe; De Liguori Carino, Nicola; De Liguori, Nicola; De Luca, Linda; Ielpo, Benedetto; Tariciotti, Laura; Angelico, Mario; Tisone, Giuseppe

    2007-01-01

    Although mycophenolate mofetil (MMF) monotherapy has been successfully used in liver transplant recipients suffering from calcineurin-inhibitor (CNI)-related chronic toxicity, still no consensus has been reached on its safety, efficacy and tolerability. We attempted the complete weaning off CNI in 42 individuals presenting chronic renal dysfunction and/or dyslipidemia and/or arterial hypertension and simultaneously introduced 1.5 gm/day MMF. CNI could be completely withdrawn in 41 cases. A total of 32 (75%) patients are currently on MMF. Mean follow-up from the introduction of MMF is 31.5 months and mean length of follow-up from the beginning of MMF monotherapy is 27.3 months. Renal function improved in 31/36 (89%) cases. Blood levels of cholesterol and triglycerides decreased in 13 of 17 (76%) and 15 of 17 (89%) patients, respectively. Arterial hypertension improved in 4 of 5 (80%) cases. A total of 8 patients showed a single episode of fluctuation of liver function tests during tapering off CNI. This feature was interpreted as an acute rejection (AR), based on the resolution of the clinical setting after escalation of MMF daily dose to 2 gm. A further patient developed a biopsy-proven AR insensitive to MMF adjustment, requiring reinstitution of the CNI dose. No deaths or major toxicity requiring MMF discontinuation occurred. In conclusion, low dose MMF monotherapy is safe, effective, and well tolerated.

  2. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

    Science.gov (United States)

    Adeneye, A A; Benebo, A S

    2016-08-30

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

  3. Effect of DTPA on the nephrotoxicity induced by uranium in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Houpert, P.; Muller, D.; Chazel, V.; Claraz, M.; Paquet, F

    2003-07-01

    The only treatment proposed after human contamination with MOX (mixed oxide of uranium and plutonium) is diethylenetriaminepentaacetic acid (DTPA), because plutonium is considered to be the major risk. However, both DTPA and uranium are nephrotoxic at high dosages and DTPA has been shown to increase in vitro the cytotoxicity induced by uranium on cultured epithelial tubular cells. This work aimed to test this effect in vivo. Rats were injected with subtoxic (57 {mu}g.kg{sup -1}) to toxic (639 {mu}g kg{sup -1}) amounts of uranium as nitrate at 0 h, they received two DTPA injections (30 {mu}mol kg{sup -1}) at 2 min and 24 h and were euthanased at 48 h. The nephrotoxic effects were evaluated by measurement of the body weight gain, food and water intake, measurement of biochemical parameters in urine and blood, and histological examination of one kidney. The main result was that DTPA did not increase the nephrotoxicity induced by uranium in the range of concentrations tested, which was inconsistent with the in vitro results. (author)

  4. 多黏菌素肾毒性的文献计量学分析%Bibliometric analysis on nephrotoxicity due to polymyxin

    Institute of Scientific and Technical Information of China (English)

    陈迁; 梁蓓蓓; 李悦; 牛卉; 邸秀珍; 储晓蒙; 白艳; 汶柯; 刘旭

    2014-01-01

    Objective To investigate the research progress in nephrotoxicity due to polymyxin and provide a reference for clinical safe use of polymyxin.Methods " Polymyxin "," colistin ","colistimethate"," nephrotoxicity",and " renal toxicity" were selected as the keywords and PubMed,Embase,Web of Science,Chinese Medical Citation Index,and Chinese BioMedical Disc were searched.All literature about nephrotoxicity due to polymyxin were enrolled.The evaluated databases of literature accepted for bibliometric study were establish by Microsoft Excel.The parameters of bibliometrics such as literature's language,literature's type,publication date,the countries and institutes ranking in the top 5 in publishing,top 5 journals in publishing number,and top 10 most frequently cited articles.The main content and hotspot of literature were analyzed.The clinical manifestations,mechanism,and prophylactico-therapeutic measures of nephrotoxicity due to polymyxin were summarized.Results A total of 95 articles (90 in English,3 in Chinese,1 in French and 1 in Portuguese) were enrolled in the study,of which 82 were original articles and 13 were reviews.The published time of first original publication of nephrotoxicity due to polymyxin was in 1952.The countries ranking in the top 5 in publishing were United States (29 pieces),Greece (12 pieces),Turkey (8 pieces),Australia (6 pieces),and Korea (5 pieces),respectively.The highest citation rate of article was 156 times.The mode of administration of polymyxin were intravenous infusion and nebulized inhalation.Kidney injury due to polymyxin usually occurred in 4-10 days after administration.The main clinical manifestations were myodynia,weakness,dark urine,hematuria,and proteinuria.Laboratory examination showed elevated serum creatinine and depressed creatinine clearance rate.After the drug withdrawal and supportive treatments,some patients' renal functions returned to the levels before administration.The incidence of nephrotoxicity due to polymyxin

  5. Role of nephrotoxic drugs in contrast-induced nephropathy

    Directory of Open Access Journals (Sweden)

    Sirisha Annavarapu

    2015-06-01

    Conclusions: The incidence of CIN is more in patients who underwent contrast studies without stopping nephrotoxic drugs and stoppage of nephrotoxic drugs for 3 days prior to the procedure is beneficial by reducing the incidence of CIN among them. [Int J Basic Clin Pharmacol 2015; 4(3.000: 458-462

  6. Chromium-induced nephrotoxicity and ameliorative effect of carvedilol in rats: Involvement of oxidative stress, apoptosis and inflammation.

    Science.gov (United States)

    Sahu, Bidya Dhar; Koneru, Meghana; Bijargi, Shriharsh R; Kota, Anudeep; Sistla, Ramakrishna

    2014-11-05

    Nephrotoxicity is a major adverse effect of chromium poisoning. In the present study, we investigated the potential renoprotective effect and underlying mechanisms of carvedilol, a non-specific β-adrenergic blocker using rat model of potassium dichromate-induced nephrotoxicity. Rats were pretreated with carvedilol (10mg/kg) for 21days. A single subcutaneous injection of potassium dichromate (15mg/kg, s.c.) resulted in a significant increase in the levels of blood urea nitrogen and serum creatinine, markers related to oxidative stress, nitrosative stress, apoptosis and inflammation accompanied with histopathological changes in kidney tissues. Exploration of the underlying renoprotective mechanisms of carvedilol revealed that carvedilol attenuated nuclear translocation and DNA binding activity of NF-κB (p65) in kidney tissues. The serum levels of TNF-α and the renal expression of iNOS and tissue nitrites were significantly decreased in carvedilol plus potassium dichromate administered rats. Carvedilol pretreatment significantly attenuated the potassium dichromate-induced DNA damage, decreased the p53, Bax and cleaved caspase-3 expression and increased the Bcl-2 expression. Moreover, pretreatment with carvedilol significantly restored the renal tissue antioxidant and mitochondrial respiratory enzyme activities and decreased the elevated lipid peroxidation biomarkers to normal. These results were further supported and confirmed by histopathological findings. In conclusion, the findings of the present study demonstrated that carvedilol is an effective chemoprotectant against potassium dichromate-induced nephrotoxicity in rats.

  7. Puerarin attenuates cisplatin-induced rat nephrotoxicity: The involvement of TLR4/NF-κB signaling pathway

    Science.gov (United States)

    Ma, Xu; Yan, Lei; Zhu, Qing; Shao, Fengmin

    2017-01-01

    Puerarin was a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen). In present study effect of puerarin on cisplatin nephrotoxicity was evaluated. Rat model of nephrotoxicity was established by a single intraperitoneal injection of cisplatin (7mg/kg). Puerarin was administrated through caudal vein injection once per day at the dose of 10mg/kg, 30mg/kg and 50mg/kg. Biochemical assays showed that after cisplatin treatment the serum urea and creatinine increased significantly compared with control (Pinduced by cisplatin were significantly attenuated by puerarin treatment in dose-dependent manner, which indicated the renal protective effect of puerarin. Cell culture experiments illustrated that puerarin alone treatment concentration-dependently inhibited COLO205 and HeLa tumor cell growth and dose-dependently promoted the antitumor activity of cisplatin in COLO205 and HeLa tumor cells. The promotion effects might be attributed to suppression of cisplatin-increased NF-κB p65 expression by puerarin. Taken together, findings in this study suggested that puerarin exhibited renal protection against cisplatin nephrotoxicity via inhibiting TLR4/NF-κB signaling, with no inhibition but promotion effect on the antitumor activity of cisplatin. Puerarin might be a promising adjuvant agent for cisplatin chemotherapy. PMID:28182789

  8. Sildenafil Ameliorates Gentamicin-Induced Nephrotoxicity in Rats: Role of iNOS and eNOS

    Directory of Open Access Journals (Sweden)

    Mohamed A. Morsy

    2014-01-01

    Full Text Available Gentamicin, an aminoglycoside antibiotic, is used for the treatment of serious Gram-negative infections. However, its usefulness is limited by its nephrotoxicity. Sildenafil, a selective phosphodiesterase-5 inhibitor, was reported to prevent or decrease tissue injury. The aim of this study is to evaluate the potential protective effects of sildenafil on gentamicin-induced nephrotoxicity in rats. Male Wistar rats were injected with gentamicin (100 mg/kg/day, i.p. for 6 days with and without sildenafil. Sildenafil administration resulted in nephroprotective effect in gentamicin-intoxicated rats as it significantly decreased serum creatinine and urea, urinary albumin, and renal malondialdehyde and nitrite/nitrate levels, with a concomitant increase in renal catalase and superoxide dismutase activities compared to gentamicin-treated rats. Moreover, immunohistochemical examination revealed that sildenafil treatment markedly reduced inducible nitric oxide synthase (iNOS expression, while expression of endothelial nitric oxide synthase (eNOS was markedly enhanced. The protective effects of sildenafil were verified histopathologically. In conclusion, sildenafil protects rats against gentamicin-induced nephrotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS production.

  9. Evaluation of risk of nephrotoxicity with high dose, extended-interval colistin administration

    Directory of Open Access Journals (Sweden)

    Arun Dewan

    2014-01-01

    Full Text Available Aim: The aim was to evaluate the risk of nephrotoxicity with high-dose, extended-interval regimen of colistin administration in critical ill patients. Materials and Methods: This prospective study was conducted on patients suffering from sepsis due to Gram-negative infection susceptible only to colistin. The dosing schedule for colistin was 9 million units stat followed by 4.5 million units at 12 hourly interval (adjusted as per body weight and renal functions. The serum creatinine and creatinine clearance were estimated at the start of therapy and daily during therapy. Results: Thirty-one patients suffering ventilator associated pneumonia (61.29%, blood stream infections (29.03% and urinary tract infections (9.67% due to Gram-negative multiple drug resistance organisms were assessed. Most commonly isolated organism were Acinetobacter baumannii (54.83%, Klebsiella pneumonia (16.12% and Pseudomonas (29.03%. Five patients (16.12% developed acute kidney injury within 4-5 days of start of therapy and returned to baseline after 6 days with no patient requiring renal replacement therapy or discontinuation of colistin. Conclusion: Our study showed that high-dose, extended-interval colistin can be given to critically ill patients without any significant risk of nephrotoxicity.

  10. Nephroprotective effect of Kabab chini (Piper cubeba in gentamycin-induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Qazi Zaid Ahmad

    2012-01-01

    Full Text Available Kabab chini (KC (Piper cubeba is an important drug in Unani Medicine, widely described to be effective in renal diseases, and physicians are using it as a protective and curative agent in various renal disorders from ancient times. The present study was designed to evaluate the nephroprotective effect of KC against gentamycin-induced nephrotoxicity in Wistar rats. This was studied in two different sets of tests, in which both the protective as well as the curative effects were evaluated in groups of albino rats. The powder of the test drug was administered orally in a dose of 810 mg/kg and 1220 mg/kg, in suspension form, in the pre- and post-treated models. The nephroprotective effect was assessed on the basis of biochemical estimation of serum urea and creatinine levels and histopathological examination of the treated kidney. The effect observed in the pre-treated and post-treated groups was compared with plain as well as negative control groups using one-way ANOVA with Dunnett′s multiple pair comparison test. The findings of the two tests demonstrated that KC produced a significant nephroprotective effect in both pre-treated and post-treated groups. The results of our study indicate that KC possesses significant benefit against gentamycin-induced nephrotoxicity.

  11. The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

    Science.gov (United States)

    Kumar, Mukesh; Dahiya, Vicky; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Lahkar, Mangala

    2017-03-14

    Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin.

  12. Protective effect of naringenin against gentamicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Fouad, Amr A; Albuali, Waleed H; Zahran, Ahmed; Gomaa, Wafaey

    2014-09-01

    The protective effect of naringenin, a flavonoid compound isolated from citrus fruits, was investigated against nephrotoxicity induced by gentamicin (80mgkg(-1)/day, i.p., for eight days) in rats. Naringenin treatment (50mgkg(-1)/day, p.o.) was administered for eight days, starting on the same day of gentamicin administration. Gentamicin caused significant elevations of serum creatinine, and kidney tissue levels of malondialdehyde, nitric oxide, and interleukin-8, and a significant decrease in renal glutathione peroxidase activity. Naringenin treatment significantly ameliorated the changes in the measured biochemical parameters resulted from gentamicin administration. Also, naringenin markedly attenuated the histopathological renal tissue injury observed with gentamicin. Immunohistochemical examinations showed that naringenin significantly reduced the gentamicin-induced expression of kidney injury molecule-1, vascular endothelial growth factor, inducible nitric oxide synthase, and caspase-9, and increased survivin expression in the kidney tissue. It was concluded that naringenin, through its antioxidant and anti-inflammatory effects, may represent a therapeutic option to protect against gentamicin nephrotoxicity.

  13. Recombinant Mitochondrial Manganese Containing Superoxide Dismutase Protects Against Ochratoxin A-Induced Nephrotoxicity.

    Science.gov (United States)

    Ciarcia, Roberto; Damiano, Sara; Squillacioti, Caterina; Mirabella, Nicola; Pagnini, Ugo; Florio, Alessia; Severino, Lorella; Capasso, Giovambattista; Borrelli, Antonella; Mancini, Aldo; Boffo, Silvia; Romano, Gaetano; Giordano, Antonio; Florio, Salvatore

    2016-06-01

    Ochratoxin A (OTA) is a natural mycotoxin, involved in the development of important human and animal diseases. In this work we have studied the role of oxidative stress in the development of OTA nephrotoxicity and the effect of a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) to prevent kidney damage induced by OTA. Blood pressure, glomerular filtration rate and renal histology were analyzed in control rats and in OTA treated rats. In addition, lipid peroxidation, catalase and superoxide dismutase productions were measured. Our data showed that animals treated with OTA presented hypertension and reduction of glomerular filtration rate (GFR). These effects are most probably related to an increase in the reactive oxygen species (ROS) productions. In fact, we have shown that treatment with rMnSOD restored the levels of blood pressure and GFR simultaneously. Moreover, we have noted that OTA induced alteration on glomerular and tubular degeneration and interstitial infiltrates and that use of rMnSOD combined with OTA prevent this renal histological damage confirming the potential therapeutic role in the treatment of rMnSOD OTA nephrotoxicity.

  14. Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Lawton, C.A.; Fish, B.L.; Moulder, J.E. (Medical College of Wisconsin, Milwaukee, WI (United States))

    1994-03-01

    Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy. 34 refs., 4 figs., 2 tabs.

  15. Attenuation of gentamycin-induced nephrotoxicity in rats by dietary inclusion of ginger (Zingiber officinale) and turmeric (Curcuma longa) rhizomes.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Ogunsuyi, Opeyemi B; Akinyemi, Ayodele J

    2012-10-01

    This study sought to investigate the modulatory effects of dietary inclusion of ginger (Zingiber officinale) and turmeric (Curcuma longa) rhizomes on antioxidant status and renal damage induced by gentamycin in rats. Renal damage was induced in albino rats pretreated with dietary inclusion of ginger and turmeric (2% and 4%) by intraperitoneal (i.p.) administration of gentamycin (100 mg/kg body weight) for three days. Assays for renal damage biomarkers (plasma creatinine, plasma urea, blood urea nitrogen and plasma uric acid), malondialdehyde (MDA) content and reduced glutathione (GSH) content as well as renal antioxidant enzymes (catalase, glutathione-S-transferase (GST), glutathione peroxidase (GPx) and superoxide dismutase (SOD)) were carried out. The study revealed significant (p turmeric rhizome (2% and 4%) prior to gentamycin administration significantly (p turmeric rhizomes may protect against gentamycin-induced nephrotoxicity and oxidative stress.

  16. Modulation of Nrf2/HO-1 by Thymoquinone During Cisplatin-Induced Nephrotoxicity

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    Ramazan ULU

    2013-05-01

    Full Text Available OBJECTIVE: Side effects of cisplatin, such as nephrotoxicity, limit its use in chemotherapeutic regimens and indicate an agent that suppresses its toxicity. Thymoquinone (TQ, the predominant bioactive constituent present in black seed oil (Nigella sativa, has antiinfl ammatory, antioxidant and antitumor effects. We propose a protective mechanism of of TQ on cisplatin-nephrotoxicity in rats that is through modulation of Nrf2-mediated antioxidant induction and reduced inflammation. MATERIAL and METHODS: Twenty-eight male Wistar rats (8 weeks-old were divided into four groups; Control (vehicle; 0.9% saline, 1 ml/kg body wt., p.o., TQ (10 mg/kg body weight/day in drinking water for 5 days, cisplatin (a single injection of 7mg/kg body wt, i.p. and TQ for 5 days in drinking water then a single injection of cisplatin. On day 10, all rats were sacrificed by cervical dislocation, kidneys were removed, and serum urea and creatinine were collected. RESULTS: Serum urea and creatinine levels were significantly higher in cisplatin-treated rats compared with control rats. TQ-treatment significantly decreased serum urea and creatinine levels. Cisplatin-treatment caused significant downregulation of the nuclear NF-E2-related factor-2 (Nrf2, heme oxygenase-1(HO-1 and caused an increase in the levels of nuclear factor-kappa B (NF-κB. Interestingly, TQ supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing the levels of Nrf-2 and HO-1 and decreasing the levels of NF-κB. CONCLUSION: This study demonstrates the TQ targets NRF2/HO-1 and can be used as a potential agent against cisplatin-induced nephrotoxicity.

  17. Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

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    Gianluigi Zaza

    2013-01-01

    Full Text Available The mammalian target of rapamycin inhibitors (mTOR-I, sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR, a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

  18. Nephrotoxicity of cyclosporin A in patients with newly diagnosed type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Feldt-Rasmussen, B; Jensen, T; Dieperink, H

    1990-01-01

    Renal function was studied in 18 patients with Type 1 diabetes mellitus. All were participating in the Canadian-European randomized placebo-controlled cyclosporin trial in newly diagnosed Type 1 diabetic patients, nine being randomized to placebo, and nine to cyclosporin A. During treatment for 12...... to 18 months, cyclosporin A caused significant reductions in the glomerular filtration rate (before drug withdrawal, cyclosporin 97 +/- 18 vs placebo 125 +/- 16 ml min-1 1.73-m-2, p less than 0.05), renal plasma flow (454 +/- 83 vs 536 +/- 70 ml min-1 1.73-m-2, p less than 0.05), and lithium clearance...... with the hypothesis that the nephrotoxic effect of cyclosporin A results from a preferential constriction of afferent glomerular vessels. One year after withdrawal of the drug, all variables were similar in the two groups, except for blood glucose control which was worse in the cyclosporin A treated group. When...

  19. Carissa carandas Linn. fruit extract ameliorates gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Jayesh B. Dhodi; Deepavali R. Thanekar; Snehal N. Mestry; Archana R. Juvekar

    2015-01-01

    Objective: To elucidate the mechanism of action of methanolic extract of Carissa carandas fruits (MCCF) in attenuation of diabetic nephropathy using gentamicin induced nephrotoxicity model.Methods:Extract was daily administered to Sprague Dawley rats at doses of 100, 200 and 400 mg/kg for 8 days along with intramuscular injection of gentamicin (80 mg/kg). After completion of the study, serum was analyzed for blood urea nitrogen, albumin and creatinine; urine (24 h) was analyzed for albumin and creatinine. Kidney was evaluated for its biochemical and morphological changes. Results: Extract at doses of 200 and 400 mg/kg significantly normalized the nephrotoxic biomarkers in serum and urine and increased the kidney antioxidant activities which were altered due to gentamicin toxicity. The histological findings reveal that MCCF was capable of protecting the kidney against gentamicin toxicity. Conclusions: Extract ameliorated oxidative stress generated by gentamicin administration, which is one of the mechanisms for its preventive action against diabetic nephropathy.

  20. Oleic acid loading does not add to the nephrotoxic effect of albumin in an amphibian and chronic rat model of kidney injury

    NARCIS (Netherlands)

    van Timmeren, Mirjan M.; Gross, Marie-Luise; Hanke, Wilfried; Klok, Pieter A.; van Goor, Harry; Stegeman, Coen A.; Bakker, Stephan J. L.

    2008-01-01

    Background. Under proteinuric conditions, ultrafiltrated albumin can induce an inflammatory and fibrotic response in proximal tubular cells. It is unclear whether albumin per se or compounds bound to albumin are nephrotoxic. Some studies have supported the toxicity of albumin-bound fatty acids; howe

  1. Oleic acid loading does not add to the nephrotoxic effect of albumin in an amphibian and chronic rat model of kidney injury

    NARCIS (Netherlands)

    van Timmeren, Mirjan M.; Gross, Marie-Luise; Hanke, Wilfried; Klok, Pieter A.; van Goor, Harry; Stegeman, Coen A.; Bakker, Stephan J. L.

    2008-01-01

    Background. Under proteinuric conditions, ultrafiltrated albumin can induce an inflammatory and fibrotic response in proximal tubular cells. It is unclear whether albumin per se or compounds bound to albumin are nephrotoxic. Some studies have supported the toxicity of albumin-bound fatty acids; howe

  2. Glyphosate, Hard Water and Nephrotoxic Metals: Are They the Culprits Behind the Epidemic of Chronic Kidney Disease of Unknown Etiology in Sri Lanka?

    Science.gov (United States)

    Jayasumana, Channa; Gunatilake, Sarath; Senanayake, Priyantha

    2014-01-01

    The current chronic kidney disease epidemic, the major health issue in the rice paddy farming areas in Sri Lanka has been the subject of many scientific and political debates over the last decade. Although there is no agreement among scientists about the etiology of the disease, a majority of them has concluded that this is a toxic nephropathy. None of the hypotheses put forward so far could explain coherently the totality of clinical, biochemical, histopathological findings, and the unique geographical distribution of the disease and its appearance in the mid-1990s. A strong association between the consumption of hard water and the occurrence of this special kidney disease has been observed, but the relationship has not been explained consistently. Here, we have hypothesized the association of using glyphosate, the most widely used herbicide in the disease endemic area and its unique metal chelating properties. The possible role played by glyphosate-metal complexes in this epidemic has not been given any serious consideration by investigators for the last two decades. Furthermore, it may explain similar kidney disease epidemics observed in Andra Pradesh (India) and Central America. Although glyphosate alone does not cause an epidemic of chronic kidney disease, it seems to have acquired the ability to destroy the renal tissues of thousands of farmers when it forms complexes with a localized geo environmental factor (hardness) and nephrotoxic metals. PMID:24562182

  3. Glyphosate, Hard Water and Nephrotoxic Metals: Are They the Culprits Behind the Epidemic of Chronic Kidney Disease of Unknown Etiology in Sri Lanka?

    Directory of Open Access Journals (Sweden)

    Channa Jayasumana

    2014-02-01

    Full Text Available The current chronic kidney disease epidemic, the major health issue in the rice paddy farming areas in Sri Lanka has been the subject of many scientific and political debates over the last decade. Although there is no agreement among scientists about the etiology of the disease, a majority of them has concluded that this is a toxic nephropathy. None of the hypotheses put forward so far could explain coherently the totality of clinical, biochemical, histopathological findings, and the unique geographical distribution of the disease and its appearance in the mid-1990s. A strong association between the consumption of hard water and the occurrence of this special kidney disease has been observed, but the relationship has not been explained consistently. Here, we have hypothesized the association of using glyphosate, the most widely used herbicide in the disease endemic area and its unique metal chelating properties. The possible role played by glyphosate-metal complexes in this epidemic has not been given any serious consideration by investigators for the last two decades. Furthermore, it may explain similar kidney disease epidemics observed in Andra Pradesh (India and Central America. Although glyphosate alone does not cause an epidemic of chronic kidney disease, it seems to have acquired the ability to destroy the renal tissues of thousands of farmers when it forms complexes with a localized geo environmental factor (hardness and nephrotoxic metals.

  4. Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka?

    Science.gov (United States)

    Jayasumana, Channa; Gunatilake, Sarath; Senanayake, Priyantha

    2014-02-20

    The current chronic kidney disease epidemic, the major health issue in the rice paddy farming areas in Sri Lanka has been the subject of many scientific and political debates over the last decade. Although there is no agreement among scientists about the etiology of the disease, a majority of them has concluded that this is a toxic nephropathy. None of the hypotheses put forward so far could explain coherently the totality of clinical, biochemical, histopathological findings, and the unique geographical distribution of the disease and its appearance in the mid-1990s. A strong association between the consumption of hard water and the occurrence of this special kidney disease has been observed, but the relationship has not been explained consistently. Here, we have hypothesized the association of using glyphosate, the most widely used herbicide in the disease endemic area and its unique metal chelating properties. The possible role played by glyphosate-metal complexes in this epidemic has not been given any serious consideration by investigators for the last two decades. Furthermore, it may explain similar kidney disease epidemics observed in Andra Pradesh (India) and Central America. Although glyphosate alone does not cause an epidemic of chronic kidney disease, it seems to have acquired the ability to destroy the renal tissues of thousands of farmers when it forms complexes with a localized geo environmental factor (hardness) and nephrotoxic metals.

  5. Effect of deferrioxamine and diethyldithiocarbamate on paracetamol-induced hepato- and nephrotoxicity. The role of lipid peroxidation.

    Science.gov (United States)

    Younes, M; Sause, C; Siegers, C P; Lemoine, R

    1988-08-01

    In mice subjected to glutathione depletion by pretreatment with phorone (diisopropylidene acetone, 200 mg/kg i.p. in 10 ml/kg olive oil) paracetamol (acetaminophen, 300 mg/kg p.o. in 10 ml/kg tylose 2 h later) led to a marked hepatotoxicity as evidenced by increased plasma activities of the liver-specific enzymes sorbitol dehydrogenase (SDH) and glutamate-pyruvate-transaminase (GPT) 3 and 24 h after treatment. Nephrotoxicity was also indicated at both timepoints by an increased creatinine concentration in plasma, while neither the urine volume nor its content in gamma-glutamyl transpeptitase over 20 h were affected. Hepato- and nephrotoxicity were also assessed histomorphologically. In vivo lipid peroxidation (LPO), as measured by ethane exhalation over 3 h, was clearly enhanced by paracetamol. Malondialdehyde content was increased and glutathione concentration diminished in the liver, but not in the kidney. Diethyldithiocarbamate (DTC, 200 mg/kg i.p.) or deferrioxamine (DFO, 500 mg/kg i.p.) both given 30 min before PA, inhibited in vivo LPO. However, only DTC was capable of antagonizing the hepato- and nephrotoxic effects of paracetamol, while DFO only delayed the onset of nephrotoxicity but left the hepatotoxicity unaffected. Both agents inhibited the rise in hepatic malondialdehyde-content, but only DTC prevented paracetamol-induced glutathione depletion. These results indicate that LPO is not mainly responsible for paracetamol toxicity towards liver or kidney.

  6. Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research.

    Science.gov (United States)

    Ali, Badreldin H; Al Moundhri, Mansour S

    2006-08-01

    Cisplatin (cis-diamminedichloroplatinum (II)) is an effective agent against various solid tumours. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity. Hundreds of platinum compounds (e.g. carboplatin, oxaliplatin, nedaplatin and the liposomal form lipoplatin) have been tested over the last two decades in order to improve the effectiveness and to lessen the toxicity of cisplatin. Several agents have been tested to see whether they could ameliorate or augment the nephrotoxicity of platinum drugs. This review summarizes these studies and the possible mechanisms of actions of these agents. The agents that have been shown to ameliorate experimental cisplatin nephrotoxicity include antioxidants (e.g. melatonin, vitamin E, selenium, and many others), modulators of nitric oxide (e.g. zinc histidine complex), agents interfering with metabolic pathways of cisplatin (e.g. procaine HCL), diuretics (e.g. furosemide and mannitol), and cytoprotective and antiapoptotic agents (e.g. amifostine and erythropoietin). Only few of these agents have been tested in humans. Those agents that have been shown to augment cisplatin nephrotoxicity include nitric oxide synthase inhibitors, spironolactone, gemcitabine and others. Combining these agents with cisplatin should be avoided.

  7. Caffeic Acid Phenethyl Ester as a Protective Agent against Nephrotoxicity and/or Oxidative Kidney Damage: A Detailed Systematic Review

    Directory of Open Access Journals (Sweden)

    Sumeyya Akyol

    2014-01-01

    Full Text Available Caffeic acid phenethyl ester (CAPE, an active component of propolis, has been attracting the attention of different medical and pharmaceutical disciplines in recent years because of its antioxidant, anti-inflammatory, antiproliferative, cytotoxic, antiviral, antifungal, and antineoplastic properties. One of the most studied organs for the effects of CAPE is the kidney, particularly in the capacity of this ester to decrease the nephrotoxicity induced by several drugs and the oxidative injury after ischemia/reperfusion (I/R. In this review, we summarized and critically evaluated the current knowledge regarding the protective effect of CAPE in nephrotoxicity induced by several special medicines such as cisplatin, doxorubicin, cyclosporine, gentamycin, methotrexate, and other causes leading to oxidative renal injury, namely, I/R models and senility.

  8. Caffeic acid phenethyl ester as a protective agent against nephrotoxicity and/or oxidative kidney damage: a detailed systematic review.

    Science.gov (United States)

    Akyol, Sumeyya; Ugurcu, Veli; Altuntas, Aynur; Hasgul, Rukiye; Cakmak, Ozlem; Akyol, Omer

    2014-01-01

    Caffeic acid phenethyl ester (CAPE), an active component of propolis, has been attracting the attention of different medical and pharmaceutical disciplines in recent years because of its antioxidant, anti-inflammatory, antiproliferative, cytotoxic, antiviral, antifungal, and antineoplastic properties. One of the most studied organs for the effects of CAPE is the kidney, particularly in the capacity of this ester to decrease the nephrotoxicity induced by several drugs and the oxidative injury after ischemia/reperfusion (I/R). In this review, we summarized and critically evaluated the current knowledge regarding the protective effect of CAPE in nephrotoxicity induced by several special medicines such as cisplatin, doxorubicin, cyclosporine, gentamycin, methotrexate, and other causes leading to oxidative renal injury, namely, I/R models and senility.

  9. 合欢皮总皂苷所致小鼠肾毒性及其机制的研究%Study of nephrotoxicity and its mechanism of saponin from Albizia julibrissin durazz in mice

    Institute of Scientific and Technical Information of China (English)

    邱丽颖; 李倩; 许天蟾; 刘玲艳; 冯磊; 金坚; 吴鹏西

    2011-01-01

    Objective To Study the nephrotoxicity and its mechanism of saponin from Albizia julibrissin Durazz in mice. Method Giving mice the toxic dose of saponin for one time,and after 14 days, observe the nephrotoxicity of mice. The morphosis was observed by Hematoxylin Eosin staining. The activities of superoxide dismutase ( SOD) and glutathione peroxidase ( CSH-Px) were measured by biochemical methods. The apoptosis of kidney cell was detected by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling(TUNEL) method. Immunohistochemical detection of renal Bcl-2, Bax, COX-1 and COX-2 gene expression. Results Toxic dose of total saponin caused pathological changes in kidney, Reduced renal SOD and CSH-Px activities; increase in the number of glomerular endothelial cell apoptosis, Bcl-2 expression decreased, COX-2 expression increased; tubular COX-1 expression increased. Conclusion It shows that total saponin has toxicity to kidney. It perhaps related to increased apoptosis, decreased ability of anti-oxygen, reduced the expression of Bcl-2, and increased the expression of COX.%目的 研究合欢皮总皂苷对小鼠肾毒性及其机制.方法 采用一次性灌胃致毒剂量总皂苷,观察14 d时,合欢皮总皂苷对小鼠肾毒性表现.苏木素-伊红(HE)染色观察病理形态的变化,生化法测定其对肾SOD和GSH-Px的影响,末端标记法检测肾细胞凋亡,免疫组织化学法检测肾组织Bcl-2、Bax、COX-1及COX-2基因蛋白的表达.结果 合欢皮总皂苷口服致毒剂量可引起肾组织形态的变化,降低肾SOD和GSH-Px的活性;肾小球内皮细胞凋亡数目增多,Bcl-2表达下降,COX-2表达增加;肾小管COX-1表达增加.结论 致毒量合欢皮总皂苷对肾有一定毒性,促使细胞凋亡,可能与总皂苷降低肾的抗氧化能力和改变凋亡相关基因的表达、升高COX-1的表达有关.

  10. Beetroot (Beta vulgaris L. Extract Ameliorates Gentamicin-Induced Nephrotoxicity Associated Oxidative Stress, Inflammation, and Apoptosis in Rodent Model

    Directory of Open Access Journals (Sweden)

    Ali A. El Gamal

    2014-01-01

    Full Text Available The present investigation was designed to investigate the protective effect of (Beta vulgaris L. beat root ethanolic extract (BVEE on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific kidney function parameters (urea, uric acid, total protein, creatinine, and histopathology of kidney tissue were evaluated to access gentamicin-induced nephrotoxicity. The oxidative/nitrosative stress (Lipid peroxidation, MDA, NP-SH, Catalase, and nitric oxide levels was assessed. The inflammatory response (TNF-α, IL-6, MPO, NF-κB (p65, and NF-κB (p65 DNA binding and apoptotic marker (Caspase-3, Bax, and Bcl-2 were also evaluated. BVEE (250 and 500 mg/kg treatment along with gentamicin restored/increased the renal endogenous antioxidant status. Gentamicin-induced increased renal inflammatory cytokines (TNF-α and IL-6, nuclear protein expression of NF-κB (p65, NF-κB-DNA binding activity, myeloperoxidase (MPO activity, and nitric oxide level were significantly down regulated upon BVEE treatment. In addition, BVEE treatment significantly reduced the amount of cleaved caspase 3 and Bax, protein expression and increased the Bcl-2 protein expression. BVEE treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. These findings suggest that BVEE treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, inflammation, and apoptosis in the kidney.

  11. Additive Renoprotection by Pioglitazone and Fenofibrate against Inflammatory, Oxidative and Apoptotic Manifestations of Cisplatin Nephrotoxicity: Modulation by PPARs.

    Science.gov (United States)

    Helmy, Mai M; Helmy, Maged W; El-Mas, Mahmoud M

    2015-01-01

    Nephrotoxicity is a major side effect for the antineoplastic drug cisplatin. Here, we employed pharmacological, biochemical, and molecular studies to investigate the role of peroxisome proliferator-activated receptors (PPARs) in cisplatin nephrotoxicity. Rats were treated with a single i.p. dose of cisplatin (5 mg/kg) alone or combined with pioglitazone (PPARγ agonist), fenofibrate (PPARα agonist), pioglitazone plus fenofibrate, or thalidomide (Tumor necrosis factor-α inhibitor; TNF-α). Cisplatin nephrotoxicity was evidenced by rises in renal indices of functional (blood urea nitrogen, BUN, and creatinine), inflammatory (TNF-α, interleukin 6, IL-6), oxidative (increased malondialdehyde, MDA, and decreased superoxide dismutase, SOD and nitric oxide metabolites, NOx), apoptotic (caspase 3), and histological (glomerular atrophy, acute tubular necrosis and vacuolation) profiles. Cisplatin effects were partly abolished upon concurrent exposure to pioglitazone, fenofibrate, or thalidomide; more renoprotection was observed in rats treated with pioglitazaone plus fenofibrate. Immunostaining showed that renal expressions of PPARα and PPARγ were reduced by cisplatin and restored to vehicle-treated values after simultaneous treatment with pioglitazone or fenofibrate. Fenofibrate or pioglitazone renoprotection remained unaltered after concurrent blockade of PPARα (GW6471) and PPARγ (GW9662), respectively. To complement the rat studies, we also report that in human embryonic kidney cells (HEK293 cells), increases caused by cisplatin in inflammatory, apoptotic, and oxidative biomarkers were (i) partly improved after exposure to pioglitazone, fenofibrate, or thalidomide, and (ii) completely disappeared in cells treated with a combination of all three drugs. These data establish that the combined use of pioglitazone and fenofibrate additively improved manifestations of cisplatin nephrotoxicity through perhaps GW6471/GW9662-insensitive mechanisms.

  12. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein

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    Kopylchuk G.P.

    2015-09-01

    Full Text Available Background. Acetaminophen is known as inducer of acute hepatotoxicity. Extrahepatic manifestations of acetaminophen toxicity are poorly understood in particular its nephrotoxicity. Objective. The purpose of this study was the morphological characteristic of rat kidneys under the conditions of acetaminophen-induced nephrotoxicity on the background of alimentary deprivation of protein. Methods. Аfter administration of the toxic dose of acetaminophen and maintenance of rats on a different regimen of protein nutrition their kidneys were sectioned and stained with hematoxylin and eosin according to a standard technique. Results. It was estimated, that in rats maintained during long period of time under the conditions of alimentary deprivation of protein, and in rats injected with toxic dose of acetaminophen morphological changes of kidney were not observed. Administration of acetaminophen on the background of previous protein deficiency causes the pathological changes of kidney morphology with papillary necrosis as a key sign. Conclusion. Alimentary deprivation of protein in case of acetaminophen injection is the critical factor for the impairment of structural integrity of kidney tissue with its subsequent dysfunction. Citation: Kopylchuk GP, Voloshchuk ON, Buchkovskaia IM, Davydenko IS. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein]. Morphologia. 2015;9(3:28-30. Russian.

  13. A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology.

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    R Brian Stevens

    Full Text Available The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI, a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand.To determine whether intensive rabbit anti-thymocyte globulin (rATG induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology-surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology.Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180. Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months.CNI withdrawal (on-treatment analysis associated with better graft function (p <0.001 and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003 and 24 (p = 0.013 months, without affecting patient (p = 0.81 or graft (p = 0.93 survival, or rejection rate (p = 0.17.CNI (tacrolimus withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function

  14. Clinical observation of the effect of tacrolimus (Prograf) against renal allograft rejection in 294 cases

    Institute of Scientific and Technical Information of China (English)

    YU Li-xin; YE Gui-rong; DENG Wen-feng; FU Shao-jie; DU Chuan-fu; MIAO Yun; YAO Bing

    2002-01-01

    Objective: To study the effect of tacrolimus (Prograf, FK506) in preventing renal allograft rejection. Methods: The curative effect, therapy index, toxicity and side effects of FK506 were observed in 294renal transplant recipients among whom 268 received FK506 24 h after the operation and the other 26 with cyclosporine (CsA) developed acute rejection after transplantation and were given FK506 to replace methylprednisolone (MP) when the latter did not result. All the patients were given oral mycophenolate mofetil (MMF, 1.0 g/d) and meticorten (Pred, 30 mg/d) 24 h later after operation. Results: In the 268 recipients previously mentioned, the incidence of acute rejection was 10. 45%, glycometabolism disorder 9.33%, nervous system disturbance 1.59%, liver function abnormality 2.99%, nephrotoxicity 1.87%, gastrointestinal disorder 17. 5%, cytomegalovirus (CMV) viremia 2.99%, and non-CMV pulmonary infection 1. 59%(4/268), with 1 fatal case for cerebral hemorrhage with normal allograft function and another 2 non-fatal cases in which function loss resulted in removal of the allografts. The blood trough concentrations of FK506were between 5 and 20μg/L. In the 26 cases of steroid-resistant rejection, 23 (88. 46%, 23/26) were reversed and the rest 3 required plasma exchange and application of OKT3 before recovery. Conclusion: As a safe and effective immunosuppressant, FK506 can reduce the incidence of allograft rejection in kidney transplant recipients with little side effects or toxicity, which is particularly applicable in patients with steroid-resistant rejection or CsA nephrotoxicity. Attention should to be paid to glycometabolism disorder due to FK506, however, the long-term effects of FK506 need further investigation.

  15. Acute renal failure by ingestion of Euphorbia paralias.

    Science.gov (United States)

    Boubaker, Karima; Ounissi, Mondher; Brahmi, Nozha; Goucha, Rym; Hedri, Hafedh; Abdellah, Taieb Ben; El Younsi, Fethi; Maiz, Hedi Ben; Kheder, Adel

    2013-05-01

    Euphorbia paralias is known in traditional medicine as an anti-inflammatory agent, a purgative and for its local anesthetic property. To the best our knowledge, renal toxicity of this substance has not been previously reported. In this paper, we report the case of a 29-year-old male who developed renal damage following ingestion of Euphorbia paralias. He had been on follow-up for nephrotic syndrome since 1986, although irregularly, with several relapses but each responding well to steroid therapy. A kidney biopsy had not been performed earlier due to refusal by the patient. He was off steroids since April 2008 because the patient developed osteoporosis. He was admitted with general malaise and oliguria to our department in May 2009, following repeated vomiting and watery diarrhea for three days. On examination, he was edematous but had normal vital signs except for a pulse rate of 120/min. Hemoglobin was only 5.5 g/dL but with normal white cell and platelet counts. Blood biochemistry showed evidence of advanced renal failure with a serum creatinine level of 1835 μmol/L and urea at 44.6 mmol/L, sodium of 132 μmol/L and potassium at 4.3 mmol/L. He had features of nephrotic syndrome with severe hypoproteinamia and 24-h urinary protein of 10.45 g. Ultrasonography revealed enlarged kidneys with a reduced echogenecity of the medulla and the papillae. Subsequently, after hemodialysis with blood transfusion, a kidney biopsy was performed that showed focal segmental glomerulosclerosis associated with an acute tubular injury. On intensive interrogation, the patient gave a history of ingesting boiled Euphorbia paralias as a native treatment for edema, ten days prior to the onset of the current illness. A diagnosis of acute renal failure (ARF) resulting from the possible nephrotoxic effect of Euphorbia paralias poisoning was made. He was treated with intermittent hemodialysis and corticosteroids. Serum creatinine values improved after 48 days. At six months following the

  16. Acute renal failure by ingestion of Euphorbia paralias

    Directory of Open Access Journals (Sweden)

    Karima Boubaker

    2013-01-01

    Full Text Available Euphorbia paralias is known in traditional medicine as an anti-inflammatory agent, a purgative and for its local anesthetic property. To the best our knowledge, renal toxicity of this substance has not been previously reported. In this paper, we report the case of a 29-year-old male who developed renal damage following ingestion of Euphorbia paralias. He had been on follow-up for nephrotic syndrome since 1986, although irregularly, with several relapses but each responding well to steroid therapy. A kidney biopsy had not been performed earlier due to refusal by the patient. He was off steroids since April 2008 because the patient developed osteoporosis. He was admitted with general malaise and oliguria to our department in May 2009, following repeated vomiting and watery diarrhea for three days. On examination, he was edematous but had normal vital signs except for a pulse rate of 120/min. Hemoglobin was only 5.5 g/dL but with normal white cell and platelet counts. Blood biochemistry showed evidence of advanced renal failure with a serum creatinine level of 1835 μmol/L and urea at 44.6 mmol/L, sodium of 132 μmol/L and potassium at 4.3 mmol/L. He had features of nephrotic syndrome with severe hypoproteinamia and 24-h urinary protein of 10.45 g. Ultrasonography revealed enlarged kidneys with a reduced echogenecity of the medulla and the papillae. Subsequently, after hemodialysis with blood transfusion, a kidney biopsy was performed that showed focal segmental glomerulosclerosis associated with an acute tubular injury. On intensive interrogation, the patient gave a history of ingesting boiled Euphorbia paralias as a native treatment for edema, ten days prior to the onset of the current illness. A diagnosis of acute renal failure (ARF resulting from the possible nephrotoxic effect of Euphorbia paralias poisoning was made. He was treated with intermittent hemodialysis and corticosteroids. Serum creatinine values improved after 48 days. At six

  17. Dietary inclusion of local salt substitutes induces oxidative stress and renal dysfunction in rats.

    Science.gov (United States)

    Akinyemi, Ayodele J; Oboh, Ganiyu; Ademiluyi, Adedayo O; Araoye, Obafemi O; Oyeleye, Sunday I

    2014-01-01

    Our earlier report has shown that salt substitutes (Obu-Otoyo) contain some toxic heavy metals. This study, therefore, investigated the effect of the dietary inclusion of salt substitutes (Obu-Otoyo), namely, salt "A" and "B", on biomarkers of oxidative stress and renal function in rats. Salt "A", which has a gray color, is the product of a process in which ash is produced by burning palm kernel shaft soaked in water overnight and extracting the residue to produce the salt substitute while Salt "B", which has a white color, is a rock salt mined from a local site at Ilobu town, Osun-State, Nigeria. Salt substitutes were fed to normal rats as dietary inclusion at 0.5% and 1.0% for 21 days. The dietary inclusion of the salt substitutes caused a significant (psalt substitutes caused a significant (psalt substitute Obu-Otoyo. Therefore, this finding indicates that Obu-Otoyo induces nephrotoxicity in rats. The nephrotoxicity of Obu-Otoyo could be attributed to the induction of oxidative stress as a result of the presence of some heavy metals, suggesting possible health hazards in subjects who consume it.

  18. Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats

    Directory of Open Access Journals (Sweden)

    Lakhera Abhijeet

    2015-06-01

    Full Text Available Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies.

  19. 肾损伤分子1在急性肾损伤与修复中的作用研究进%Kidney injury molecule-1 in acute kidney injury and renal repair: a review

    Institute of Scientific and Technical Information of China (English)

    Takaharu ICHIMURA; 牟姗

    2008-01-01

    @@ 1 Introduction Ac1ute kidney injury is very important in clinic [1,2].The primary etiologies of acute kidney injury and its severe condition,acute renal failure(ARF), are ischemia,sepsis and nephrotoxicity associated with therapeutic agents.In addition,nephrotoxicity is a central concern in pharmaceutical developmerit because of its implications for patient safety.

  20. Effect of chronic accumulation of aluminum on renal function, cortical renal oxidative stress and cortical renal organic anion transport in rats.

    Science.gov (United States)

    Mahieu, Stella T; Gionotti, Marisa; Millen, Néstor; Elías, María Mónica

    2003-11-01

    The aim of the present work was to study the nephrotoxicity of aluminum lactate administered for 3 months (0.57 mg/100 g bodyweight aluminum, i.p., three times per week) to male Wistar rats. Renal function was studied after 6 weeks of treatment (urine was obtained from rats in metabolic cages) and at the end of the treatment using clearance techniques. Another group of rats was used as kidneys donors at the end of treatment. The renal cortex was separated and homogenized to determine glutathione (GSH) level, glutathione S-transferase (GST) activity and lipid peroxidation (LPO) level. Renal cortex slices were also used to study the p-aminohippuric acid (PAH) accumulation during steady-state conditions and the kinetics of uptake process. Clearance results, at the end of the treatment, indicated that renal functions in treated-rats were not different from those measured in control rats, although the renal concentration parameters differ when they were measured in treated rats after 24 h of food and water deprivation. Balances of water and sodium were also modified at both 1.5 and 3 months of treatment. The activity of alkaline phosphatase (AP) relative to inulin excreted in urine was significantly impaired: controls 2.2+/-0.6 IUI/mg, Al-treated 5.1+/-0.5 IU/mg, Prats. Renal accumulation of PAH, estimated as slice-to-medium ratio, decreased significantly in the Al-treated rats: control rats 3.06+/-0.02 ( n=12), Al-treated rats 2.26+/-0.04 ( n=12), Prats, while the apparent affinity remained unchanged. All these results indicate that aluminum accumulation in renal tissue affects cellular metabolism, promotes oxidative stress and induces alterations in renal tubular PAH transport, together with an impairment in sodium and water balance only detected under conditions of water deprivation, without other evident changes in glomerular filtration rate or other global functions measured by clearance techniques at least at this time of chronic toxicity.

  1. Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure.

    Science.gov (United States)

    Yaqoob, Noreen; Evans, Andrew; Foster, John R; Lock, Edward A

    2014-09-02

    Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500mg/kg/day) or TCE-OH at (100mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism

  2. Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats.

    Science.gov (United States)

    Ibrahim, Abdelazim; Eldaim, Mabrouk A Abd; Abdel-Daim, Mohamed M

    2016-08-01

    Cisplatin is one of the most potent and effective chemotherapeutic agents. However, its antineoplastic use is limited due to its cumulative nephrotoxic side effects. Therefore, the present study was undertaken to examine the nephroprotective potential of dietary bee honey and royal jelly against subchronic cisplatin toxicity in rats. Male Wistar rats were randomly divided into controls, cisplatin-treated, bee honey-pretreated cisplatin-treated and royal jelly-pretreated cisplatin-treated groups. Bee honey and royal jelly were given orally at doses of 20 and 100 mg/kg, respectively. Subchronic toxicity was induced by cisplatin (1 mg/kg bw, ip), twice weekly for 10 weeks. Cisplatin treated animals revealed a significant increase in serum level of renal injury products (urea, creatinine and uric acid). Histopathologically, cisplatin produced pronounced tubulointerstitial injuries, upregulated the fibrogenic factors, α-smooth muscle actin (α-SMA) and transforming growth factor β1(TGF-β1), and downregulated the cell proliferation marker, bromodeoxyuridine (Brdu). Dietary bee honey and royal jelly normalized the elevated serum renal injury product biomarkers, improved the histopathologic changes, reduced the expression of α-SMA and TGF-β1 and increased the expression of Brdu. Therefore, it could be concluded that bee honey, and royal jelly could be used as dietary preventive natural products against subchronic cisplatin-induced renal injury.

  3. Antagonistic effects of Spirulina platensis against sub-acute deltamethrin toxicity in mice: Biochemical and histopathological studies.

    Science.gov (United States)

    Abdel-Daim, Mohamed; El-Bialy, Badr E; Rahman, Haidy G Abdel; Radi, Abeer M; Hefny, Hany A; Hassan, Ahmed M

    2016-02-01

    Spirulina platensis (SP); a microalga with high antioxidant and anti-inflammatory activities, acts as a food supplement in human and as many animal species. Deltamethrin (DLM) is a synthetic pyrethroid with broad spectrum activities against acaricides and insects and widely used for veterinary and agricultural purposes. Exposure to DLM leads to hepatotoxic, nephrotoxic and neurotoxic side effects for human and many species, including birds and fish. The present study was undertaken to examine the potential hepatoprotective, nephroprotective, neuroprotective and antioxidant effects of SP against sub-acute DLM toxicity in male mice. DLM intoxicated animals revealed a significant increase in serum hepatic and renal injury biomarkers as well as TNF-α level and AChE activity. Moreover, liver, kidney and brain lipid peroxidation and oxidative stress markers were altered due to DLM toxicity. Spirulina normalized the altered serum levels of AST, ALT, APL, LDH, γ-GT, cholesterol, uric acid, urea, creatinine AChE and TNF-α. Furthermore, it reduced DLM-induced tissue lipid peroxidation, nitric oxide and oxidative stress in a dose-dependent manner. Collectively, that Spirulina supplementation could overcome DLM-induced hepatotoxicty, nephrotoxicity and neurotoxicity by abolishing oxidative tissue injuries.

  4. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

    Science.gov (United States)

    Nassar, Inthisham; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio

    2010-06-01

    Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

  5. Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress.

    Science.gov (United States)

    Valentovic, Monica A; Ball, John G; Brown, J Mike; Terneus, Marcus V; McQuade, Elizabeth; Van Meter, Stephanie; Hedrick, Hayden M; Roy, Amy Allison; Williams, Tierra

    2014-03-01

    Cisplatin, a cancer chemotherapy drug, is nephrotoxic. The aim of this study was to investigate whether resveratrol (RES) reduced cisplatin cytotoxicity and oxidative stress. Rat renal cortical slices were pre-incubated 30min with 0 (VEH, ethanol) or 30μg/ml RES followed by 60, 90 or 120min co-incubation with 0, 75, or 150μg/ml cisplatin. Lactate dehydrogenase (LDH) leakage was unchanged at 60 and 90min by cisplatin. Cisplatin increased (pCisplatin induced oxidative stress prior to LDH leakage as cisplatin depressed glutathione peroxidase and superoxide dismutase (SOD) activity, increased lipid peroxidation, protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins within 60min. RES failed to reverse glutathione (GSH) depression by cisplatin. In order to eliminated an extracellular interaction between RES and cisplatin, additional studies (RINSE studies) allowed a 30min RES uptake into slices, transfer of slices to buffer lacking RES, followed by 120min cisplatin incubation. RES in the RINSE studies prevented LDH leakage by cisplatin indicating that RES protection was not via a physical interaction with cisplatin in the media. These findings indicate that RES diminished cisplatin in vitro renal toxicity and prevented the development of oxidative stress.

  6. Renal function and histology in children after small bowel transplantation.

    Science.gov (United States)

    Boyer, Olivia; Noto, Cristian; De Serre, Natacha Patey-Mariaud; Gubler, Marie-Claire; Dechaux, Michèle; Goulet, Olivier; Niaudet, Patrick; Lacaille, Florence

    2013-02-01

    CKD is a frequent long-term complication after SBTx. CNIs are a well-known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC-based maintenance immunosuppression. Median follow-up was seven yr (3-21). A renal biopsy was performed in 14 patients, 1-18 yr post-SBTx. A reduced GFR was observed in 17 children (63%) during the follow-up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post-transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow-up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.

  7. The Protective Effects of Sika Deer Antler Protein on Cisplatin-Induced Nephrotoxicity

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    Huihai Yang

    2017-08-01

    Full Text Available Background/Aims: This study measured the effect of Sika deer (Cervus nippon Temminck antler protein (SDAPR, glycoproteins (SDAG, and polysaccharides (SDAPO on cisplatin-induced cytotoxicity in HEK 293 cells, and investigated the effect of SDAPR against cisplatin-induced nephrotoxicity in mice. Methods: Cell viability was measured by MTT assay. ICR mice were randomly divided into five groups: control, cisplatin with vehicle, and cisplatin with SDAPR at three concentrations: 5, 10, or 20 mg/kg, p.o., 10 d. Cisplatin was injected on 7th day (25 mg/kg, i.p.. Renal function, oxidative stress, levels of inflammatory factors, and expression of apoptosis-related proteins were measured in vivo. Renal tissues were stained with TUNEL and H&E to observe renal cell apoptosis and pathological changes. Results: Pretreatment with SDAPR (125-2000 µg/mL significantly improved cell viability, with an EC50 of approximately 1000 µg/mL. SDAPR also ameliorated cisplatin-induced histopatholo- gic changes, and decreased blood urea nitrogen (BUN and creatinine (Cr (P < 0.05. Western blotting analysis showed SDAPR clearly decreased expression levels of cleaved-caspase-3 and Bax, and increased the expression level of Bcl-2 (P < 0.01. Additionally, SDAPR markedly regulated oxidative stress markers and inflammatory cytokines (P<0.05. TUNEL staining showed decreased apoptosis after SDAPR treatment (P < 0.01. Conclusions: These results indicate that SDAPR can be an effective dietary supplement, to relieve cisplatin-induced nephrotoxicity by improved antioxidase activity, suppressed inflammation, and inhibited apoptosis in vivo.

  8. Microproteinuria for detecting calcineurin inhibitor-related nephrotoxicity after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Jing Li; Bin Liu; Lu-Nan Yan; Lan-Lan Wang; Wan Y Lau; Bo Li; Wen-Tao Wang; Ming-Qing Xu; Jia-Yin Yang; Fu-Gui Li

    2009-01-01

    AIM: To investigate whether microproteinuria could be used as an early and sensitive indicator to detect calcineurin inhibitor (CNI)-related nephrotoxicity after liver transplantation. METHODS: All liver transplant recipients with normal serum creatinine (SCr) and detectable microproteinuria at baseline were included in this study. The renal function was monitored by the blood clearance of 99mTc-diethylenetriaminepentaacetic acid every 6 mo. Microproteinuria, SCr and blood urea nitrogen (BUN) were measured at entry and at subsequent follow-up visits. The patients were divided into different groups according to the mean values of glomerular filtration rate (GFR) at the follow-up time points: Group 1, GFR decreased from baseline by 0%-10%; Group 2, GFR decreased from baseline by 11%-20%; Group 3, GFR decreased from baseline by 21%-40%; Group 4, GFR decreased from baseline by > 40% and/or SCr was increasing. RESULTS: A total of 143 patients were enrolled into this study (23 females and 120 males). The mean follow-up was 32 mo (range 16-36 mo). Downward trends in renal function over time were observed in the study groups. SCr and BUN increased significantly only in Group 4 patients ( P < 0.001). β2-microglobulin (β2m) and α1-microglobulin (α1m) significantly increased with the subtle change of renal function in recipients who were exposed to CNI-based immunosuppression regimens. The reductions in GFR were closely correlated with elevated α1m ( r2 = -0.728, P < 0.001) and β2m ( r2 = -0.787, P < 0.001). CONCLUSION: β2m and α1m could be useful as early and sensitive indicators of CNI-induced nephrotoxicity.

  9. Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats

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    Faddah Laila M

    2012-05-01

    Full Text Available Abstract Background Nanoparticles are small-scale substances ( Method ZnO nanoparticles were administered orally in two doses (either 600 mg or 1 g/Kg body weight/day for 5 conscutive days to Wister albino rats. In order to detect the protective effects of the studied antioxidants against n-ZnO induced nepherotoxicity, different biochemical parameters were investigated. Moreover, histopathological examination of kidney tissue was performed. Results Nano zinc oxide-induced nephrotoxicity was confirmed by the elevation in serum inflammatory markers including: tumor necrosis factor alpha (TNF-α, interleukin-6 (IL-6; and C-reactive protein (CRP. Moreover, immunoglobulin (IGg, vascular endothelium growth factor (VEGF, and nitric oxide (NO were significantly increased in rat serum. Serum urea and creatinine levels were also significantly increased in rats intoxicated with n-ZnO particles compared with the control group. Additionally, a significant decrease in the non-enzymatic antioxidant reduced glutathione (GSH was shown in kidney tissues and serum glucose levels were increased. These biochemical findings were supported by a histopathological examination of kidney tissues, which showed that in the animals that received a high dose of n-ZnO, numerous kidney glomeruli underwent atrophy and fragmentation. Moreover, the renal tubules showed epithelial desquamation, degeneration and necrosis. Some renal tubules showed casts in their lumina. Severe congestion was also observed in renal interstitium. These effects were dose dependent. Cotreatment of rats with Qur and/or Arg along with n-ZnO significantly improved most of the deviated tested parameters. Conclusions The data show that Qur has a beneficial effect against n-ZnO oxidative stress and related vascular complications. Also, its combination with Arg proved to be even more effective in ameliorating nano zinc oxide nephrotoxicity.

  10. Role of Free Radicals and Biotransformation in Trichloronitrobenzene-Induced Nephrotoxicity In Vitro

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    Gary O. Rankin

    2017-05-01

    Full Text Available This study determined the comparative nephrotoxic potential of four trichloronitrobenzenes (TCNBs (2,3,4-; 2,4,5-; 2,4,6-; and 3,4,5-TCNB and explored the effects of antioxidants and biotransformation inhibitors on TCNB-induced cytotoxicity in isolated renal cortical cells (IRCC from male Fischer 344 rats. IRCC were incubated with a TCNB up to 1.0 mM for 15–120 min. Pretreatment with an antioxidant or cytochrome P450 (CYP, flavin monooxygenase (FMO, or peroxidase inhibitor was used in some experiments. Among the four TCNBs, the order of decreasing nephrotoxic potential was approximately 3,4,5- > 2,4,6- > 2,3,4- > 2,4,5-TCNB. The four TCNBs exhibited a similar profile of attenuation of cytotoxicity in response to antioxidant pretreatments. 2,3,4- and 3,4,5-TCNB cytotoxicity was attenuated by most of the biotransformation inhibitors tested, 2,4,5-TCNB cytotoxicity was only inhibited by isoniazid (CYP 2E1 inhibitor, and 2,4,6-TCNB-induced cytotoxicity was inhibited by one CYP inhibitor, one FMO inhibitor, and one peroxidase inhibitor. All of the CYP specific inhibitors tested offered some attenuation of 3,4,5-TCNB cytotoxicity. These results indicate that 3,4,5-TCNB is the most potent nephrotoxicant, free radicals play a role in the TCNB cytotoxicity, and the role of biotransformation in TCNB nephrotoxicity in vitro is variable and dependent on the position of the chloro groups.

  11. Role of Free Radicals and Biotransformation in Trichloronitrobenzene-Induced Nephrotoxicity In Vitro.

    Science.gov (United States)

    Rankin, Gary O; Tyree, Connor; Pope, Deborah; Tate, Jordan; Racine, Christopher; Anestis, Dianne K; Brown, Kathleen C; Dial, Mason; Valentovic, Monica A

    2017-05-31

    This study determined the comparative nephrotoxic potential of four trichloronitrobenzenes (TCNBs) (2,3,4-; 2,4,5-; 2,4,6-; and 3,4,5-TCNB) and explored the effects of antioxidants and biotransformation inhibitors on TCNB-induced cytotoxicity in isolated renal cortical cells (IRCC) from male Fischer 344 rats. IRCC were incubated with a TCNB up to 1.0 mM for 15-120 min. Pretreatment with an antioxidant or cytochrome P450 (CYP), flavin monooxygenase (FMO), or peroxidase inhibitor was used in some experiments. Among the four TCNBs, the order of decreasing nephrotoxic potential was approximately 3,4,5- > 2,4,6- > 2,3,4- > 2,4,5-TCNB. The four TCNBs exhibited a similar profile of attenuation of cytotoxicity in response to antioxidant pretreatments. 2,3,4- and 3,4,5-TCNB cytotoxicity was attenuated by most of the biotransformation inhibitors tested, 2,4,5-TCNB cytotoxicity was only inhibited by isoniazid (CYP 2E1 inhibitor), and 2,4,6-TCNB-induced cytotoxicity was inhibited by one CYP inhibitor, one FMO inhibitor, and one peroxidase inhibitor. All of the CYP specific inhibitors tested offered some attenuation of 3,4,5-TCNB cytotoxicity. These results indicate that 3,4,5-TCNB is the most potent nephrotoxicant, free radicals play a role in the TCNB cytotoxicity, and the role of biotransformation in TCNB nephrotoxicity in vitro is variable and dependent on the position of the chloro groups.

  12. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    Energy Technology Data Exchange (ETDEWEB)

    Kandasamy, Neelamegam; Ashokkumar, Natarajan, E-mail: npashokkumar1@gmail.com

    2014-09-01

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

  13. Gentamicin-mediated ototoxicity and nephrotoxicity: A clinical trial study

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    Parviz Saleh

    2016-01-01

    Full Text Available Background: Aminoglycosides and mainly gentamicin are the most important antimicrobial agents. Two different methods of administration exist: Single and multiple doses. There has always been a controversy about the less harmful administration method, to minimize adverse effects of gentamicin - deafness and renal insufficiency. In this study, it was aimed to compare two different methods of administration to figure out the least harmful treatment method. Materials and Methods: In a clinical study, eighty patients aged 12-55 years who were admitted with sepsis syndrome were included in the study; they were divided into two groups: The first group received single-dose treatment (5 mg/kg whereas the second group was treated with multiple doses (1.7 mg/kg three times a day of gentamicin. Results: The results show that blood urea nitrogen (BUN and creatinine (CR levels were decreased in the first group. Both blood urea nitrogen and creatinine and also mean glomerular filtration rate was increased in the same group. In the second group, mean BUN and CR levels were increased while the GFR was decreased in the same group. There was also a gradual increase in GFR in the first group. GFR <80 was decreased from 20% to 5.1% in the first group while increased from 5% to 27.5% in the second group. Results of audiometric studies show 6.1% hearing problem in the first group and 12.8% in the second one. Conclusions: Results of the present study showed that nephrotoxicity and ototoxicity are minimized in single-dose administration compared to multiples doses.

  14. Comparison of the effectiveness and renal safety of tenofovir versus entecavir in patients with chronic hepatitis B

    Directory of Open Access Journals (Sweden)

    Beatriz López Centeno

    2016-07-01

    Full Text Available Objective: To compare the effectiveness and renal safety of treatment with tenofovir versus entecavir in patients with chronic hepatitis-B. Methods: Retrospective study in hepatitis-B patients who initiated treatment with tenofovir or entecavir since January 1998 until 2013. The primary effectiveness variable was defined as viral DNA < 20 UI/ml (HBV-DNA and the variable for renal safety was variations in glomerular filtration rate (eGFR after 48 weeks of treatment. Results: The analysis was conducted in 64 patients (1:1, with similar characteristics except for the prevalence of naive patients (p=0.036, comorbidities (p=0.077 and nephrotoxic drugs (p=0.088 in the entecavi arm, while the tenofovir arm presented a prevalence of patients with HBV-DNA < 20 UI/ml (p=0.032 and HBeAg-positive (p=0.050. Statistical univariate analysis and adjustment for confounding variables was conducted through the Propensity Score (PS. The outcomes for the primary effectiveness variable showed tenofovir superiority after PS adjustment, with an ORadj=6.7 (95% CI:1.2-35.3; p=0.028. Three patients on tenofovir experienced seroconversion (p=0.148. The outcomes for the primary safety variable (eGFR < 60 ml/min/1.73m2 showed no difference between both arms after adjustment, achieving an ORadj=0.6 (95% CI:0.1-2.8; p=0.521. The tenofovir arm registered two cases of treatment interruption due to renal toxicity, with subsequent recovery, including one Fanconi Syndrome. Conclusions: In our study, there are significant differences between both treatments regarding effectiveness, with tenofovir demonstrating superiority. In terms of renal safety, we have not found any significant differences, but two cases of treatment interruption due to renal toxicity with tenofovir lead us to the conclusion that treatment decision in patients with renal function alteration should include an individualized assessment of each case.

  15. Nicotine Exposure Augments Renal Toxicity of 5-aza-cytidine Through p66shc: Prevention by Resveratrol.

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    Arany, Istvan; Hall, Samuel; Faisal, Amir; Dixit, Mehul

    2017-08-01

    We have shown that either chronic nicotine (NIC) exposure or 5-aza-cytidine (AZA) augments oxidative stress-dependent injury through stimulating p66shc in renal cells. Hence, NIC could exacerbate adverse effects of AZA while antioxidants such as resveratrol (RES) could prevent it. Renal proximal tubule cells (NRK52E) were treated with 20 μM RES prior to 200 μM NIC plus 100 nM AZA and cell injury (LDH release) was determined. Reporter luciferase assays determined p66shc activation and RES-induced antioxidant responses. Genetic manipulations identified the mechanism of RES action. NIC exacerbated AZA-dependent injury via augmenting p66shc transcription. While RES suppressed NIC+AZA-mediated injury, -surprisingly-it further enhanced activity of the p66shc promoter. RES protected cells via the cytoplasmic p66shc/Nrf2/heme oxygenase-1 (HO-1) axis. RES can protect the kidney from adverse effects of NIC in patients undergoing anticancer therapy. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Acute administration of tramadol and tapentadol at effective analgesic and maximum tolerated doses causes hepato- and nephrotoxic effects in Wistar rats.

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    Barbosa, Joana; Faria, Juliana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2017-08-15

    Tramadol and tapentadol are two atypical synthetic opioid analgesics, with monoamine reuptake inhibition properties. Mainly aimed at the treatment of moderate to severe pain, these drugs are extensively prescribed for multiple clinical applications. Along with the increase in their use, there has been an increment in their abuse, and consequently in the reported number of adverse reactions and intoxications. However, little is known about their mechanisms of toxicity. In this study, we have analyzed the in vivo toxicological effects in liver and kidney resulting from an acute exposure of a rodent animal model to both opioids. Male Wistar rats were intraperitoneally administered with 10, 25 and 50mg/kg tramadol and tapentadol, corresponding to a low, effective analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively, for 24h. Toxicological effects were assessed in terms of oxidative stress, biochemical and metabolic parameters and histopathology, using serum and urine samples, liver and kidney homogenates and tissue specimens. The acute exposure to tapentadol caused a dose-dependent increase in protein oxidation in liver and kidney. Additionally, exposure to both opioids led to hepatic commitment, as shown by increased serum lipid levels, decreased urea concentration, increased alanine aminotransferase and decreased butyrylcholinesterase activities. It also led to renal impairment, as reflected by proteinuria and decreased glomerular filtration rate. Histopathological findings included sinusoidal dilatation, microsteatosis, vacuolization, cell infiltrates and cell degeneration, indicating metabolic changes, inflammation and cell damage. In conclusion, a single effective analgesic dose or the maximum recommended daily dose of both opioids leads to hepatotoxicity and nephrotoxicity, with tapentadol inducing comparatively more toxicity. Whether these effects reflect risks during the therapeutic use or human overdoses requires focused

  17. Involvement of oxidative stress in the mechanism of p,p'-DDT-induced nephrotoxicity in adult rats.

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    Marouani, Neila; Hallegue, Dorsaf; Sakly, Mohsen; Benkhalifa, Moncef; Ben Rhouma, Khémais; Tebourbi, Olfa

    2017-07-01

    The 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (p,p'-DDT) is an organochlorine pesticide that persists in the environment and has a risk to human health. We investigated whether p,p'-DDT-induces nephrotoxicity in rats and whether oxidative stress and apoptosis are involved in the pathogenesis of this process. Male rats received the pesticide at doses of 50 and 100 mg/kg for 10 days. Renal damage was evaluated by histopathological examination and serum markers. The oxidative stress was evaluated by lipid peroxidation (LPO), metallothioneins (MTs) and protein carbonyl levels. Antioxidant enzymes were assessed by determination of superoxide dismutase (SOD) and catalase (CAT) activities. Glutathione-dependent enzymes and reducing power in kidney were evaluated by glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) activities. Renal tubular cells apoptosis was assessed through the TUNEL assay. After 10 days of treatment, an increase of serum creatinine and urea levels occurred, LPO and protein carbonyl levels were increased, while MTs level, SOD and CAT activities were decreased. Besides, the GPx, GR, GST, and GSH activities were decreased. Histological alterations in kidney tissue and intense apoptosis in renal tubular cells were observed. These results suggest that DDT sub-acute treatment causes oxidative stress and apoptosis, which may be the chief mechanisms of DDT-induced nephrotoxicity.

  18. Bee Venom Mitigates Cisplatin-Induced Nephrotoxicity by Regulating CD4+CD25+Foxp3+ Regulatory T Cells in Mice

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    Hyunseong Kim

    2013-01-01

    Full Text Available Cisplatin is used as a potent anticancer drug, but it often causes nephrotoxicity. Bee venom (BV has been used for the treatment of various inflammatory diseases, and its renoprotective action was shown in NZB/W mice. However, little is known about whether BV has beneficial effects on cisplatin-induced nephrotoxicity and how such effects might be mediated. In the present study, the BV-injected group showed a significant increase in the population of Tregs in spleen. Although there was no significant difference in the numbers of Tregs 3 days after cisplatin injection between the BV- and PBS-injected groups, more migration of Tregs into the ki