Full Text Available Fernando Giron, Yenny BaezKidney Transplant Service, Colombiana de Trasplantes, Bogota, ColombiaAbstract: Everolimus is a proliferation inhibitor designed to target chronic allograft nephropathy including prevention of acute rejection. Acute renal allograft rejection incidence varies with the therapy used for immunosuppression. Registry data show that 15% to 35% of kidney recipients will undergo treatment for at least one episode of acute rejection within the first post-transplant year. Everolimus has been used as therapy with full- or reduced-dose cyclosporine A without evidence of increasing the acute rejection incidence. This review will summarize the available clinical trial data on the use of everolimus and its role in preventing acute rejection incidence in renal transplantation.Keywords: calcineurin inhibitors, cyclosporine, everolimus, biopsy-proven acute rejection, renal transplantation, acute rejection
... Shortness of breath and less ability to exercise (heart transplant) Yellow skin color and easy bleeding (liver transplant) ... accountability. A.D.A.M. is among the first to achieve this important distinction for online health ...
Tabbara, Khalid F
Corneal transplantation remains one of the most successful organ transplantation procedures in humans. The unique structure of the cornea, with its absence of blood vessels and corneal lymphatic, allows the survival of corneal allograft. Recent advances in sutures, storage media, microsurgical instrumentation, and new pharmacological strategies have greatly improved the success of corneal transplantation and the prevention of corneal allograft rejection. Our strategies in the management and prevention of corneal graft rejection can modify and improve the survival of corneal allografts. Preoperative evaluation, understanding the risk factors, and management of ocular surface disorders may greatly improve the survival of the corneal transplant. Early recognition of corneal allograft rejection and aggressive treatment may improve the survival of the corneal graft. Furthermore, patients who undergo corneal transplantation should be maintained under close ophthalmic surveillance and patients should be informed to report immediately whenever symptoms of corneal graft rejection occur. The mainstay of therapy is topical corticosteroids. In severe cases, periocular, intravenous, and oral corticosteroids therapy can be rendered. New therapeutic modalities such as cyclosporine, tacrolimus, daclizumab, mycophenolate mofetil, leflunomide, rapamycin, and others may prove to be of help in the prevention and treatment of corneal graft rejection. Early recognition of corneal graft rejection and prompt treatment are mandatory for the successful survival of the corneal allograft.
Full Text Available Chuan-Jiang Li,1,* Liang Li2,* 1Department of Surgery, Nanfang Hospital, 2Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People’s Republic of China *The authors contributed equally to this work Abstract: Tacrolimus is a product of fermentation of Streptomyces, and belongs to the family of calcineurin inhibitors. It is a widely used immunosuppressive drug for preventing solid-organ transplant rejection. Compared to cyclosporine, tacrolimus has greater immunosuppressive potency and a lower incidence of side effects. It has been accepted as first-line treatment after liver and kidney transplantation. Tacrolimus has specific features in Chinese transplant patients; its in vivo pharmacokinetics, treatment regimen, dose and administration, and adverse-effect profile are influenced by multiple factors, such as genetics and the spectrum of primary diseases in the Chinese population. We reviewed the clinical experience of tacrolimus use in Chinese liver- and kidney-transplant patients, including the pharmacology of tacrolimus, the immunosuppressive effects of tacrolimus versus cyclosporine, effects of different factors on tacrolimus metabolism on Chinese patients, personalized medicine, clinical safety profile, and patient satisfaction and adherence. This article provides guidance for the rational and efficient use of tacrolimus in Chinese organ-transplant patients. Keywords: tacrolimus, liver transplantation, kidney transplant, Chinese, personalized medicine
Full Text Available Michael E Reschen, Christopher A O’Callaghan Henry Wellcome Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Abstract: Tacrolimus is the key immunosuppressant used to prevent allograft rejection in kidney and liver transplant recipients. Despite the efficacy of tacrolimus and adjunctive immunosuppressants, a substantial number of patients experience episodes of acute rejection and late graft loss. Nonadherence is an etiological factor in both acute rejection and graft loss. In 2007, a prolonged release version of tacrolimus became available that allows once daily administration, thus halving the pill burden compared to the standard twice-daily tacrolimus. An increasing number of studies in de novo transplantation and in treatment conversion have evaluated the pharmacokinetic profile, efficacy, and safety of prolonged-release tacrolimus. We have reviewed the literature on the use of prolonged-release tacrolimus and hope that this will be of value in the design of protocols for transplant immunosuppression.Keywords: immunosuppression, kidney, hepatic, allograft, adherence
Kim, I. H.; Ha, S. W.; Park, C. I.; Kim, S. T.
From 1979 to 1984, 39 local allograft irradiations were given to 29 patients: 10 irradiations were administered for prevention and 29 for reversal of acute rejection of transplanted kidney. Three doses of 150 cGy every other day were combined with high-dose of methylprednisolone pulse (1 gm/day) for 3 days. For prevention of acute rejection, local irradiation was delivered on the days 1, 3, and 5 after the transplantation, and for reversal, irradiation started after the diagnosis of acute rejection. Eight out of 10 patients irradiated for prevention had acute allograft rejection, and, what is more, there was no surviving graft at 15 months after transplantation. Reversal of acute rejection was achieved in 71%. When the pre-irradiation level of serum creatinine was below 5.5 mg%, the reversal rate was 93%, but above 5.5 mg% the reversal rate was only 17% (p<0.01). Reirradiation after failure was not successful. Among 15 reversed patients, 7 (47%) had subsequent rejection (s). The functional graft survivals at 6 month, 1, 2, and 3 year were 70%, 65%, 54%, and 65%, respectively. Therapeutic irradiation resulted in better graft survival when serum creatinine was below 5.5 mg% (p<0.001) or when irradiation started within 15 days after the diagnosis of acute rejection (p<0.001)
investigators successfully performed initial control experiments in unsensitized animals applying the proposed induction and maintenance immunosuppressive...transplantation was performed across a full SLA mismatch from a CC donor to an AD recipient animal . The animal was treated with non-myeloablative...reconstructive transplantation. The investigators will test their central hypothesis that that the impact and mechanisms, of AMR in reconstructive
Full Text Available Junichiro Sageshima, Gaetano Ciancio, Linda Chen, George W Burke IIIDewitt Daughtry Family Department of Surgery, Division of Kidney and Pancreas Transplantation, The Lillian Jean Kaplan Renal Transplant Center, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USAAbstract: The use of antibody induction after kidney transplantation has increased from 25% to 63% in the past decade and roughly one half of the induction agent used is anti-interleukin-2 receptor antibody (IL-2RA, ie, basiliximab or daclizumab. When combined with calcineurin inhibitor (CNI-based immunosuppression, IL-2RAs have been shown to reduce the incidence of acute rejection, one of the predictors of poor graft survival, without increasing risks of infections and malignancies in kidney transplantation. For low-immunological-risk patients, IL-2RAs, as compared with lymphocyte-depleting antibodies, are equally efficacious and have better safety profiles. For high-risk patients, however, IL-2RAs may be inferior to lymphocyte-depleting antibodies for the prophylaxis of acute rejection. In an effort to reduce toxicities of other immunosuppressive medications without increasing the risk of acute rejection and chronic graft loss, IL-2RAs have often been combined with steroid- and CNI-sparing immunosuppression protocols. More data support the benefits of early steroid withdrawal with IL-2RA in low-risk patients, but preferred induction therapy for high-risk patients has yet to be determined. Although CNI-sparing protocols with IL-2RA may preserve renal function and improve long-term survival in selected patients, further studies are needed to identify those who benefit most from this strategy.Keywords: basiliximab, daclizumab, interleukin-2 receptor antagonist, kidney transplantation, monoclonal antibody
Full Text Available Teresa Casanovas Liver Transplant Unit, Bellvitge University Hospital, Barcelona, Spain Abstract: Liver transplantation remains the therapy of choice for patients with end-stage liver disease and in selected cases of hepatocellular carcinoma. While short-term allograft survival has improved significantly in recent years, there has been little improvement in long-term survival after liver transplantation. A growing body of evidence on factors influencing the long-term outcomes and the safety profiles of existing immunosuppressive agents after liver transplant points to a need to continue searching for alternative strategies. The calcineurin inhibitors (CNIs (cyclosporine and tacrolimus currently represent the backbone of most immunosuppressor regimens. They have had a revolutionary effect on the overall success of transplantation, as is reflected in greatly reduced rates of acute rejection. However, the CNIs have significant toxicities that produce renal dysfunction, cardiovascular disease, and other unwanted effects, such as malignancies. The recognition of these risk factors has sparked interest in regimens that limit exposure to CNIs. Nowadays, the use of immunosuppressive drugs with different mechanisms of action, which allow for a reduction or avoidance of CNIs, is common. Everolimus, which belongs to the mammalian target-of-rapamycin inhibitor family and is best known for its use in kidney and heart transplantation, has recently been approved for liver transplantation. This overview discusses the emerging evidence on the role of everolimus in the prevention of rejection after liver transplantation, in de novo transplants, conversion regimens, or as a rescue therapy. In addition, some of the most relevant and current clinical problems related to everolimus in this field are discussed. Keywords: everolimus, mTOR inhibitors, tacrolimus, liver transplant, cyclosporine, renal impairment
Combined HLA matched limbal stem cells allograft with amniotic membrane transplantation as a prophylactic surgical procedure to prevent corneal graft rejection after penetrating keratoplasty: case report
Full Text Available Purpose. To determine if the use of combined HLA matched limbal stem cells allograft with amniotic membrane transplantation (AMT is a safe and effective prophylactic surgical procedure to prevent corneal graft after penetrating keratoplasty (PK. Methods. We report the case of a 17 years old patient with a history of congenital glaucoma, trabeculectomy and multiple corneal graft rejections, presenting total limbal cell deficiency. To reduce the possibility of graft rejection in the left eye after a new PK, a two step procedure was performed. At first the patient underwent a combined HLA matched limbal stem cells allograft (LAT and AMT and then, 10 months later, a new PK. Results. During 12 months of follow-up, the corneal graft remained stable and smooth, with no sign of graft rejection. Conclusions. In our patient, the prophylactic use of LAT from HLA-matched donors and AMT before PK, may result in a better prognosis of corneal graft survival.
Hanna, S.; Helenon, O.; Legendre, C.; Chichie, J.F.; Di Stefano, D.; Kreis, H.; Moreau, J.F.; Hopital Necker, 75 - Paris
The results of 62 consecutive MR examinations were correlated with the subsequent clinical course and histologic results. Twenty-six cases of rejection showed a marked diminution of cortico-medullary differentiation (CMD). The renal parenchymal vascular pattern and visibility of renal sinus fat were not markedly altered in rejection and there was no difference between normal and rejected allograft shape. The ability of MR imaging to diagnose renal transplant rejection is only based on CMD, which, however, is non-specific. In 2 cases of severe rejection, T2 weighted images showed an abnormal signal intensity of the cortex due to renal infarction. Our preliminary results in 8 patients with Gd-DOTA injection showed 2 cases with necrosis seen as areas with absent contrast enhancement. This technique seems to be promising in the detection of perfusion defects. (orig.)
Johnson, L.L.; Cannon, P.J.
Fab fragments of antibodies specific for cardiac myosin have been labeled with indium-111 and injected intravenously into animals and into patients with heart transplants. The antibodies, developed by Khaw, Haber, and co-workers, localize in cardiac myocytes that have been damaged irreversibly by ischemia, myocarditis, or the rejection process. After clearance of the labeled antibody from the cardiac blood pool, planar imaging or single photon emission computed tomography is performed. Scintigrams reveal the uptake of the labeled antimyosin in areas of myocardium undergoing transplant rejection. In animal studies, the degree of antimyosin uptake appears to correlate significantly with the degree of rejection assessed at necropsy. In patients, the correlation between scans and pathologic findings from endomyocardial biopsy is not as good, possibly because of sampling error in the endomyocardial biopsy technique. The scan results at 1 year correlate with either late complications (positive) or benign course (negative). Current limitations of the method include slow blood clearance, long half-life of indium-111, and hepatic uptake. Overcoming these limitations represents a direction for current research. It is possible that from these efforts a noninvasive approach to the diagnosis and evaluation of cardiac transplantation may evolve that will decrease the number of endomyocardial biopsies required to evaluate rejection. This would be particularly useful in infants and children. 31 references
Dácio Carvalho Costa
Full Text Available A rejeição do transplante de córnea é um processo imunológico celular de ataque a córnea transplantada que pode resultar em sua descompensação. É a causa mais comum de falência de transplantes. Os fatores de risco mais comuns para rejeição são a vascularização corneana, falência prévia por rejeição, sinéquias anteriores, botão doador grande ou descentrado, inflamação intra-ocular e cirurgias no segmento anterior. O quadro clínico é caracterizado por hiperemia, dor ocular, edema corneano e inflamação na câmara anterior. As rejeições podem ser classificadas em epitelial, subepitelial, estromal, endotelial, mista e em retransplantes. A prevenção de rejeições pode ser realizada através de técnica cirúrgica meticulosa, utilização de transplantes lamelares, histocompatibilidade receptor-doador e estratégias farmacológicas. Os corticosteróides são a terapia de escolha para o tratamento da rejeição de transplante de córnea e podem ser utilizados em diversas vias e dosagens. Os autores propõem protocolo de tratamento para rejeições.Corneal transplant rejection is an immunological cellular process that attacks the donor cornea and may cause its failure. It is the most common cause of corneal transplant failure.The most common factors for rejection are corneal neovascularization, previous graft failure, anterior synechiae, large or descentered graft, intraocular inflammation and previous anterior segment surgeries. It commonly presents with hyperemia, ocular pain, corneal edema, and anterior chamber inflammation. Corneal graft rejection can be classified as epithelial rejection, subepithelial rejection, stromal rejection, endothelial rejection, combined stromal and endothelial rejection, and rejection in a repeat graft. Prevention of immune-mediated graft rejection can be achieved through meticulous surgical technique, lamellar surgery, enhanced compatibility between donor tissue and receptor cornea, and
Preventing acute rejection, Epstein-Barr virus infection, and posttransplant lymphoproliferative disorders after kidney transplantation: Use of aciclovir and mycophenolate mofetil in a steroid-free immunosuppressive protocol
Birkeland, S.A.; Andersen, H.K.; Hamilton-Dutoit, Stephen Jacques
Background: A widely held view is that any increase in the potency of an immunosuppressive agent will lead to an increase in infection and malignancy, such as life-threatening Epstein-Barr virus (EBV) induced posttransplant lymphoproliferative disorders (PTLD), We tested this paradigm by studying......; the effect of adding mofetil to a steroid-free protocol under cover of high-dose aciclovir prophylaxis on the number of acute rejections, EBV infections and PTLDs after kidney transplantation. Methods: EBV serology was performed in 267 consecutive renal transplantations (1990-1997), All were treated...
Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection.
Jabado, N; Le Deist, F; Cant, A; De Graeff-Meeders, E R; Fasth, A; Morgan, G; Vellodi, A; Hale, G; Bujan, W; Thomas, C; Cavazzana-Calvo, M; Wijdenes, J; Fischer, A
For children with life-threatening inborn errors of metabolism without a matched related bone marrow donor, transplantation from an HLA genetically nonidentical donor is the only therapeutic option. To reduce the high risk of graft rejection in this setting without increasing the conditioning regimen, a protocol based on the infusion of an antiadhesion antibody directed against the CD11a (leukocyte function-associated antigen 1 [LFA-1]) molecule was performed by the European Bone Marrow Transplantation-European Society for Immunodeficiency group with promising results. To optimize engraftment, and thereby survival, further, the additional blockade of a second important leukocyte adhesion and signalization pathway mediated by the CD2 and LFA-3 interaction was attempted in a multicenter protocol conducted by the European Bone Marrow Transplantation-European Society for Immunodeficiency group. Results of this study (ie, engraftment and survival) were compared with a historical control group that received the anti-LFA-1 antibody alone. Factors that may have affected engraftment and survival were also considered in this study. Forty-four children with inborn errors, including inherited immunodeficiencies (excluding severe combined immunodeficiencies), Chédiak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis, and malignant osteopetrosis, received bone marrow from HLA-nonidentical related donors or from HLA-identical unrelated donors at 13 European centers between August 1990 and June 1993. Bone marrow was depleted of T cells by use of either erythrocyte (E) rosetting or monoclonal antibodies (MoAbs) to prevent graft-versus-host disease. The conditioning regimen consisted of busulfan and cyclophosphamide for all patients plus etoposide for patients with osteopetrosis, familial hemophagocytic lymphohistiocytosis, and Chédiak-Higashi syndrome. Infusions of MoAbs specific for the CD11a and the CD2 molecules were started 4 and 3 days, respectively, before and
Full Text Available Purpose of review: P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine’s relevance to the various stages of the kidney transplant cycle. Sources of information: A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016 using a combination of subject headings (MeSH and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. Findings: Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients’ care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. Limitations: For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. Implications: Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care.
Maier, Mirela; Takano, Tomoko; Sapir-Pichhadze, Ruth
Purpose of review: P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine’s relevance to the various stages of the kidney transplant cycle. Sources of information: A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. Findings: Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients’ care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. Limitations: For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. Implications: Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care. PMID:28270929
Gude, Einar; Gullestad, Lars; Andreassen, Arne K
De-novo introduction of everolimus (Eve) in heart transplant recipients opens for early reduction of calcineurin inhibitors (CNI) and potential of preserving renal function, attenuate progression of coronary allograft vasculopathy (CAV) and maintain rejection efficacy. The first trials demonstrated adequate rejection prophylaxis and favorable outcomes on CAV, but observed enhanced nephrotoxicity because of insufficient CNI reduction. The SCHEDULE trial compared de-novo Eve with significantly reduced CNI exposure and conversion to CNI-free treatment week 7-11 postheart transplant, with standard CNI immunosuppression. Improved renal function and attenuation of CAV was found among Eve patients, with higher numbers of treated acute rejections observed. With sustained superior renal and CAV related data also after 36 months with the Eve protocol, cardiac function was equally well preserved in both groups. According to the International Society of Heart and Lunge Transplantation registry, mammalian target of rapamycin inhibitor treatment is uncommon during the first postoperative year, with a prevalence of 20% in patients after 5 years. Current evidence suggests a greater benefit from these immunosuppressives if introduced at an earlier timepoint. Immunosuppressive protocols based on Eve treatment in de-novo patients should be further investigated and developed, enabling CNI avoidance before accelerating side-effects lead to irreversible damage.
A. A. Korzenewsky
Full Text Available The patient in the remote period after cadaveric kidney allotransplantation developed leukopenia, which required a dose reduction of immunosuppressive drugs. The transplant rejection crisis developed against this background. Thus, the presence of leukopenia in a patient after cadaveric kidney allograft transplantation requires detecting early signs ofnot only infectious complications, but also a crisis of rejection.
Chandler, S.T.; Buckels, J.; Hawker, R.J.; Smith, N.; Barnes, A.D.; McCollum, C.N.
The uptake of 111 In autologous platelets in transplanted kidneys was measured in 16 patients shortly after operation. Each patient was then observed for two years. When transplant radioactivity had increased, despite treatment for acute rejection, the kidney was ultimately lost because of rejection
Lagaaij, E.L.; Cramer-Knijnenburg, G.F.; Kemenade, F.J. van; Es, L.A. van; Bruijn, J.A.; Krieken, J.H.J.M. van
BACKGROUND: The blood vessels of a transplanted organ are the interface between donor and recipient. The endothelium in the blood vessels is thought to be the major target for graft rejection. Endothelial cells of a transplanted organ are believed to remain of donor origin after transplantation. We
Full Text Available Acute rejection episodes (AREs are a major determinant of renal allograft survival. The incorporation of new immunosuppressive agents explains, at least partially, the improvement seen in the results of transplantation in recent years. The objectives of this study are to analyze the incidence and severity of AREs, their risk factors and their influence on graft and patient survival. We retrospectively studied 280 kidney transplants performed in adults at the Charles Nicolle Hospital, Tunis, between 1986 and 2004. The diagnosis of ARE was based on clinical data and response to treatment. Allograft biopsies were performed in ten cases. The treatment of AREs consisted of pulse methylprednisolone and anti-thymocyte globulin. There were 186 males (66.4% and 94 females (33.6%, and their mean age was 31 ± 8.9 years. Overall, the 280 study patients experienced a total of 113 AREs. Of them, 85 had only one ARE, 28 had two to three and none had more than three AREs. A total of 68 AREs were completely re-versible, 42 were partially reversible while three could not be reversed with treatment. The mean inci-dence of AREs was 40.4%. The incidence was > 45% between 1986 and 1997, decreased to 20.5% between 1998 and 2000 and to 9% between 2001 and 2004. Graft survival rates in patients with and without AREs were respectively 91% and 93% at three years, 82% and 90% at five years and 73% and 83% at 10 years. We found a decrease in the incidence of AREs in recent years in our study patients, and this was related to the introduction of sensitized cross-match and the newer immunosuppressive agents, particularly MMF. Additionally, AREs had a deleterious impact on late graft survival in our study population.
MacAulay, Calum E.; Whitehead, Peter D.; McManus, Bruce; Zeng, Haishan; Wilson-McManus, Janet; MacKinnon, Nick; Morgan, David C.; Dong, Chunming; Gerla, Paul; Kenyon, Jennifer
Patients receiving heart or other organ transplants usually require some level of anti-rejection drug therapy, most commonly cyclosporine. The rejection status of the organ must be monitored to determine the optimal anti-rejection drug therapy. The current method for monitoring post-transplant rejection status of heart transplant patients consists of taking biopsies from the right ventricle. In this work we have developed a system employing optical and signal-processing techniques that will allow a cardiologist to measure spectral changes associated with tissue rejection using an optical catheter probe. The system employs time gated illumination and detection systems to deal with the dynamic signal acquisition problems associated with in vivo measurements of a beating heart. Spectral data processing software evaluates and processes the data to produce a simple numerical score. Results of measurements made on 100 excised transplanted isograft and allograft rat hearts have demonstrated the ability of the system to detect the presence of rejection and to accurately correlate the spectroscopic results with the ISHLT (International Society for Heart and Lung Transplantation) stage of rejection determined by histopathology. In vivo measurements using a pig transplant model are now in process.
Arbon, Kate S; Albers, Erin; Kemna, Mariska; Law, Sabrina; Law, Yuk
Allograft rejection and long-term immunosuppression remain significant challenges in pediatric heart transplantation. Pediatric recipients are known to have fewer rejection episodes and to develop more allergic conditions than adults. A T-helper 2 cell dominant phenotype, manifested clinically by allergies and an elevated eosinophil count, may be associated with immunologic quiescence in transplant recipients. This study assessed whether the longitudinal eosinophil count and an allergic phenotype were associated with freedom from rejection. This single-center, longitudinal, observational study included 86 heart transplant patients monitored from 1994 to 2011. Post-transplant biannual complete blood counts, allergic conditions, and clinical characteristics related to rejection risk were examined. At least 1 episode of acute cellular rejection (ACR) occurred in 38 patients (44%), antibody-mediated rejection (AMR) occurred in 11 (13%), and 49 patients (57%) were diagnosed with an allergic condition. Patients with ACR or AMR had a lower eosinophil count compared with non-rejectors (p = 0.011 and p = 0.022, respectively). In the multivariable regression analysis, the presence of panel reactive antibodies to human leukocyte antigen I (p = 0.014) and the median eosinophil count (p = 0.011) were the only independent covariates associated with AMR. Eosinophil count (p = 0.010) and female sex (p = 0.009) were independent risk factors for ACR. Allergic conditions or young age at transplant were not protective from rejection. This study demonstrates a novel association between a high eosinophil count and freedom from rejection. Identifying a biomarker for low rejection risk may allow a reduction in immunosuppression. Further investigation into the role of the T-helper 2 cell phenotype and eosinophils in rejection quiescence is warranted. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Sopko, Nikolai A; Matsui, Hotaka; Lough, Denver M; Miller, Devin; Harris, Kelly; Kates, Max; Liu, Xiaopu; Billups, Kevin; Redett, Richard; Burnett, Arthur L; Brandacher, Gerald; Bivalacqua, Trinity J
Penile transplantation is a potential treatment option for severe penile tissue loss. Models of human penile rejection are lacking. Evaluate effects of rejection and immunosuppression on cavernous tissue using a novel ex vivo mixed lymphocyte reaction (MLR) model. Cavernous tissue and peripheral blood mononuclear cells (PBMCs) from 10 patients undergoing penile prosthesis operations and PBMCs from a healthy volunteer were obtained. Ex vivo MLRs were prepared by culturing cavernous tissue for 48h in media alone, in media with autologous PBMCs, or in media with allogenic PBMCs to simulate control, autotransplant, and allogenic transplant conditions with or without 1μM cyclosporine A (CsA) or 20nM tacrolimus (FK506) treatment. Rejection was characterized by PBMC flow cytometry and gene expression transplant array. Cavernous tissues were evaluated by histomorphology and myography to assess contraction and relaxation. Data were analyzed using two-way analysis of variance and unpaired Student t test. Flow cytometry and tissue array demonstrated allogenic PBMC activation consistent with rejection. Rejection impaired cavernous tissue physiology and was associated with cellular infiltration and apoptosis. CsA prevented rejection but did not improve tissue relaxation. CsA treatment impaired relaxation in tissues cultured without PBMCs compared with media and FK506. Study limitations included the use of penile tissue with erectile dysfunction and lack of cross-matching data. This model could be used to investigate the effects of penile rejection and immunosuppression. Additional studies are needed to optimize immunosuppression to prevent rejection and maximize corporal tissue physiology. This report describes a novel ex vivo model of human penile transplantation rejection. Tissue rejection impaired erectile tissue physiology. This report suggests that cyclosporin A might hinder corporal physiology and that other immunosuppressant agents, such as FK506, might be better suited
Bergmann, S.R.; Lerch, R.A.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.
To determine whether rejections of cardiac transplants could be detected specifically and non-invasively by lymphocytes labeled with indium-111 (111In), we studied 36 allogeneic and 14 isogeneic heterotopic cardiac transplants in rats. Allogeneic grafts accumulated autologous 111In-lymphocytes, detectable scintigraphically 24 hours after i.v. injection of the labeled cells. At the time of peak histologic rejection, the allogeneic grafts accumulated 92. +/- 4.8 times more activity than the native hearts (determined by well counting). The tissue-to-blood ratio in the rejecting transplants was 3.7 +/- 2.2; total uptake by the graft was 2.9 +/- 2.1% of the injected dose. Autoradiography confirmed that graft radioactivity was associated with labeled lymphocytes. In contrast, isogeneic grafts showed no signs of rejection and did not accumulate radioactivity. Because conventionally isolated and labeled lymphocytes are often contaminated with platelets, we prepared both 111In-platelets and purified 111In-lymphocytes for use in additional experiments. Allogeneic grafts accumulated platelets and purified lymphocytes independently. Thus, deposition of immunologically active cells in the rejecting graft representing specific pathophysiologic events can be detected. The results suggest that rejection of cardiac transplants can be detected noninvasively, potentially facilitating objective early clinical detection of rejection and titration of antirejection therapy
Hamida, Fethi Ben; Barbouch, Samia; Helal, Imed; Kaaroud, Hayet; Fatma, Lilia Ben; Hedri, Hafedh; Abderrahim, Ezzeddine; Kheder, Adel; Bardi, Rafika; Abdallah, Taieb Ben; Ayed, Khaled; Maiz, Hedi Ben
Obesity in nontransplant patients has been associated with hypertension, hyperlipidemia, diabetes, and proteinuria. To determine whether renal transplant recipients with an elevated BMI have worse long term graft survival, we prospectively studied 92 patients transplanted between April 1999 and July 2000. Weight (Wt) and height of the patients were recorded prior to transplantation and two weeks, one, two and three years post transplantation. Blood urea nitrogen (BUN), creatinine (Cr) and blood pressure were checked monthly, while triglyceride, cholesterol, high density lipoprotein (HDL), and low density lipoprotein (LDL) were obtained 3 monthly for 3 years post transplantation. Graft dysfunction was defined as serum Cr> 1.8 mg/dL. While BMI and Wt of the patients before transplantation did not show any significant correlation with chronic renal allograft dysfunction (CRAD), patients with higher Wt and BMI two weeks after transplantation showed an increased risk of developing CRAD during the three year post transplant independent of other risk factors (P< 0.05). Patients with greater Wt loss in the first two weeks post transplantation showed a decreased risk of developing CRAD in the following 3 years (P< 0.001). Our study suggests that high Wt and BMI are significantly associated with worse graft survival 3 years post renal transplantation. (author)
Full Text Available Chad A Witt, Ramsey R Hachem Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, Saint Louis, MO, USA Abstract: The role of donor-specific antibodies (DSA to human leukocyte antigens and the burden of antibody-mediated rejection (AMR in lung transplantation remain enigmatic. Over the past several years, evidence has been emerging that humoral immunity plays an important role in the development of both acute and chronic lung allograft dysfunction (CLAD. Multiple case reports and case series have identified lung allograft recipients with clinical findings consistent with acute AMR. However, there is currently no widely accepted definition for AMR in lung transplantation, and this has been a significant barrier to furthering our understanding of this form of rejection. Nonetheless, the development of DSA after transplantation has consistently been identified as an independent risk factor for persistent and high-grade acute cellular rejection and CLAD. This has raised the possibility that chronic AMR may be a distinct phenotype of CLAD although evidence supporting this paradigm is still lacking. Additionally, antibodies to lung-restricted self-antigens (collagen V and K-α 1 tubulin have been associated with primary graft dysfunction early and the development of CLAD late after transplantation, and emerging evidence underscores significant interactions between autoimmunity and alloimmunity after transplantation. There is currently an active International Society for Heart and Lung Transplantation working group that is developing an operational definition for AMR in lung transplantation. This will be critical to improve our understanding of this form of rejection and conduct clinical trials to identify optimal treatment strategies. This review will summarize the literature on DSA and AMR in lung transplantation and discuss the impact of antibodies to self-antigens on lung
Morozumi, Kunio; Takeda, Asami; Otsuka, Yasuhiro; Horike, Keiji; Gotoh, Norihiko; Narumi, Shunji; Watarai, Yoshihiko; Kobayashi, Takaaki
The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure. © 2016 Asian Pacific Society of Nephrology.
Schubert, S; Abdul-Khaliq, H; Lehmkuhl, H B; Hübler, M; Abd El Rahman, M Y; Miera, O; Ewert, P; Weng, Y; Wei, H; Krüdewagen, B; Hetzer, R; Berger, F
Inadequate cyclosporine (CsA) blood levels are a major risk factor for acute rejection in transplant recipients. The CsA trough level (C0 level) measured just before the next dose is commonly used to adjust the oral dosage. However, the 2-hour post-CsA dose concentration (C2 level) is favored as the best single-point correlate of CsA area-under-the-curve concentration and may better reflect the immunosuppressive effect of CsA. Because an adequate C2 level has not yet been defined, this study was performed to assess the value of C2 monitoring for the prevention of acute rejection and to define target levels in pediatric heart transplant recipients. C2 levels were assessed in 50 pediatric heart transplant patients with oral CsA therapy and compared with trough C0 levels using full blood sampling, mass spectrometry and a blinded analysis. Acute graft rejection was detected using intramyocardial electrocardiogram (IMEG) and serial conventional and tissue Doppler echocardiography (TDE). Rejection was confirmed or excluded by endomyocardial biopsy. C2 and not C0 levels were significantly reduced in patients with acute graft rejection (ISHLT Grade > or =2). Patients with a C2 level 600 ng/ml should be the target to prevent acute rejection.
Full Text Available Peter Abrams, Abhinav Humar, Henkie P TanDepartment of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pennsylvania, USAAbstract: Successful management of the solid-organ transplant recipient begins with prevention of rejection and achieving a balance between insufficient and excessive immunosuppression. Standard tacrolimus therapy for prevention of solid-organ transplant rejection consists of 2 divided doses per day. In an effort to simplify tacrolimus dosing to once daily, a new formulation (tacrolimus prolonged release [PR] was chosen for its combination of a similar extent of bioavailability and a substantially reduced rate of clearance. Several clinical conversion studies have now been completed using PR to clarify its pharmacokinetics, efficacy at prevention of allograft rejection, and safety profiles in solid-organ transplant patients. A cohort of 67 stable kidney transplant recipients was converted from standard tacrolimus to PR in an open-label, multicenter study in the United States and Canada. A second open-label, multicenter study was performed in liver transplant recipients with stable graft function on standard tacrolimus therapy converted to PR. A third conversion study was performed as an open-label study at 5 centers in the United States in stable pediatric liver transplant recipients. As medication noncompliance can significantly contribute to the incidence of graft rejection and graft loss in transplant recipients, a potentially significant advance in the transplant community’s ongoing mission to optimize prevention of rejection occurred with the development of a once-daily tacrolimus PR. The results of these preliminary studies suggest that select solid-organ transplant recipients converted to PR can be safely maintained using the same monitoring and patient care techniques historically used for standard tacrolimus therapy.Keywords: immunosuppression, tacrolimus allograft
Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial
Background Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients. Methods/Design Recipients >1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate >30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes. Discussion We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to
Full Text Available The concept of CNS as an immune-privileged site has been challenged by the occurrence of immune surveillance and allogeneic graft rejection in the brain. Here we examined whether the immune response to allogeneic neural grafts is determined by the site of implantation in the CNS. Dramatic regional differences were observed between immune responses to allogeneic neural precursor/stem cell (NPC grafts in the striatum vs. the hippocampus. Striatal grafts were heavily infiltrated with IBA-1+ microglia/macrophages and CD3+ T cells and completely rejected. In contrast, hippocampal grafts exhibited milder IBA-1+ cell infiltration, were not penetrated efficiently by CD3+ cells, and survived efficiently for at least 2 months. To evaluate whether the hippocampal protective effect is universal, astrocytes were then transplanted. Allogeneic astrocyte grafts elicited a vigorous rejection process from the hippocampus. CD200, a major immune-inhibitory signal, plays an important role in protecting grafts from rejection. Indeed, CD200 knock out NPC grafts were rejected more efficiently than wild type NPCs from the striatum. However, lack of CD200 expression did not elicit NPC graft rejection from the hippocampus. In conclusion, the hippocampus has partial immune-privilege properties that are restricted to NPCs and are CD200-independent. The unique hippocampal milieu may be protective for allogeneic NPC grafts, through host-graft interactions enabling sustained immune-regulatory properties of transplanted NPCs. These findings have implications for providing adequate immunosuppression in clinical translation of cell therapy.
O. P. Shevchenko
Full Text Available This review summarizes the current literature devoted to the analysis of prognostic role of ST2 biomarker in rejection of the transplanted heart. ST2 is one of the most promising diagnostic markers of the development and severity of heart failure as well as the mortality risk in patients with cardiovascular diseases. ST2 is expressed in cardiomyocytes in response to a variety of pathological processes and mechanical damage to the heart, which allows diagnosing cardiovascular diseases before clinical manifestations. Presumably, measuring the level of ST2 in heart transplant may have diagnostic and prognostic value in the assessment of graft and risk of rejection. Currently, accumulated clinical data on the role of given biomarker in heart transplantation are not enough, and further research on the relation of ST2 levels with different clinical and laboratory parameters in heart recipients is necessary.
Sigdel, Tara K.; NG, Yolanda; Lee, Sangho; Nicora, Carrie D.; Qian, Weijun; Smith, Richard D.; Camp, David G.; Sarwal, Minnie M.
Background: Urine exosomes, vesicles exocytosed into urine by all renal epithelial cell types, occur under normal physiologic and disease states. Exosome contents may mirror disease-specific proteome perturbations in kidney injury. Analysis methodologies for the exosomal fraction of the urinary proteome were developed and for comparing the urinary exosomal fraction versus unfractionated proteome for biomarker discovery. Methods: Urine exosomes were isolated by centrifugal filtration from mid-stream, second morning void, urine samples collected from kidney transplant recipients with and without biopsy matched acute rejection. The proteomes of unfractionated whole urine (Uw) and urine exosomes (Uexo) underwent mass spectrometry-based quantitative proteomics analysis. The proteome data were analyzed for significant differential protein abundances in acute rejection (AR). Results: Identifications of 1018 and 349 proteins, Uw and Uexo fractions, respectively, demonstrated a 279 protein overlap between the two urinary compartments with 25%(70) of overlapping proteins unique to Uexoand represented membrane bound proteins (p=9.31e-7). Of 349 urine exosomal proteins identified in transplant patients 220 were not previously identified in the normal urine exosomal fraction. Uexo proteins (11), functioning in the inflammatory / stress response, were more abundant in patients with biopsy-confirmed acute rejection, 3 of which were exclusive to Uexo. Uexo AR-specific biomarkers (8) were also detected in Uw, but since they were observed at significantly lower abundances in Uw, they were not significant for AR in Uw. Conclusions: A rapid urinary exosome isolation method and quantitative measurement of enriched Uexo proteins was applied. Urine proteins specific to the exosomal fraction were detected either in unfractionated urine (at low abundances) or by Uexo fraction analysis. Perturbed proteins in the exosomal compartment of urine collected from kidney transplant patients were
Flynn, E. R.; Bryant, H. C.; Larson, R. S.; Sergatskov, D. A.
Superparamagnetic nanoparticles are being used to develop methodology for the in-vivo detection and imaging of immune system attacks on transplanted organs. The signature for impending rejection of a transplant is enhanced presence of T-cells. Magnetic nanoparticles coated with specific antibodies (CD-2 and CD-3) will target and attach to these T-cells. Approximately 3 .10^5 nanoparticles can attach to each cell. When a pulsed external magnetic field is applied to the decorated cells for a fraction of a second, magnetic moments of the nanoparticles aligned with the field. After the pulse is switched off, the net magnetic moment decays over several seconds by the Nèel mechanism. The resulting magnetic remanence field (typically 10-11 T) is measured using a multi-channel SQUID array. We present the data from live T-cells placed in realistic kidney phantom. The detection sensitivity was ˜2.10^3 T-cells - a small fraction of the number actually invading the rejected transplant. The 7-channel SQUID array allows us to image the cell clusters with a few millimeters resolution.
Full Text Available Urine exosomes are small vesicles exocytosed into the urine by all renal epithelial cell types under normal physiologic and disease states. Urine exosomal proteins may mirror disease specific proteome perturbations in kidney injury. Analysis methodologies for the exosomal fraction of the urinary proteome were developed for comparing the urinary exosomal fraction versus unfractionated proteome for biomarker discovery. Urine exosomes were isolated by centrifugal filtration of urine samples collected from kidney transplant patients with and without acute rejection, which were biopsy matched. The proteomes of unfractionated whole urine (Uw and urine exosomes (Ue underwent mass spectroscopy-based quantitative proteonomics analysis. The proteome data were analyzed for significant differential protein abundances in acute rejection (AR. A total of 1018 proteins were identified in Uw and 349 proteins in Ue. 279 overlapped between the two urinary compartments and 70 proteins were unique to the Ue compartment. Of 349 exosomal proteins identified from transplant patients,220 had not been previously identified in the normal Ue fraction. 11 Ue proteins, functionally involved in an inflammatory and stress response, were more abundant in urine samples from patients with acute rejection, 3 of which are exclusive to the Ue fraction. Ue AR-specific biomarkers(8 were also detected in Uw, but since they were observed at significantly lower abundances in Uw, they were not significant for AR in Uw. A rapid urinary exosome isolation method and quantitative measurement of enriched Ue proteins was applied. Perturbed proteins in the exosomal compartment of urine collected from kidney transplant patients were specific to inflammatory responses, and were not observed in the Ue fraction from normal healthy subjects. Ue specific protein alterations in renal disease provide potential mechanistic insights and offer a unique panel of sensitive biomarkers for monitoring AR.
Full Text Available Case histories of 2 renal transplant recipients are reported who had presenting features of fever, leukocytosis and pain/tenderness over right iliac fossa and were diagnosed to be due to acute appendicitis rather than more commonly suspected acute rejection episode which has very similar features. Diagnosis of acute appendicitis was suspected on the basis of rectal examination and later confirmed by laparotomy. The purpose of this communication is to emphasize the need for proper diagnosis in patient with such presentation; otherwise wrong treatment may be received.
Ratajczak , Philippe; Murata , Hideyuki; Meignin , Véronique; Groussard , Odile; Fournier , Michel; Socié , Gérard; Mal , Hervé; Janin , Anne
International audience; Endotheliitis is a major sign of graft rejection. Recipient-derived endothelial cells found in two series of liver and kidney transplants were related to graft rejection. Here, we assessed the presence and the number of chimeric endothelial cells in lung transplants, and their relation with graft rejection. In six males grafted with female lungs out of 193 lung transplantations, endothelial chimerism was studied by combined XY-fluorescent in situ hybridization with CD3...
McIntire, J.N.; Angtuaco, T.L.; Boyd, C.; Flanigan, W.J.
The authors performed 65 duplex US examinations in 28 patients within 2 years of transplantation. During this time 15 episodes of rejection were diagnosed by US and confirmed clinically. Of the remaining 50 examinations, 14 showed negligible or absent diastolic flow (suggesting rejection) in the arcuate arteries with normal diastolic flow in the main renal, segmental, and interlobar branches. No other criteria for rejection were present in these patients. It is concluded that the arcuate artery is an insensitive indicator of transplant rejection
Wang, Jue; Geissler, Edward K.; Fechner, John H.; Burlingham, William J.; Knechtle, Stuart J.
Organ transplantation in presensitized recipients continues to be contraindicated for heart and kidney recipients due to the risk of hyperacute rejection, which has no known treatment at this time. We tested whether donor serum, which contains soluble MHC class I antigen, is able to neutralize the effect of anti-donor antibody in the recipient and prevent hyperacute or accelerated rejection. A rat model of passive immunization was used to test the role of anti-donor antibody in hyperacute rej...
Tillou, Xavier; Poirier, Nicolas; Le Bas-Bernardet, Stéphanie; Hervouet, Jeremy; Minault, David; Renaudin, Karine; Vistoli, Fabio; Karam, Georges; Daha, Mohamed; Soulillou, Jean Paul; Blancho, Gilles
Acute antibody-mediated rejection is an unsolved issue in transplantation, especially in the context of pretransplant immunization. The deleterious effect of preformed cytotoxic anti-HLA antibodies through complement activation is well proven, but very little is known concerning complement blockade to prevent/cure this rejection. Here, we used a baboon model of preimmunization to explore the prevention of acute antibody-mediated rejection by an early inhibition of the classical complement pathway using human recombinant C1-inhibitor. Baboons were immunized against peripheral blood mononuclear cells from allogeneic donors and, once a specific and stable immunization had been established, they received a kidney from the same donor. Rejection occurred at day 2 posttransplant in untreated presensitized recipients, with characteristic histological lesions and complement deposition. As recombinant human C1-inhibitor blocks in vitro cytotoxicity induced by donor-specific antibodies, other alloimmunized baboons received the drug thrice daily intravenously during the first 5 days after transplant. Rejection was prevented during this treatment but occurred after discontinuation of treatment. We show here that early blockade of complement activation by recombinant human C1-inhibitor can prevent acute antibody-mediated rejection in presensitized recipients. This treatment could also be useful in other forms of acute antibody-mediated rejection caused by induced antibodies.
Sigdel, Tara K.; Kaushal, Amit; Gritsenko, Marina A.; Norbeck, Angela D.; Qian, Weijun; Xiao, Wenzhong; Camp, David G.; Smith, Richard D.; Sarwal, Minnie M.
Acute rejection (AR) remains the primary risk factor for renal transplant outcome; development of non-invasive diagnostic biomarkers for AR is an unmet need. We used shotgun proteomics using LC-MS/MS and ELISA to analyze a set of 92 urine samples, from patients with AR, stable grafts (STA), proteinuria (NS), and healthy controls (HC). A total of 1446 urinary proteins were identified along with a number of NS specific, renal transplantation specific and AR specific proteins. Relative abundance of identified urinary proteins was measured by protein-level spectral counts adopting a weighted fold-change statistic, assigning increased weight for more frequently observed proteins. We have identified alterations in a number of specific urinary proteins in AR, primarily relating to MHC antigens, the complement cascade and extra-cellular matrix proteins. A subset of proteins (UMOD, SERPINF1 and CD44), have been further cross-validated by ELISA in an independent set of urine samples, for significant differences in the abundance of these urinary proteins in AR. This label-free, semi-quantitative approach for sampling the urinary proteome in normal and disease states provides a robust and sensitive method for detection of urinary proteins for serial, non-invasive clinical monitoring for graft rejection after
Full Text Available Melinda Látos,1 György Lázár,1 Zoltán Horváth,1 Victoria Wittmann,1 Edit Szederkényi,1 Zoltán Hódi,1 Pál Szenohradszky,1 Márta Csabai2 1Department of Surgery, Faculty of Medicine, 2Psychology Institute, University of Szeged, Szeged, Hungary Abstract: Interdisciplinary studies suggest that the mental representations of the transplanted organ may have a significant effect on the healing process. The objective of this study was to examine the representations of the transplanted organ and their relationship with emotional and mood factors, illness perceptions, and the functioning of the transplanted organ. One hundred and sixty-four kidney transplant patients were assessed using the Spielberger Anxiety Inventory, the Beck’s Depression Scale, the Posttraumatic Growth Inventory, the Brief Illness Perception Questionnaire, and the Transplanted Organ Questionnaire. Medical parameters were collected from the routine clinical blood tests (serum creatinine and estimated glomerular filtration rate levels and biopsy results. Our most outstanding results suggest that kidney-transplanted patients’ illness representations are associated with health outcomes. The Transplanted Organ Questionnaire “psychological rejection” subscale was connected with higher serum creatinine and estimated glomerular filtration rate levels. Logistic regression analysis showed that psychological rejection subscale, Brief Illness Perception Questionnaire, and Posttraumatic Growth Questionnaire total scores were associated with graft rejection. These results may serve as a basis for the development of complex treatment interventions, which could help patients to cope with the bio-psycho-social challenges of integrating the new organ as part of their body and self. Keywords: anxiety, depression, illness representations, posttraumatic growth, psychological rejection, renal transplantation
González-Molina, Miguel; Ruiz-Esteban, Pedro; Caballero, Abelardo; Burgos, Dolores; Cabello, Mercedes; Leon, Miriam; Fuentes, Laura; Hernandez, Domingo
The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.
A. O. Shevchenko
Full Text Available Allograft rejection would entail an increase in certain blood biomarkers and active substances derived from activated inflammatory cells which could influence entire vascular endothelial function and deteriorate arterial wall stiffness. We propose that carotid wall functional indices measured with non-invasive ultrasound could we valuable markers of the subclinical cardiac allograft rejection. Aim. Our goal was to analyze the clinical utility of functional common carotid wall (CCW variables measured with high-resolution Doppler ultrasound as a non-invasive screening tool for allograft rejection in cardiac transplant patients (pts. Methods. One hundred and seventy one pts included 93 cardiac recipients, 30 dilated cardiomyopathy waiting list pts, and 48 stable coronary artery disease (SCAD pts without decompensated heart failure were included. Along with resistive index (Ri, pulsative index (Pi, and CCW intima-media thickness (IMT, CCW rigidity index (iRIG was estimated using empirical equation. Non-invasive evaluation was performed in cardiac transplant recipients prior the endomyo- cardial biopsy. Results. Neither of Ri, Pi, or CCW IMT were different in studied subgroups. iRIG was signifi- cantly lower in SCAD pts when compared to the dilated cardiomyopathy subgroup. The later had similar values with cardiac transplant recipients without rejection. Antibody-mediated and cellular rejection were found in 22 (23.7% and 17 (18.3% cardiac recipients, respectively. Mean iRIG in pts without rejection was significantly lower in comparison to antibody-mediated rejection and cell-mediated (5514.7 ± 2404.0 vs 11856.1 ± 6643.5 and 16071.9 ± 10029.1 cm/sec2, respectively, p = 0.001. Area under ROC for iRIG was 0.90 ± 0.03 units2. Analysis showed that iRIG values above estimated treshold 7172 cm/sec2 suggested relative risk of any type of rejection 17.7 (95%CI = 6.3–49.9 sensitivity 80.5%, specificity – 81.1%, negative predictive value – 84
Full Text Available Antibody-mediated rejection (AMR is a relatively rare but severe complication in kidney transplantation associated with increased risk of graft loss. Diagnosis of acute and chronic AMR is based on typical histological hallmarks, deposition of C4d in peritubular capillaries and presence of donor-specific antibodies (DSA. Many novel and attractive treatment options have become available in recent years: antibody removal and production inhibition (plasmapheresis, IVIg, B cell depletion (rituximab, plasma cell depletion and apoptosis (bortezomib, and complement activation inhibition (eculizumab. Standard therapy is based on PP and IVIg. Preliminary results with new agents are encouraging but require randomised clinical trials and long-term follow-up.
Liang, Jackson J; Geske, Jennifer R; Boilson, Barry A; Frantz, Robert P; Edwards, Brooks S; Kushwaha, Sudhir S; Kremers, Walter K; Weinshilboum, Richard M; Pereira, Naveen L
Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA. We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies. There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, Prejection earlier (Prejection score was higher (P=0.02) than WT. AZA was discontinued more frequently in HZ (P=0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P=1.0). HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.
Fan, Hua; Li, Li-Xin; Han, Dong-Dong; Kou, Jian-Tao; Li, Ping; He, Qiang
Although many human inflammatory and autoimmune diseases were previously considered to be mediated by T helper type 1 (Th1) cells, the recently described Th17 cells play dominant roles in several of these diseases. We and others speculated that allograft rejection after organ transplantation may also involve Th17 cells. Episodes of acute rejection occur in 30% of liver transplants. This study aimed to determine the frequency of circulating Th17 cells in patients who had received liver transplants for benign end-stage liver disease and to identify any association between acute rejection episodes and levels of Th17 cells in the peripheral blood. A prospective study compared Th17 cells from 76 consecutive benign end-stage liver disease patients who had undergone orthotopic liver transplantation from 2007 to 2011 with those from 20 age-matched healthy individuals. Peripheral blood samples were collected at different time points within one year after transplant. Blood samples and liver biopsies were also collected at the diagnosis of acute rejection. Percentages of circulating CD4+IL-17+ cells were measured by flow cytometry. The transplant patients were classified into two groups: a rejection group consisting of 17 patients who had an episode of acute rejection, and a non-rejection group comprising the remaining 59 patients with no acute rejection episodes. Percentages of circulating Th17 cells were compared between the two groups and controls. The levels of circulating CD4+IL-17+ T cells in the rejection group were higher during acute rejection than those in the non-rejection group (2.56+/-0.43% versus 1.79+/-0.44%, Pblood was positively correlated with the rejection activity index (r=0.79, P=0.0002). Circulating Th17 cells may be useful as a surrogate marker for predicting acute rejection in liver transplant recipients.
Leithner, C.; Pohanka, E.; Schwarz, M.; Sinzinger, H.; Syre, G.
33 patients were examined daily under a gamma camera after weekly injections of 111-In-labelled autologous platelets over a period of at least 4 weeks after transplantation. A group of 33 patients with long-term stable and well-functioning grafts served as controls. By means of a computerized recording technique, platelet trapping in the graft was measured and expressed as platelet-uptake index (PUI). The method worked well for the early diagnosis of acute rejection signified by an increase in PUI, accompanied by a shortening of platelet half life (t/2). 6 patients suffering from acute rejection received infusions of prostacyclin in addition to conventional high-dose methylprednisolone therapy. In 4 cases the PUI decreased again and an improvement in graft function was observed. Prostacyclin infusion treatment was applied also in 12 patients with histologically-proven chronic transplant rejection. Decreased platelet consumption by the graft and a temporary improvement in transplant function were achieved. We suggest that prostacyclin could enrich the possibilities of anti-rejection treatment by providing a tool for the suppression of platelet trapping in the graft. The platelet scan served as a useful method for the early detection of acute rejection, as well as the monitoring of prostacyclin anti-rejection treatment. (Autor)
A. de Weerd (Annelies); A.G. Vonk (Alieke); H. van der Hoek (Hans); M. van Groningen (Marian); W. Weimar (Willem); M.G.H. Betjes (Michiel); M. Agteren (Madelon)
textabstractBackground: The major challenge in ABO-incompatible transplantation is to minimize antibody-mediated rejection. Effective reduction of the anti-ABO blood group antibodies at the time of transplantation has made ABO-incompatible kidney transplantation a growing practice in our hospital
Hetzer, R; Potapov, E V; Müller, J; Loebe, M; Hummel, M; Weng, Y; Warnecke, H; Lange, P E
Acute rejection episodes and transplant vasculopathy (TVP) account for most of the late deaths after heart transplantation in both adults and children. Accumulating evidence indicates that fatal acute rejection and TVP are related to unrecognized and untreated early and ongoing acute rejection. Day-by-day surveillance of the heart and prompt treatment of any rejection may yield improved long-term survival. In almost all patients having transplantation at our institution (978 patients since 1986), the intramyocardial electrogram (IMEG) was recorded routinely every day through a telemetry pacemaker and transmitted to our center by telephone modem. Earlier studies showed a substantial voltage drop in the IMEG QRS complex is highly indicative of acute rejection, including humoral rejection. In this study, we reviewed the data from 69 pediatric patients up to 16 years old for the incidence of acute rejection, TVP, and long-term outcome. Diagnostic endomyocardial biopsies were performed in only 10 patients, and recent coronary angiograms from 29 children were reviewed. In 50 children discharged after heart transplantation, IMEG surveillance data for a mean of 2.9 years indicated 72 acute rejection episodes. During follow-up of 1 month to 10.5 years (mean follow-up, 4.4 years), 2 patients died late of causes unrelated to either rejection or TVP. Another patient died of rejection during unrecognized underimmunosuppression nearly 8 years after transplantation and nearly 31/2 years after discontinuing IMEG recordings. Two patients without IMEG recording died of acute rejection or late TVP. In 1 patient, moderate TVP was seen on an angiogram after 41/2 years (incidence, 2.0%; 5-year incidence, 5.6%). Daily recording of the IMEG can reliably detect early stages of acute rejection episodes, and immediate rejection treatment seems to keep the incidence of TVP low. The IMEG appears better than all the other rejection monitoring protocols currently in use.
Sylos, Cristina de; Azeka, Estela; Kajita, Luis; Benvenutti, Luis; Strunz, Célia Cassaro; Branco, Klébia Castello; Riso, Arlindo Almeida; Tanamati, Carla; Jatene, Marcelo; Barbero-Marcial, Miguel
Rejection is one of the major causes of mortality following pediatric heart transplant. B-type natriuretic peptide (BNP) has been studied as a method for the diagnosis of acute rejection, especially in adult patients undergoing heart transplant. To correlate serum BNP levels with acute rejection as diagnosed by endomyocardial biopsy in patients of the pediatric heart transplant group. A total of 50 BNP samples were collected from 33 children in the postoperative period of heart transplant, and data on age, gender, skin color, blood group, immune panel, follow-up time after transplant, functional class, immunosuppressive regimen used and number of rejections were analyzed. Thirty three children with median age of 10.13 years were analyzed; of these, 54% were females and 78% were Caucasians. BNP levels were determined at a mean time from transplant of 4.25 years. Nine episodes of rejection were diagnosed in eight patients (27%) by means of endomyocardial biopsy; of these, three were grade 3A, five were grade 2, and one had humoral rejection. At the moment of biopsy, most patients were asymptomatic. The mean serum BNP level was 77.18 pg/ml, with 144.22 pg/ml in the group with rejection and 62.46 pg/ml in the group without rejection, with p = 0.02. Asymptomatic children can present acute rejection in the postoperative period of heart transplant. Serum BNP levels show a statistically significant difference in the group with rejection and thus can be an additional method in the diagnosis of cardiac rejection.
Butts, Ryan J; Savage, Andrew J; Atz, Andrew M; Heal, Elisabeth M; Burnette, Ali L; Kavarana, Minoo M; Bradley, Scott M; Chowdhury, Shahryar M
This study aimed to develop a reliable and feasible score to assess the risk of rejection in pediatric heart transplantation recipients during the first post-transplant year. The first post-transplant year is the most likely time for rejection to occur in pediatric heart transplantation. Rejection during this period is associated with worse outcomes. The United Network for Organ Sharing database was queried for pediatric patients (age heart transplantation from January 1, 2000 to December 31, 2012. Transplantations were divided into a derivation cohort (n = 2,686) and a validation (n = 509) cohort. The validation cohort was randomly selected from 20% of transplantations from 2005 to 2012. Covariates found to be associated with rejection (p heart transplantation recipients. The score has the potential to be used in clinical practice to aid in determining the immunosuppressant regimen and the frequency of rejection surveillance in the first post-transplant year. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Chen, Yan; Zhang, Haibo; Xiao, Xue; Jia, Yixin; Wu, Weili; Liu, Licheng; Jiang, Jun; Zhu, Baoli; Meng, Xu; Chen, Weijun
Peripheral blood-based gene expression patterns have been investigated as biomarkers to monitor the immune system and rule out rejection after heart transplantation. Recent advances in the high-throughput deep sequencing (HTS) technologies provide new leads in transcriptome analysis. By performing Solexa/Illumina's digital gene expression (DGE) profiling, we analyzed gene expression profiles of PBMCs from 6 quiescent (grade 0) and 6 rejection (grade 2R&3R) heart transplant recipients at more than 6 months after transplantation. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out in an independent validation cohort of 47 individuals from three rejection groups (ISHLT, grade 0,1R, 2R&3R). Through DGE sequencing and qPCR validation, 10 genes were identified as informative genes for detection of cardiac transplant rejection. A further clustering analysis showed that the 10 genes were not only effective for distinguishing patients with acute cardiac allograft rejection, but also informative for discriminating patients with renal allograft rejection based on both blood and biopsy samples. Moreover, PPI network analysis revealed that the 10 genes were connected to each other within a short interaction distance. We proposed a 10-gene signature for heart transplant patients at high-risk of developing severe rejection, which was found to be effective as well in other organ transplant. Moreover, we supposed that these genes function systematically as biomarkers in long-time allograft rejection. Further validation in broad transplant population would be required before the non-invasive biomarkers can be generally utilized to predict the risk of transplant rejection. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M
Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.
Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten
Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design. PMID:24127489
Hollander, Zsuzsanna; Chen, Virginia; Sidhu, Keerat; Lin, David; Ng, Raymond T; Balshaw, Robert; Cohen-Freue, Gabriela V; Ignaszewski, Andrew; Imai, Carol; Kaan, Annemarie; Tebbutt, Scott J; Wilson-McManus, Janet E; McMaster, Robert W; Keown, Paul A; McManus, Bruce M
Acute rejection in cardiac transplant patients remains a contributory factor to limited survival of implanted hearts. Currently, there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplant acute cellular rejection. Such a development would be of great value in personalizing immunosuppressive treatment. Recipient age, donor age, cold ischemic time, warm ischemic time, panel-reactive antibody, gender mismatch, blood type mismatch and human leukocyte antigens (HLA-A, -B and -DR) mismatch between recipients and donors were tested in 53 heart transplant patients for their power to predict post-transplant acute cellular rejection. Donor transplant biopsy and recipient pre-transplant blood were also examined for the presence of genomic biomarkers in 7 rejection and 11 non-rejection patients, using non-targeted data mining techniques. The biomarker based on the 8 clinical variables had an area under the receiver operating characteristic curve (AUC) of 0.53. The pre-transplant recipient blood gene-based panel did not yield better performance, but the donor heart tissue gene-based panel had an AUC = 0.78. A combination of 25 probe sets from the transplant donor biopsy and 18 probe sets from the pre-transplant recipient whole blood had an AUC = 0.90. Biologic pathways implicated include VEGF- and EGFR-signaling, and MAPK. Based on this study, the best predictive biomarker panel contains genes from recipient whole blood and donor myocardial tissue. This panel provides clinically relevant prediction power and, if validated, may personalize immunosuppressive treatment and rejection monitoring. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Sindhi, Rakesh; Ashokkumar, Chethan; Higgs, Brandon W; Levy, Samantha; Soltys, Kyle; Bond, Geoffrey; Mazariegos, George; Ranganathan, Sarangarajan; Zeevi, Adriana
The Pleximmune? test (Plexision Inc., Pittsburgh, PA, USA) is the first cell-based test approved by the US FDA, which predicts acute cellular rejection in children with liver- or intestine transplantation. The test addresses an unmet need to improve management of immunosuppression, which incurs greater risks of opportunistic infections and Epstein?Barr virus-induced malignancy during childhood. High-dose immunosuppression and recurrent rejection after intestine transplantation also result in ...
Kreijveld, E.; Meer, A. van der; Tijssen, H.J.; Hilbrands, L.B.; Joosten, I.
BACKGROUND: The identification of transplant patients at high risk for rejection after reduction of immunosuppression would allow minimization of immunosuppression and avoidance of side effects in low-risk patients. Next to T cells, innate natural killer (NK) cells may contribute to graft rejection.
Ueda, Yoshihide; Kaido, Toshimi; Ito, Takashi; Ogawa, Kohei; Yoshizawa, Atsushi; Fujimoto, Yasuhiro; Mori, Akira; Miyagawa-Hayashino, Aya; Haga, Hironori; Marusawa, Hiroyuki; Chiba, Tsutomu; Uemoto, Shinji
Chronic rejection (CR) has been reported to be associated with antiviral therapy for recurrent hepatitis C in liver transplant (LT) recipients. The aims of this study were to clarify the details of antiviral therapy-associated CR after living-donor liver transplantation (LDLT) and to identify the factors associated with CR. A retrospective chart review was performed on 125 recipients who had received antiviral therapy for recurrent hepatitis C after LDLT between January 2001 and September 2012. The characteristics of patients who developed CR during or within 6 months after antiviral therapy were compared with those of 76 patients who did not develop CR despite receiving antiviral therapy for more than 1 year. Seven of 125 (6%) patients developed CR during or within 6 months after the end of antiviral therapy. CR was diagnosed after a median (range) of 9 (1-16) months of antiviral therapy. In five patients, rejection progressed rapidly and resulted in death within 3 months after diagnosis. Analysis revealed two significant factors associated with CR: reduction of the immunosuppressant dose during antiviral therapy and a low fibrosis score as the indication for antiviral therapy. CR developed in association with antiviral therapy for recurrent hepatitis C after LDLT. This complication may be prevented by ensuring that the immunosuppressant dose is not reduced during antiviral therapy.
Schiemann, Martin; Puchhammer-Stöckl, Elisabeth; Eskandary, Farsad; Kohlbeck, Philip; Rasoul-Rockenschaub, Susanne; Heilos, Andreas; Kozakowski, Nicolas; Görzer, Irene; Kikić, Željko; Herkner, Harald; Böhmig, Georg A; Bond, Gregor
Antibody-mediated rejection (AMR) represents one of the cardinal causes of late allograft loss after kidney transplantation, and there is great need for noninvasive tools improving early diagnosis of this rejection type. One promising strategy might be the quantification of peripheral blood DNA levels of the highly prevalent and apathogenic Torque Teno virus (TTV), which might mirror the overall level of immunosuppression and thus help determine the risk of alloimmune response. To assess the association between TTV load in the peripheral blood and AMR, 715 kidney transplant recipients (median, 6.3 years posttransplantation) were subjected to a systematical cross-sectional AMR screening and, in parallel, TTV quantification. Eighty-six of these recipients had donor-specific antibodies and underwent protocol biopsy, AMR-positive patients (n = 46) showed only 25% of the TTV levels measured in patients without AMR (P = 0.003). In a generalized linear model, higher TTV levels were associated with a decreased risk for AMR after adjustment for potential confounders (risk ratio 0.94 per TTV log level; 95% confidence interval 0.90-0.99; P = 0.02). Future studies will have to clarify whether longitudinal assessment of TTV load might predict AMR risk and help guide the type and intensity of immunosuppression to prevent antibody-mediated graft injury.
Lee, Ga Yeon; Choi, Jin-Oh; Ju, Eun-Seon; Lee, Yoo-Jung; Jeon, Eun-Seok
Background and Objectives Endomyocardial biopsy is obligatory during the first year after heart transplant (HTx) for the surveillance of acute rejection. Previous attempts using cardiac biomarkers for the detection of rejection failed to show enough evidence to substitute endomyocardial biopsy. Therefore, this study sought the possibility of using soluble ST2 (sST2), a novel cardiovascular marker, as a surrogate marker for acute allograft rejection after HTx. Subjects and Methods A total of 4...
Ana Cristina Aoun Tannuri
Full Text Available OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%. In 10 patients (10/29, 34.5%, remission of chronic rejection was achieved with immunosuppression (favorable outcomes group. In the remaining 19 patients (19/29, 65.5%, rejection could not be controlled (adverse outcomes group and resulted in re-transplantation (7 patients, 24.1% or death (12 patients, 41.4%. Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01. CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.
Full Text Available Recent advances in corneal graft technology, including donor tissue retrieval, storage and surgical techniques, have greatly improved the clinical outcome of corneal grafts. Despite these advances, immune mediated corneal graft rejection remains the single most important cause of corneal graft failure. Several host factors have been identified as conferring a "high risk" status to the host. These include: more than two quadrant vascularisation, with associated lymphatics, which augment the afferent and efferent arc of the immune response; herpes simplex keratitis; uveitis; silicone oil keratopathy; previous failed (rejected grafts; "hot eyes"; young recipient age; and multiple surgical procedures at the time of grafting. Large grafts, by virtue of being closer to the host limbus, with its complement of vessels and antigen-presenting Langerhans cells, also are more susceptible to rejection. The diagnosis of graft rejection is entirely clinical and in its early stages the clinical signs could be subtle. Graft rejection is largely mediated by the major histocompatibility antigens, minor antigens and perhaps blood group ABO antigens and some cornea-specific antigens. Just as rejection is mediated by active immune mediated events, the lack of rejection (tolerance is also sustained by active immune regulatory mechanisms. The anterior chamber associated immune deviation (ACAID and probably, conjunctiva associated lymphoid tissue (CALT induced mucosal tolerance, besides others, play an important role. Although graft rejection can lead to graft failure, most rejections can be readily controlled if appropriate management is commenced at the proper time. Topical steroids are the mainstay of graft rejection management. In the high-risk situations however, systemic steroids, and other immunosuppressive drugs such as cyclosporin and tacrolimus (FK506 are of proven benefit, both for treatment and prevention of rejection.
Priscila Cilene León Bueno de Camargo
Full Text Available Our objective was to determine the levels of lactate dehydrogenase, IL-6, IL-8, and VEGF, as well as the total and differential cell counts, in the pleural fluid of lung transplant recipients, correlating those levels with the occurrence and severity of rejection. We analyzed pleural fluid samples collected from 18 patients at various time points (up to postoperative day 4. The levels of IL-6, IL-8, and VEGF tended to elevate in parallel with increases in the severity of rejection. Our results suggest that these levels are markers of acute graft rejection in lung transplant recipients.
Leithner, C.; Syre, G.
Increased deposition of 111 In-oxine labelled autologous platelets in chronically rejected kidney transplants was demonstrated using a gamma-camera and by measurement of a platelet uptake index (PUI). In this group of patients the PUI correlated indirectly with the platelet half-life and was statistically different from the PUI found in stable transplant patients who acted as controls. It is therefore suggested that platelets may play a key role in chronic rejection by the release of a mitogenic factor which promotes the development of obliterative arterial lesions in the transplant. (orig.)
Forstrom, L.A.; Loken, M.K.; Cook, A.; Chandler, R.; McCullough, J.
Indium-111-labeled (In-111) leukocytes have been shown to be useful in the localization of inflammatory processes, including renal transplant rejection. Using previously reported labeling methods, 63 studies with this agent have been performed in 53 renal transplant patients. Indications for study included suspected rejection or cytomegalovirus (CMV) infection. Studies were performed in 33 men and 20 women, with ages ranging from 6 to 68 years. Autologous cells were normally used for labeling, although leukocytes obtained from ABO-compatible donors were used in three subjects. Rectilinear scanner and/or scintillation camera images were obtained at 24 hours after intravenous administration of 0.1 to 0.6 mCi of In-111-leukocytes. There was abnormal uptake of In-111-leukocytes in the transplanted kidney in 11 of 15 cases of rejection. In three additional cases of increased transplant uptake, CMV infection was present in two. Abnormal lung uptake was present in 13 of 14 patients with CMV infection. In four additional cases, increased lung uptake was associated with other pulmonary inflammatory disease. Increased lung activity was not seen in patients with uncomplicated transplant rejection. These results suggest that In-111-leukocyte imaging may be useful in the differential diagnosis of rejection versus CMV infection in renal transplant patients
Forstrom, L.A.; Loken, M.K.; Cook, A.; Chandler, R.; McCullough, J.
Indium-111-labelled (In-111) leukocytes have been shown to be useful in the localization of inflammatory processes, including renal transplant rejection. Using previously reported labelling methods, 63 studies with this agent have been performed in 53 renal transplant patients. Indications for study included suspected rejection or cytomegalovirus (CMV) infection. Studies were performed in 33 men and 20 women, with ages ranging from 6 to 68 years. Autologous cells were normally used for labeling, although leukocytes obtained from ABO-compatible donors were used in three subjects. Rectilinear scanner and/or scintillation camera images were obtained at 24 hours after intravenous administration of 0.1 to 0.6 mCi of In-111 leukocytes. There was abnormal uptake of In-111-leukocytes in the transplanted kidney in 11 of 15 cases of rejection. In three additional cases of increased transplant uptake, CMV infection was present in two. Abnormal lung uptake was present in 13 of 14 patients with CMV infection. In four additional cases, increased lung uptake was associated with other pulmonary inflammatory disease. Increased lung activity was not seen in patients with uncomplicated transplant rejection. These results suggest that In-111-leukocyte imaging may be useful in the differential diagnosis of rejection versus CMV infection in renal transplant patients
Chandler, S.T.; Buckels, J.A.C.; Drolc, Z.; Hawker, R.J.; Barnes, A.D.; McCollum, C.N.
A total of 33 patients was studied with the aim of developing a bedside method for providing early diagnosis of acute rejection using 111-In labelled platelets. Platelet deposition was detected in all patients suffering acute rejection. A significant increase in kidney/aortic arch ratio, as measured by the portable bedside system, preceded the clinical diagnosis in 70% of patients. Using this system, it appeared possible not only to diagnose acute rejection at an earlier stage but also to predict irrecoverable transplant loss even in the presence of tubular necrosis. By labelling the platelets repeatedly for at least two weeks after transplantation, the period of highest risk for acute rejection and other complications. The gamma camera should still be employed in the event of markedly increased platelet deposition to differentiate between rejection and vascular complications
Full Text Available Bone marrow mesenchymal stem cells (BMMSCs have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats.Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control, isogeneically transplanted rats (BN-BN and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg cells were assessed at each time point.Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF-α, and interferon (IFN-γ while upregulating IL-10 and transforming growth factor (TGF-β expression and increasing Treg levels.BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation.
textabstractThe justification for clinical cardiac transplantation is that it should solve end-stage cardiac disease when no other medical or surgical treatment is available (76). However, after cardiac transplantation the main barriers to long-term survival and complete rehabilitation include the
Cainelli, Francesca; Vento, Sandro
Although evidence is far from being conclusive, several studies have suggested that infections could trigger rejection in different transplant settings. In this review we examine the evidence linking cytomegalovirus (CMV), adenovirus, enterovirus, parvovirus, and herpes simplex virus infections to the vasculopathy leading to cardiac allograft rejection, the association between CMV and chronic kidney, lung, and liver graft rejection, and the association of human herpesvirus 6 reactivation with CMV-related disease in kidney and liver transplant recipients. We also review the numerous antiviral prophylactic or pre-emptive treatments in use to control CMV infection, and suggest that they do not limit immune reactions leading to graft rejection or lower the risk of developing post-transplantation atherosclerosis in allograft recipients. Finally, we emphasise the need for prospective, international studies to clarify the role of infections in transplant rejection, to look at virus-to-virus interactions, and to establish specific therapeutic strategies. Such strategies must not rely exclusively on expensive antiviral agents but also on vaccination or other, innovative approaches, such as the use of agents able to inhibit the activity of natural killer cells, which might have an important role in acute allograft rejection.
Full Text Available Chronic allograft nephropathy is a worldwide issue with the major feature of progressive allograft fibrosis, eventually ending with graft loss. Adenosine has been demonstrated to play an important role in process of fibrosis. Our study aimed to investigate the relationship between adenosine and fibrosis in renal allograft acute rejection in rat.Wistar rats and SD rats were selected as experimental animals. Our study designed two groups. In the allograft transplantation group, kidneys of Wistar rats were orthotopically transplanted into SD rat recipients, the same species but not genetically identical, to induce acute rejection. Kidney transplantations of SD rats to SD rats which were genetically identical were served as the control. We established rat models and detected a series of indicators. All data were analyzed statistically. P<0.05 was considered statistically significant.Compared with the control group, levels of adenosine increased significantly in the allograft transplantation group, in which acute rejection was induced (P<0.05. Progressive allograft fibrosis as well as collagen deposition were observed.These findings suggested that level of adenosine was upregulated in acute rejection after kidney allograft transplantation in rat. Acute rejection may promote renal allograft fibrosis via the adenosine signaling pathways.
Full Text Available Marion Lee Sanders,1 Anthony James Langone2 1Department of Medicine, Division of Nephrology and Hypertension, University of Iowa, Iowa City, IA, 2Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Transplantation is the preferred treatment option for individuals with end-stage renal disease. Individuals who undergo transplantation must chronically be maintained on an immunosuppression regimen for rejection prophylaxis to help ensure graft survival. Current rejection prophylaxis consists of using a combination of calcineurin inhibitors, mTOR inhibitors, antimetabolite agents, and/or corticosteroids. These agents have collectively improved the short-term outcomes of renal transplantation, but improvements in late/chronic graft loss and recipient survival have lagged significantly behind challenging the field of transplantation to develop novel prophylactic agents. There have been several clinical trials conducted within the last 5 years in an attempt to bring such novel agents to the commercial market. These trials have resulted in the US Food and Drug Administration (FDA approval of extended-release tacrolimus, as well as belatacept, which has the potential to replace calcineurin inhibitors for rejection prophylaxis. Other trials have focused on the development of novel calcineurin inhibitors (voclosporin, costimulation blockade (ASKP1240 and alefacept, kinase inhibitors (tofacitinib and sotrastaurin, and inhibitors of leukocyte migration (efalizumab. While these later agents have not been FDA-approved for use in transplantation, they remain noteworthy, as these agents explore pathways not previously targeted for allograft-rejection prophylaxis. The purpose of this review was to consolidate available clinical trial data with regard to the recent developments in rejection prophylaxis in kidney transplantation. Keywords: rejection, prophylaxis, immunosuppression
Rodríguez Castellanos, Francisco E; Domínguez Quintana, Francisco; Soto Abraham, Virgilia; Mancilla Urrea, Eduardo
Kidney transplantation is considered the ideal treatment for end-stage renal disease. Acute rejection can influence graft survival. The aim of this study was to propose a classification system for acute rejection based on factor analysis. Data were collected from kidney transplant recipients with acute rejection diagnosis based on standard histological variables, the presence of peritubular eosinophils, and immunolabeling for lysozyme and myeloperoxidase in kidney tissue. Factor analysis was employed for data reduction and generation of a new case classification, with orthogonal rotation as a strategy to simplify factors, and principal component analysis was used as an extraction method. Seventy-nine kidney biopsies were obtained from 74 patients. The total population was divided into humoral rejection (39.2%), cellular rejection (34.1%), and mixed acute rejection (26.7%). No significant differences were found between the three groups in clinical and biochemical variables. We extracted 4 factors using factor analysis. The 1st factor was characterized by the presence of capillaritis, plasma cells infiltration, tubulitis, and inflammation. The 2nd factor included positivity for lysozyme and myeloperoxidase, while the 3rd factor included the presence of eosinophils and glomerulitis. The 4th component consisted of the presence of C4d and endarteritis. The cases belonging to the 3rd factor showed the greatest increase in serum creatinine. The cases belonging to the 4th factor exhibited greater urinary excretion of proteins. This proposal of classification of acute rejection could contribute to evaluate the prognosis of kidney transplant recipients.
Velidedeoglu, Ergun; Cavaillé-Coll, Marc W; Bala, Shukal; Belen, Ozlem A; Wang, Yan; Albrecht, Renata
Despite major advances in understanding the pathophysiology of antibody mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T-cell mediated rejection (TCMR), de novo donor specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. On April 12-13, 2017, the Food and Drug Administration (FDA) sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in GFR, and challenges of clinical trial design for the prevention and treatment of AMR.Results and ConclusionsKey messages from the workshop are summarized in Table 2. Distinction between type 1 (due to preexisting DSA) and type 2 (due to dnDSA) phenotypes of AMR needs to be considered in patient management and clinical trial design. Standardization and more widespread adoption of routine posttransplant DSA monitoring may permit timely diagnosis and understanding of the natural course of type 2 and chronic AMR. Clinical trial design, especially as related to type 2 and chronic AMR, have specific challenges including the high prevalence of nonadherence in the population at risk, indolent nature of the process until the appearance of graft dysfunction and the absence of accepted surrogate endpoints (SEP). Other challenges include sample size and study duration, which could be mitigated by enrichment strategies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Olivia R. Blume
Full Text Available Antibody-mediated rejection (AMR is a major cause of late kidney transplant failure. It is important to have an understanding of human-leukocyte antigen (HLA typing including well-designed studies to determine anti-MHC-class-I-related chain A (MICA and antibody rejection pathogenesis. This can allow for more specific diagnosis and treatment which may improve long-term graft function. HLA-specific antibody detection prior to transplantation allows one to help determine the risk for AMR while detection of DSA along with a biopsy confirms it. It is now appreciated that biopsy for AMR does not have to include diffuse C4d, but does require a closer look at peritubular capillary microvasculature. Although plasmapheresis (PP is effective in removing alloantibodies (DSAs from the circulation, rebound synthesis of alloantibodies can occur. Splenectomy is used in desensitization protocols for ABO incompatible transplants as well as being found to treat AMR refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade which are bortezomib rituximab and eculizumab, respectively.
Vítor Nogueira Mendes
Full Text Available Background: Heart transplant rejection originates slow and fragmented conduction. Signal-averaged ECG (SAECG is a stratification method in the risk of rejection. Objective: To develop a risk score for rejection, using SAECG variables. Methods: We studied 28 transplant patients. First, we divided the sample into two groups based on the occurrence of acute rejection (5 with rejection and 23 without. In a second phase, we divided the sample considering the existence or not of rejection in at least one biopsy performed on the follow-up period (rejection pm1: 18 with rejection and 10 without. Results: On conventional ECG, the presence of fibrosis was the only criterion associated with acute rejection (OR = 19; 95% CI = 1.65-218.47; p = 0.02. Considering the rejection pm1, an association was found with the SAECG variables, mainly with RMS40 (OR = 0.97; 95% CI = 0.87-0.99; p = 0.03 and LAS40 (OR = 1.06; 95% IC = 1.01-1.11; p = 0.03. We formulated a risk score including those variables, and evaluated its discriminative performance in our sample. The presence of fibrosis with increasing of LAS40 and decreasing of RMS40 showed a good ability to distinguish between patients with and without rejection (AUC = 0.82; p < 0.01, assuming a cutoff point of sensitivity = 83.3% and specificity = 60%. Conclusion: The SAECG distinguished between patients with and without rejection. The usefulness of the proposed risk score must be demonstrated in larger follow-up studies.
Salter, Susan P.; Salter, Merle M.; Kirklin, James K.; Bourge, Robert C.; Naftel, David C.
Purpose: Recurrent acute cardiac allograft rejection is an important cause of repeat hospitalization and a major mode of mortality, particularly during the 6 months immediately following transplant. Total lymphoid irradiation (TLI) has been shown experimentally to induce a state of partial tolerance when administered prior to transplantation. Anecdotal reports of clinical experience have also suggested efficacy of TLI in treatment of recurrent cardiac rejection. The purpose of this study is to evaluate the safety and efficacy of TLI for treatment of early or recurrent heart transplant rejection. Materials and Methods: Between January 1990 and June 1992, 49 patients postallograft cardiac transplant were given courses of TLI for treatment of early or recurrent rejection after conventional therapy with Methylprednisolone, antithymocyte globulin, OKT3, and methotrexate. Two patients failed to complete their therapy and were not evaluated. Two other patients received a second TLI course, making a total of 49 courses delivered. Indications for TLI were early rejection (n = 5), recurrent rejection (n = 38), and recurrent rejection with vasculitis (n = 6). The dose goal of the TLI protocol was 8 Gy in 10 fractions given twice weekly. Three separate fields were used to encompass all major lymph node-bearing areas. The actual mean dose was 7 Gy (range 2.4-8.4 Gy), and the duration of treatment was 8 to 106 days. These variations were secondary to leukopenia or thrombocytopenia. Results: The mean posttransplant follow-up is 15 ± 1.2 months (maximum 27 months). Among patients initiating TLI within 1 month posttransplant (n = 15), the rejection frequency decreased from 1.83 episodes/patient/month pre-TLI to 0.13 episodes/patient/month post-TLI (p < 0.0001). For those who began TLI 1-3 months after transplant (n = 21), rejection decreased from 1.43 to 0.10 episodes/patient/month (p < 0.0001). When TLI was started more than 3 months posttransplant (n = 11), the pre-TLI and post
Bos, Ineke G. A.; ten Berge, Ineke J. M.; Hack, C. Erik
Activation of the complement system may significantly contribute to the inflammatory reaction after solid organ transplantation. In allotransplantation, the complement system may be activated by ischemia/reperfusion and, possibly, by antibodies directed against the graft. In xenotransplantation from
Lee, Ga Yeon; Choi, Jin-Oh; Ju, Eun-Seon; Lee, Yoo-Jung; Jeon, Eun-Seok
Endomyocardial biopsy is obligatory during the first year after heart transplant (HTx) for the surveillance of acute rejection. Previous attempts using cardiac biomarkers for the detection of rejection failed to show enough evidence to substitute endomyocardial biopsy. Therefore, this study sought the possibility of using soluble ST2 (sST2), a novel cardiovascular marker, as a surrogate marker for acute allograft rejection after HTx. A total of 494 blood samples acquired at the time of endomyocardial biopsy were analyzed in 67 HTx cases from September 2006 to August 2014. Significant rejection was defined as International Society of Heart and Lung Transplant (ISHLT) score ≥2R and humoral rejection accompanied by hemodynamic instability. Twenty cases of HTx with 22 blood samples showed significant rejection in endomyocardial biopsy at 4.0 (2.0-9.0) months after HTx. The level of sST2 showed positive correlation with cardiac troponin I, and N-terminal pro-B-type natriuretic peptide (all prejection) (p=0.003). However, when we studied within-subject effects of sST2 using a mixed model, the sST2 level according to the predefined time point was not different according to the presence of significant rejection (p for interaction=0.94). Although sST2 is known as a promising predictor for cardiovascular events, its role in HTx patients to predict acute allograft rejection seems to be limited.
Full Text Available Acute skin rejection in vascularized composite allotransplantation (VCA is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection.
Chimerism Vascularized Composite Allograft Tolerance Induction Protocol PRINCIPAL INVESTIGATORS: Dr. Curtis L. Cetrulo CONTRACTING ORGANIZATION...Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance...tacrolimus, FK506, vascularized composite allografts, immune rejection, preclinical, transplant, nonhuman primate model, degradable polymer, tyrosine
Maehana, Takeshi; Tanaka, Toshiaki; Kitamura, Hiroshi; Fukuzawa, Nobuyuki; Ishida, Hideki; Harada, Hiroshi; Tanabe, Kazunari; Masumori, Naoya
Heat shock protein 90 (HSP90), a molecular chaperone associated with the activation of client proteins, was recently reported to play an important role in immunologic reactions. To date, the role of HSP90 in solid organ transplantations has remained unknown. The aim of this study was to evaluate the relationship between serum HSP90α levels and acute allograft rejection after organ and tissue transplantation using serum samples from kidney allograft recipients, an in vitro antibody-mediated rejection model, and a murine skin transplantation. Serum HSP90α levels were significantly higher in kidney recipients at the time of acute rejection (AR) than in those with no evidence of rejection. In most cases with AR, serum HSP90 decreased to baseline after the treatment. On the other hand, serum HSP90α was not elevated as much in patients with chronic rejection, calcineurin inhibitor nephrotoxicity, or BK virus nephropathy as in AR patients. In vitro study showed that HSP90α concentration in the supernatant was significantly higher in the supernatant of human aortic endothelial cells cocultured with specific anti-HLA IgG under complement attack than in that of cells cocultured with nonspecific IgG. In mice receiving skin transplantation, serum HSP90α was elevated when the first graft was rejected and the level further increased during more severe rejection of the second graft. The results suggest that HSP90α is released into the serum by cell damage due to AR in organ and tissue transplantation, and it is potentially a new biomarker to help detect AR in kidney recipients.
Full Text Available Heat shock protein 90 (HSP90, a molecular chaperone associated with the activation of client proteins, was recently reported to play an important role in immunologic reactions. To date, the role of HSP90 in solid organ transplantations has remained unknown. The aim of this study was to evaluate the relationship between serum HSP90α levels and acute allograft rejection after organ and tissue transplantation using serum samples from kidney allograft recipients, an in vitro antibody-mediated rejection model, and a murine skin transplantation.Serum HSP90α levels were significantly higher in kidney recipients at the time of acute rejection (AR than in those with no evidence of rejection. In most cases with AR, serum HSP90 decreased to baseline after the treatment. On the other hand, serum HSP90α was not elevated as much in patients with chronic rejection, calcineurin inhibitor nephrotoxicity, or BK virus nephropathy as in AR patients. In vitro study showed that HSP90α concentration in the supernatant was significantly higher in the supernatant of human aortic endothelial cells cocultured with specific anti-HLA IgG under complement attack than in that of cells cocultured with nonspecific IgG. In mice receiving skin transplantation, serum HSP90α was elevated when the first graft was rejected and the level further increased during more severe rejection of the second graft.The results suggest that HSP90α is released into the serum by cell damage due to AR in organ and tissue transplantation, and it is potentially a new biomarker to help detect AR in kidney recipients.
Jacobsen, I M; Claesson, Mogens Helweg
on the surface of the veto-active cell. Data from a large number of experimental and clinical studies strongly indicate that veto-active cells function in vivo and are capable of preventing allograft rejection. Thus, donor-cell-mediated veto activity is the most likely explanation for the well-known graft...
Heyns, A. du P.; Pieters, H.; Badenhorst, P.N.; Wessels, P.; Loetter, M.G.; Minnaar, P.C.; Pauw, F.H.
Thirteen patients were investigated on 22 occasions at times varying from 1 day to 10 years after living family donor or cadaver renal transplantation. Platelet survival in the circulation, and in vivo platelet distribution and sites of deposition and sequestration was quantitatively determined with Indium-111-oxine (In-111-oxine) labelled platelets and a scintillation camera interfaced with a computer assisted imaging system. In all patients platelet survival was shortened and the platelet survival curve exponential. In patients with no evidence of transplant rejection and those with chronic rejection, there was no measurable or visible accumulation of labelled platelets in the kidney. The sequestration pattern of In-111 labelled platelets at the end of platelet life span was within normal limits and located in the reticuloendothelial system. In those patients with acute transplant rejection, platelet survival was shortened. Labelled platelets accumulated in the kidney: this was clearly visualized on scintigraphy and reflected by a significant increase in the radioactivity count density of the kidney. Platelets not deposited in the transplant were sequestrated in the reticuloendothelial system. This study demonstrates the diagnostic value of In-111 labelled platelet kinetics in the investigation of acute renal failure after renal transplantation. This investigation appears of limited clinical value in chronic rejection. (orig.)
Valette, H.; Bourguignon, M.H.; Desruennes, M.; Merlet, P.; Le Guludec, D.; Syrota, A.
Twenty patients who had undergone a heterotopic heart transplant were studied prospectively to determine the relationship between rejection and ventricular dysfunction assessed from gated blood pool studies. A fully automated method for detecting ventricular edges was implemented; its success rate for the grafted left and right ventricles was 94% and 77%, respectively. The parameters, peak ejection and filling rates, were calculated pixel per pixel using a two-harmonic Fourier algorithm and then averaged over the ventricular region of interest. Peak filling and ejection rates were closely related with the severity of the rejection, while the left ventricular ejection fraction was not. Peak filling rates of both ventricles were the indices closely related to the presence of moderate rejection. Despite the low number of patients, these data suggested that gated blood pool derived indices of ventricular function are associated with ventricular dysfunction resulting from myocarditis rejection. Radionuclide ventriculography provides parametric data which are accurate and reliable for the diagnosis of rejection. (orig.)
Eisen, H.J.; Eisenberg, S.B.; Saffitz, J.E.; Bolman, R.M. III; Sobel, B.E.; Bergmann, S.R.
To determine whether cardiac transplant rejection can be detected noninvasively with indium-111 ( 111 In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 muCi of autologous 111 In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 +/- 7.0 (SD) in transplanted hearts undergoing rejection and 0.4 +/- 1.1 in native hearts on the day before animals were killed. In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 +/- 0.4) and increased to 22.9 +/- 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE greater than 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures
Haga, Hironori; Egawa, Hiroto; Fujimoto, Yasuhiro; Ueda, Mikiko; Miyagawa-Hayashino, Aya; Sakurai, Takaki; Okuno, Tomoko; Koyanagi, Itsuko; Takada, Yasutsugu; Manabe, Toshiaki
Complement C4d deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in kidney and other solid organ transplantation. The correlation of C4d deposits and humoral rejection in liver transplants, however, is not well understood. We investigated the C4d immunostaining pattern in 34 patients whose liver biopsy was taken within the first 3 postoperative weeks for suspected acute rejection after ABO blood type-incompatible liver transplantation. The staining pattern was classified as positive (portal stromal staining), indeterminate (endothelial staining only), and negative (no staining). Positive C4d immunostaining was seen in 17 (50%) patients and was significantly associated with high (x64 or more) postoperative antidonor A/B antibody (immunoglobulin M (IgM)) titers (88 vs. 35%, P = 0.002) and poorer overall survival rate (41 vs. 88%, P = 0.007). Ten of 11 (91%) cases with histological acute humoral rejection (periportal edema and necrosis (PEN) or portal hemorrhagic edema) were positive for C4d, all of which showed high postoperative antibody titers. The other histologies associated with C4d positivity was purulent cholangitis (n = 4), coagulative hepatocyte necrosis (n = 1), acute cellular rejection (n = 1), and hepatocanalicular cholestasis (n = 1). Full clinical recovery was observed in only 6 of 17 (35%) C4d-positive patients, and tended to be associated with a lower rejection activity index (RAI). In conclusion, our study indicates that C4d deposits in the portal stroma can be a hallmark of acute humoral rejection in ABO-incompatible liver transplantation, and allograft damage can be reversible in a minority of cases. Copyright 2006 AASLD
Grauhan, O; Müller, J; Knosalla, C; Pfitzmann, R; Cohnert, T; Siniawski, H; Volk, H D; Fietze, E; Hetzer, R
Measuring intramyocardial ECG amplitude is a clinical non-invasive procedure used for diagnosing rejection after heart transplantation. In recent years, as the importance of humoral mediated rejection has increasingly been recognized, the fact that endomyocardial biopsies often produce false negative results due to the absence of lymphocytic infiltrates has become a matter of concern. In order to test the reliability of IMEG diagnosis of this form of rejection, heterotopic neck-heart transplantation was performed on eight beagles which were previously sensitized through several skin transplantations. Over the course of the study IMEG registrations were performed daily as well as echocardiographic examinations to determine left ventricular wall thickness and maximal diastolic relaxation velocity. Donor-specific antibodies in serum (IgG, IgM) were also determined daily. Myocardial biopsies, performed once every 2 days, were examined for the presence of edema and lymphocytic infiltrate (according to the guidelines of the International Society of Heart and Lung Transplantation, ISHLT) and examined under immunofluorescent microscopy of IgG and IgM. Under triple drug immunosuppression with cyclosporine A, azathioprine, and cortisone accelerated rejection occurred on the fifth postoperative day (range: 4th-5th). All eight episodes were detected through IMEG diagnosis (sensitivity 100%), while the myocardial biopsies graded according to ISHLT guidelines indicated only one case of relevant lymphocytic infiltrate (Grade 3A) (sensitivity 12.5%). In each case rejection was recognized so early that it was possible to perform therapy with restitutio ad integrum. This proved that, as opposed to endomyocardial biopsy, IMEG diagnosis detected humoral mediated rejection early and with high reliability. Furthermore, the immediate recovery in IMEG during therapy indicates that the voltage decrease cause by rejection cannot be explained by an irreversible loss of myocardium
Salvalaggio, Paolo R; Graff, Ralph J; Pinsky, Brett; Schnitzler, Mark A; Takemoto, Steven K; Burroughs, Thomas E; Santos, Luiz S; Lentine Krista L
Methods of crossmatch testing prior to kidney transplantation are not standardized and there are limited large-scale data on the use and outcomes implications of crossmatch modality. Data describing the most sensitive crossmatch modality for crossmatch-negative kidney transplants were drawn from the Organ Procurement and Transplant Network Registry. Within the cohort transplanted in 1999-2005, we identified patient and transplant characteristics predictive of each testing modality by multivariate logistic regression. We assessed associations of crossmatch modality with rejection risk by logistic regression and with graft survival by Cox's hazards analysis. Among 230,995 transplants, use of flow cytometry with T-and B-lymphocytes (T and B FC) increased progressively in 1987-2005. Among the recent transplants performed in 1999-2005 (n=64,320), negative T and B FC crossmatch was associated with 15% lower relative risk of first-year acute rejection (adjusted HR 0.85, 95% CI 0.80-0.89) compared to negative T-antihuman-globulin and B-National Institutes of Health/Wash (T AHG and B) crossmatch. Five-year graft survival after transplant with negative T and B FC (82.6%) was modestly better than after negative T AHG and B (81.4%, P0.008) or T AHG crossmatch (81.1%, P 60 years. Many subgroups for whom negative T and B FC crossmatch predicted lower rejection risk (Caucasians, deceased donor recipients, re-transplants) were not more likely to be crossmatched by this method. We conclude that current practice patterns have not aligned utilization of T and B FC crossmatch with associated benefits. Prospective evaluation of the relationship of crossmatch modality with outcomes is warranted. (author)
Tang, Ying; Zhao, Jingwen; Yu, Huimin; Wu, Hongtao; Niu, Ningning
The aim of our study was to evaluate the clinical application of color Doppler flow imaging (CDFI) and acoustic radiation force impulse (ARFI) for the diagnosis of acute rejection after liver transplantation. B-Mode CDFI and ARFI assessments were performed in 76 patients who underwent biopsy after liver transplantation at our institution, between October 2011 and October 2014. The study group included 56 patients with acute rejection confirmed by biopsy, with 20 patients whose liver function recovered within 1 month of transplantation forming the control group. Anteroposterior diameter of the liver, hemodynamic index (consisting of the portal vein diameter, portal vein flow velocity, and hepatic vein flow waveform), and ARFI shear wave velocity (SWV) were measured. We used logistic regression modeling and receiver operating curve to evaluate between-group differences. Compared with the control group, patients with acute rejection exhibited increased anteroposterior diameter (P = .035) and change in hemodynamic index (P = .021), including increased portal vein diameter, decreased portal vein flow, and loss of triphasic waveform of hepatic vein flow. Acoustic radiation force impulse SWV was markedly increased in the acute rejection group (P liver transplantation. © 2017 by the American Institute of Ultrasound in Medicine.
Full Text Available Purpose. The most recent International Society for Heart and Lung Transplantation (ISHLT biopsy scale classifies cellular and antibody-mediated rejections. However, there are cases with acute decline in left ventricular ejection fraction (LVEF ≤ 45% but no evidence of rejection on biopsy. Characteristics and treatment response of this biopsy negative rejection (BNR have yet to be elucidated. Methods. Between 2002 and 2012, we found 12 cases of BNR in 11 heart transplant patients as previously defined. One of the 11 patients was treated a second time for BNR. Characteristics and response to treatment were noted. Results. 12 cases (of 11 patients were reviewed and 11 occurred during the first year after transplant. 8 cases without heart failure symptoms were treated with an oral corticosteroids bolus and taper or intravenous immunoglobulin. Four cases with heart failure symptoms were treated with thymoglobulin, intravenous immunoglobulin, and intravenous methylprednisolone followed by an oral corticosteroids bolus and taper. Overall, 7 cases resulted in return to normal left ventricular function within a mean of 14 ± 10 days from the initial biopsy. Conclusion. BNR includes cardiac dysfunction and can be a severe form of rejection. Characteristics of these cases of rejection are described with most cases responding to appropriate therapy.
T. V. Stavenchuk
Full Text Available Aim. To identify new predictors of heart transplant rejection by using speckle-tracking echocardiography technique. Materials and methods. 117 recipients were included into research. The follow-up period in S.V. Ochapovsky Region Clinical Hospital No 1 was from March 2010 to April 2015. The groups were allocated based on results of the retrospective analysis of biopsies: group 1 (n = 68, recipients without signs of cellular and humoral rejection (AMR0 ACR0; group 2 (n = 28, recipients with ACR1; group 3 (n = 16, patients with ACR2; group 4 (n = 5, patients with chronic rejection. The analysis of the results was carried out with endomyocardial biopsy, coronary angiography, transthoracic echocardiography (TTE, tissue Doppler imaging, speckle-tracking echocardiography. Results. Early complications include infections and rejection of heart transplant. Cellular rejection is diagnosed in 70% of cases, humoral rejection in 30% of cases. The disease of coronary arteries is a kind of late complications. It was diagnosed in 13.7%. Fraction rejection sensitivity was 63%, specificity was 97% in recipients with ACR1 while carrying out TTE for the purpose of identification of early diagnostic criterion of rejection; recipients with ACR2 had 75% and 96%, respectively. While carrying out PW sensitivity and specificity Е/А in recipients with ACR1 were 83% and 53%, respectively; recipients with ACR2 had 85% and 52%, respectively. While carrying out PW-TDI sensitivity and specificity Е in recipients with ACR1 were 83% and 58%, respectively; recipients with ACR2 had 88% and 60%, respectively. The assessment of myocardial deformation of the left ventricle is as follows: global peak systolic strain in recipients without rejection (GLPS LV – (–17.54 ± 3.71%, р = 0.0012; recipients with (ACR1, AMR1 had GLPS LV (–10.52 ± 1.8%, p = 0.0012; recipients with ACR2 had (–6.44 ± 1.8%, p = 0.002; recipients with chronic rejection had (–9.43 ± 1.8%, p = 0
Lear, J.L.; Raff, U.; Jain, R.; Horgan, J.G.
The authors incorporated their recently developed radionuclide first pass-technique for the quantitative measurement of renal transplant perfusion into routine DTPA imaging. Using this technique they investigated the effects of acute tubular necrosis (ATN), rejection, and cyclosporing toxicity on renal blood flow in a series of 80 studies in 35 patients, with independent evaluation of renal function. Transplant flow values were as follows: normal functioning, 439 mL/min +-83; ATN 248 mL/min +-63; rejection, 128 mL/min +-58; cyclosporing toxicity, 284 mL/min +-97; (normal flow in nontransplanted kidneys, approximately 550 mL/min). Differences between normal functioning, ATN, and rejection were significant (P < .05). Interestingly, immediate postsurgical hyperemia frequently occurred, with flow values sometimes exceeding 700 mL/min
Patel, Seema R; Zimring, James C
Traditionally, alloimmunization to transfused blood products has focused exclusively on recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunologic sequelae of alloimmunization have been antibody mediated effects (ie, hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection-under reduced intensity conditioning with HLA-matched or HLA-identical marrow. Bone marrow transplant of this nature is the only existing cure for a series of nonmalignant hematologic diseases (eg, sickle cell disease, thalassemias, etc); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion-induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or natural killer cells. In this case, rejection occurs in the absence of alloantibodies and would not be detected by existing immune-hematologic methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion, which current blood bank methodologies are unable to detect. © 2013.
Desmarets, Maxime; Cadwell, Chantel M.; Peterson, Kenneth R.; Neades, Renee; Zimring, James C.
When successful, human leukocyte antigen (HLA)–matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization t...
Sterneck, M; Fischer, L; Gahlemann, C; Gundlach, M; Rogiers, X; Broelsch, C
Mycophenolate Mofetil (M MF) is a new immunosuppressive agent with proven efficacy for the prevention of kidney allograft rejection. However, only little experience is available with the use of MMF in liver transplant recipients. In this prospective, controlled trial the efficacy and safety of MMF and Azathioprine (AZA) were compared in a Neoral based quadruple immunosuppressive regimen after orthotopic liver transplantation. Between 12/96 and 12/98 57 adult patients were enrolled in the study at the University of Hamburg. 28 patients were randomised to MMF, 29 patients to AZA in combination with equivalent doses of lymphocyte antibodies, Neoral and methylprednisolone. After a median follow-up of 10+/-3.2 months patient or graft survival did not differ significantly between the MMF and AZA group. However, MMF treated patients experienced less frequently acute rejection episodes (MMF: 6/28; 21.4% versus AZA: 13/29; 44.8%) (p=0.06). Furthermore, thrombocytopenia (MMF: 6/28; 21.4% versus AZA: 14/29; 48.3%) (ppreliminary data suggest that after liver transplantation primary immunosuppression with MMF is advantageous over AZA with regard to safety and efficacy.
van den Bosch, Thierry P. P.; Caliskan, Kadir; Kraaij, Marina D.; Constantinescu, Alina A.; Manintveld, Olivier C.; Leenen, Pieter J. M.; von der Th?sen, Jan H.; Clahsen-van Groningen, Marian C.; Baan, Carla C.; Rowshani, Ajda T.
textabstractBackground: During acute heart transplant rejection, infiltration of lymphocytes and monocytes is followed by endothelial injury and eventually myocardial fibrosis. To date, no information is available on monocyte-macrophage-related cellular shifts and their polarization status during rejection. Here, we aimed to define and correlate monocyte-macrophage endomyocardial tissue profiles obtained at rejection and time points prior to rejection, with corresponding serial blood samples ...
Pfitzmann, R; Müller, J; Grauhan, O; Cohnert, T; Hetzer, R
12 beagle dogs underwent neck-heart transplantation and were immunosuppressed with cyclosporine and methylprednisolone. Intramyocardial impedance was determined twice daily with four screw-in electrodes in the right and left ventricle. Transmyocardial biopsies and the intra-myocardial electrogram (IMEG) were performed as reference methods. 19 rejection episodes were induced. When acute rejection was seen in histology the animals were treated with pulsed 125 mg methylprednisolone over 5 consecutive days and immunosuppression was raised to sufficient levels. Successful treatment of rejection was controlled by biopsy. All hearts showed a uniform decrease of impedance of about 28.3% +/- 5.5% immediately after implantation, then reaching a stable plateau after 7 to 8 days. Impedance values then remained unchanged as long as rejection was absent. Biopsy findings of grade 1A to 1B (ISHLT) were accompanied by a statistically significant increase of impedance of 12.2% +/- 2.5%, of grade 2 to 3A of 19.2% +/- 3.2%, and of grade 3B to 4 of 27.0% +/- 2.9%. Sensitivity was 95%, specificity 91%. Successful treatment of rejection led to a uniform decrease of impedance to intramyocardial impedance for high frequencies can reliably indicate alterations of the cell membrane and the intracellular space during acute cardiac allograft rejection. The amount of increase of impedance is a reliable noninvasive parameter to graduate acute cardiac allograft rejection. The success of treatment of rejection can also be monitored by impedance. This noninvasive method is applicable for telemetric rejection monitoring via an implantable device, which would allow continuous rejection surveillance of a patient at home without hospital admission.
Zhang, Yan; Wroblewski, Matthew; Hertz, Marshall I; Wendt, Christine H; Cervenka, Tereza M; Nelsestuen, Gary L
While lung transplant is an effective therapy for advanced lung disease, chronic allograph rejection remains a primary basis for lower survival rates than those for other solid organ transplants. This study used carefully controlled Zip-Tip extraction of bronchoalveolar lavage fluid (BALF) followed by MALDI-TOF MS to identify biomarkers of chronic lung transplant rejection. Many differences were observed between controls, those who did not develop chronic rejection within 100 months, and patients who had developed chronic rejection, diagnosed as bronchiolitis obliterans syndrome (BOS). Intensity ratios of peaks within the same MALDI-TOF profile were used to quantify the result. One of the best identifiers of BOS was a lowered ratio of clara cell protein (CCP m/z = 15,835) to lysozyme (m/z = 14,700), which gave 94% specificity and 74% sensitivity for diagnosis. Furthermore, low values for CCP/Lysozyme (<0.3) were observed in 66% of samples taken at 1 to 15 months prior to the diagnosis of BOS. Many other components of the profile gave similar or better outcomes for diagnosis but tended to be less valuable for the prediction of future disease. Overall, this study demonstrated the feasibility of this approach for the detection of disease biomarkers.
Grauhan, O; Müller, J; Pfitzmann, R; Knosalla, C; Siniawski, H; Fietze, E; Volk, H D; Hetzer, R
In recent years, as the importance of humoral-mediated rejection has increasingly become recognized, the fact that endomyocardial biopsies (BX) evaluated according to the criteria of the International Society for Heart and Lung Transplantation often produce false-negative results has become a matter of concern. To evaluate the reliability of measuring intramyocardial ECG amplitude (IMEG) and immunofluorescence evaluation (FITC-labeled anti-IgG/ IgM staining) of endomyocardial biopsies (IFM), heterotopic neck-heart transplantation (HTX) was performed on eight beagles previously sensitized through skin transplantations. After HTX, IMEG, echo, and donor-specific antibodies in serum (IgG, IgM) were determined daily and myocardial biopsies (IFM, BX) were performed once every 2 days. Accelerated (humoral) rejection occurred on the 5th (4th-5th) postoperative day and sensitivity of IMEG, IFM, and BX was 100%, 75%, and 12.5%, respectively. In each case rejection was recognized so early that it was possible to initiate therapy with "restitutio ad integrum". Our results show that, as opposed to endomyocardial biopsy (IFM, BX), IMEG diagnosis detected humoral-mediated rejection early and with high reliability.
Kikuchi, S.; Egami, N.
The effects of gamma-irradiation on allograft rejection in the teleost, Oryzias latipes, were examined at 25 degrees C. The survival of melanophores in the transplanted scale was observed as an index of rejection. Allografts were rejected in non-irradiated fish within 7 days. In the gamma-irradiated recipients (2kR), the grafts were rejected more slowly, but still within 20 days. The gamma-ray effects, however, disappeared almost completely within 25 days after the irradiation. If the same recipient again received transplants, the secondary response occurred clearly and the melanophores were rejected very rapidly. The secondary response was suppressed by gamma-rays if the fish was irradiated just before the second transplantation. Immunologic memory against the first transplants disappeared within 30 days, a period shorter than that of mammals
Bader, Feras M; Rogers, R Kevin; Kfoury, Abdallah G; Gilbert, Edward M; Horne, Ben D; Stehlik, Josef; Renlund, Dale G
Endomyocardial biopsy is the gold standard to diagnose cardiac allograft rejection, although a noninvasive modality such as brain natriuretic peptide (BNP) is attractive. The authors examined the correlation of BNP levels with rejection patterns and allograft function in cardiac allograft recipients followed up to 8 years. One hundred forty-four consecutive patients underwent endomyocardial biopsy, right heart catheterization, and blood sampling. BNP levels decreased during the first 6 months after transplant but then reached a plateau. Time-dependent correlations were made between BNP levels and allograft rejection, left ventricular ejection fraction, pulmonary capillary wedge pressure, right atrial pressure, and serum creatinine. BNP levels were not different between patients with any rejection pattern and no rejection prior to or after 6 months following transplant. BNP levels did not correlate with ejection fraction, pulmonary capillary wedge pressure, right atrial pressure, or creatinine in the first 6 months after transplant. Statistically significant correlations existed between BNP and these parameters after 6 months following transplant. In cardiac transplant recipients, BNP levels decrease in the first 6 months following transplant and then reach a plateau regardless of the presence, type, or severity of allograft rejection. BNP levels do predict allograft rejection but correlate with allograft function after 6 months following transplant.
Sindhi, Rakesh; Ashokkumar, Chethan; Higgs, Brandon W; Levy, Samantha; Soltys, Kyle; Bond, Geoffrey; Mazariegos, George; Ranganathan, Sarangarajan; Zeevi, Adriana
Summary The Pleximmune™ test (Plexision Inc., Pittsburgh, PA, USA) is the first cell-based test approved by the US FDA, which predicts acute cellular rejection in children with liver- or intestine transplantation. The test addresses an unmet need to improve management of immunosuppression, which incurs greater risks of opportunistic infections and Epstein–Barr virus-induced malignancy during childhood. High-dose immunosuppression and recurrent rejection after intestine transplantation also result in a 5-year graft loss rate of up to 50%. Such outcomes seem increasingly unacceptable because children can experience rejection-free survival with reduced immunosuppression. Pleximmune test sensitivity and specificity for predicting acute cellular rejection is 84% and 81% respectively in training set–validation set testing of 214 children. Among existing gold standards, the biopsy detects but cannot predict rejection. Anti-donor antibodies, which presage antibody-mediated injury, reflect late-stage allosensitization as a downstream effect of engagement between recipient and donor cells. Therefore, durable graft and patient outcomes also require an accurate management of cellular immune responses in clinical practice. PMID:26760313
Noyes, William R.; Rodriguez, Rey; Knechtle, Stuart J.; Pirsch, John D.; Sollinger, Hans W.; D'Alessandro, Anthony M.; Chappell, Rick; Belzer, Folkert O.; Kinsella, Timothy J.
Purpose: To determine the response rate and kidney graft survival following local irradiation to the transplanted renal graft undergoing persistent rejection after medical management including pulse steroids and OKT3. The role of radiation for renal transplant rejection after failure of OKT3 has not been previously reported. Methods and Materials: From July 1, 1988 to July 1, 1994, 72 consecutive patients with kidney graft rejection were treated with local irradiation to the transplanted renal graft following failure of medical management. All patients received pulse steroids and OKT3, an anti-CD3 immunosuppressant. Patients who failed to respond to methylprednisolone and OKT3 therapy were referred for radiation therapy. The median time from the diagnosis of rejection to irradiation was 8 days. All kidney grafts received local graft irradiation to a total of 8 Gy delivered in four daily fractions. Results: Sixty (83%) patients initially responded to radiotherapy at 7 days after completion of radiotherapy, as defined by a decrease in serum creatinine. Thirty-five responding patients have not experienced a second episode of graft rejection. Overall, 43 (60%) patients have renal graft survival, with a median follow-up of 16 months (range of 6-73 months). Conclusion: It is concluded that there is a subgroup of kidney graft patients undergoing graft rejection who are refractory to pulse steroids and OKT3 therapy where irradiation may be an effective modality with high rates of response and a moderate rate of graft survival. However, a prospective, randomized trial in these medically refractory patients is needed to ascertain whether these results are clinically significant
A. I. Sushkov
Full Text Available Much attention has been placed recently in transplantation in highly HLA-sensitized patients. In attempts to remove these antibodies and enable successful renal transplantation, several approaches have been developed. Intravenous immunoglobulin (IVIG was found to be effective in the treatment of autoimmune and inflammatory disorders (e. g. Kawasaki disease, Guillain-Barre syndrome. Recently, a beneficial effect of IVIG on the reduc- tion of anti-HLA antibodies was described. The anti-inflammatory effect of IVIG provides hopeful opportunities in antibody-mediated rejection (AMR management. There are several protocols of IVIG administration for pre-transplant desensitization and AMR treatment: high-dose IVIG, low-dose IVIG + plasmapheresis, IVIG + plasmapheresis + rituximab. These advancements have enabled transplantation in patients previously considered untransplantable and in concert with new diagnostic techniques has resulted in new approaches to management of AMR.
Porubsky, Stefan; Wang, Shijun; Kiss, Eva
Rhoh is a hematopoietic system-specific GTPase. Rhoh-deficient T cells have been shown to have a defect in TCR signaling manifested during their thymic development. Our aims were to investigate the phenotype of peripheral Rhoh-deficient T cells and to explore in vivo the potential benefit of Rhoh...... deficiency in a clinically relevant situation, in which T-cell inhibition is desirable. In murine allogenic kidney transplantation, Rhoh deficiency caused a significant 75% reduction of acute and chronic transplant rejection accompanied by 75% lower alloantigen-specific antibody levels and significantly...
AshokKumar, Chethan; Talukdar, Anjan; Sun, Qing; Higgs, Brandon W; Janosky, Janine; Wilson, Patrick; Mazariegos, George; Jaffe, Ronald; Demetris, Anthony; Dobberstein, Jennifer; Soltys, Kyle; Bond, Geoffrey; Thomson, Angus; Zeevi, Adriana; Sindhi, Rakesh
Antigen-specific T-cells, which express CD154 rapidly, but remain untested in alloimmunity, were measured with flow cytometry in 16-hour MLR of 58 identically-immunosuppressed children with liver transplantation (LTx), to identify Rejectors (who had experienced biopsy-proven rejection within 60 days post-transplantation). Thirty one children were sampled once, cross-sectionally. Twenty seven children were sampled longitudinally, pre-LTx, and at 1–60 and 61–200 days after LTx. Results were cor...
Full Text Available The outbreak of Pneumocystis jirovecii pneumonia (PJP among kidney transplant recipients is emerging worldwide. It is important to control nosocomial PJP infection. A delay in diagnosis and treatment increases the number of reservoir patients and the number of cases of respiratory failure and death. Owing to the large number of kidney transplant recipients compared to other types of organ transplantation, there are greater opportunities for them to share the same time and space. Although the use of trimethoprim-sulfamethoxazole (TMP-SMX as first choice in PJP prophylaxis is valuable for PJP that develops from infections by trophic forms, it cannot prevent or clear colonization, in which cysts are dominant. Colonization of P. jirovecii is cleared by macrophages. While recent immunosuppressive therapies have decreased the rate of rejection, over-suppressed macrophages caused by the higher levels of immunosuppression may decrease the eradication rate of colonization. Once a PJP cluster enters these populations, which are gathered in one place and uniformly undergoing immunosuppressive therapy for kidney transplantation, an outbreak can occur easily. Quick actions for PJP patients, other recipients, and medical staff of transplant centers are required. In future, lifelong prophylaxis may be required even in kidney transplant recipients.
Scheel, Jennifer; Reber, Sandra; Stoessel, Lisa; Waldmann, Elisabeth; Jank, Sabine; Eckardt, Kai-Uwe; Grundmann, Franziska; Vitinius, Frank; de Zwaan, Martina; Bertram, Anna; Erim, Yesim
Different measures of non-adherence to immunosuppressant (IS) medication have been found to be associated with rejection episodes after successful transplantation. The aim of the current study was to investigate whether graft rejection after renal transplantation is associated with patient-reported IS medication non-adherence and IS trough level variables (IS trough level variability and percentage of sub-therapeutic IS trough levels). Patient-reported non-adherence, IS trough level variability, percentage of sub-therapeutic IS trough levels, and acute biopsy-proven late allograft rejections were assessed in 267 adult renal transplant recipients who were ≥12 months post-transplantation. The rate of rejection was 13.5%. IS trough level variability, percentage of sub-therapeutic IS trough levels as well as patient-reported non-adherence were all significantly and positively associated with rejection, but not with each other. Logistic regression analyses revealed that only the percentage of sub-therapeutic IS trough levels and age at transplantation remained significantly associated with rejection. Particularly, the percentage of sub-therapeutic IS trough levels is associated with acute rejections after kidney transplantation whereas IS trough level variability and patient-reported non-adherence seem to be of subordinate importance. Patient-reported non-adherence and IS trough level variables were not correlated; thus, non-adherence should always be measured in a multi-methodological approach. Further research concerning the best combination of non-adherence measures is needed.
Jia, Yi-xin; Meng, Xu; Sun, Ling-bo; Han, Jie; Chen, Yang-tian
Acute allograft rejection in heart transplantation remains as one of the major complications. Obligatory graft surveillance is still achieved with the invasive and expensive endomyocardial biopsy (EMB). Our study aimed to study the use of intramyocardial electrograms combined with other noninvasive methods for the monitoring of acute rejection after human heart transplantation. Permanent pacemakers were implanted in 58 patients undergoing heart transplantations. Intramyocardial electrograms (IMEG) were recorded periodically and the results were compared with those from EMBs. The R wave amplitude of the IMEG was used as the index value, the average R wave amplitude at the third week following transplantation was considered as the baseline, and a reduction of > 20% compared with the baseline was regarded as a positive result. EMB was performed in cases of positive IMEG results and also at other times. Other noninvasive methods were used to help the diagnosis. Acute rejection (AR) was defined as International Society of Heart-Lung Transplantation grade IIIA or higher. We obtained 1231 IMEG records and 127 EMBs. Of the total 127 EMBs, 53 were positive, in which there were 42 IMEG positive results and 11 negative, while in the rest 74 negative EMBs, there were 9 IMEG positive results and 65 negative. The sensitivity of IMEG for the diagnosis of AR was 79.2%, and the specificity was 87.8%. The positive predictive value was 82.4% and the negative predictive value was 85.5%. Of the total of 1231 IMEG records, 51 were positive and 1180 were negative. Excluding 11 proved by EMB to be false negative, if the other 1169 were considered as no evidence of rejection, through the other noninvasive methods, AR diagnosed by this noninvasive monitoring strategy, the sensitivity was 79.2%, and the specificity was 99.2%. The positive predictive value was 82.4% and the negative predictive value was 99.1%. IMEG can be used as a noninvasive method for monitoring AR following heart
Full Text Available OKT3, a murine monoclonal antibody specific to the human CD3 complex, induces immunosuppression by depletion of T cells. Administration of OKT3 results in significant release of proinflammatory cytokines, such as TNFα and IL1β. Liver recipients who experience rejection within 3 weeks after transplantation with OKT3 prophylaxis recover their T cells by postoperative day 10 despite complete initial clearance.
Brown, C M
Antibody-mediated rejection (AMR) continues to pose a serious challenge in renal transplantation with potentially devastating consequences. Treatment options for this condition include plasmapheresis, high-dose intravenous immunoglobulin (IVIG), plasmapheresis with low-dose IVIG, and the use of rituximab (anti-CD20 chimeric antibody). We previously reported on the short-term outcome of plasmapheresis as a rescue therapy for AMR in our centre. We now report on the long-term follow up.
Azarpira, Negar; Namazi, Soha; Malahi, Sayan; Kazemi, Kourosh
Polymorphisms of the endothelial nitric oxide synthase gene have been associated with altered endothelial nitric oxide synthase activity. The purpose of this study was to investigate the relation between endothelial nitric oxide synthase -786T/C and 894G/T polymorphism and their haplotypes on the occurrence of acute rejection episodes in liver transplant recipients. We conducted a case control study in which 100 liver transplant recipients and 100 healthy controls were recruited from Shiraz Transplant Center. The patients used triple therapy including tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression maintenance. DNA was extracted from peripheral blood and endothelial nitric oxide synthase polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. Patients included 60 men and 40 women (mean age, 32.35 ± 10.2 y). There was a significant association of endothelial nitric oxide synthase 894G/T and acute rejection episode. The GT* gen-otype and acute rejection episodes had a significant association (odds ratio, 2.42; 95% confidence interval, 0.97-6.15; P = .03). The GG and GT* genotype and T* allele frequency were significantly different between patients and control subjects (P = .001). Haplotype TT* was higher in recipients than control subjects (odds ratio, 2.17; 95% confidence interval, 1.12-4.25; P = .01). Haplotype TG was higher in the control group (odds ratio, 0.62; 95% confidence interval, 0.40-0.96; P = .02). Our results suggest a relation between different endothelial nitric oxide synthase geno-types and risk of acute rejection episodes. However, further study is necessary to determine genetic susceptibility for transplant patients.
Full Text Available Abstract Background Combining the results of studies using highly parallelized measurements of gene expression such as microarrays and RNAseq offer unique challenges in meta analysis. Motivated by a need for a deeper understanding of organ transplant rejection, we combine the data from five separate studies to compare acute rejection versus stability after solid organ transplantation, and use this data to examine approaches to multiplex meta analysis. Results We demonstrate that a commonly used parametric effect size estimate approach and a commonly used non-parametric method give very different results in prioritizing genes. The parametric method providing a meta effect estimate was superior at ranking genes based on our gold-standard of identifying immune response genes in the transplant rejection datasets. Conclusion Different methods of multiplex analysis can give substantially different results. The method which is best for any given application will likely depend on the particular domain, and it remains for future work to see if any one method is consistently better at identifying important biological signal across gene expression experiments.
Park, Jongmin; Lin, Hsing-Ying; Assaker, Jean Pierre; Jeong, Sangmoo; Huang, Chen-Han; Kurdi, A; Lee, Kyungheon; Fraser, Kyle; Min, Changwook; Eskandari, Siawosh; Routray, Sujit; Tannous, Bakhos; Abdi, Reza; Riella, Leonardo; Chandraker, Anil; Castro, Cesar M; Weissleder, Ralph; Lee, Hakho; Azzi, Jamil R
Kidney transplant patients require life-long surveillance to detect allograft rejection. Repeated biopsy, albeit the clinical gold standard, is an invasive procedure with the risk of complications and comparatively high cost. Conversely, serum creatinine or urinary proteins are noninvasive alternatives but are late markers with low specificity. We report a urine-based platform to detect kidney transplant rejection. Termed iKEA (integrated kidney exosome analysis), the approach detects extracellular vesicles (EVs) released by immune cells into urine; we reasoned that T cells, attacking kidney allografts, would shed EVs, which in turn can be used as a surrogate marker for inflammation. We optimized iKEA to detect T-cell-derived EVs and implemented a portable sensing system. When applied to clinical urine samples, iKEA revealed high level of CD3-positive EVs in kidney rejection patients and achieved high detection accuracy (91.1%). Fast, noninvasive, and cost-effective, iKEA could offer new opportunities in managing transplant recipients, perhaps even in a home setting.
T.P.P. van den Bosch (Thierry); K. Caliskan (Kadir); M.D. Kraaij (Marina); A.A. Constantinescu (Alina); O.C. Manintveld (Olivier); P.J. Leenen (Pieter); J. von der Thusen (Jan); M.C. Clahsen-van Groningen (Marian); C.C. Baan (Carla); A.T. Rowshani (Ajda)
textabstractBackground: During acute heart transplant rejection, infiltration of lymphocytes and monocytes is followed by endothelial injury and eventually myocardial fibrosis. To date, no information is available on monocyte-macrophage-related cellular shifts and their polarization status during
Tripti Singh, MD
Conclusions. Patients with MN have higher incidence of acute rejection after kidney transplant but have similar 10-year allograft survival in comparison to the other glomerular diseases like IgAN, FSGS, and LN.
Full Text Available The kidney is a very important complicated filtering organ of the body. When the kidney reaches stage 5 chronic kidney disease, end stage renal failure, the preeminent therapy is renal transplantation. Although it is the best form of treatment, lack of kidney donors is still challenging. Therefore, all efforts should be employed to prolong the survival rate of the transplanted kidney. However, graft dysfunction (e.g., acute rejection is one of the serious barriers to long term kidney transplant survival. Currently, graft dysfunction’s gold standard of diagnosis is renal biopsy. Although renal biopsy is helpful, it is not preferred due to its invasive nature, high morbidity rates, and expensiveness. Therefore, noninvasive imaging techniques have become the subject of extensive research and interest, giving a strong promise to replace, or at least to decrease, biopsy usage in diagnosing graft dysfunction. This survey will discuss not only the current diagnosis and treatment of graft dysfunction but also the state-of-the-art imaging techniques in detecting acute renal transplant rejection.
van den Bosch, Thierry P P; Caliskan, Kadir; Kraaij, Marina D; Constantinescu, Alina A; Manintveld, Olivier C; Leenen, Pieter J M; von der Thüsen, Jan H; Clahsen-van Groningen, Marian C; Baan, Carla C; Rowshani, Ajda T
During acute heart transplant rejection, infiltration of lymphocytes and monocytes is followed by endothelial injury and eventually myocardial fibrosis. To date, no information is available on monocyte-macrophage-related cellular shifts and their polarization status during rejection. Here, we aimed to define and correlate monocyte-macrophage endomyocardial tissue profiles obtained at rejection and time points prior to rejection, with corresponding serial blood samples in 25 heart transplant recipients experiencing acute cellular rejection. Additionally, 33 healthy individuals served as control. Using histology, immunohistochemistry, confocal laser scan microscopy, and digital imaging expression of CD14, CD16, CD56, CD68, CD80, and CD163 were explored to define monocyte and macrophage tissue profiles during rejection. Fibrosis was investigated using Sirius Red stainings of rejection, non-rejection, and 1-year biopsies. Expression of co-stimulatory and migration-related molecules on circulating monocytes, and production potential for pro- and anti-inflammatory cytokines were studied using flow cytometry. At tissue level, striking CD16+ monocyte infiltration was observed during rejection ( p rejection compared to barely present CD68+CD80+ M1 macrophages. Rejection was associated with severe fibrosis in 1-year biopsies ( p rejection status, decreased frequencies of circulating CD16+ monocytes were found in patients compared to healthy individuals. Rejection was reflected by significantly increased CD54 and HLA-DR expression on CD16+ monocytes with retained cytokine production potential. CD16+ monocytes and M2 macrophages hallmark the correlates of heart transplant acute cellular rejection on tissue level and seem to be associated with fibrosis in the long term.
WINTER, JB; CLELLAND, C; GOUW, ASH; PROP, J
To differentiate between acute and chronic lung rejection in an early stage, phenotypes of infiltrating inflammatory cells were analyzed in 34 transbronchial biopsies (TBBs) of 24 patients after heart-lung transplantation. TBBs were taken during during acute lung rejection and chronic lung
Wagner, F M; Tugtekin, S M; Matschke, K; Platzbecker, U; Gulielmos, V; Schüler, S
We introduce our concept of non-invasive transplant monitoring. The introduction of individualized immunosuppression by means of flow cytometry leads to a lower incidence of acute graft rejection and preserves immuncompetence. With the simultaneous use of echocardiography and intramyocardial electrogram (IMEG) acute graft rejections can be safely identified without using any invasive method.
Full Text Available Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients' biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures.
Tiwari, Saumya; Reddy, Vijaya B; Bhargava, Rohit; Raman, Jaishankar
Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR) spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients' biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures.
AshokKumar, Chethan; Talukdar, Anjan; Sun, Qing; Higgs, Brandon W; Janosky, Janine; Wilson, Patrick; Mazariegos, George; Jaffe, Ronald; Demetris, Anthony; Dobberstein, Jennifer; Soltys, Kyle; Bond, Geoffrey; Thomson, Angus; Zeevi, Adriana; Sindhi, Rakesh
Antigen-specific T-cells, which express CD154 rapidly, but remain untested in alloimmunity, were measured with flow cytometry in 16-hour MLR of 58 identically-immunosuppressed children with liver transplantation (LTx), to identify Rejectors (who had experienced biopsy-proven rejection within 60 days post-transplantation). Thirty one children were sampled once, cross-sectionally. Twenty seven children were sampled longitudinally, pre-LTx, and at 1–60 and 61–200 days after LTx. Results were correlated with proliferative alloresponses measured by CFSE-dye dilution (n=23), and CTLA4, a negative T-cell costimulator, which antagonizes CD154-mediated effects (n=31). In cross-sectional observations, logistic regression and leave-one-out cross-validation identified donor-specific, CD154+T-cytotoxic (Tc)-memory cells as best associated with rejection outcomes. In the longitudinal cohort, 1) the association between CD154+Tc-memory cells and rejection outcomes was replicated with sensitivity/specificity 92.3%/84.6% for observations at 1–60 days, and 2) elevated pre-LTx CD154+Tc-memory cell responses were associated with significantly increased incidence (p=0.02) and hazard (HR=7.355) of rejection in survival/proportional hazard analysis. CD154 expression correlated with proliferative alloresponses (r=0.835, p=7.1e-07), and inversely with CTLA4 expression of allospecific CD154+Tc-memory cells (r=−0.706, p=3.0e-05). Allospecific CD154+T-helper-memory cells, not CD154+Tc-memory, were inhibited by increasing Tacrolimus concentrations (p=0.026). Collectively, allospecific CD154+T-cells provide an estimate of rejection risk in children with LTx. PMID:18976293
Motyka, Bruce; Fisicaro, Nella; Wang, Szu-I; Kratochvil, Annetta; Labonte, Katrina; Tao, Kesheng; Pearcey, Jean; Marshall, Thuraya; Mengel, Michael; Sis, Banu; Fan, Xiaohu; dʼApice, Anthony J F; Cowan, Peter J; West, Lori J
ABO-incompatible (ABOi) organ transplantation is performed owing to unremitting donor shortages. Defining mechanisms of antibody-mediated rejection, accommodation, and tolerance of ABOi grafts is limited by lack of a suitable animal model. We report generation and characterization of a murine model to enable study of immunobiology in the setting of ABOi transplantation. Transgenesis of a construct containing human A1- and H-transferases under control of the ICAM-2 promoter was performed in C57BL/6 (B6) mice. A-transgenic (A-Tg) mice were assessed for A-antigen expression by histology and flow cytometry. B6 wild-type (WT) mice were sensitized with blood group A-human erythrocytes; others received passive anti-A monoclonal antibody and complement after heart transplant. Serum anti-A antibodies were assessed by hemagglutination. "A-into-O" transplantation (major histocompatibility complex syngeneic) was modeled by transplanting hearts from A-Tg mice into sensitized or nonsensitized WT mice. Antibody-mediated rejection was assessed by morphology/immunohistochemistry. A-Tg mice expressed A-antigen on vascular endothelium and other cells including erythrocytes. Antibody-mediated rejection was evident in 15/17 A-Tg grafts in sensitized WT recipients (median titer, 1:512), with 2 showing hyperacute rejection and rapid cessation of graft pulsation. Hyperacute rejection was observed in 8/8 A-Tg grafts after passive transfer of anti-A antibody and complement into nonsensitized recipients. Antibody-mediated rejection was not observed in A-Tg grafts transplanted into nonsensitized mice. A-Tg heart grafts transplanted into WT mice with abundant anti-A antibody manifests characteristic features of antibody-mediated rejection. These findings demonstrate an effective murine model to facilitate study of immunologic features of ABOi transplantation and to improve potential diagnostic and therapeutic strategies.
Nasiri, M; Geramizadeh, B; Nabavizadeh, S H; Male-Hosseini, S A; Karimi, M H; Saadat, I
Interferon regulatory factors (IRFs) can play a critical role in the regulation of many facets of innate and adaptive immune responses through transcriptional activation of type I interferons, other proinflammatory cytokines, and chemokines. However, their roles in transplantation immunity still remain to be elucidated. To evaluate the time course of mRNA expression of all 9 members of IRFs family of transcription factors during liver allograft acute rejection. Blood samples of 19 patients with autoimmune hepatitis receiving liver transplants were collected on days 1, 3, 5, and 7 post-transplantation. The patients were followed for 6 months after transplantation and divided into two groups of acute rejection (AR) (n=4) and non-acute rejection (non-AR) (n=15). All of the studied transcription factors were down-regulated in AR-group on days 3, 5, and 7 post-transplantation compared to non-AR group. The mean±SEM IRF5 on day 7 post-transplantation was significantly (p=0.005) lower in AR-group than in non-AR group (0.7±0.21 vs . 1.91±0.27, respectively); expression of other IRFs family members was not significantly different between the two groups on days 3, 5, and 7 post-transplantation. IRF5 may have an important role during the acute rejection of liver transplants.
de Groot-Kruseman, Hester A; Mol, Wendy M; Niesters, Hubert G M; Maat, Alex P W; van Gelder, Teun; Balk, Aggie H M M; Weimar, Willem; Baan, Carla C
After clinical heart transplantation, ischemia, acute rejection, and repair mechanisms can trigger the up-regulation of cytokines. To investigate the cytokine profile early after transplantation, we monitored messenger RNA (mRNA) expression levels of tumor necrosis factor-alpha (TNF-alpha), monocyte
Ladhani, Maleeka; Lade, Samantha; Alexander, Stephen I; Baur, Louise A; Clayton, Philip A; McDonald, Stephen; Craig, Jonathan C; Wong, Germaine
Obesity is prevalent in children with chronic kidney disease (CKD), but the health consequences of this combination of comorbidities are uncertain. The aim of this study was to evaluate the impact of obesity on the outcomes of children following kidney transplantation. Using data from the ANZDATA Registry (1994-2013), we assessed the association between age-appropriate body mass index (BMI) at the time of transplantation and the subsequent development of acute rejection (within the first 6 months), graft loss and death using adjusted Cox proportional hazards models. Included in our analysis were 750 children ranging in age from 2 to 18 (median age 12) years with a total of 6597 person-years of follow-up (median follow-up 8.4 years). Overall, at transplantation 129 (17.2%) children were classified as being overweight and 61 (8.1%) as being obese. Of the 750 children, 102 (16.2%) experienced acute rejection within the first 6 months of transplantation, 235 (31.3%) lost their allograft and 53 (7.1%) died. Compared to children with normal BMI, the adjusted hazard ratios (HR) for graft loss in children who were underweight, overweight or diagnosed as obese were 1.05 [95% confidence interval (CI) 0.70-1.60], 1.03 (95% CI 0.71-1.49) and 1.61 (95% CI 1.05-2.47), respectively. There was no statistically significant association between BMI and acute rejection [underweight: HR 1.07, 95% CI 0.54-2.09; overweight: HR 1.42, 95% CI 0.86-2.34; obese: HR 1.83, 95% CI 0.95-3.51) or patient survival (underweight: HR 1.18, 95% CI 0.54-2.58, overweight: HR 0.85, 95% CI 0.38-1.92; obese: HR 0.80, 95% CI 0.25-2.61). Over 10 years of follow-up, pediatric transplant recipients diagnosed with obesity have a substantially increased risk of allograft failure but not acute rejection of the graft or death.
Venkat, Veena L; Nick, Todd G; Wang, Yu; Bucuvalas, John C
Non-adherence to a prescribed immunosuppressive regimen increases risk for late allograft rejection (LAR). We implemented a protocol for immunosuppression management which decreased variation in calcineurin inhibitor blood levels in pediatric liver transplant recipients by controlling for confounders such as physician practice variability. We hypothesized that patients with increased variation in tacrolimus blood levels despite implementation of the immunosuppression management protocol were at increased risk for LAR. We conducted a single center retrospective cohort study of 101 pediatric liver transplant recipients who were at least one year post liver transplantation and receiving tacrolimus for immunosuppression. The primary outcome variable was biopsy proven allograft rejection. Primary candidate predictor variables were the standard deviation (SD) of tacrolimus blood levels (a marker of drug level variability), mean tacrolimus blood level, age, and insurance type. SD of tacrolimus blood levels was determined for each patient from a minimum of four outpatient levels during the study period. Unadjusted and adjusted logistic regression models were used to determine the prognostic value of candidate predictors. The median and interquartile range of the SD of tacrolimus blood levels was 1.6 (1.1, 2.1). Eleven episodes of LAR occurred during the study period. Ten of the 11 episodes occurred in patients with tacrolimus blood level SD > 2. Insurance type, mean tacrolimus blood level and SD of tacrolimus blood levels were significantly related to LAR in the unadjusted analyses (ptype, mean and SD of tacrolimus blood levels was significantly associated with LAR (validated C-statistic = 0.88, p = 0.012). The adjusted odds of rejection for a one unit increase in the SD of tacrolimus blood level was 3.49 (95% CI 1.31 to 9.29). Effects of age and insurance status on LAR did not provide independent prognostic value after controlling for SD. Variation in tacrolimus blood
Grgic, I; Wulff, H; Eichler, I
Currently, there is an unmet clinical need for novel immunosuppressive agents for long-term prevention of kidney transplant rejection as alternatives to the nephrotoxic calcineurin inhibitor cyclosporine (CsA). Recent studies have shown that K(+) channels have a crucial role in T-lymphocyte activ......Currently, there is an unmet clinical need for novel immunosuppressive agents for long-term prevention of kidney transplant rejection as alternatives to the nephrotoxic calcineurin inhibitor cyclosporine (CsA). Recent studies have shown that K(+) channels have a crucial role in T......-lymphocyte activity. We investigated whether combined blockade of the T-cell K(+) channels K(Ca)3.1 and K(v)1.3, both of which regulate calcium signaling during lymphocyte activation, is effective in prevention of rejection of kidney allografts from Fisher rats to Lewis rats. All recipients were initially treated...
Piotti, Giovanni; Palmisano, Alessandra; Maggiore, Umberto; Buzio, Carlo
This review of clinical and experimental studies aims at analyzing the interplay between graft endothelium and host immune system in renal transplantation, and how it affects the survival of the graft. Graft endothelium is indeed the first barrier between self and non-self that is encountered by host lymphocytes upon reperfusion of vascularized solid transplants. Endothelial cells (EC) express all the major sets of antigens (Ag) that elicit host immune response, and therefore represent a preferential target in organ rejection. Some of the Ag expressed by EC are target of the antibody-mediated response, such as the AB0 blood group system, the human leukocyte antigens (HLA), and MHC class I related chain A antigens (MICA) systems, and the endothelial cell-restricted Ag; for each of these systems, the mechanisms of interaction and damage of both preformed and de novo donor-specific antibodies are reviewed along with their impact on renal graft survival. Moreover, the rejection process can force injured EC to expose cryptic self-Ag, toward which an autoimmune response mounts, overlapping to the allo-immune response in the damaging of the graft. Not only are EC a passive target of the host immune response but also an active player in lymphocyte activation; therefore, their interaction with allogenic T-cells is analyzed on the basis of experimental in vitro and in vivo studies, according to the patterns of expression of the HLA class I and II and the co-stimulatory molecules specific for cytotoxic and helper T-cells. Finally, as the response that follows transplantation has proven to be not necessarily destructive, the factors that foster graft endothelium functioning in spite of rejection, and how they could be therapeutically harnessed to promote long-term graft acceptance, are described: accommodation that is resistance of EC to donor-specific antibodies, and endothelial cell ability to induce Foxp3+ regulatory T-cells, that are crucial mediators of tolerance. PMID
Full Text Available Osama Gheith, Torki Al-Otaibi, Hany MansourDepartment of Nephrology, Hamed Al-Essa Organ Transplant Center, Ibn Sina Hospital, Shuwaikh, KuwaitAbstract: Calcineurin inhibitors (CNIs remain the cornerstone of immunosuppression after renal transplantation despite their adverse effects. Some CNIs have well known negative impacts on the cardiovascular system, including hypertension, hyperlipidemia, new onset diabetes after transplantation (NODAT, neurotoxicity, hypertrichosis, and nephrotoxicity. Many clinical trials dealing with CNI avoidance or elimination were associated with higher risk of rejection of the transplanted organ. New generation CNIs are concerned with modifying CNI molecules so that they become more potent and are suitable for patients with suboptimal adherence with less adverse effects. In this review, we address these issues.Keywords: calcineurin inhibitors, organ transplant, rejection
Tisdale, P.L.; Collier, B.D.; Kauffman, H.M.
A prospective evaluation of 111 In-labeled platelet scintigraphy (IPS) for the early diagnosis of acute postoperative renal transplant rejection (TR) was undertaken. The results of IPS were compared with in vitro biochemical tests, the clinical finding of graft tenderness, and combined [/sup 99m/Tc]DTPA and [ 131 I]orthoiodohippurate scintigraphy. With a sensitivity of 0.93 and a specificity of 0.95, IPS provided otherwise unavailable diagnostic information. Furthermore, postoperative IPS was a good predictor of long-term allograft survival
Full Text Available BACKGROUND: The intestinal chronic rejection (CR is the major limitation to long-term survival of transplanted organs. This study aimed to investigate the interaction between intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplantation, and to find out whether fish oil enhances recovery of intestinal microbiota and epithelial integrity. METHODS/PRINCIPAL FINDINGS: The luminal and mucosal microbiota composition of CR rats were characterized by DGGE analysis at 190 days after intestinal transplant. The specific bacterial species were determined by sequence analysis. Furthermore, changes in the localization of intestinal TJ proteins were examined by immunofluorescent staining. PCR-DGGE analysis revealed that gut microbiota in CR rats had a shift towards Escherichia coli, Bacteroides spp and Clostridium spp and a decrease in the abundance of Lactobacillales bacteria in the intestines. Fish oil supplementation could enhance the recovery of gut microbiota, showing a significant decrease of gut bacterial proportions of E. coli and Bacteroides spp and an increase of Lactobacillales spp. In addition, CR rats showed pronounced alteration of tight junction, depicted by marked changes in epithelial cell ultrastructure and redistribution of occuldin and claudins as well as disruption in TJ barrier function. Fish oil administration ameliorated disruption of epithelial integrity in CR, which was associated with an improvement of the mucosal structure leading to improved tight junctions. CONCLUSIONS/SIGNIFICANCE: Our study have presented novel evidence that fish oil is involved in the maintenance of epithelial TJ integrity and recovery of gut microbiota, which may have therapeutic potential against CR in intestinal transplantation.
Full Text Available Early detection and proper management of kidney rejection are crucial for the long-term health of a transplant recipient. Recipients are normally monitored by serum creatinine measurement and sometimes with graft biopsies. Donor-derived cell-free deoxyribonucleic acid (cfDNA in the recipient's plasma and/or urine may be a better indicator of acute rejection. We evaluated digital PCR (dPCR as a system for monitoring graft status using single nucleotide polymorphism (SNP-based detection of donor DNA in plasma or urine. We compared the detection abilities of the QX200, RainDrop, and QuantStudio 3D dPCR systems. The QX200 was the most accurate and sensitive. Plasma and/or urine samples were isolated from 34 kidney recipients at multiple time points after transplantation, and analyzed by dPCR using the QX200. We found that donor DNA was almost undetectable in plasma DNA samples, whereas a high percentage of donor DNA was measured in urine DNA samples, indicating that urine is a good source of cfDNA for patient monitoring. We found that at least 24% of the highly polymorphic SNPs used to identify individuals could also identify donor cfDNA in transplant patient samples. Our results further showed that autosomal, sex-specific, and mitochondrial SNPs were suitable markers for identifying donor cfDNA. Finally, we found that donor-derived cfDNA measurement by dPCR was not sufficient to predict a patient's clinical condition. Our results indicate that donor-derived cfDNA is not an accurate predictor of kidney status in kidney transplant patients.
Lim, Sun Woo; Kim, Young Kyun; Park, Narae; Jin, Long; Jin, Jian; Doh, Kyoung Chan; Ju, Ji Hyeon; Yang, Chul Woo
Recently, it has been reported that minicircle vectors could allow the expression of transgenes using the protein synthesis system of the host. Here, we tested a novel strategy to permit the production of synthetic biologics using minicircle technology and evaluated their feasibility as a therapeutic tool in a skin allograft model. We engineered vectors to carry cassette sequences for tocilizumab [anti-soluble interleukin-6 receptor (sIL-6R) antibody] and/or etanercept [tumor necrosis factor receptor 2 (TNFR2)-Fc fusion protein], and then isolated minicircle vectors from the parent vectors. We verified the production of proteins from minicircles and their duration in HEK293T cells and mice. We also evaluated whether these proteins were expressed at levels sufficient to ameliorate skin allograft rejection in mice. Each minicircle transfected into cells was detectable for at least 30 days. In mice, the drugs were mainly expressed in the liver and were detectable for at least 10 days after a single injection. These drugs were also detected in the blood. Treatment of mice with minicircles prolonged skin allograft survival, which was accompanied by a reduction of the number of interferon-γ+ or interleukin-17+ lymphocytes and an induction of forkhead box P3 expression. These findings suggest that blocking of sIL-6R and/or TNF-α using minicircles encoding tocilizumab and/or etanercept was functionally active and relevant for preventing acute allograft rejection. Self-reproducing synthetic protein drugs produced using minicircle technology are potentially powerful tools for preventing acute rejection in transplantation.
E. S. Stolyarevich
Full Text Available Tасrolimus (Tac has been used for rescuing of renal allografts from refractory rejection that occurred during treatment with conventional cyclosporine A (CsA mostly in the early posttransplant period. Less is known about effect of Tac in cases of late acute rejection. Aim of the study was to examine the long-term effects of switching from CyA-based therapy to Tac-based therapy versus continuation of CsA in renal transplant patients with acute rejection occurred 3 month after transplantation or later. In this comparative prospective clinical study 176 patients experiencing a late biopsy-proven acute or active chronic rejection were followed-up for up to 6 months. 61 pati- ents were converted from a CуA-based therapy to the Tac one; in 115 patients CsA-based therapy was continued. During the first month after the rejection episode the median serum creatinine concentration had decreased in both groups (from 0.27 (0.18; 0.4 to 0.25 (0.16; 0.41 mmol/l in the CsA group and from 0.25 (0.18; 0.3 to 0.18 (0.14; 0.25 mmol/l in the Tac group. During the follow-up graft function remained stable in the Tac group 0,17 (0,14; 0,3 mmol/l, while in the CsA group a trend to progression of graft failure was observed 0.33 (0.19; 0.8 mmol/l. The 3-year Kaplan-Meier estimates for graft loss were 57,1% (Tac and 40,9% (CsA, respectively (р < 0.01. Conclusion: early switch from the CsA- to the Tac-based therapy after a late biopsy-confirmed rejection resulted in a significant improvement in the clinical output in renal graft recipients compared to patients for whom the CyA therapy was continued.
Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik
ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated reje......ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody......-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest...... that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime....
Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik
ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated reje......ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody......-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest...... that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime....
Flynn, Edward R.; Bryant, H. C.; Bergemann, Christian; Larson, Richard S.; Lovato, Debbie; Sergatskov, Dmitri A.
Acute rejection in organ transplant is signaled by the proliferation of T-cells that target and kill the donor cells requiring painful biopsies to detect rejection onset. An alternative non-invasive technique is proposed using a multi-channel superconducting quantum interference device (SQUID) magnetometer to detect T-cell lymphocytes in the transplanted organ labeled with magnetic nanoparticles conjugated to antibodies specifically attached to lymphocytic ligand receptors. After a magnetic field pulse, the T-cells produce a decaying magnetic signal with a characteristic time of the order of a second. The extreme sensitivity of this technique, 10 5 cells, can provide early warning of impending transplant rejection and monitor immune-suppressive chemotherapy.
Borges, T J; O'Malley, J T; Wo, L; Murakami, N; Smith, B; Azzi, J; Tripathi, S; Lane, J D; Bueno, E M; Clark, R A; Tullius, S G; Chandraker, A; Lian, C G; Murphy, G F; Strom, T B; Pomahac, B; Najafian, N; Riella, L V
Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Full Text Available Acute Antibody Mediated Rejection (AMR is rarely reported as a long-term com-plication of renal transplantation, and it can present on top of another chronic pathology affecting the graft. A 45-year-old gentleman with chronic kidney disease due to unknown etiology received renal transplantation from his sister with 4 HLA mismatches. He received antithymocte globulin induction therapy and was maintained on steroids, azathioprine (AZA and cyclosporine A (CsA. Up to eight years post-transplantation he was clinically and biochemically stable. He lost follow-up for about one year, and then presented with nephritic nephrotic syndrome and rise of serum creatinine (SCr. to 210 μmol/L. Graft biopsy revealed picture suggestive of acute AMR on top of de novo membranoprolipherative glomerulonephritis (MPGN with focal crescent formation, diffuse immune complex deposition and peri-tubular capillaries C4d positivity. Anti-HLA donor specific antibodies were highly positive for B and T cells class I and class II. The patient was treated with intravenous immunoglobulin, plasma exchange and anti-CD20 (rituximab. AZA was changed to mycophenolate mofetil and CsA to tacrolimus. He had partial response, but SCr. continued at 220 μmol/L.
Bergsland, J.; Hwang, K.; Driscoll, R.; Carr, E.A.; Wright, J.R.; Curran-Everett, D.C.; Carroll, M.; Krasney, E.; Krasney, J.A.
The effects of rejection on coronary flow (CAF) in heart allografts are unclear, although previous evidence with cardiac imaging agents indicates impaired flow during advanced rejection. The purpose of this study was to measure CAF in heterotopically placed heart grafts. Lewis rats (LEW) received grafts from either syngeneic Lewis rats (LEW/LEW group) or allogeneic ACI rats (ACI/LEW group). CAF was measured in both the transplanted and native hearts with radiolabeled microspheres. Rejection was measured histologically (grades 0 [absent] to 4+ [severe]). In addition systemic blood pressure and cardiac outputs of the native hearts were determined with microspheres. Different animals were studied during relatively early (4 days) and late (6 days) rejection. Among the 4-day animals a cyclosporine-treated group was included (ACI/LEW CyA). In 6-day rats CAF in allografts was lower (0.56 +/- .06 ml/gm/min) compared with syngeneic grafts (1.72 +/- 0.4 ml/gm/min) (p less than 0.05). The CAF in the native hearts did not differ significantly but was higher than in the grafts in both groups. Heart rates were reduced in allografts (p less than 0.05). It is interesting that arterial pressure and cardiac output were significantly lower in animals bearing allogeneic than syngeneic grafts. In rats studied at 4 days graft CAF was lower than in the native heart in both the LEW/LEW and ACI/LEW groups, but there was no significant difference in behavior between groups. The same was true for a cyclosporine-treated group. Graft heart rates were similar in all 4-day rats
Belmar Vega, L; Rodrigo Calabia, E; Gómez Román, J J; Ruiz San Millán, J C; Martín Penagos, L; Arias Rodríguez, M
Antibody-mediated rejection is the main cause of deterioration of kidney transplants and frequently is detected only by means of protocol biopsies. The aim of this study was to relate the presence of albuminuria throughout the 1st year to the histologic findings detected by 1-year protocol biopsies in kidney graft recipients. Retrospective observational study of 86 protocol biopsies 1 year after transplantation. Albuminuria was measured at 3, 6, 9, and 12 months in urine samples and expressed as albumin/creatinine (mg/g). Analysis of biopsies, reflected according to the Banff criteria, the following categories: fibrosis and tubular atrophy, 35 (40.7%); cellular rejection, 13 (15.1%); antibody-mediated rejection, 8 (9.3%); chronic glomerulopathy, 10 (11.6%); normal, 14 (16.3%); recurrence, 1 (1.2%); and other, 5 (5.8%). The proportions of patients with albuminuria for Banff scale scores (0 vs ≥1, respectively) at 6 and 12 months, respectively, after transplantation, were: for marker glomerulitis, 45.5% versus 59.3% (P = .021) and 36.4% versus 70.4% (P albuminuria after renal transplantation is common, especially in patients with proteinuria. Persistent albuminuria after transplantation, even at low levels, can be indicative of subclinical antibody-mediated rejection. Additional broader studies to relate the albuminuria to histologic changes observed in protocol biopsies are required. Copyright Â© 2016 Elsevier Inc. All rights reserved.
Schaffer, S A; Husain, S; Delgado, D H; Kavanaugh, L; Ross, H J
During the H1N1 influenza virus pandemic, vaccination of high risk groups including solid-organ transplant recipients was advised. A retrospective case control study of 60 heart transplant patients, 15 having received the H1N1 virus antigen and ASO3 adjuvant vaccine (GlaxoSmithKline, Mississauga, ON, Canada) within 21 days and 45 having not been vaccinated, all undergoing routine surveillance endmyocardial biopsies, was performed. The overall rate of cellular rejection (all grades) was not statistically different between groups; however, acute cellular rejection, ≥grade 2 (1990 ISHLT criteria), was more frequent among those having recently vaccinated (control: 1/45 vs. 6/15, p = 0.001). On multivariate analysis, the only risk factor found to be associated with acute cellular rejection was recent H1N1 viral antigen and adjuvant vaccination (OR 26.5: 95% CI 02.59-270.5). Vaccine adjuvants increase host response to vaccine antigens by immune upregulation potentially increasing risk of rejection in solid-organ transplant recipients. The potential hazard of vaccination this study raises must be weighed with the clear benefit vaccination has proven to be. ©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Kaufman, Arnauld; de Souza Pontes, Luciane Faria; Queiroz Marques, Maria Teresa; Sampaio, José Cavaliere; de Moraes Sobrino Porto, Luís Cristóvão; de Moraes Souza, Edison Régio
Many centers determined a significant correlation between post-transplant anti-HLA antibodies production and clinical outcome. In order to confirm this correlation and ascertain the sequential appearance of anti-HLA antibodies, we compared the ELISA (ELISA-PRA) and the anti-human globulin enhanced complement-dependent lymphocytotoxicity panel-reactive antibodies test (AHG-PRA) with the occurrence of acute rejection episodes. Thirty patients who underwent kidney transplantation between December 1998 and October 1999 were assayed. One pre-transplant and 10 post-transplant serum samples were tested from each recipient except from one of them who lost his graft on the 1 week post-transplant. The diagnosis of acute rejection episode was based on classical criteria (fever, graft swelling and tenderness, oliguria, weight gain) and a rapid rise in serum creatinine levels, confirmed by an allograft biopsy graded by the Banff working classification. The 322 pre- and post-transplant serum specimens were tested by AHG-PRA methodology and 298 of them by the ELISA-PRA. The agreement coefficient (kappa) for both methodologies was 0.63. There were 27 acute rejection episodes in 19 patients. AHG-PRA results were significantly correlated (Hazard ratio=10.06; P=0.006) with this occurrence. These data were not confirmed with the ELISA-PRA procedure. Our results suggest that a routine post-transplant AHG-PRA test offers an early risk assessment of acute rejection episodes and may be a useful method for monitoring the kidney transplant evolution.
Bijkerk, Roel; Florijn, Barend W; Khairoun, Meriem; Duijs, Jacques M G J; Ocak, Gurbey; de Vries, Aiko P J; Schaapherder, Alexander F; Mallat, Marko J K; de Fijter, Johan W; Rabelink, Ton J; van Zonneveld, Anton Jan; Reinders, Marlies E J
Acute rejection (AR) of kidney transplants is associated with the loss of endothelial integrity, microvascular rarefaction and, ultimately, graft dysfunction. Circulating angiogenic microRNAs (miRNAs) may serve as markers for microvascular injury. Here, we investigated the short- and long-term effects of AR after kidney transplantation on systemic vascular injury and the associated circulating miRNA profile. Systemic vascular injury was determined by measuring capillary tortuosity and density within the oral mucosa as well as by assessing circulating levels of angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor and soluble thrombomodulin. After a pilot study, we selected 48 miRNAs to assess the AR- and microvascular injury associated circulating miRNAs. In stable transplant recipients (n = 25) and patients with AR (n = 13), which were also studied longitudinally (1, 6, and 12 months post-AR), we found an AR-associated increase in markers of systemic vascular injury, of which vascular endothelial growth factor and soluble thrombomodulin normalized within 1 year after AR. Of the 48 selected miRNAs, 8 were either decreased (miR-135a, miR-199a-3p, and miR-15a) or increased (miR-17, miR-140-3p, miR-130b, miR-122 and miR-192) in AR. Of these, miR-130b, miR-199a, and miR-192 associated with markers of vascular injury, whereas miR-140-3p, miR-130b, miR-122, and miR-192 normalized within 1 year after AR. AR after kidney transplantation is characterized by systemic microvascular injury and associates with specific circulating miRNA levels.
Full Text Available Binding of chemokines to glycosaminoglycans (GAGs is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts.Analysis of GAG or CC chemokine receptor 2 (CCR2 deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs in mouse aortic allograft transplants (n = 239 mice. Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1(f/fTekCre(+ heparan sulfate (GAG-deficient (Ndst1(-/-, p<0.044 and CCR2-deficient (Ccr2(-/-, p<0.04 donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT (Ccr2(+/+, p< or =0.003 and Ccr2(-/-, p=0.027 aortic allografts, but not in Ndst1(-/- aortic allografts (p = 0.933. M-T1 and M3 inhibited WT (Ccr2(+/+ and Ndst1(+/+, p< or =0.006 allograft vasculopathy, but did not block vasculopathy in Ccr2(-/- (p = 0.61. M-T7 treatment alone, even without immunosuppressive drugs, also significantly prolonged survival of renal allograft transplants (p< or =0.001.Interruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of
Tillou, Xavier; Poirier, Nicolas; Le Bas-Bernardet, Stephanie; Hervouet, Jeremy; Minault, David; Renaudin, Karine; Vistoli, Fabio; Karam, Georges; Daha, Mohamed; Soulillou, Jean Paul; Blancho, Gilles
Acute antibody-mediated rejection is an unsolved issue in transplantation, especially in the context of pretransplant immunization. The deleterious effect of preformed cytotoxic anti-HLA antibodies through complement activation is well proven, but very little is known concerning complement blockade
Håugaa, Håkon; Thorgersen, Ebbe B; Pharo, Anne; Boberg, Kirsten M; Foss, Aksel; Line, Pål Dag; Sanengen, Truls; Almaas, Runar; Grindheim, Guro; Pischke, Soeren Erik; Mollnes, Tom Eirik; Tønnessen, Tor Inge
This study was performed to explore whether lactate, pyruvate, glucose, and glycerol levels sampled via microdialysis catheters in the transplanted liver could be used to detect ischemia and/or rejection. The metabolites were measured at the bedside every 1 to 2 hours after the operation for a median of 10 days. Twelve grafts with biopsy-proven rejection and 9 grafts with ischemia were compared to a reference group of 39 grafts with uneventful courses. The median lactate level was significantly higher in both the ischemia group [5.8 mM (interquartile range = 4.0-11.1 mM)] and the rejection group [2.1 mM (interquartile range = 1.9-2.4 mM)] versus the reference group [1.5 mM (interquartile range = 1.1-1.9 mM), P interquartile range = 155-206 μM)] versus the reference group [124 μM (interquartile range = 102-150 μM), P interquartile range = 23.9-156.7) and 138 μM (interquartile range = 26-260 μM)] versus the reference group [11.8 (interquartile range = 10.6-13.6), P interquartile range = 9-24 μM), P = 0.002]. Ischemia was detected with 100% sensitivity and greater than 90% specificity when a positive test was repeated after 1 hour. In 3 cases of hepatic artery thrombosis, ischemia was detected despite normal blood lactate levels. Consecutive pathological measurements for 6 hours were used to diagnose rejection with greater than 80% sensitivity and specificity at a median of 4 days before the activity of alanine aminotransferase, the concentration of bilirubin in serum, or both increased. In conclusion, bedside measurements of intrahepatic lactate and pyruvate levels were used to detect ischemia and rejection earlier than current standard methods could. Discrimination from an uneventful patient course was achieved. Consequently, intrahepatic graft monitoring with microdialysis may lead to the earlier initiation of graft-saving treatment. Copyright © 2012 American Association for the Study of Liver Diseases.
Furness, P N; Levesley, J; Luo, Z; Taub, N; Kazi, J I; Bates, W D; Nicholson, M L
To develop and test a neural network to assist in the histological diagnosis of early acute renal allograft rejection. We used three sets of biopsies to train and test the network: 100 'routine' biopsies from Leicester; 21 selected difficult biopsies which had already been evaluated by most of the renal transplant pathologists in the UK, in a study of the Banff classification of allograft pathology and 25 cases which had been classified as 'borderline' according to the Banff classification in a review of transplant biopsies from Oxford. The correct diagnosis for each biopsy was defined by careful retrospective clinical review. Biopsies where this review did not provide a clear diagnosis were excluded. Each biopsy was graded for 12 histological features and the data was entered into a simple single layer perception network, designed using the MATLAB neural network toolbox. Results were compared with logistic regression using the same data, and with 'conventional' histological diagnosis. If the network was trained only with the 100 'routine' cases, its performance with either of the other sets was poor. However, if either of the 'difficult' sets was added to the training group, testing with the other 'difficult' group improved dramatically; 19 of the 21 'Banff' study cases were diagnosed correctly. This was achieved using observations made by a trainee pathologist. The result is better than was achieved by any of the many experienced pathologists who had previously seen these biopsies (maximum 18/21 correct), and is considerably better than that achieved by using logistic regression with the same data. A neural network can provide a considerable improvement in the diagnosis of early acute allograft rejection, though further development work will be needed before this becomes a routine diagnostic tool. The selection of cases used to train the network is crucial to the quality of its performance. There is scope to improve the system further by incorporating clinical
van der Heide, J. J.; Bilo, H. J.; Donker, J. M.; Wilmink, J. M.; Tegzess, A. M.
Dietary fish oil exerts effects on renal hemodynamics and the immune response that may benefit renal-transplant recipients treated with cyclosporine. To evaluate this possibility, we studied the effect of fish oil on renal function, blood pressure, and the incidence of acute rejection episodes in
de Groot-Kruseman, H A; Baan, C C; Hagman, E M; Mol, W M; Niesters, H G; Maat, A P; Zondervan, P E; Weimar, W; Balk, A H
OBJECTIVE: To assess whether diastolic graft function is influenced by intragraft interleukin 2 (IL-2) messenger RNA (mRNA) expression in rejecting cardiac allografts. DESIGN: 16 recipients of cardiac allografts were monitored during the first three months after transplantation. The presence of IL-2
Dai, Y.; Lv, T.; Wang, K.; Li, D.; Huang, Y.; Liu, J.
At present, the diagnosis of renal allograft rejection requires a renalbiopsy. Clinical management of renal transplant patients would be improved ifrapid, noninvasive and reliable biomarkers of rejection were available. Thisstudy is designed to determine whether such protein biomarkers can be foundin renal graft tissue proteomic approach. Orthotopic kidney transplantationswere performed using Fisher (F344) or Lewis rats as donors and Lewis rats asrecipients. Hence, there were two groups of renal transplant models: one isallograft (from F344 to Lewis rats); another is syngrafts (from Lewis toLewis rats) serving as control. Renal tissues were collected 3, 7 and 14 daysafter transplantation. As many 18 samples were analyzed by 2-DElectrophoresis and mass spectrometry (MALDI-TOF-TOF-MS). Elevendifferentially expressed proteins were identified between groups. Inconclusion, proteomic technology can detect renal tissue proteins associatedwith acute renal allograft rejection. Identification of these proteins asdiagnostic markers for rejection in patient's urine or sera may be useful andnon-invasive, and these proteins might serve as novel therapeutic targetsthat also help to improve the understanding of mechanisms of renal rejection.(author)
Ishida, Hideki; Kondo, Tsunenori; Shimizu, Tomokazu; Nozaki, Taiji; Tanabe, Kazunari
The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies. © 2014 Steunstichting ESOT.
Full Text Available The 4-1BB signal pathway plays a key role in organ transplantation tolerance. In this study, we have investigated the effect of gene silencing of 4-1BB by RNA interference (RNAi on the acute rejection in rats with liver transplantation. The recombination vector of lentivirus that contains shRNA targeting the 4-1BB gene (LV-sh4-1BB was constructed. The liver transplantation was performed using the two-cuff technique. Brown-Norway (BN recipient rats were infected by the recombinant LVs. The results showed that gene silencing of 4-1BB by RNAi downregulated the 4-1BB gene expression of the splenic lymphocytes in vitro, and the splenic lymphocytes isolated from the rats with liver transplantation. LV-sh4-1BB decreased the plasma levels of liver injury markers including AST, ALT, and BIL and also decreased the level of plasma IL-2 and IFN-γ in recipient rats with liver transplantation. Lentivirus-mediated delivery of shRNA targeting 4-1BB gene prolonged the survival time of recipient and alleviated the injury of liver morphology in recipient rats with liver transplantation. In conclusion, our results demonstrate that gene silencing of 4-1BB by RNA interference inhibits the acute rejection in rats with liver transplantation.
Full Text Available Antibody-mediated rejection (AMR has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients’ immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients’ humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR.
Kimball, Pamela M; Gupta, Gaurav; McDougan, Felecia
Presence of antibody [Ab] against angiotensin receptor [AT1R] indicates heightened risk for antibody mediated rejection [AMR] after transplantation but is insufficient as a marker. We speculated AT1R might be released systemically because of AMR and might be a useful biomarker. AT1R was measured in blood from 73 Normals and 72 renal patients pre- and post-transplantation. Patients were stratified as AMR-free [Gp1], AMR1yr [Gp3]. AT1R was higher [13±26vs.367±537, p<0.01)] and more prevalent [20% vs. 92%, p<0.01] among renal patients than Normals. Pretransplant levels were similar [p=ns] between groups. One-year posttransplant levels approached [p<0.01] normalcy for Gps1+3 but spiked during AMR and remained elevated [155±58, p<0.01] for 50% Gp2 patients. One-year AT1R levels were higher among subsequent graft failures than surviving grafts [171±267vs. 38±50, p<0.01]. Pretransplant AT1R was abnormally elevated: possibly indicating ongoing tissue injury. Pretransplant AT1R didn't predict risk for AMR. However, AT1R spiked during early AMR and sustained elevations were associated with poorer outcomes. Copyright © 2017. Published by Elsevier Inc.
Burton, C.M.; Iversen, M.; Carlsen, J.
: A multivariate survival and competing risk analysis of a large consecutive series of patients (n = 389) from a national center 1992 to 2004. Exclusion criteria were patients not surviving at least 3 months after transplantation (n = 39) and no available lung function measurements (n = 4). RESULTS: The first......BACKGROUND: Post-transplant baseline forced expiratory volume in 1 second (FEV(1)) constitutes a systematic bias in analyses of bronchiolitis obliterans syndrome (BOS). This retrospective study evaluates risk factors for BOS adjusting for the confounding of post-transplant baseline FEV(1). METHODS...... maximum FEV(1) occurred at a median 183 days post-transplant. Freedom from BOS was 81%, 53%, 38% and 15%, and cumulative incidence of BOS was 18%, 43%, 57% and 77% at 1, 3, 5 and 10 years post-transplantation, respectively. Acute cellular rejection was independently associated with an increased cause...
Haytham M Shebel
Full Text Available To evaluate the role of power Doppler in the identification and differentiation bet-ween acute renal transplant rejection and acute tubular necrosis (ATN, we studied 67 live donor renal transplant recipients. All patients were examined by spectral and power Doppler sono-graphy. Assessment of cortical perfusion (CP by power Doppler was subjective, using our grading score system: P0 (normal CP; homogenous cortical blush extending to the capsule, P1 (reduced CP; cortical vascular cut-off at interlobular level, P2 (markedly reduced CP; scattered cortical color flow at the interlobar level. Renal biopsies were performed during acute graft dysfunction. Pathological diagnoses were based on Banff classification 1997. The Mann- Whitney test was used to test the difference between CP grades with respect to serum creatinine (SCr, and resistive index (RI. For 38 episodes of acute graft rejection grade I, power Doppler showed that CP was P1 and RI ranging from 0.78 to 0.89. For 21 episodes of acute graft rejection grade II, power Doppler showed that CP was P1, with RI ranging from 0.88 to >1. Only one case of grade III rejection had a CP of P2. Twelve biopsies of ATN had CP of P0 and RI ranging from 0.80 to 0.89 There was a statistically significant correlation between CP grading and SCr (P <0.01 as well as between CP grading and RI (P <0.05. CP grading had a higher sensitivity in the detection of early acute rejection compared with RI and cross-sectional area measurements. We conclude that power Doppler is a non-invasive sensitive technique that may help in the detection and differentiation between acute renal transplant rejection and ATN, particularly in the early post-transplantation period.
Dunn, Steven P; Stark, Walter J; Stulting, R Doyle; Lass, Jonathan H; Sugar, Alan; Pavilack, Mark A; Smith, Patricia W; Tanner, Jean Paul; Dontchev, Mariya; Gal, Robin L; Beck, Roy W; Kollman, Craig; Mannis, Mark J; Holland, Edward J
To determine whether corneal graft survival over a 5-year follow-up period was affected by ABO blood type compatibility in participants in the Cornea Donor Study undergoing corneal transplantation principally for Fuchs dystrophy or pseudophakic corneal edema, conditions at low-risk for graft rejection. Multi-center prospective, double-masked, clinical trial. ABO blood group compatibility was determined for 1,002 donors and recipients. During a 5-year follow-up period, episodes of graft rejection were documented, and graft failures were classified as to whether or not they were attributable to immunologic rejection. Endothelial cell density was determined by a central reading center for a subset of subjects. ABO donor-recipient incompatibility was not associated with graft failure attributable to any cause including graft failure because of rejection, or with the occurrence of a rejection episode. The 5-year cumulative incidence of graft failure attributable to rejection was 32 (6%) for recipients with ABO recipient-donor compatibility and 12 (4%) for those with ABO incompatibility (hazard ratio, 0.65; 95% confidence interval, 0.33 to 1.25; P = .20). The 5-year incidence for a definite rejection episode, irrespective of whether graft failure ultimately occurred, was 64 (12%) for ABO compatible compared with 25 (8%) for ABO incompatible cases (P = .09). Among clear grafts at 5 years, percent loss of endothelial cells was similar in ABO compatible and incompatible cases. In patients undergoing penetrating keratoplasty for Fuchs dystrophy or pseudophakic corneal edema, ABO matching is not indicated since ABO incompatibility does not increase the risk of transplant failure attributable to graft rejection.
Full Text Available A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. We have recently reported the results of the first six double lung transplantations performed with donor lungs reconditioned ex vivo that had been deemed unsuitable for transplantation by the Scandiatransplant, Eurotransplant, and UK Transplant organizations because the arterial oxygen pressure was less than 40 kPa. The three-month survival of patients undergoing transplant with these lungs was 100%. One patient died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are still alive and well 24 months after transplantation, with no signs of bronchiolitis obliterans syndrome. The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation circuit using STEEN solution mixed with erythrocytes, to dehydrate edematous lung tissue. Functional evaluation was performed with deoxygenated perfusate at different inspired fractions of oxygen. The arterial oxygen pressure was significantly improved in this model. This ex vivo evaluation model is thus a valuable addition to the armamentarium in increasing the number of acceptable lungs in a donor population with inferior arterial oxygen pressure values, thereby, increasing the lung donor pool for transplantation. In the following paper we present our clinical experience from the first six patients in the world. We also present the technique we used in detail with flowchart.
David, N.; Escanye, J.M.; Marwan, N.S.; Marie, P.Y.; Perlot, P.; Angioi, M.; Walker, P.; Quiri, N.; Arsena, T.; Hassan, N.; Villemot, J.P.; Mattei, S.; Karcher, G.; Bertrand, A.
A echocardiography and a MRI (Magnetic Resonance Imaging) investigation were achieved at 3 months to 7 years after heart transplant in 61 patients among whose 35 were suspected of rejection and 32 have had a myocardial biopsy. The myocardial (T 2 ) transversal relaxation time was determined by using an inversion-recovery/spin-echo upon a magnet of 0.5 T. The rejection diagnosis criteria by echography was compared with that of a anomalistic high value of T 2 : 1. the MRI was positive but the echography not in 5 cases, all having positive biopsies; 2. the echography was positive but the MRI was not in 10 cases among which all the biopsies were negative; 3. the MRI and the echography gave concordant results in 46 cases (7 positives and 39 negatives) among which an agreement with the biopsy results was observed in 91% (20/22) of cases. The 12 patients having a positive MRI have had a new examination at 2 to 15 days after the anti-rejection treatment; the T 2 values got normalized. In conclusion, the determination of the myocardial T 2 by means of a 'black blood' MRI sequence appears to be superior to an echocardiography in detecting the rejections after heart transplant and could be utilised to evaluate the efficiency of anti-rejection treatment
Penno, E.; Johnsson, C.; Johansson, L.; Ahlstroem, H. [Uppsala Univ. Hospital (Sweden). Depts. of Diagnostic Radiology and of Transplantation Surgery
Purpose: To discriminate between acutely rejecting and non-rejecting transplanted hearts using a blood pool contrast agent and T2 magnetic resonance imaging (MRI) in a clinical 1.5T scanner. Material and Methods: Allogeneic and syngeneic heterotopic heart transplantations were performed in rats. One allogeneic and one syngeneic group each received either the ultra-small iron oxide particle (USPIO), at two different doses, or no contrast agent at all. MRI was performed on postoperative day 6. Immediately after the MR scanning, contrast agent was injected and a further MRI was done 24 h later. Change in T2 was calculated. Results: No significant difference in change in T2 could be seen between rejecting and non-rejecting grafts in either of the doses, or in the control groups. There was a difference between the allogeneic group that received the higher contrast agent dose and the allogeneic group that did not receive any contrast agent at all. Conclusion: In our rat model, measurements of T2 after myocardial macrophage uptake of AMI-227 in a clinical 1.5T scanner were not useful for the diagnosis of acute rejection.
Full Text Available Transplant rejection is the critical clinical end-point limiting indefinite survival after histocompatibility antigen (HLA mismatched organ transplantation. The predominant cause of late graft loss is antibody-mediated rejection (AMR, a process whereby injury to the organ is caused by donor-specific antibodies, which bind to HLA and non-HLA (nHLA antigens. AMR is incompletely diagnosed as donor/recipient (D/R matching is only limited to the HLA locus and critical nHLA immunogenic antigens remain to be identified. We have developed an integrative computational approach leveraging D/R exome sequencing and gene expression to predict clinical post-transplant outcome. We performed a rigorous statistical analysis of 28 highly annotated D/R kidney transplant pairs with biopsy-confirmed clinical outcomes of rejection [either AMR or T-cell-mediated rejection (CMR] and no-rejection (NoRej, identifying a significantly higher number of mismatched nHLA variants in AMR (ANOVA—p-value = 0.02. Using Fisher’s exact test, we identified 123 variants associated mainly with risk of AMR (p-value < 0.001. In addition, we applied a machine-learning technique to circumvent the issue of statistical power and we found a subset of 65 variants using random forest, that are predictive of post-tx AMR showing a very low error rate. These variants are functionally relevant to the rejection process in the kidney and AMR as they relate to genes and/or expression quantitative trait loci (eQTLs that are enriched in genes expressed in kidney and vascular endothelium and underlie the immunobiology of graft rejection. In addition to current D/R HLA mismatch evaluation, additional mismatch nHLA D/R variants will enhance the stratification of post-tx AMR risk even before engraftment of the organ. This innovative study design is applicable in all solid organ transplants, where the impact of mitigating AMR on graft survival may be greater, with considerable benefits on
Chi, Jingmao; Chen, Hui; Tolias, Peter; Du, Henry
We have explored the use of a fiber-optic probe with surface-enhanced Raman scattering (SERS) sensing modality for early, noninvasive and, rapid diagnosis of potential renal acute rejection (AR) and other renal graft dysfunction of kidney transplant patients. Multimode silica optical fiber immobilized with colloidal Ag nanoparticles at the distal end was used for SERS measurements of as-collected urine samples at 632.8 nm excitation wavelength. All patients with abnormal renal graft function (3 AR episodes and 2 graft failure episodes) who were clinically diagnosed independently show common unique SERS spectral features in the urines collected just one day after transplant. SERS-based fiber-optic probe has excellent potential to be a bedside tool for early diagnosis of kidney transplant patients for timely medical intervention of patients at high risk of transplant dysfunction.
Gerald S Lipshutz
the surface of bacterial cell wall occurring before the firm establishment of accommodation can trigger the onset of acute antibody-mediated rejection. We herein report a case of delayed hyperacute rejection in an A1 to O, ABO incompatible transplant recipient following an episode of Clostridium difficile infection.Keywords: ABO incompatible transplantation, delayed hyperacute rejection, kidney transplantation, Clostridium difficile infection
Klos, Dušan; Orság, Jiří; Loveček, Martin; Skalický, Pavel; Havlík, Roman; Zadražil, Josef; Neoral, Čestmír
Acute pancreatitis is a rare but frequently fatal complication in patients following kidney transplantation. The first case of acute pancreatitis in patients following a kidney transplant was described by Starzl in 1964. The incidence of acute pancreatitis is stated at between 1 and 5%. The mortality rate amongst these patients reaches as high as 50-100%. Here we present a case of acute pancreatic abscess in a caucasian female - shortly following a kidney transplant complicated by the development of acute rejection, in which immunosuppressant therapy is a potential etiological agent. Emergency surgical treatment was indicated, which included drainage of the abscesses irrigation of the abdominal cavity. Immunosuppressive medication was considered a possible etiological factor, and as a result administration of tacrolimus and mycophenolate mofetil was discontinued. This was successful and three months later, diagnostic rebiopsy of the graft was performed without signs of rejection. The etiology of this illness is multifactorial. The clinical manifestation of acute pancreatitis in patients following kidney transplantation is the same as in the remainder of the population. However, in patients following transplantation with long-term immunosuppression, it usually manifests a more rapid development and a more severe, frequently fatal course. With regard to the patient's comorbidities, early surgical therapy was indicated - drainage and closed lavage and immunosuppressive medication as a suspected tobe ethiological factor was discontinued. This course of treatment led to a complete recovery with preservation of good function of the cadaverous kidney.
Rascio, Federica; Pontrelli, Paola; Accetturo, Matteo; Oranger, Annarita; Gigante, Margherita; Castellano, Giuseppe; Gigante, Maddalena; Zito, Anna; Zaza, Gianluigi; Lupo, Antonio; Ranieri, Elena; Stallone, Giovanni; Gesualdo, Loreto; Grandaliano, Giuseppe
Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control
A. V. Vatazin
Full Text Available Introduction. The development of immunological confl ict in the form of host-versus-graft reaction has always been main problem in transplantation. The worst case is the development of humoral rejection with the presence of circulating immune complexes and antibodies. There are several methods for quick removal of antibodies; among those are traditional plasmapheresis (PA and double fi ltration plasmapheresis (DFPF. In this paper we present our experience with these two methods and give a comparative evaluation of the effectiveness in the treatment of acute humoral rejection in renal allograft. Aim: to compare the effectiveness of traditional and double fi ltration plasmapheresis while processing different volumes of plasma in the treatment of host-versus-graft disease after kidney transplantation.Methods. The study included 58 patients after kidney transplantation. All patients had increased activity of humoral immunity, which was confi rmed by immunofl uorescence with luminescence C4d complement component. In 26 patients we performed DFPF, in 32 patients – traditional PA. We divided the DFPF patients into 4 subgroups depending on the amount of processed plasma: > 50% (5 patients, 50–100% (8 patients, 100–150% (7 patients, 150–200% (6 patients of circulating plasma volume. We also divided PA patients into four subgroups depending on the volume of plasma removed: >50% (8 patients, 50–70% (12 patients, 70–90% (7 patients, 90–110% (5 patients of the volume of circulating plasma. We monitored the immune status with markers of humoral immunity activation IgM, IgG before and after each of the procedures.Results. Each procedure of traditional PA and DFPF was accompanied by a marked decrease in blood concentrations of IgM and IgG antibodies. Their level decreased by an average of 30–55% of the original. However, some patients in both groups showed an increase in the concentration of these immunoglobulins in 1–2 days
Mannaerts, H. F.; Balk, A. H.; Simoons, M. L.; Tijssen, J.; van der Borden, S. G.; Zondervan, P.; Sutherland, G. R.; Roelandt, J. R.
OBJECTIVE: Assessment of changes in left ventricular diastolic function and wall thickness after heart transplantation to verify whether these changes predicted acute rejection assessed by endomyocardial biopsy. DESIGN: Follow up according to a predefined protocol of consecutive patients from the
Fosby, Bjarte; Næss, Sigrid; Hov, Johannes R; Traherne, James; Boberg, Kirsten M; Trowsdale, John; Foss, Aksel; Line, Pål-Dag; Franke, Andre; Melum, Espen; Scott, Helge; Karlsen, Tom H
To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX). In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR. Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to
Raimondi, Giorgio [Johns Hopkins Univ., Baltimore, MD (United States); Wood, Kathryn [Univ. of Oxford (United Kingdom); Perelson, Alan S. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Arciero, Julia C [Indiana Univ.-Purdue Univ., Indianapolis, IN (United States)
This Research Topic provides a venue for stimulating these interdisciplinary conversations in the context of transplantation. The articles collected under this Research Topic introduce new theoretical and experimental studies that describe novel techniques and methods for understanding the interactions between the immune response and transplants and for establishing more effective strategies of diagnosis and intervention that will promote transplant tolerance.
Honsova, Eva; Lodererova, Alena; Balaz, Peter; Oliverius, Martin
Small bowel transplantations (SBT) are being increasingly performed to treat patients with irreversible intestinal failure or short-bowel syndrome. Histologic evaluation of small bowel allograft biopsies is important for the diagnosis of acute cellular rejection (ACR). Serotonin (5-hydroxytriptamin) is a biogenous amine of which up to 95% is present in the enterochromaffin cells of the gastrointestinal tract. The aim of our study was to analyze rejection and number of serotonin positive cells in the intestinal graft biopsy samples early after SBT in pigs. 24 pigs were used and divided into 4 groups. Group A, autologous SBT (n = 3) as a control group; group B, allogeneic SBT with tacrolimus monotherapy (n = 7); group C, allogeneic SBT immunosuppressed with tacrolimus and sirolimus (n = 8); and group D, without immunosuppression (n = 6). Observation period was 30 days. Mucosal biopsies were obtained on days 0, 3, 5, 7, 10, 14, 20, 28 after transplantation. ACR was classified according to standardized grading schema on a scale of indeterminate, mild, moderate, and severe. Serotonin positive cells were quantified as the number of positive cells in 20 high power fields. There were no significant differences in the number of serotonin positive cells and different grades of ACR. In our experiment the number of serotonin positive cells was not a sensitive marker of ACR in the early period after small bowel transplantation.
George, E.A.; Codd, J.E.; Newton, W.T.; Haibach, H.; Donati, R.M.
The diagnostic accuracy, ease, and technical feasibility of imaging with 131 I- or 125 I-fibrinogen, 99 /sup m/Tc-sulfur colloid, and 67 Ga-citrate in renal transplant rejection are compared. Radiofibrinogen data resulted from literature review, radio-colloid data from 125 studies in 52 transplant patients, and gallium citrate data from 24 examinations in seven renal transplant patients performed simultaneously with the radiocolloid studies. Specificity of graft labeling during rejection appears to be similar with radiofibrinogen, 99 /sup m/Tc-sulfur colloid, and 67 Ga-citrate. For routine clinical use 99 /sup m/Tc-sulfur colloid surpasses radiofibrinogen and radiogallium because of its better imaging qualities with a permissible radiation dose, leading to better separation of positive and negative results. The 99 /sup m/Tc-sulfur colloid accumulates in areas of intravascular fibrin thrombosis in acute and chronic rejecting renal transplants. Hence, the mechanisms for accumulation of 99 /sup m/Tc-sulfur colloid and labeled fibrinogen in rejecting transplants would seem to be similar. Such physiologic properties as rapid blood clearance and such physical properties as short physical half-life combine to produce reliable graft visualization with adequate definition, thus favoring 99 /sup m/Tc-sulfur colloid as the single agent of choice for clinical evaluation of renal transplant rejection at this time
Desir, G.V.; Bia, M.; Lange, R.C.; Smith, E.O.; Flye, W.; Kashgarian, M.; Schiff, M.; Ezekowitz, M.D.
It is demonstrated that indium-111 labelled platelet scintigraphy is a highly accurate test for detecting acute untreated renal allograft rejection and it is shown that changes in platelet uptake can precede signs and symptoms of rejection by at least 48 hours. (author). 34 refs.; 2 figs.; 1 tab
Mostapha, Mahmoud; Khalifa, Fahmi; Alansary, Amir; Soliman, Ahmed; Gimel'farb, Georgy; El-Baz, Ayman
Early detection of renal transplant rejection is important to implement appropriate medical and immune therapy in patients with transplanted kidneys. In literature, a large number of computer-aided diagnostic (CAD) systems using different image modalities, such as ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), and radionuclide imaging, have been proposed for early detection of kidney diseases. A typical CAD system for kidney diagnosis consists of a set of processing steps including: motion correction, segmentation of the kidney and/or its internal structures (e.g., cortex, medulla), construction of agent kinetic curves, functional parameter estimation, diagnosis, and assessment of the kidney status. In this paper, we survey the current state-of-the-art CAD systems that have been developed for kidney disease diagnosis using dynamic MRI. In addition, the paper addresses several challenges that researchers face in developing efficient, fast and reliable CAD systems for the early detection of kidney diseases.
Full Text Available End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR.222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters.Of the 222 patients analyzed, 30 (14% developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively and the number of related donor kidney transplantation was significantly lower (p = 0.018 in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01 and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08. No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028. In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001.Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.
Madill-Thomsen, K S; Wiggins, R C; Eskandary, F; Böhmig, G A; Halloran, P F
Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes (e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL, and REN). Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the molecular microscope diagnostic system. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had Molecular scores for antibody-mediated rejection, T cell-mediated rejection, and injury were independent of proportion cortex. Rejection was diagnosed in many biopsies that were mostly or all medulla. Agreement in molecular diagnoses in paired cortex/medulla samples (23/26) was similar to biological replicates (32/37). We conclude that NPHS2 expression can estimate proportion cortex; that proportion cortex has little influence on molecular diagnosis of rejection; and that, although histology cannot assess medulla, rejection does occur in medulla as well as cortex. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.
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Chanana, Nitin; Van Dorn, Charlotte S; Everitt, Melanie D; Weng, Hsin Yi; Miller, Dylan V; Menon, Shaji C
The objective of this study is to assess changes in cardiac deformation during acute cellular- and antibody-mediated rejection in pediatric HT recipients. Pediatric HT recipients aged ≤18 years with at least one episode of biopsy-diagnosed rejection from 2006 to 2013 were included. Left ventricular systolic S (SS) and SR (SSr) data were acquired using 2D speckle tracking on echocardiograms obtained within 12 h of right ventricular endomyocardial biopsy. A mixed effect model was used to compare cardiac deformation during CR (Grade ≥ 1R), AMR (pAMR ≥ 2), and mixed rejection (CR and AMR positive) versus no rejection (Grade 0R and pAMR 0 or 1). A total of 20 subjects (10 males, 50%) with 71 rejection events (CR 35, 49%; AMR 21, 30% and mixed 15, 21%) met inclusion criteria. The median time from HT to first biopsy used for analysis was 5 months (IQR 0.25-192 months). Average LV longitudinal SS and SSr were reduced significantly during rejection (SS: -17.2 ± 3.4% vs. -10.7 ± 4.5%, p < 0.001 and SSr: -1.2 ± 0.2 s - 1 vs. -0.9 ± 0.3 s - 1 ; p < 0.001) and in all rejection types. Average LV short-axis radial SS was reduced only in CR compared to no rejection (p = 0.04), while average LV circumferential SS and SSr were reduced significantly in AMR compared to CR (SS: 18.9 ± 4.2% vs. 20.8 ± 8.8%, p = 0.03 and SSr: 1.35 ± 0.8 s - 1 vs. 1.54 ± 0.9 s - 1 ; p = 0.03). In pediatric HT recipients, LV longitudinal SS and SSr were reduced in all rejection types, while LV radial SS was reduced only in CR. LV circumferential SS and SSr further differentiated between CR and AMR with a significant reduction seen in AMR as compared to CR. This novel finding suggests mechanistic differences between AMR- and CR-induced myocardial injury which may be useful in non-invasively predicting the type of rejection in pediatric HT recipients.
Full Text Available Serum proteins are routinely used to diagnose diseases, but are hard to find due to low sensitivity in screening the serum proteome. Public repositories of microarray data, such as the Gene Expression Omnibus (GEO, contain RNA expression profiles for more than 16,000 biological conditions, covering more than 30% of United States mortality. We hypothesized that genes coding for serum- and urine-detectable proteins, and showing differential expression of RNA in disease-damaged tissues would make ideal diagnostic protein biomarkers for those diseases. We showed that predicted protein biomarkers are significantly enriched for known diagnostic protein biomarkers in 22 diseases, with enrichment significantly higher in diseases for which at least three datasets are available. We then used this strategy to search for new biomarkers indicating acute rejection (AR across different types of transplanted solid organs. We integrated three biopsy-based microarray studies of AR from pediatric renal, adult renal and adult cardiac transplantation and identified 45 genes upregulated in all three. From this set, we chose 10 proteins for serum ELISA assays in 39 renal transplant patients, and discovered three that were significantly higher in AR. Interestingly, all three proteins were also significantly higher during AR in the 63 cardiac transplant recipients studied. Our best marker, serum PECAM1, identified renal AR with 89% sensitivity and 75% specificity, and also showed increased expression in AR by immunohistochemistry in renal, hepatic and cardiac transplant biopsies. Our results demonstrate that integrating gene expression microarray measurements from disease samples and even publicly-available data sets can be a powerful, fast, and cost-effective strategy for the discovery of new diagnostic serum protein biomarkers.
quantify the number and diversity of donor vs. recipient T cells within face transplants over time using cutting edge high throughput TCR sequencing (HTS...area code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Nothing listed TABLE OF CONTENTS Page No. 1. Introduction 4 2. Keywords...use cutting- edge single nucleus RNA sequencing (which only recently became available) of the banked skin biopsies from face transplant patients
Shi, Jiahai; Qian, Shiguo; Meng, Xu; Han, Jie; Chen, Yangtian; Wang, Jiangang; Zhang, Haibo; Jia, Yixin
To examine the reliability of the QRS amplitude of the autonomous intramyocardial electrogram (IMEG) and the maximum slope of the descending T wave (Tslew) of the ventricular evoked response (VER) for surveillance of acute allograft rejection (AR) after heart transplantation in rats. Forty rats underwent heterotopic heart transplantation, including ten isograft (isograft group) and 30 allograft (allograft group) recipients. Autonomous IMEG and VER were recorded with epicardiac pacing leads. Isograft recipients were sacrificed on postoperative day 7 and allograft recipients on postoperative days 3, 5 and 7. Graft heart histopathological examinations were performed at the corresponding time points. Postoperative QRS amplitude and Tslew gradually decreased in the allograft group, but were unaltered in the isograft group. Decreases in the allograft group QRS amplitudes and Tslew values correlated with the histopathological results. At the optimal cutoff point of 90%, Tslew had 94.74% sensitivity, 81.82% specificity, 82.61% positive and 90% negative predictive values. QRS had 68.42% sensitivity, 90.91% specificity, 92.86% positive and 62.50% negative predictive values at its optimal cutoff point of 72.3%. The QRS amplitude of the autonomous IMEG and Tslew of VER are reliable markers for monitoring AR after heart transplantation in rats.
Full Text Available Background: The objective of this study was to evaluate graft survival among the recipients of second renal transplant in Imam Khomeini centre hospital in Urmia. Methods: The study population consisted of 50 patients receiving renal grafts for the second time between 1988 and 2008 in Imam Khomeini centre hospital in Urmia. Two survival outcomes, first and second graft survival, were analyzed. Graft survival was defined from date of transplant until its rejection. For the purpose of graft survival analysis, graft failure was defined as return to dialysis, and death due to the functioning graft. Data were collected through individual patient questionnaires. Demographic and clinical factors, transfusion history, type of immunosuppressive drugs, levels of serum creatinine, triglyceride, cholesterol, and LDL at 3 and 6 months after transplantation were collected. Cox-proportional hazard model and Kaplan-Meier were used to data analysis. Results: First graft survival at 1, 2, 3, and 5 years was 74%, 66%, 53%, and 41%, respectively. Second graft survival at 1, 2, 3, and 5 years was 81%, 74%, 70%, and 61%, respectively. Causes of graft loss in first renal transplantation were 6% sever acute graft rejection, 12% acute graft rejection and 82% chronic graft rejection. In the multivariate analysis, only serum creatinine, blood pressure, and immunosuppressive drugs predicted first graft loss and serum creatinine, immunosuppressive drugs, and related donor family predicted second graft rejection. Conclusion: The serum creatinine and immunosuppressive drugs including cyclosporine, cellcept, and prednisolone are the most influential factors on graft survival.
Sandesh Parajuli, MD
Conclusion. Treatment of late ABMR with steroids/IVIG ± rituximab was effective in reducing DSA and microcirculation inflammation. The addition of rituximab was associated with better graft survival. Follow-up biopsies could be considered in the management of acute rejection to monitor the effect of therapy. Randomized studies on the best therapeutic options for ABMR are needed.
Mannaerts, H. F.; Simoons, M. L.; Balk, A. H.; Tijssen, J.; van der Borden, S. G.; Zondervan, P. E.; Mochtar, B.; Weimar, W.; Roelandt, J. R.
The value of pulsed-wave transmitral Doppler for the diagnosis of moderate acute rejection was examined in a total of 347 Doppler recordings obtained in 32 consecutive cardiac allograft recipients. Serial Doppler examinations (median, 11 per patient; range, 1 to 23) were performed simultaneously
MANNAERTS, HF; SIMOONS, ML; BALK, AH; TIJSSEN, J; VANDERBORDEN, SG; ZONDERVAN, PE; MOCHTAR, B; WEIMAR, W; ROELANDT, [No Value
The value of pulsed-wave transmitral Doppler for the diagnosis of moderate acute rejection was examined in a total of 347 Doppler recordings obtained in 32 consecutive cardiac allograft recipients. Serial Doppler examinations (median, 11 per patient; range, 1 to 23) were performed simultaneously
Clinical Value of Left Ventricular Wall Motion Assessment with Pulsed-Wave Tissue Doppler Echocardiography for Rejection Monitoring and Allograft Coronary Artery Disease Surveillance After Heart Transplantation
The usefulness of pulsed-wave tissue Doppler imaging (PW-TDI) for detection of ventricular dysfunction linked to acute rejection (AR) and transplant coronary disease (TxCAD) in order to optimize invasive examination timing was assessed over several years in a large number of heart transplant recipients. The results validate wall motion assessment by PW-TDI as being particularly suited for the early detection of LV functional alterations linked to AR and TxCAD and commend this simple echocardi...
Larcos, G.; McLarty, A.J.; McGregor, C.G.A.; Brown, M.L.; Hung, J.C.; O'Connor, M.K.; Tazelaar, H.D.
Acute rejection is an important cause of graft failure in single lung transplantation, however, current noninvasive tests are neither sensitive nor specific for this diagnosis. The aim of this study was to determine whether 99 Tc m -labelled human nonspecific polyclonal IgG ( 99 Tc m -IgG) may serve as a marker for acute pulmonary rejection following allotransplantation in a dog model. Seventeen mongrel dogs were studied, including four controls and thirteen dogs which underwent surgery [right autotransplant recipient right unmodified allotransplant recipient, and right immunosuppressed allotransplant recipient]. At 6 days following surgery, all dogs received 67 Ga-citrate and 99 Tc m -IgG. Two days later all dogs were sacrified. Post-mortem examination revealed acute lung rejection in nine animals. No significant difference was found in the percentage uptake of both 99 Tc m -IgG and 67 Ga-citrate per gram of tissue between rejecting and nonrejecting transplanted lungs. In cases of moderate to severe rejection, only 67 Ga-citrate showed a significant difference in uptake between rejecting and contralateral native lungs, respectively. We conclude that 99 Tc m -IgG does not accurately identify acute lung rejection in the early postoperative period. (author)
Del Bello, Arnaud; Danjoux, Marie; Congy-Jolivet, Nicolas; Lavayssière, Laurence; Esposito, Laure; Muscari, Fabrice; Kamar, Nassim
Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Postrach, Johannes; Schmidt, Maximilian; Thormann, Michael; Thein, Eckart; Burdorf, Lars; Reichart, Bruno; Sotlar, Karl; Walz, Christoph; Faber, Claudius; Bauer, Andreas; Schmoeckel, Michael; Kupatt, Christian; Hinkel, Rabea
Graft survival is the most important factor for morbidity and mortality in cardiac transplantation. Improved immunosuppression significantly reduced early graft rejection. However, acute rejection may predispose to chronic rejection. Targeting both phases of the recipient's immune-reactivity by means of long-acting recombinant adeno-associated viral vectors (AAVs) encoding anti-inflammatory and cardioprotective factors appears to be a promising therapeutic approach. We investigate thymosin ß4 (Tß4) possessing anti-inflammatory and prosurvival abilities, as a means for pretransplant gene therapy. Heterotopic, abdominal transplantation of cardiac allografts into landrace or into Munich mini pigs (n=5 per group) was performed. Transplants were transduced with AAV2.9 before transplantation by means of in situ perfusion of the donor organ. Vascuar endothelial growth factor and AAV2.9.Tß4 or AAV2.9.LacZ were added to the autologous blood used for perfusing the grafts for a period of 45 min. Immunosuppression was applied for 10 days after the operation. Transgene expression, capillary density, graft function, survival, and rejection were assessed. The AAV2.9 transduction induced robust overexpression of the transgene. In addition, Tß4 ameliorated inflammation, necrosis, vascular reaction (acute rejection) and in parallel improved capillary density. In addition, graft survival was significantly prolonged (10±3 days AAV2.9.LacZ vs. 31±4 days AAV2.9.Tß4). In the mini pig model, regional myocardial function of the grafts was improved by Tß4 transduction compared to LacZ (9.1%±0.9% subendocardial segment shortening in AAV2.9.LacZ vs. 15.8%±2.3% in AAV2.9.Tß4). In situ AAV2.9-mediated gene transfer of thymosin β4 attenuated graft rejection in a heterotopic heart transplantation model. Perioperative cardioprotection by means of gene therapy might improve graft survival in cardiac allotransplantation.
Full Text Available CD4(+CD25(+FoxP3(+ regulatory T cells (Tregs and Th17 cells are known to be involved in the alloreactive responses in organ transplantation, but little is known about the relationship between Tregs and Th17 cells in the context of liver alloresponse. Here, we investigated whether the circulating Tregs/Th17 ratio is associated with acute allograft rejection in liver transplantation. In present study, thirty-eight patients who received liver transplant were enrolled. The patients were divided into two groups: acute allograft rejection group (Gr-AR (n = 16 and stable allograft liver function group (Gr-SF (n = 22. The frequencies of circulating Tregs and circulating Th17 cells, as well as Tregs/Th17 ratio were determined using flow cytometry. The association between Tregs/Th17 ratio and acute allograft rejection was then analyzed. Our results showed that the frequency of circulating Tregs was significantly decreased, whereas the frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection. Tregs/Th17 ratio had a negative correlation with liver damage indices and the score of rejection activity index (RAI after liver transplantation. In addition, the percentages of CTLA-4(+, HLA-DR(+, Ki67(+, and IL-10(+ Tregs were higher in Gr-SF group than in Gr-AR group. Our results suggested that the ratio of circulating Tregs/Th17 cells is associated with acute allograft rejection, thus the ratio may serve as an alternative marker for the diagnosis of acute rejection.
Full Text Available Organ transplantation can be considered as replacement therapy for patients with end-stage organ failure. The percent of one-year allograft survival has increased due, among other factors, to a better understanding of the rejection process and new immunosuppressive drugs. Immunosuppressive therapy used in transplantation prevents activation and proliferation of alloreactive T lymphocytes, although not fully preventing chronic rejection. Recognition by recipient T cells of alloantigens expressed by donor tissues initiates immune destruction of allogeneic transplants. However, there is controversy concerning the relative contribution of CD4+ and CD8+ T cells to allograft rejection. Some animal models indicate that there is an absolute requirement for CD4+ T cells in allogeneic rejection, whereas in others CD4-depleted mice reject certain types of allografts. Moreover, there is evidence that CD8+ T cells are more resistant to immunotherapy and tolerance induction protocols. An intense focal infiltration of mainly CD8+CTLA4+ T lymphocytes during kidney rejection has been described in patients. This suggests that CD8+ T cells could escape from immunosuppression and participate in the rejection process. Our group is primarily interested in the immune mechanisms involved in allograft rejection. Thus, we believe that a better understanding of the role of CD8+ T cells in allograft rejection could indicate new targets for immunotherapy in transplantation. Therefore, the objective of the present review was to focus on the role of the CD8+ T cell population in the rejection of allogeneic tissue.
Imamura, Teruhiko; Kinugawa, Koichiro; Ono, Minoru; Kagami, Yukie; Endo, Miyoko; Minatsuki, Shun; Muraoka, Hironori; Kato, Naoko; Inaba, Toshiro; Maki, Hisataka; Hatano, Masaru; Yao, Atsushi; Kyo, Shunei; Komuro, Issei
The long-term survival of heart transplantation (HTx) recipients has increased significantly in recent years, however, the nephrotoxic adverse effects of calcineurin inhibitors (CNIs) are still a major concern. Recently, an inhibitor of mammalian target of rapamycin, everolimus (EVL), has emerged as an alternative immunosuppressant drug that may allow CNI dosage reduction and thereby spare renal function. Data were collected from 20 HTx recipients who had received EVL (target trough level 3-8 ng/mL) along with a dose reduction of CNIs and/or mycophenolate mophetil (MMF) and had been followed for 1 year. Estimated glomerular filtration rate increased significantly with a reduction in the CNI dosage in a dose-dependent manner (P EVL administration among all candidates without any antiviral agents (P = 0.001). There were no significant increases in the acute rejection rates among recipients with EVL compared to those without EVL (P = 0.132). An immunosuppressant strategy incorporating EVL could reduce the CNI and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients.
Kim, Sung Jung; Won, Je Hwan; Kim, Young Bae; Wang, Hee-Jung; Kim, Bong-Wan; Kim, Haeryoung; Kim, Jinoo
Background Percutaneous biopsy is a widely-accepted technique for acquiring histologic samples of the liver. When there is concern for bleeding, plugged percutaneous biopsy (PPB) may be performed, which involves embolization of the biopsy tract. Purpose To evaluate the efficacy and safety of PPB of the liver in patients suspected to have graft rejection after living-donor liver transplantation (LDLT). Material and Methods During January 2007 and December 2013, 51 patients who underwent PPB of the liver under the suspicion of post-LDLT graft rejection were retrospectively analyzed. A total of 73 biopsies were performed. Biopsy was performed with a 17-gauge core needle and 18-gauge cutting needle. The needle tract was embolized using gelatin sponge (n = 44) or N-butyl cyanoacrylate (NBCA) (n = 29). The specimens were reviewed to determine their adequacy for histologic diagnosis. We reviewed all medical records after PPB. Results Specimens were successfully acquired in all procedures (100%). They were adequate for diagnosis in 70 cases (95.9%) and inadequate in three (1.3%). Average of 9.8 complete portal tracts was counted per specimen. One minor complication (1.4%) occurred where the patient had transient fever after the procedure. Conclusion PPB is easy and safe to perform in LDLT recipients and provides high diagnostic yield.
Holweg, C T J; Peeters, A M A; Balk, A H M M; Uitterlinden, A G; Niesters, H G M; Maat, A P W M; Weimar, W; Baan, C C
IL-2 and IFN-gamma are associated with acute rejection (AR) and graft vascular disease (GVD) after clinical heart transplantation. Polymorphisms in the genes of IL-2 (T-330G in the promoter) and IFN-gamma (CA repeat in the first intron) influence the production levels of these cytokines. Therefore,
van der Heide, Jaap J. Homan; Bilo, Henk J. G.; Donker, J. M.; Wilmink, J. M.; Tegzess, Adam M.
Background. Dietary fish oil exerts effects on renal hemodynamics and the immune response that may benefit renal-transplant recipients treated with cyclosporine. To evaluate this possibility, we studied the effect of fish oil on renal function, blood pressure, and the incidence of acute rejection
Full Text Available Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90, to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67. We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction
Nakano, T; Ono, K; Goto, S; Lai, C-Y; Hsu, L-W; Kawamoto, S; Lin, Y-C; Kao, Y-H; Chiang, K-C; Ohmori, N; Goto, T; Sato, S; Jawan, B; Cheng, Y-F; Chen, C-L
In a rat tolerogenic orthotopic liver transplantation (OLT) model, the recipient serum (post-OLT serum) shows strong immunosuppressive activity. In our previous reports, we suggested that autoreactive antibody (Ab) against histone H1 is a major immunosuppressive factor in this serum. The present study sought to determine whether up-regulation of anti-histone H1 Ab by histone H1 vaccination led to tolerance. Using mixed lymphocyte reactions (MLR) and heterotopic heart transplantations (HHT), the alloreactive T-cell responses and allograft survivals of histone H1-immunized rats were compared with those of control rats. Cytokine and cellular profiles were determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The alloreactive T-cell response of histone H1-immunized rats was significantly lower than that of control rats, although there was no difference in nonspecific T-cell activation between the 2 groups. The allograft survival of histone H1-immunized rats was significantly prolonged after HHT. The major histocompatibility complex (MHC) class II and CD25 molecules of histone H1-immunized rats were significantly down-regulated compared with those of control rats. Moreover, the serum cytokine profile was modified by the immunization with histone H1. These results suggest that histone H1 vaccination of transplant recipients leads to the production of immunosuppressive factors and the modification of cytokine/cellular profiles.
Borges, T. J.; O’Malley, J. T.; Wo, L.; Murakami, N.; Smith, B.; Azzi, J.; Tripathi, S.; Lane, J. D.; Bueno, E. M.; Clark, R. A.; Tullius, S. G.; Chandraker, A.; Lian, C. G.; Murphy, G. F.; Strom, T. B.; Pomahac, B.; Najafian, N.; Riella, L. V.
Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean followup of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-c/interleukin-17–producing cells in peripheral blood and in the allograft’s skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17–mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development. PMID:26749226
Alice Tung Wan Song
Full Text Available Histology is the gold standard for diagnosing acute rejection and hepatitis C recurrence after liver transplantation. However, differential diagnosis between the two can be difficult. We evaluated the role of C4d staining and quantification of hepatitis C virus (HCV RNA levels in liver tissue. This was a retrospective study of 98 liver biopsy samples divided into four groups by histological diagnosis: acute rejection in patients undergoing liver transplant for hepatitis C (RejHCV+, HCV recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+, acute rejection in patients undergoing liver transplant for reasons other than hepatitis C and chronic hepatitis C not transplanted (HCVTx-. All samples were submitted for immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of C4d was observed in the portal vessels and was highest in the HCVTx- group. There was no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However, tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+ group samples. Additionally, there was a significant correlation between tissue and serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to be an efficient diagnostic test for the recurrence of HCV infection.
Miranda, B; Cañón, J; Naya, M T; Cuende, N; Garrido, G; Fernández-Zincke, E
During recent years organ donation in Spain has increased by 100%, with important changes seen in the donor profile. Mean age has increased by more than 10 years, being nowadays more than 33% of our donors over 60 years. Ten years ago road traffic trauma was the main cause of death, while now most of our donors die due to stroke and only 21% die in a traffic accident. This changes lead to an increase in the number of kidneys discarded for transplantation every year. Among the 2517 kidneys retrieved during 2001, 567 were discarded, mainly due to different glomerular, interstitial or vascular pathologic damage. The older is the donor the higher is the percentage of kidneys discarded. It has to be underlined that an increased number of livers from donors, whose kidneys could not be used, are being grafted (141 in 2001 over 281 donors from whom no kidney could be grafted and over a total number of 1335 donors). Only 5% of kidneys were discarded due to technical problems. An important number of kidneys were discarded due to malignancy suspicion or diagnosis (12.3%). Organ donation has improved but kidney transplantation did not in parallel, due to the increasing number of kidneys discarded for transplantation in close relation with the evolution of donor's characteristics. Organ donation rate is around 33 donors per million population while efficient organ donation rate is around 30 donors per million. Only from 67% of donors both kidneys can be grafted and from 20% of donors no kidney can be used. These data will not change our policy, at least by the moment, we will continue to evaluate every potential brain death donor with the aim of studying if organs can be used. It is true that in 50% of cases over 70 years no organ can be used after retrieval and microscopic exam, but in the other 50% we can proceed.
Hagedorn, Peter; Burton, Christopher M.; Carlsen, Jørn
Obliterative bronchiolitis (OB) continues to be the major limitation to long-term survival after lung transplantation. The specific aetiology and pathogenesis of OB are not well understood. To explore the role of autoreactivity in OB, we spotted 751 different self molecules onto glass slides...... be differentiated by a profile of autoantibodies binding to 28 proteins or their peptides. The informative autoantibody profile included down-regulation as well as up-regulation of both IgM and IgG specific reactivities. This profile was evaluated for robustness using a panel of six independent test patients...
Kidney Failure, Chronic; End-Stage Renal Disease; Transplant Glomerulopathy; Transplant;Failure,Kidney; Kidney Transplant Failure and Rejection; Antibody-mediated Rejection; Kidney Transplant; Complications
Amersi, Farin; Nelson, Sally K.; Shen, Xiu Da; Kato, Hirohisa; Melinek, Judy; Kupiec-Weglinski, Jerzy W.; Horwitz, Lawrence D.; Busuttil, Ronald W.; Horwitz, Marcus A.
Ischemia/reperfusion (I/R) injury is a serious potential threat to outcomes in organ transplantation and other clinical arenas in which there is temporary interruption of blood flow. I/R is a frequent cause of primary failure in organ transplantation. We hypothesized that the antioxidant bucillamine, a potent sulfhydryl donor, would protect against I/R injury in high-risk organ transplants. Because livers subjected to prolonged ischemia and very fatty livers are highly susceptible to severe I/R injury, we studied the effect of bucillamine in three animal models of liver transplantation: two ex vivo models of isolated perfused livers, either normal or fatty rat livers, and an in vivo model of syngenic orthotopic liver transplants in rats. In all models, livers were deprived of oxygen for 24 h before either ex vivo reperfusion or transplantation. In the ex vivo models, bucillamine treatment significantly improved portal vein blood flow and bile production, preserved normal liver architecture, and significantly reduced liver enzyme release and indices of oxidative stress. Moreover, bucillamine treatment significantly increased levels of reduced glutathione in the liver and lowered levels of oxidized glutathione in both liver and blood. In rats subjected to liver transplants, bucillamine significantly enhanced survival and protected against hepatic injury. Possible mechanisms of this protection include prevention of excessive accumulation of toxic oxygen species, interruption of redox signaling in hepatocytes, and inhibition of macrophage activation. This study demonstrates the potential utility of bucillamine or other cysteine-derived thiol donors for improving outcomes in organ transplantation and other clinical settings involving I/R injury. PMID:12084933
Chan, Laurence; Hartmann, Erica; Cibrik, Diane; Cooper, Matthew; Shaw, Leslie M
Everolimus (Evl) plus tacrolimus (Tac) in de novo renal transplantation is effective and safe. Whether the concentration of Evl affects efficacy and safety in a Tac-based regimen has not been previously reported. To evaluate whether the concentration of Evl affects biopsy-proven acute rejection (BPAR), renal function, adverse events (AEs); and to assess for pharmacokinetic (PK) interactions. Data were from a prospective, multicenter, open-label, randomized, exploratory 6-month study of 92 renal transplant patients treated de novo with concentration-controlled Evl (target trough levels > or =3 ng/mL) plus low-dose Tac or Evl plus standard-dose Tac; both groups received basiliximab and corticosteroids. Data were pooled across study arms to examine BPAR rates in patients with Evl trough levels less than 3 (n=26), 3 to 8 (n=62), or more than 8 ng/mL (n=4). Groups were stratified by both Evl and Tac trough levels to evaluate glomerular filtration rate and AEs. Evl and Tac PK interactions were evaluated in a subset of 14 patients. Evl trough level of more than or equal to 3 ng/mL was associated with significantly lower rates of BPAR as compared with a trough level of less than 3 ng/mL. Glomerular filtration rate was similar at 6 months for both the low and standard Tac groups. No apparent PK interactions were observed between Evl and Tac. AEs were infrequent and did not seem to be associated with the Evl or Tac level. Evl trough levels > or =3 ng/mL plus Tac are associated with low rates of BPAR without adversely affecting renal function. No evident PK interaction exists between Evl and Tac.
Shigeta, Takanobu; Sakamoto, Seisuke; Uchida, Hajime; Sasaki, Kengo; Hamano, Ikumi; Kanazawa, Hiroyuki; Fukuda, Akinari; Kawai, Toshinao; Onodera, Masafumi; Nakazawa, Atsuko; Kasahara, Mureo
An IL-2 receptor antagonist, basiliximab, decreases the frequency of ACR in liver transplant (LT) recipients as induction therapy. The aim of this study was to evaluate the effectiveness of basiliximab against SRR as rescue therapy in pediatric LT patients with ALF. Forty pediatric ALF patients underwent LT between November 2005 and July 2013. Among them, seven patients suffering from SRR were enrolled in this study. The median age at LT was 10 months (6-12 months). SRR was defined as the occurrence of refractory rejection after more than two courses of steroid pulse therapy. Basiliximab was administered to all patients. The withdrawal of steroids without deterioration of the liver function was achieved in six patients treated with basiliximab therapy without patient mortality, although one patient developed graft loss and required retransplantation for veno-occlusive disease. The pathological examinations of liver biopsies in the patients suffering from SRR revealed severe centrilobular injuries, particularly fibrosis within one month after LT. We demonstrated the effectiveness and safety of rescue therapy consisting of basiliximab for SRR in pediatric LT recipients with ALF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Full Text Available The presence of donor-specific alloantibodies (DSAs against the MICA antigen results in high risk for antibody-mediated rejection (AMR of a transplanted kidney, especially in patients receiving a re-transplant. We describe the incidence of acute C4d+ AMR in a patient who had received a first kidney transplant with a zero HLA antigen mismatch. Retrospective analysis of post-transplant T and B cell crossmatches were negative, but a high level of MICA alloantibody was detected in sera collected both before and after transplant. The DSA against the first allograft mismatched MICA*018 was in the recipient. Flow cytometry and cytotoxicity tests with five samples of freshly isolated human umbilical vein endothelial cells demonstrated the alloantibody nature of patient's MICA-DSA. Prior to the second transplant, a MICA virtual crossmatch and T and B cell crossmatches were used to identify a suitable donor. The patient received a second kidney transplant, and allograft was functioning well at one-year follow-up. Our study indicates that MICA virtual crossmatch is important in selection of a kidney donor if the recipient has been sensitized with MICA antigens.
Katsuma, Ai; Yamamoto, Izumi; Komatsuzaki, Yo; Niikura, Takahito; Kawabe, Mayuko; Okabayashi, Yusuke; Yamakawa, Takafumi; Katsumata, Haruki; Nakada, Yasuyuki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi
A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection. © 2016 Asian Pacific Society of Nephrology.
Thrush, Philip T; Pahl, Elfriede; Naftel, David C; Pruitt, Elizabeth; Everitt, Melanie D; Missler, Heather; Zangwill, Steven; Burch, Michael; Hoffman, Timothy M; Butts, Ryan; Mahle, William T
Current knowledge of antibody-mediated rejection (AMR) after heart transplantation (HT) stems largely from adult data. Using the Pediatric Heart Transplant Study (PHTS) database, we report the incidence of AMR, describe treatment, and evaluate outcomes for treated AMR in children after HT. We queried the PHTS database for patients <18 years of age undergoing primary HT between January 2010 and December 2014. An AMR episode was defined as either a biopsy consistent with pathologic AMR or a rejection event based on immunotherapy augmentation directed against antibody production. Biopsy data, treatment strategies and survival were analyzed. An episode of AMR was identified in 179 of 1,596 (11%) HT recipients and in 246 of 705 (35%) rejection episodes. AMR was diagnosed by biopsy in 182 of 246 episodes and by immunotherapy in 64 of 179 episodes. Mixed rejection was identified in 179. Freedom from AMR was 88% and 82% at 1 and 3 years, respectively. AMR therapies included intravenous immunoglobulin (IVIg) (58%), plasmapheresis (40%), rituximab (40%), bortezomib (11%) and eculizumab (0.4%). The most commonly used combination therapies included IVIg/plasmapheresis/rituximab (13%). Thirty-three patients (16%) died after developing AMR. Patient and graft survival were lower for the AMR + group. One- and 3-year survival after initial AMR diagnosis was 88% and 77%, respectively. In his study we report the largest experience of AMR in pediatric HT recipients. AMR was common and often occurred concurrently with acute cellular rejection. There is wide variability in the treatment of AMR. Short-term patient and graft outcomes were worse for those with treated AMR. Copyright Â© 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Full Text Available Jian Zhou,* Weiqiang Ju,* Xiaopeng Yuan, Xiaofeng Zhu, Dongping Wang, Xiaoshun HeOrgan Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China *These authors contributed equally to this work Abstract: Hyperosmolar nonketotic hyperglycemic coma (HNKHC is a serious, rare complication induced by methylprednisolone (MP pulse therapy for acute rejection after orthotopic liver transplantation (OLT. Herein, we report an unusual case of a 58-year-old woman who experienced acute rejection at 30 months after OLT, only one case in which HNKHC resulted in MP pulse therapy for acute rejection in all 913 recipients in our center. The general morbidity of HNKHC was 1.09‰ in this study. HNKHC is characterized by rapid onset, rapid progression, and a lack of specific clinical manifestations. High-dose MP management was a clear risk factor. The principle of treatment included rapid rehydration, low-dose insulin infusion, and correcting disorders of electrolytes and acidosis. In conclusion, clinicians considering MP pulse therapy after OLT should be alert to the occurrence of HNKHC. Keywords: liver transplantation, complications, hyperosmolar nonketotic hyperglycemic coma, methylprednisolone pulse therapy, principle of treatment
... type matches or is compatible to your own. Blood-type incompatible transplants are also possible but require additional medical treatment before and after transplant to reduce the risk of organ rejection. These are known as ABO incompatible kidney transplants. ...
Full Text Available It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412 that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without. We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95% CI -0.968 to -0.523, p = 0.0014, as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9% and a specificity of 82.0% (95% CI 72.1% to 89.1% (cell-free donor-derived DNA as noninvasive gold standard. To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the
Jafari, Davood; Nafar, Mohsen; Yekaninejad, Mir Saeed; Abdolvahabi, Razieh; Lesan Pezeshki, Mahboob; Razaghi, Efat; Amirzargar, Ali Akbar
After kidney transplantation, natural killer (NK) cells play a pivotal role in triggering the immune response to the allogeneic grafts primarily by their killer-cell immunoglobulin-like receptors (KIR). This process may be one mechanism that contributes to graft rejection. In this study, we have evaluated whether acute rejection after kidney transplantation was associated with predicted NK cell alloreactivity based on KIR gene and ligand along with KIR/HLA compound genotype analysis. After kidney transplantation, natural killer (NK) cells play a pivotal role in triggering the immune response to the allogeneic grafts primarily by their killer-cell immunoglobulin-like receptors (KIR). This process may be one mechanism that contributes to graft rejection. In this study, we have evaluated whether acute rejection after kidney transplantation was associated with predicted NK cell alloreactivity based on KIR gene and ligand along with KIR/HLA compound genotype analysis. DNA from 65 patients with biopsy-proven acute kidney allograft rejection (AKAR), 61 clinically stable graft function (SGF) recipients and 176 healthy subjects were identified for the presence or absence of 10 variable KIR genes (both activating and inhibitory receptors) and their HLA ligands using polymerase chain reaction-sequence specific primers (PCR-SSP) assay. Although no significant difference in the frequency of individual KIR genes, was found the gene content, and the haplotypic distribution between the three categories were detected, the frequency of the KIR3DL1+HLA-Bw4*A allele combination was significantly lower in AKAR patients compared to SGF recipients (p=0.004, OR=0.34, CI=0.16-0.72) and healthy subjects (p=0.019, OR=0.47, CI=0.25-0.89). Kaplan-Meier survival test showed that the KIR3DL1+HLA-Bw4*A allele combination could be considered protective for AKAR (p=0.04 by log-rank). The results of this study suggest that KIR/HLA polymorphism may be a genetic susceptibility factor to alloreactivity
Nie Wei; Tang Yiya; Rong Pengfei; Ye Bin; Ye Zheng; Tong Qiongjuan; Wang Wei
Objective: To evaluate the feasibility of the diagnosis of the early immunologic rejection after xeno-islet transplantation by MR imaging enhanced with superparamagnetic iron oxide (SPIO) marking CD4 + T cell antibody. Methods: Two thousand neonatal porcine islets (NPI)were transplanted under the left renal capsule of BALB/C nude mice. When the grafts could be observed by MRI, 10 7 human PBMC was intraperitoneal injected to nude mouse models to reconstitute the human immunologic system, 20 mice were reconstituted. Before and 3,7,14 days after reconstitution of human immunologic system on BALB/C nude mice, MRI imaging was performed half an hour after intravenous injection of nano-immunomagnetic beads via vena caudatis to observe the grafts' MRI signal. BALB/C nude mice were sacrificed after MRI scanning immediately, the histopathologic examination was assessed on grafts, the results were compared with MRI results. And calculate the sensitivity, specificity, Youden index number and coincidence of the MRI for immunologic rejection. Results: Grafts can be observed by MRI 3 weeks after islet cell transplantation (before immunologic rejection modeling), there is no abnormal MRI signal detected in nude mice' graft region after microbeads injected. Seven days after building of immunologic rejection model, MRI hypo-signal in graft site is shown in the T 2 WI sequence after nano-bioprober injected. Histopathologic assessments were employed on grafts in nude mice immediately (HE and immunohistochemistry staining), the results shown that there are a lot of T lymphocyts infiltrated in graft region, implying the occurrence of immunologic rejection. And the sensitivity, specificity, Youden index number and coincidence is: (72.96±0.24)%, 100%, 0.73±0.24, (88.46±0.13)% respectively. The correct Kappa between the MRI and the imunohistochemistry staining was 0.76. Conclusion: The cellular immunological rejection to xeno-islet grarts can be assessed with nano-bioprobe with anti-CD4
Full Text Available Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR.We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART study. Gene expression was assessed by quantitative real-time PCR (QPCR in one center. A 17-gene set--the Kidney Solid Organ Response Test (kSORT--was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91-0.98, validated in 124 independent samples (AUC = 0.95; 95% CI 0.88-1.0 and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy. A novel reference-based algorithm (using 13 12-gene models was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86-0.99. Further validation of kSORT is planned in prospective clinical observational and interventional trials.The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants. Please see later in the article for the Editors' Summary.
Donato, Maria Francesca; Morelli, Cristina; Romagnoli, Renato; Invernizzi, Federica; Mazzarelli, Chiara; Iemmolo, Rosa Maria; Montalbano, Marzia; Lenci, Ilaria; Bhoori, Sherrie; Pieri, Giulia; Berardi, Sonia; Caraceni, Paolo; Martini, Silvia
Hepatitis C virus (HCV) re-infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF-regimen from pre- to post-transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV-RNA undetectability at the time of transplant. From July 2014 SOF/R was given in 233 waitlisted HCV cirrhotics with/without hepatocellular carcinoma (HCC) within an Italian Compassionate Program. One hundred patients were transplanted and 31 patients (31%) treated with SOF/R bridging therapy were studied. Liver transplant indication in bridge subgroup was HCC in 22 and decompensated cirrhosis in 9. HCV-genotype was 1/4 in 18 patients. SOF 400 mg/day and R (median dosage 800 mg/day) were given for a median of 35 days before LT. At transplant time, 19 patients were still HCV-RNA positive (median HCV-RNA 58 IU/mL). One recipient had a virological breakthrough at week 4 post-transplant; one died, on treatment, 1-month post-transplant for sepsis and 29/31 achieved a 12-week sustained virological response (94%). Acute cellular rejection occurred in three recipients. On September 2016, 30 recipients (97%) were alive with a median follow-up of 18 months (range 13-25). In patients with suboptimal virological response at LT, a bridging SOF/R regimen helps avoiding post-transplant graft reinfection. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Boleslawski, Emmanuel; BenOthman, Samia; Grabar, Sophie; Correia, Leonor; Podevin, Philippe; Chouzenoux, Sandrine; Soubrane, Olivier; Calmus, Yvon; Conti, Filomena
The aim of this study was to determine whether the expression of CD25, CD28 and CD38 (which reflects the degree of T-cell activation) by peripheral blood mononuclear cells constitutes a useful means of measuring the immune status of liver transplant recipients. Fifty-two patients enrolled in a prospective randomized study comparing cyclosporine and tacrolimus as the principal immunosuppressive drugs were monitored prospectively. The expression of CD25, CD28 and CD38 was analyzed on CD3-, CD4- and CD8-positive cells from whole blood using flow cytometry. The prognostic value of baseline and day 14 measurements regarding acute rejection was examined using Kaplan-Meier estimates for univariate analyses and the Cox model for multivariate analyses. The mean frequencies of CD28 and CD38-expressing T cells were significantly higher in patients with acute rejection (p = 0.01 and p = 0.001, respectively), whereas the frequency CD25-expressing T cells did not differ significantly. Under univariate analysis, baseline CD25 levels, the type of calcineurin inhibitor, as well as the CD28 and CD38 frequencies obtained at day 14 were associated with the subsequent development of acute rejection. Under multivariate analysis, only CD28 and CD38 frequencies obtained at day 14 were independently associated with acute rejection. The evaluation of CD28 and CD38 expression in peripheral blood lymphocytes is a simple marker that could be used routinely in clinical practice to assess the level of immunosuppression.
Good, R A; Verjee, T
Primary immunodeficiency diseases often fully meet the definition of "experiments of nature." Much of the expanding understanding of the lymphoid systems and immunologic functions generated in recent years has been derived from studying patients with primary, generally genetically determined immunodeficiency diseases, as well as other relatively rare secondary immunodeficiency diseases. Increasing knowledge of immunologic defenses, their interacting cellular and molecular components, the evolving details of sequential stages of cellular differentiation, and the nature and control of the cellular and molecular interactions in immunity have now made it possible to define precisely many primary immunodeficiency diseases in full molecular genetic terms. With this wealth of scientific information based on experimental and clinical research, incredible advances have also been made in using bone marrow transplantation (BMT) often as a curative treatment for immunodeficiency, some 60 to 70 other diseases, leukemias, lymphomas, other cancers, and a rapidly expanding constellation of metabolic diseases or enzyme deficiencies. Also, progress in applying allogeneic BMT to prevent, treat, and cure complex autoimmune diseases, primary immunodeficiency diseases and certain forms of cancers, is considered. Further, mixed BMT (syngeneic plus allogeneic) that establishes a form of stable mixed chimerism has also been employed in animal experiments, which revealed that BMT can be used to treat not only immunodeficiency diseases, but also systemic and organ-specific autoimmune diseases, eg, diabetes and erythematous lupus-like diseases. Moreover, performing BMT in conjunction with organ allografts, eg, thymus or pancreatic transplants, has successfully prevented rejection of these allografts, sometimes without recourse to long-term irradiation or toxic chemical immunosuppressive agents. A crucial role for stromal cells in cellular engineering has now also been realized in animal
Lange, Sandra; Steder, Anne; Glass, Änne; Killian, Doreen; Wittmann, Susanne; Machka, Christoph; Werner, Juliane; Schäfer, Stephanie; Roolf, Catrin; Junghanss, Christian
The canine hematopoietic stem cell transplantation (HSCT) model has become accepted in recent decades as a good preclinical model for the development of new transplantation strategies. Information on factors associated with outcome after allogeneic HSCT are a prerequisite for designing new risk-adapted transplantation protocols. Here we report a retrospective analysis aimed at identifying risk factors for allograft rejection in the canine HSCT model. A total of 75 dog leukocyte antigen-identical sibling HSCTs were performed since 2003 on 10 different protocols. Conditioning consisted of total body irradiation at 1.0 Gy (n = 20), 2.0 Gy (n = 40), or 4.5 Gy (n = 15). Bone marrow was infused either intravenously (n = 54) or intraosseously (n = 21). Cyclosporin A alone or different combinations of cyclosporine A, mycophenolate mofetil, and everolimus were used for immunosuppression. A median cell dose of 3.5 (range, 1.0 to 11.8) total nucleated cells (TNCs)/kg was infused. Cox analyses were used to assess the influence of age, weight, radiation dose, donor/recipient sex, type of immunosuppression, and cell dose (TNCs, CD34(+) cells) on allograft rejection. Initial engraftment occurred in all dogs. Forty-two dogs (56%) experienced graft rejection at median of 11 weeks (range, 6 to 56 weeks) after HSCT. Univariate analyses revealed radiation dose, type of immunosuppression, TNC dose, recipient weight, and recipient age as factors influencing long-term engraftment. In multivariate analysis, low radiation dose (P rejection. Peripheral blood mononuclear cell chimerism ≥30% (P = .008) and granulocyte chimerism ≥70% (P = .023) at 4 weeks after HSCT were independent predictors of stable engraftment. In summary, these data indicate that even in low-dose total body irradiation-based regimens, the irradiation dose is important for engraftment. The level of blood chimerism at 4 weeks post-HSCT was predictive of long-term engraftment in the canine HSCT
Ali, J M; Catarino, P; Dunning, J; Giele, H; Vrakas, G; Parmar, J
Accurate diagnosis of allograft rejection can be hazardous and challenging. A strategy that has emerged from experience with vascularized composite allografts (VCAs) is the use of sentinel skin transplants (SSTs)-portions of donor skin transplanted synchronously to an allograft. Work in nonhuman animal models and experience with VCAs suggest concordance between rejection occurring in the primary allograft and the SST, and that appearance of rejection in the SST may precede rejection in the primary allograft, permitting early therapeutic intervention that may improve outcomes with lower rates of chronic rejection. The encouraging findings reported in VCA transplantation raise the possibility that SST may also be useful in solid organ transplantation. Some evidence is provided by experience with abdominal wall transplantation in some intestinal and multivisceral transplant recipients. Results from those reports raise the possibility that rejection may manifest in the skin component before emergence in the intestinal allograft, providing a "lead time" during which treatment of rejection of the abdominal wall could prevent the emergence of intestinal rejection. It is plausible that these findings may be extrapolated to other solid organ allografts, especially those for which obtaining an accurate diagnosis of acute rejection can be hazardous and challenging, such as the lung or pancreas. However, more data are required to support widespread adoption of this technique. Copyright © 2016 Elsevier Inc. All rights reserved.
Zhao, Xiangli; Zhang, Kai; Daniel, Peter; Wisbrun, Natali; Fuchs, Hendrik; Fan, Hua
Organ transplantation is an effective therapeutic tool for treating many terminal diseases. However, one of the biggest challenges of transplantation is determining how to achieve the long-term survival of the allogeneic or xenogeneic transplant by, for example, preventing transplant rejection. In the current study, CD26 gene-knockout mice were used to investigate the potential role of CD26/dipeptidyl peptidase-4 (DPPIV) in allogeneic skin graft rejection by tail-skin transplantation. Compared with wild-type (CD26 +/+ ) counterparts, CD26 -/- mice showed reduced necrosis of grafts and delayed graft rejection after skin transplantation. Concentrations of serum IgG, including its subclasses IgG1 and IgG2a, were significantly reduced in CD26 -/- mice during graft rejection. Moreover, after allogeneic skin transplantation, the secretion levels of the cytokines IFN-γ, IL-2, IL-6, IL-4, and IL-13 were significantly reduced, whereas the level of the cytokine IL-10 was increased in the serum of CD26 -/- mice compared with that in the serum of CD26 +/+ mice. Additionally, the concentration of IL-17 in serum and the percentage of cells secreting IL-17 in mouse peripheral blood lymphocytes (MPBLs) were both significantly lower, while the percentage of regulatory T cells (Tregs) was significantly higher in MPBLs of CD26 -/- mice than in those of CD26 +/+ mice. Furthermore, a lower percentage of CD8 + T cells in MPBLs and fewer infiltrated macrophages and T cells in graft tissues of CD26 -/- mice were detected during graft rejection. These results indicate that CD26 is involved in allogeneic skin graft rejection and provides another hint that CD26 deficiency leads to less rejection due to lower activation and proliferation of host immune cells.
Tulio B Abud
Full Text Available The cornea is the most commonly transplanted tissue in the body. Although corneal grafts generally have high success rates, transplantation onto inflamed and vascularized host beds, or so-called high-risk corneal transplantation, has a high rate of graft rejection. The management of this high-risk corneal transplantation is challenging and involves numerous measures. One of the key measures to prevent graft rejection in these cases is the use of systemic immunosuppressive agents. In this article, we will review the systemic immunosuppressive agents most commonly used for high-risk corneal transplantation, which include corticosteroids, cysclosporine A, tacrolimus, mycophenolate mofetil, and rapamycin. Benefits, risks, and published data on the use of these medications for high-risk corneal transplantation will be detailed. We will also summarize novel immunoregulatory approaches that may be used to prevent graft rejection in high-risk corneal transplantation.
Haddad, E M; McAlister, V C; Renouf, E
Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies...
Risk of early, intermediate, and late rejection following heart transplantation: Trends over the past 25 years and relation to changes in medical management. Tertiary center experience: The Sheba Heart Transplantation Registry.
Katz, Moshe; Freimark, Dov; Raichlin, Eugenia; Har-Zahav, Yedael; Arad, Michael; Kassif, Yigal; Peled, Amir; Asher, Elad; Elian, Dan; Kogan, Alexander; Shlomo, Nir; Ofek, Efrat; Lavee, Jacob; Goldenberg, Ilan; Peled, Yael
To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management. The study population comprised 216 HT patients. Rejection periods were defined as follows: 0-3 months (early), 3-12 months (intermediate), and 12+ months (late). HT era was dichotomized as follows: 1991-1999 (remote era) and 2000-2016 (recent era). Medication combination was categorized as newer (TAC, MMF, and everolimus) vs older therapies (AZA, CSA). Multivariate analysis showed that patients who underwent HT during the recent era experienced a significant reduction in the risk for major rejection. These findings were consistent for early (OR = 0.44 [95% CI 0.22-0.88]), intermediate (OR = 0.02 [95% CI 0.003-0.11]), and late rejections (OR = 0.18 [95% CI 0.05-0.52]). Using the year of HT as a continuous measure showed that each 1-year increment was independently associated with a significant reduction in the risk for early, intermediate, and late rejections (5%, 21%, 18%, respectively). In contrast, the risk reduction associated with newer types of immunosuppressive therapies was not statistically significant after adjustment for the treatment period. Major rejection rates following HT have significantly declined over the past 2 decades even after adjustment for changes in immunosuppressive therapies, suggesting that other factors may also play a role in the improved outcomes of HT recipients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Full Text Available In renal transplantation, the unresponsiveness of patients undergoing chronic antibody mediated rejection (CAMR to classical treatment stress on the need for accurate biomarkers to improve its diagnosis. We aim to determine whether microRNA expression patterns may be associated with a diagnosis of CAMR. We performed expression profiling of miRNAs in peripheral blood mononuclear cells (PBMC of kidney transplant recipients with CAMR or stable graft function. Among 257 expressed miRNAs, 10 miRNAs associated with CAMR were selected. Among them, miR-142-5p was increased in PBMC and biopsies of patients with CAMR as well as in a rodent model of CAMR. The lack of modulation of miR-142-5p in PBMC of patients with renal failure, suggests that its over-expression in CAMR was associated with immunological disorders rather than renal dysfunction. A ROC curve analysis performed on independent samples showed that miR-142-5p is a potential biomarker of CAMR allowing a very good discrimination of the patients with CAMR (AUC = 0.74; p = 0.0056. Moreover, its expression was decreased in PHA-activated blood cells and was not modulated in PBMC from patients with acute rejection, excluding a non-specific T cell activation expression. The absence of modulation of this miRNA in immunosuppressed patients suggests that its expression was not influenced by treatment. Finally, the analysis of miR-142-5p predicted targets under-expressed in CAMR PBMC in a published microarray dataset revealed an enrichment of immune-related genes. Altogether, these data suggest that miR-142-5p could be used as a biomarker in CAMR and these finding may improve our understanding of chronic rejection mechanisms.
M. Moors-Tielen (Mirjam)
markdownabstract__Background:__ Patients have to take immunosuppressive medication after kidney transplantation to prevent rejection of the graft. This thesis investigated patients’ adherence behavior, attitudes and beliefs about the immunosuppressive regime. The research questions were (1) What is
Corneal Allograft Rejection: Topical Treatment Vs. Pulsed Intravenous Methylprednisolone - Ten Years' Result [rejeição De Transplantes De Córnea: Tratamento Tópico Vs. Pulsoterapia - Resultados De 10 Anos
Costa D.C.; de Castro R.S.; Ferraz de Camargo M.S.; Kara-Jose N.
Purpose: To evaluate the efficacy of intravenous 500 mg methylprednisolone in addition to topical treatment with 1% prednisolone in the treatment of the first episode of corneal endothelial rejection in patients that were submitted to corneal allograft transplantation. Methods: Retrospective casecontrol study with 81 patients that presented the first episode of corneal endothelial rejection and were treated within the first 15 days of the onset of symptoms. Results: 67 patients were treated w...
O'Seaghdha, C M
We analyzed the association between whole-blood trough tacrolimus (TAC) levels in the first days post-kidney transplant and acute cellular rejection (ACR) rates. Four hundred and sixty-four consecutive, deceased-donor kidney transplant recipients were included. All were treated with a combination of TAC, mycophenolate mofetil and prednisolone. Patients were analyzed in four groups based on quartiles of the mean TAC on days 2 and 5 post-transplant: Group 1: median TAC 11 ng\\/mL (n = 122, range 2-13.5 ng\\/mL), Group 2: median 17 ng\\/mL (n = 123, range 14-20 ng\\/mL), Group 3: median 24 ng\\/mL (n = 108, range 20.5-27 ng\\/mL) and Group 4: median 33.5 ng\\/mL (n = 116, range 27.5-77.5 ng\\/mL). A graded reduction in the rates of ACR was observed for each incremental days 2-5 TAC. The one-yr ACR rate was 24.03% (95% CI 17.26-32.88), 22.20% (95% CI 15.78-30.70), 13.41% (95% CI 8.15-21.63) and 8.69% (95% CI 4.77-15.55) for Groups 1-4, respectively (p = 0.003). This study suggests that higher early TACs are associated with reduced rates of ACR at one yr.
Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice.
Full Text Available Allogeneic transplantation (Tx of induced pluripotent stem cells (iPSCs is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET imaging targets translocator protein (TSPO, which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714 is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group, or Balb/c mice as an allogeneic model (allogeneic Tx group. 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune
... and suppresses the patient’s immune system to prevent rejection of the transplant. Unlike traditional BMT or PBSCT, ... be given an injection of the donor’s white blood cells. This procedure is called a “ donor ... “tandem transplant” is a type of autologous transplant. This method is being studied ...
H.A. de Groot-Kruseman; C.C. Baan (Carla); E.M. Hagman; W.M. Mol (Wendy); H.G.M. Niesters (Bert); P.E. Zondervan (Pieter); W. Weimar (Willem); A.H.M.M. Balk (Aggie); A.W.P.M. Maat (Alex)
textabstractOBJECTIVE: To assess whether diastolic graft function is influenced by intragraft interleukin 2 (IL-2) messenger RNA (mRNA) expression in rejecting cardiac allografts. DESIGN: 16 recipients of cardiac allografts were monitored during the first three months after
Vítová, Andrea; Filipec, M.; Zajícová, Alena; Krulová, Magdalena; Holáň, Vladimír
Roč. 88, - (2004), s. 1338-1342 ISSN 0007-1161 R&D Projects: GA MZd NR7816; GA MZd NI7531; GA MŠk LN00A026; GA ČR GP310/02/D162; GA ČR GD310/03/H147 Institutional research plan: CEZ:AV0Z5052915 Keywords : Corneal allograft, rejection Subject RIV: EC - Immunology Impact factor: 2.000, year: 2004
Cardiac Transplant Disorder; Cardiac Death; Heart Failure; Acute Cellular Graft Rejection; Antibody-Mediated Graft Rejection; Cardiac Allograft Vasculopathy; Heart Transplant Rejection; Immune Tolerance
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Amersi, Farin; Nelson, Sally K.; Shen, Xiu Da; Kato, Hirohisa; Melinek, Judy; Kupiec-Weglinski, Jerzy W.; Horwitz, Lawrence D.; Busuttil, Ronald W.; Horwitz, Marcus A.
Ischemia/reperfusion (I/R) injury is a serious potential threat to outcomes in organ transplantation and other clinical arenas in which there is temporary interruption of blood flow. I/R is a frequent cause of primary failure in organ transplantation. We hypothesized that the antioxidant bucillamine, a potent sulfhydryl donor, would protect against I/R injury in high-risk organ transplants. Because livers subjected to prolonged ischemia and very fatty livers are highly susceptible to severe I...
stage kidney disease. There is good evidence that transplantation improves both the quality and quantity of life in renal transplant recipients when compared with dialysis.1,2. Living donor kidney transplantation has gained popularity, not only owing ...
Dohna-Schwake, C.; Fiedler, M.; Gierenz, N.; Gerner, P.; Ballauf, A.; Breddemann, A.; Laer, S.; Baba, H.A.; Hoyer, P.F.
HHV type 6 has been reported with enhanced pathogenicity in immunocompromised patients. Herein, we report about a two-yr-old girl who experienced primary HHV 6 infection after liver transplantation. She clinically presented with graft rejection and necrotic hepatitis as well as high fever,
Kamei, Hideya; Masuda, Satohiro; Nakamura, Taro; Oike, Fumitaka; Takada, Yasutsugu; Hamajima, Nobuyuki
Despite improvements in immunosuppressive therapy, acute cellular rejection (ACR) remains an important cause of mortality and graft loss in patients undergoing liver transplantation. Recently, associations between gene polymorphisms and the incidence of ACR have been reported, though few studies have investigated those polymorphisms in donors. Transporter associated with antigen processing (TAP1 and TAP2) are involved in major histocompatibility complex (MHC) class I antigen-mediated processing and presentation to cytotoxic CD8+ T lymphocytes. The aim of this study was to determine whether TAP1 and TAP2 gene polymorphisms in the donor have affected on ACR incidence in living donor liver transplantation (LDLT). We examined 155 LDLTs treated at Nagoya University or Kyoto University from 2004 to 2009 and analyzed the gene polymorphisms of TAP-1 p.Ile333Val, TAP-1 p.Asp697Gly, TAP-2 p.Arg651Cys, and TAP-2 p.Gln687Stop. Thirty-seven recipients developed early ACR. Of the investigated gene polymorphisms, the TAP-1 p.697Gly allele in donors was associated with incidence of early ACR (OR=2.97, 95%CI 1.33-6.63, p=0.008). The TAP-1 p.697Gly allele in donors was associated with increased incidence of early ACR following LDLT. The TAP-1 697 polymorphism in donors can be genotyped prior to LDLT, which may contribute to individualize immunosuppression strategies for recipients and donor selection.
Diane M Harper
Full Text Available OBJECTIVE: Only a portion of the US population is willing to consider HPV vaccination to date. The primary aim of this study is to determine the decisional satisfaction associated with HPV vaccination. STUDY DESIGN: This is a prospective survey conducted at an urban college where women 18-26 years old completed a decisional satisfaction survey about their HPV vaccine experience. RESULTS: Regardless of the decision to accept or reject HPV vaccination, the decisional satisfaction was very high (mean 5-item score = 21.2 (SD 3.8. Women without HPV vaccination were decisionally neutral significantly more often than those already vaccinated; 22% were decisionally neutral for the option to accept HPV vaccination at that visit. Cervical cancer prevention was preferred significantly more often than genital wart prevention in all analyses. CONCLUSIONS: Targeting those who are decisionally neutral about HPV vaccination may result in a higher uptake of HPV vaccination.
Fabricio Ferreira Coelho
Full Text Available PURPOSE: To study the indications and results of tacrolimus as rescue therapy for acute cellular or chronic rejection in liver transplantation. PATIENTS AND METHODS: Eighteen liver transplant recipients who underwent rescue therapy with tacrolimus between March 1995 and August 1999 were retrospectively studied. The treatment indication, patients, and graft situation were recorded as of October 31st, 1999. The response to tacrolimus was defined as patient survival with a functional graft and histological reversal of acute cellular, or for chronic rejection, bilirubin serum levels decreasing to up to twice the upper normal limit. RESULTS: Fourteen cases (77.8% presented a good response. The response rate for the different indications was: (1 acute cellular + sepsis - 0/1 case; (2 recurrent acute cellular - 1/1 case; (3 OKT3-resistant acute cellular - 2/2 cases; (4 steroid-resistant acute cellular + active viral infection - 3/3 cases; (5 chronic rejection - 8/11 cases (72.7% response rate. The 4 patients who did not respond died. CONCLUSION: Tacrolimus rescue therapy was successful in most cases of acute cellular and chronic rejection in liver transplantation.OBJETIVO: Estudar os critérios de indicação e o resultado do uso de tacrolimus na terapia de resgate de rejeições agudas ou crônicas no transplante de fígado. CASUÍSTICA E MÉTODO: Foram estudados 18 pacientes transplantados de fígado, submetidos a terapia de resgate com tacrolimus entre março de 1995 e agosto de 1999. Foram registradas a indicação do tratamento e a situação de pacientes e enxertos em 31/10/1999. Considerou-se "respondendores" pacientes vivos, com enxerto funcionante e regressão histológica da terapia de resgate de rejeições agudas, ou com bilirrubina até 2 vezes o valor normal, no caso de terapia de resgate de rejeições crônicas. RESULTADO: Observou-se resposta em 14 casos (77,8%. A taxa de resposta nas diferentes indicações foi: (1 terapia de resgate
Gabardi, Steven; Waikar, Sushrut S; Martin, Spencer; Roberts, Keri; Chen, Jie; Borgi, Lea; Sheashaa, Hussein; Dyer, Christine; Malek, Sayeed K; Tullius, Stefan G; Vadivel, Nidyanandh; Grafals, Monica; Abdi, Reza; Najafian, Nader; Milford, Edgar; Chandraker, Anil
Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.
Hongo, David; Tang, Xiaobin; Zhang, Xiangyue; Engleman, Edgar G; Strober, Samuel
The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8 + dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8 + DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8 + DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8 + DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8 + DCs initiates tolerance induction. Tolerogenic CD8 + DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8 + DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol. © 2017 by The American Society of Hematology.
Andrews, Peter A; Emery, Vincent C; Newstead, Chas
The third edition of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease after Solid Organ Transplantation was published in March 2011. This article summarizes the important changes and advances in management in this rapidly evolving field. The pros and cons of universal, or targeted anti-cytomegalovirus (CMV) prophylaxis, and pre-emptive anti-CMV therapy are discussed, especially with respect to advances in CMV polymerase chain reaction monitoring. The evidence for oral anti-CMV prophylaxis using valganciclovir is presented, together with a summary of the treatment of CMV disease and emerging fields such as CMV vaccination, CMV genotyping, and drug resistance.
Cozzi, E; Calabrese, F; Schiavon, M; Feltracco, P; Seveso, M; Carollo, C; Loy, M; Cardillo, M; Rea, F
Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ET A R) and the angiotensin II receptor type 1 (AT 1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ET A R and anti-AT 1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Thorp, Edward B; Stehlik, Christian; Ansari, M Javeed
The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance.
Covert, Kelly L; Fleming, James N; Staino, Carmelina; Casale, Jillian P; Boyle, Kimberly M; Pilch, Nicole A; Meadows, Holly B; Mardis, Caitlin R; McGillicuddy, John W; Nadig, Satish; Bratton, Charles F; Chavin, Kenneth D; Baliga, Prabhakar K; Taber, David J
A lack of research exploring post-transplant process optimization to reduce readmissions and increasing readmission rates at our center from 2009 to 2013 led to this study, aimed at assessing the effect of patient and process factors on 30-d readmission rates after kidney transplantation. This was a retrospective case-control study in adult kidney transplant recipients. Univariate and multivariate analyses were utilized to assess patient and process determinants of 30-d readmissions. 384 patients were included; 30-d readmissions were significantly associated with graft loss and death (p = 0.001). Diabetes (p = 0.049), pharmacist identification of poor understanding or adherence, and prolonged time on hemodialysis prior to transplant were associated with an increased risk of 30-d readmissions. After controlling for risk factors, readmission rates were only independently predicted by pharmacist identification of patient lack of understanding or adherence regarding post-transplant medications and dialysis exposure for more than three yr (OR 2.3, 95% CI 1.10-4.71, p = 0.026 and OR 2.1, 95% CI 1.22, 3.70, respectively), both of which were significantly modified by history of diabetes. Thirty-d readmissions are attributable to both patient and process-level factors. These data suggest that a lack of post-transplant medication knowledge in high-risk patients drives early hospital readmission. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Martin, Dominique E; Van Assche, Kristof; Domínguez-Gil, Beatriz; López-Fraga, Marta; Budiani-Saberi, Debra; Lavee, Jacob; Tibell, Annika; Moazam, Farhat; Muller, Elmi; Danovitch, Gabriel M; Codreanu, Igor; Naicker, Saraladevi; Al Rukhaimi, Mona; McGuinness, Sheelagh; Bakr, Mohamed A; Moniruzzaman, Monir; Capron, Alexander M; Delmonico, Francis L
Many nations are able to prosecute transplant-related crimes committed in their territory, but transplant recipients, organ sellers and brokers, and transplant professionals may escape prosecution by engaging in these practices in foreign locations where they judge the risk of criminal investigation and prosecution to be remote. The Declaration of Istanbul Custodian Group convened an international working group to evaluate the possible role of extraterritorial jurisdiction in strengthening the enforcement of existing laws governing transplant-related crimes across national boundaries. Potential practical and ethical concerns about the use of extraterritorial jurisdiction were examined, and possible responses were explored. Extraterritorial jurisdiction is a legitimate tool to combat transplant-related crimes. Further, development of a global registry of transnational transplant activities in conjunction with a standardized international referral system for legitimate travel for transplantation is proposed as a mechanism to support enforcement of national and international legal tools. States are encouraged to include provisions on extraterritorial jurisdiction in their laws on transplant-related crimes and to collaborate with professionals and international authorities in the development of a global registry of transnational transplant activities. These actions would assist in the identification and evaluation of illicit activities and provide information that would help in developing strategies to deter and prevent them.
Xu, Xiaoguang; Huang, Haiyan; Wang, Qiang; Cai, Ming; Qian, Yeyong; Han, Yong; Wang, Xinying; Gao, Yu; Yuan, Ming; Xu, Liang; Yao, Chen; Xiao, Li; Shi, Bingyi
IFN-γ is a protypical proinflammatory cytokine that plays a central role in inflammation and acute graft rejection. Accumulating evidence indicates that IFN-γ can exert previously unexpected immunoregulatory activities. However, little is known about the role of IFN-γ secreted by Th1-like regulatory T cells in human kidney transplantation. To determine the function of IFN-γ in acute T cell-mediated renal allograft rejection (ACR), we examined serum cytokine expression profiles in ACR patients by human cytokine multiplex immunoassay and analyzed the cellular origins of IFN-γ in peripheral blood and renal allograft biopsies from ACR cases and controls by flow cytometry and immunohistochemistry, respectively. The results showed significant reduction in serum concentrations of Th1-inducing cytokines IL-12p70 and IFN-γ as well as Th2-related cytokine IL-4 in ACR patients compared with stable controls. However, levels of several Th1-, Th2- and Th17-related cytokines, such as IL-2, TNF-α, TNF-β, IL-12 (p40), IL-10, IL-15, IL-17, IL-21, and IL-23, as well as the frequencies of Th1 and Th17 cell, did not differ between ACR cases and stable controls. Moreover, we found the levels of IFN-γ were correlated with those of the anti-inflammatory factor, IL-1 receptor antagonist (IL-1Ra) in ACR. Notably, the Th1-like Treg cell-to-Foxp3 - Th1 cell ratio was significantly lower in ACR patients compared with that in stable controls. In graft biopsies from ACR patients, Treg cells and Th1-like Treg cells were less abundant than those without ACR. Our study indicates that IFN-γ secreted from Th1-like Treg cells negatively modulates ACR. Copyright © 2016 Elsevier GmbH. All rights reserved.
Battes, Linda C; Caliskan, Kadir; Rizopoulos, Dimitris; Constantinescu, Alina A; Robertus, Jan L; Akkerhuis, Martijn; Manintveld, Olivier C; Boersma, Eric; Kardys, Isabella
Studies on the prognostic value of serial biomarker assays for future occurrence of allograft rejection (AR) are scarce. We examined whether repeated measurements of NT-pro-B-type natriuretic peptide (NT-proBNP), troponin T (TropT) and C-reactive protein (CRP) predict AR. From 2005 to 2010, 77 consecutive heart transplantation (HTx) recipients were included. The NT-proBNP, TropT, and CRP were measured at 16 ± 4 (mean ± standard deviation) consecutive routine endomyocardial biopsy surveillance visits during the first year of follow-up. Allograft rejection was defined as International Society for Heart and Lung Transplantation (ISHLT) grade 2R or higher at endomyocardial biopsy. Joint modeling was used to assess the association between repeated biomarker measurements and occurrence of future AR. Joint modeling accounts for dependence among repeated observations in individual patients. The mean age of the patients at HTx was 49 ± 9.2 years, and 68% were men. During the first year of follow-up, 1,136 biopsies and concurrent blood samples were obtained, and 56 patients (73%) experienced at least one episode of AR. All biomarkers were elevated directly after HTx and achieved steady-state after ∼ 12 weeks, both in patients with or without AR. No associations were present between the repeated measurements of NT-proBNP, TropT, or CRP and AR both early (weeks 0-12) and late (weeks 13-52) in the course after HTx (hazard ratios for weeks 13-52: 0.96 (95% confidence interval, 0.55-1.68), 0.67 (0.27-1.69), and 1.44 (0.90-2.30), respectively, per ln[unit]). Combining the three biomarkers in one model also rendered null results. The temporal evolution of NT-proBNP, TropT, and CRP before AR did not predict occurrence of acute AR both in the early and late course of the first year after HTx.
L.M. Andrews (Louise); Li, Y. (Yi); B.C.M. de Winter (Brenda); Y.Y. Shi (Yunjing); C.C. Baan (Carla); T. van Gelder (Teun); D.A. Hesselink (Dennis)
textabstractIntroduction: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several
Padilla, Benita; Danovitch, Gabriel M; Lavee, Jacob
We describe the parallel changes that have taken place in recent years in two countries, Israel and The Philippines, the former once an "exporter" of transplant tourists and the latter once an "importer" of transplant tourists. These changes were in response to progressive legislation in both countries under the influence of the Declaration of Istanbul. The annual number of Israeli patients who underwent kidney transplantation abroad decreased from a peak of 155 in 2006 to an all-time low of 35 in 2011 while in the Philippines the annual number of foreign transplant recipients fell from 531 in 2007 to two in 2011. The experience of these two countries provides a "natural experiment" on the potential impact of legal measures to prevent transplant tourism.
Loutfi, I.; Batchelor, J.R.; Lavender, J.P.
It has been described in this report, non-invasive and specific method for imaging and assessment of acute kidney transplant rejection in rat model. This model can serve as a basis for application in man using a cocktail of monoclonal antibodies with different specificities starting with monoclonal antibodies labelled with indium-111 which have been used in this technique. 3 refs., 1 tab., 2 figs
Williams, Allison Fiona; Manias, Elizabeth; Gaskin, Cadeyrn J; Crawford, Kimberley
The increasing prevalence of chronic kidney disease, the relative shortage of kidney donors and the economic- and health-related costs of kidney transplant rejection make the prevention of adverse outcomes following transplantation a healthcare imperative. Although strict adherence to immunosuppressant medicine regimens is key to preventing kidney rejection, evidence suggests that adherence is sub-optimal. Strategies need to be developed to help recipients of kidney transplants adhere to their prescribed medicines. This review has found that a number of factors contribute to poor adherence, for example, attitudes towards medicine taking and forgetfulness. Few investigations have been conducted, however, on strategies to enhance medicine adherence in kidney transplant recipients. Strategies that may improve adherence include pharmacist-led interventions (incorporating counselling, medicine reviews and nephrologist liaison) and nurse-led interventions (involving collaboratively working with recipients to understand their routines and offering solutions to improve adherence). Strategies that have shown to have limited effectiveness include supplying medicines free of charge and providing feedback on a participant's medicine adherence without any educational or behavioural interventions. Transplantation is the preferred treatment option for people with end-stage kidney disease. Medicine non-adherence in kidney transplantation increases the risk of rejection, kidney loss and costly treatments. Interventions are needed to help the transplant recipient take all their medicines as prescribed to improve general well-being, medicine safety and reduce healthcare costs. © 2014 European Dialysis and Transplant Nurses Association/European Renal Care Association.
Colpitts, Che C; Chung, Raymond T; Baumert, Thomas F
Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct-acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation. The role of DAAs in transplantation, while still under clinical investigation, carries the risk of recipient infection and HCV-induced disease, since DAAs act only after infection is established. Thus, entry inhibitors provide a perspective to improve patient outcomes during organ transplantation. Applying this approach for transplant of organs from HCV-positive donors to HCV-negative recipients may also contribute to alleviate the medical burden of organ shortage.
Storb, R.; Santos, G.W.
Bone marrow transplantation has been increasingly used to treat patients with severe combined immunodeficiency diseases, severe aplastic anemia, and malignant hematologic diseases, especially leukemia. At the Workshop a number of problems were discussed, e.g., conditioning regimens aimed at overcoming the problem of marrow graft rejection and reducing the incidence of recurrent leukemia, prevention of graft-versus-host disease (GVHD), possible mechanisms involved in stable graft-host tolerance, graft-versus-leukemia effect in mice, and finally, the possible use of autologous marrow transplantation
Howell, Jessica; Balderson, Glenda; Hellard, Margaret; Gow, Paul; Strasser, Simone; Stuart, Katherine; Wigg, Alan; Jeffrey, Gary; Gane, Ed; Angus, Peter W
Hepatitis C (HCV), hepatitis B (HBV), alcohol-related liver disease (ALD), and non-alcohol-related fatty liver disease (NAFLD) are leading indications for adult liver transplantation in Australia and New Zealand. However, these diseases are potentially preventable through effective primary and/or secondary prevention strategies. This study evaluates the relative contribution of potentially preventable liver diseases to liver transplant numbers in Australia and New Zealand over time. Prospectively recorded clinical, demographic, and outcome data were collected from the Australian and New Zealand Liver Transplant Registry for all primary adult liver transplants performed in Australia and New Zealand from 1 January 1985 until 31 December 2012. Potentially preventable liver disease was defined as HBV, HCV, NAFLD, ALD, and HCC. The etiology of liver disease leading to liver transplantation and the proportion of preventable liver disease-related liver transplantation was compared between Era 1 (1985-1993), Era 2 (1994-2003), and Era 3 (2004-2012). Overall, 1252 of 3266 adult primary liver transplants (38.3%) were performed for potentially preventable liver disease. There was a significant increase in the proportion of liver transplants because of preventable liver disease from 21.2% (93 of 439) in Era 1, to 49.8% (623 of 1252) in Era 2 and 63.5% (1000 of 1575) in Era 3 (P New Zealand have been because of potentially preventable liver diseases and the prevalence of these diseases has increased over time. This finding represents an opportunity for clinicians to make a significant impact on the overall burden of advanced liver disease in Australia and New Zealand by improving primary and secondary prevention measures. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Although chronic rejection is the most important cause of late allograft loss, none of the currently available immunosuppressive agents successfully target this problem. Clinical and laboratory studies suggest that 3-hydroxy-3-methyl-glutaryl co-enzyme A (HMG-CoA) reductase inhibitors (HRIs) may decrease the incidence of and pathophysiologic factors leading to chronic rejection. A number of clinical and laboratory investigations have been designed to evaluate the effect of HRIs on chronic rejection. Clinical trials in heart transplant patients suggest that HRIs decrease the incidence of chronic rejection in a manner that may be independent of lipid lowering. Subsequent studies in animal transplant models confirm that HRIs reduce chronic rejection. In further studies to elucidate the possible mechanisms of this effect, it has been observed that HRIs have an inhibitory effect on an number of lymphoid cell lines and vascular smooth muscle cells. HRIs may also prevent chronic rejection by protecting the endothelium from injury and dysfunction, perhaps by up-regulating nitric oxide synthesis. HRIs may be the first agents to be effective in preventing chronic rejection. Although the mechanism behind this protective effect is unclear, it seems likely that HRIs may affect multiple factors that could lead to chronic rejection.
Full Text Available James E Cooper¹, Uwe Christians², Alexander C Wiseman¹¹Division of Renal Diseases and Hypertension, Transplant Center, ²iC42 Integrated Solutions in Systems Biology for Clinical Research and Development, University of Colorado Denver, Aurora, CO, USAAbstract: Everolimus is a novel target of rapamycin (mTOR-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.Keywords: mTOR inhibitors, kidney transplantation, everolimus
Lladó, Laura; Fabregat, Joan; Castellote, Jose; Ramos, Emilio; Xiol, Xavier; Torras, Jaume; Serrano, Teresa; Baliellas, Carme; Figueras, Joan; Garcia-Gil, Agustin; Rafecas, Antoni
The purpose of this study was to evaluate the influence of a steroid-free immunosuppression on hepatitis C virus (HCV) recurrence. A total of 198 liver transplantation (LT) patients were randomized to receive immunosuppression with basiliximab and cyclosporine, either with prednisone (steroid [St] group) or without prednisone (no steroids [NoSt] group). The group of 89 HCV-infected patients was followed up with protocol biopsies for 2 years after LT. This group of HCV patients are the patients evaluated in the present study. The rejection rate was 19% (St: 21% versus NoSt: 17%; P = 0.67). Patients in the St group had a slightly higher rate of bacterial infections (59% versus 38%; P = 0.05). Almost all patients had histological HCV-recurrence (St: 39/40 (97%) versus NoSt: 40/41 (97%); P = 1). The percentage of accumulated biopsies with grade 4 portal inflammation at 6 months, 1 year, and 2 years were, 23%, 49%, and 49% in the NoSt group, compared to 33%, 55%, and 69% in the St group, respectively (P = 0.04 at 2 years). The percentage of accumulated biopsies with grade 3 or 4 fibrosis at 6 months, 1 year, and 2 years were 0%, 8%, and 22% in the NoSt group, compared to 8%, 19%, and 31% in the St group, respectively. Immunosuppression without steroids in HCV patients is safe, reduces bacterial infections and metabolic complications, and improves histological short-term evolution of HCV recurrence.
Contribuição do enfermeiro para possível redução de rejeição ao Transplante de Córnea Contribución del enfermero para posible reducción del rechazo al Transplante de Córnea Nursing contribution to reduce potential rejection of corneal transplants
Andréa Lima de Castro Souza
Full Text Available OBJETIVO: Verificar as contribuições do Enfermeiro para a possível redução dos índices de rejeição ao transplante de córnea em Sergipe. MÉTODOS: Estudo exploratório, retrospectivo e quantitativo em prontuários de doadores e receptores de córnea de 2003 a 2008 da Central de Notificação, Captação e Distribuição de Órgãos de Sergipe (CNCDO-SE. RESULTADOS: Foram analisados 350 captações, 309 transplantes, 185 doadores e 39 rejeições. Das córneas captadas pelo enfermeiro, 83,73% foram aproveitadas, 15,44% foram descartadas e 6,50% apresentaram rejeição. Das córneas captadas por outro profissional, 72,72% foram aproveitadas, 27,27% foram descartadas e 13,65% apresentaram rejeição. CONCLUSÃO: As córneas captadas pelo enfermeiro apresentaram menor índice de rejeição e maior aproveitamento. As variáveis ligadas ao receptor e ao doador não influenciaram nas rejeições.OBJETIVO: Verificar las contribuciones del Enfermero para la posible reducción de los índices de rechazo al transplante de córnea en Sergipe. MÉTODOS: Se trata de un estudio exploratorio, retrospectivo y cuantitativo con historias clínicas de donadores y receptores de córnea de 2003 a 2008 de la Central de Notificación, Captación y Distribución de Órganos de Sergipe (CNCDO-SE. RESULTADOS: Fueron analizadas 350 captaciones, 309 transplantes, 185 donadores y 39 rechazos. De las córneas captadas por el enfermero, 83,73% fueron aprovechadas, 15,44% fueron descartadas y 6,50% presentaron rechazo. De las córneas captadas por otro profesional, 72,72% fueron aprovechadas, 27,27% fueron descartadas y 13,65% presentaron rechazo. CONCLUSIÓN: Las córneas captadas por el enfermero presentaron menor índice de rechazo y mayor aprovechamiento. Las variables ligadas al receptor y al donador no influenciaron en los rechazos.OBJECTIVE: To assess the nursing contributions that reduce rejection rates of corneal transplants in Sergipe. METHODS: A retrospective
... Swelling of the cornea Signs and symptoms of cornea rejection In some cases, your body's immune system ... the risks of the procedure. Finding a donor cornea Most corneas used in cornea transplants come from ...
Borges, T. J.; O’Malley, J. T.; Wo, L.; Murakami, N.; Smith, B.; Azzi, J.; Tripathi, S.; Lane, J. D.; Bueno, E. M.; Clark, R. A.; Tullius, S. G.; Chandraker, A.; Lian, C. G.; Murphy, G. F.; Strom, T. B.
Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean followup of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectivel...
J. van de Wetering (Jacqueline)
textabstractGiving a patient immunosuppressive medication is creating an environment in which a transplanted organ will be accepted and rejection will be prevented. Unfortunately, the use of immunosuppression is complicated by serious side effects. After dealing with acute rejection in solid organ
Togsverd-Bo, K; Omland, S H; Wulf, H C
Organ transplant recipients (OTRs) are at high risk of developing cutaneous squamous cell carcinoma (SCC); prevention includes early treatment of premalignant actinic keratosis (AK). Photodynamic therapy (PDT) is a noninvasive field therapy that reduces new AKs in patients with existing AK...... and delays SCC development in mice. We investigated the effect of repeated PDT over 5 years for primary prophylaxis of skin dysplasia. These data represent an interim analysis of an on-going randomized controlled trial. During 2008-2011, 25 renal transplant recipients with clinically normal skin were...
Jiang, Wei; Sun, Hui-Min; Li, Xiao-Rong; Yuan, Xu-Bo; Wang, Yu-Qing; Zhang, Shu-Xian; Tian, En-Jiang; Yuan, Jia-Qin
To evaluate the combined effect of topical rapamycin (RAPA) eye drop in nanometer vector and poly (lactic acid) (PLA) wafers of cyclosporine A (CsA) in the prevention of acute allograft rejection after rabbit corneal transplantation. Methods It was an experimental study. RAPA was incorporated into the nanometer particles and CsA was incorporated into PLA wafers. A was syngeneic control whose both donor and recipient are New Zealand rabbit. Gray donor corneas were implanted into the 102 recipients of New Zealand albino rabbits with corneal neovascularization who were randomly divided into B, C, D, E, F, G 6 groups to receive the different types of therapy: B was no therapy control; C was eye drop of nanometer vector but no RAPA twice a day, 28 days; D was PLA wafers in the anterior chamber of rabbit eyes but no drugs; E was 0.5% RAPA eye drop of nanometer vector twice a day, 28 days; F was PLA wafers of CsA in the anterior chamber of rabbit eyes; G was PLA wafers of CsA in the anterior chamber of rabbit eyes and 0.5% RAPA eye drop of nanometer vector eye drop twice a day for 28 days together. Postoperative evaluation included slit-lamp biomicroscopy, histopathology and immunohistology, Cytokines related with neovascularization and immunosuppression in the corneal tissue by RT-PCR. The graft survival was assessed by One-Way ANOVA and q test. Corneal allograft survival time: A (100.00 +/- 0.00), B (8.44 +/- 1.24), C (8.89 +/- 2.57), D (8.56 +/- 2.30), E (43.11 +/- 5.58), F (43.67 +/- 9.54), G (72.00 +/- 15.34) d. Group G led to a statistically significant prolongation of transplant survival and was superior than group E and F which was a statistical prolongation compared with group B, C and D (qGE = 11.42, qGF = 11.24, qEB = 13.64, qEC = 13.38, qED = 13.46, qFB = 13.82, qFC = 13.56, qFD = 13.64; P < 0.01). Immunohistopathologically, the grafts were subjected to an immune response contained a dense infiltrate of neutrophils, CD4+ and CD8+ T lymphocytes in the group B
Gaetano Andrea De
Full Text Available Abstract Background Transplantation is often the only way to treat a number of diseases leading to organ failure. To overcome rejection towards the transplanted organ (graft, immunosuppression therapies are used, which have considerable side-effects and expose patients to opportunistic infections. The development of a model to complement the physician’s experience in specifying therapeutic regimens is therefore desirable. The present work proposes an Ordinary Differential Equations model accounting for immune cell proliferation in response to the sudden entry of graft antigens, through different activation mechanisms. The model considers the effect of a single immunosuppressive medication (e.g. cyclosporine, subject to first-order linear kinetics and acting by modifying, in a saturable concentration-dependent fashion, the proliferation coefficient. The latter has been determined experimentally. All other model parameter values have been set so as to reproduce reported state variable time-courses, and to maintain consistency with one another and with the experimentally derived proliferation coefficient. Results The proposed model substantially simplifies the chain of events potentially leading to organ rejection. It is however able to simulate quantitatively the time course of graft-related antigen and competent immunoreactive cell populations, showing the long-term alternative outcomes of rejection, tolerance or tolerance at a reduced functional tissue mass. In particular, the model shows that it may be difficult to attain tolerance at full tissue mass with acceptably low doses of a single immunosuppressant, in accord with clinical experience. Conclusions The introduced model is mathematically consistent with known physiology and can reproduce variations in immune status and allograft survival after transplantation. The model can be adapted to represent different therapeutic schemes and may offer useful indications for the optimization of
De Gaetano, Andrea; Matone, Alice; Agnes, Annamaria; Palumbo, Pasquale; Ria, Francesco; Magalini, Sabina
Transplantation is often the only way to treat a number of diseases leading to organ failure. To overcome rejection towards the transplanted organ (graft), immunosuppression therapies are used, which have considerable side-effects and expose patients to opportunistic infections. The development of a model to complement the physician's experience in specifying therapeutic regimens is therefore desirable. The present work proposes an Ordinary Differential Equations model accounting for immune cell proliferation in response to the sudden entry of graft antigens, through different activation mechanisms. The model considers the effect of a single immunosuppressive medication (e.g. cyclosporine), subject to first-order linear kinetics and acting by modifying, in a saturable concentration-dependent fashion, the proliferation coefficient. The latter has been determined experimentally. All other model parameter values have been set so as to reproduce reported state variable time-courses, and to maintain consistency with one another and with the experimentally derived proliferation coefficient. The proposed model substantially simplifies the chain of events potentially leading to organ rejection. It is however able to simulate quantitatively the time course of graft-related antigen and competent immunoreactive cell populations, showing the long-term alternative outcomes of rejection, tolerance or tolerance at a reduced functional tissue mass. In particular, the model shows that it may be difficult to attain tolerance at full tissue mass with acceptably low doses of a single immunosuppressant, in accord with clinical experience. The introduced model is mathematically consistent with known physiology and can reproduce variations in immune status and allograft survival after transplantation. The model can be adapted to represent different therapeutic schemes and may offer useful indications for the optimization of therapy protocols in the transplanted patient.
textabstractAfter the initial focus on the biology of graft rejection and its prevention, now the main concern of transplantation research is donor shortage. In 1979, the introduction of cyc1osporine A (esA) improved the outcome of clinical organ transplantation significantly. Technical developments
textabstractAfter the initial focus on the biology of graft rejection and its prevention, now the main concern of transplantation research is donor shortage. In 1979, the introduction of cyc1osporine A (esA) improved the outcome of clinical organ transplantation significantly. Technical
André Dong Won Lee
Full Text Available RACIONAL: O transplante de intestino delgado é procedimento cirúrgico em estudo visando sua aplicação no tratamento dos pacientes portadores da síndrome do intestino curto, com vistas à reabilitação oral. Porém a grande barreira se deve à "rejeição" pela grande quantidade de tecido linfóide presente no intestino delgado. OBJETIVO: Avaliar a atuação das citocinas, interleucina-6 e interferon-gama em alotransplante heterotópico intestinal. MATERIAL E MÉTODOS: Realizaram-se 24 alotransplantes intestinais em ratos da raça Brown-Norway (doador para Lewis (receptor, sendo subdivididos em três subgrupos de oito animais, sacrificados respectivamente no terceiro dia de pós-operatório (Tx(3, no quinto dia de pós-operatório (Tx(5 e no sétimo dia de pós-operatório (Tx(7 para coleta das biopsias dos enxertos intestinais. Enquanto que no grupo isotransplante (C envolveu oito animais da raça Lewis (doador para Lewis (receptor, porém neste grupo realizaram-se biopsias seriadas no mesmo animal, sendo subdivididos em três momentos: biopsia no terceiro dia de pós-operatório (C(3, no quinto dia de pós-operatório (C(5 e sacrificados no sétimo dia de pós-operatório (C(7 para coleta da biopsia. Realizou-se inicialmente análise intragrupo entre os momentos C(3, C(5 e C(7 para todos os parâmetros de rejeição citados anteriormente, como também para os três subgrupos Tx(3, Tx(5 e Tx(7. Posteriormente, realizou-se a análise intergrupo de forma transversal e pareada comparando-se o grupo isotransplante com o grupo alotransplante (C(3 com Tx(3; C(5 com Tx(5 e C(7 com Tx(7. RESULTADOS: No grupo isotransplante não houve diferença estatisticamente significante quanto à imunoexpressão das citocinas estudadas, todavia no grupo alotransplante observou-se que alterações da interleucina-6 e de interferon-gama ocorreram a partir do quinto dia de pós-operatório.BACKGROUND: Intestinal transplantation is a possible treatment for
André Dong Won Lee
Full Text Available RACIONAL: O transplante de intestino delgado é procedimento cirúrgico em estudo visando sua aplicação no tratamento dos pacientes portadores da síndrome do intestino curto, com vistas à reabilitação oral. A grande barreira, porém, se deve à rejeição pela grande quantidade de tecido linfóide presente no intestino delgado. OBJETIVO: Estudo da apoptose em alotransplante heterotópico intestinal. MATERIAL E MÉTODOS: Realizaram-se 24 alotransplantes intestinais em ratos da raça Brown-Norway (doador para Lewis (receptor, sendo subdivididos em três subgrupos de oito animais, sacrificados respectivamente no terceiro dia de pós-operatório (Tx(3, no quinto dia de pós-operatório (Tx(5 e no sétimo dia de pós-operatório (Tx(7 para coleta das biopsias dos enxertos intestinais. Compararam-se os resultados com o grupo isotransplante (C que envolveu oito animais da raça Lewis (doador para Lewis (receptor, porém neste grupo realizaram-se biopsias seriadas no mesmo animal, sendo subdivididos em três momentos: biopsia no terceiro dia de pós-operatório (C(3, no quinto dia de pós-operatório (C(5 e sacrificados no sétimo dia de pós-operatório (C(7 para coleta da biopsia. Realizou-se, inicialmente, análise intragrupo entre os momentos C(3, C(5 e C(7 para todos os parâmetros de rejeição citados anteriormente, como também para os três subgrupos Tx(3, Tx(5 e Tx(7. Posteriormente, realizou-se a análise intergrupo de forma transversal e pareada comparando-se o grupo isotransplante com o grupo alotransplante. (C(3 com Tx(3; C(5 com Tx(5 e C(7 com Tx(7. No grupo isotransplante não houve expressão estatística quanto aos marcadores analisados. Porém, no grupo alotransplante observou-se que alterações da apoptose foram marcantes a partir do terceiro dia de pós-operatório.BACKGROUND: Intestinal transplantation is a possible treatment for patients with short bowel syndrome, aiming the reintroduction of oral diet. However, the major
Interaction with one or more anatomical and physiopathological characteristics of the rejecting renal allograft is suggested by those radioagents utilized specifically for the diagnosis of allograft rejection. Rejection, the most common cause of declining allograft function, is frequently mimicked clinically or masked by other immediate or long term post transplant complications. Understanding of the anatomical pathological features and kinetics of rejection and their modification by immunosuppressive maintenance and therapy are important for the proper clinical utilization of these radioagents. Furthermore, in selecting these radionuclides, one has to consider the comparative availability, preparatory and procedural simplicity, acquisition and display techniques and the possibility of timely report. The clinical utilities of radiofibrinogen, /sup 99m/Tc sulfur colloid and 67 Ga in the diagnosis of allograft rejection have been evaluated to a variable extent in the past. The potential usefulness of the recently developed preparations of 111 In labeled autologous leukocytes and platelets are presently under investigation
Iwami, Daiki; Harada, Hiroshi; Morita, Ken; Oba, Koji; Fukuzawa, Nobuyuki; Hotta, Kiyohiko; Sasaki, Hajime; Miyazaki, Chihoko; Nonomura, Katsuya
The deep inferior epigastric artery (DIEA), which feeds the lower rectus abdominis muscle (lower RAM), is usually transected in kidney transplantation. In this study, we investigated whether preservation of DIEA can prevent lower RAM atrophy. Two hundred and forty-five kidney transplant recipients (150 men and 95 women) were enrolled in the study (mean age 39.9 years) and were divided into two groups according to whether DIEA was transected (group A, n = 175) or preserved (group B, n = 70). The extent of lower RAM atrophy calculated in computed tomography (performed 1 year after transplantation) and incidence of lower RAM atrophy were compared between the two groups. The most predictive factors for lower RAM atrophy were assessed using a multivariate logistic regression model. The extent of lower RAM atrophy was significantly lower in group B (15.0 ± 18.5%) than that in group A (38.9 ± 25.4%, P = 0.003). The incidence of lower RAM atrophy was less prevalent in group B (20.0%) compared with that in group A (62.9%, P DIEA was the only independent predictive factor for lower RAM atrophy (P DIEA during kidney transplant can prevent lower RAM atrophy.
Evan, Elana E; Patel, Payal A; Amegatcher, Alison; Halnon, Nancy
Traumatic experiences are not unusual in pediatric heart transplant (HT) recipients before and after transplantation. Post-traumatic stress symptoms (PTSS) present at the time of transplant evaluation and developing afterward occur with an unknown frequency. We sought to determine the burden of these symptoms in heart transplant patients. We reviewed 51 consecutive HTs between 2003-2007, including 40 primary transplants and 11 re-transplants. Symptoms were present in 17 of the 51 patients (34%) at the time of orthotopic heart transplantation evaluation. None met the criteria for full post traumatic stress disorder. Transplant complications were examined. Nineteen subjects of the total sample had rejection in the first year following transplant. Rejection rates in the first year was 41% for those with PTSS (7 of 17 patients) and 36% for those without (12 of 33 patients) (P=n.s). Of those patients presenting for a second heart transplant, 55% had PTSS at the time of transplant evaluation and/or the peritransplant period; whereas, (28%) undergoing a primary transplant had PTSS. In addition to symptoms resulting from the disease process leading to HT and other prior experiences, the HT itself seems to present a large psychiatric burden on patients. All patients need to be followed before and after HT for signs and symptoms related to PTSS. Future studies should be undertaken to determine if preventative detection and treatment of patients with these PTSS symptoms early can lead to better outcomes.
Castells, Lluís; Baliellas, Carme; Bilbao, Itxarone; Cantarell, Carme; Cruzado, Josep Maria; Esforzado, Núria; García-Valdecasas, Juan Carlos; Lladó, Laura; Rimola, Antoni; Serón, Daniel; Oppenheimer, Federico
Renal failure is a frequent complication in liver transplant recipients and is associated with increased morbidity and mortality. A variety of risk factors for the development of renal failure in the pre- and post-transplantation periods have been described, as well as at the time of surgery. To reduce the negative impact of renal failure in this population, an active approach is required for the identification of those patients with risk factors, the implementation of preventive strategies, and the early detection of progressive deterioration of renal function. Based on published evidence and on clinical experience, this document presents a series of recommendations on monitoring RF in LT recipients, as well as on the prevention and management of acute and chronic renal failure after LT and referral of these patients to the nephrologist. In addition, this document also provides an update of the various immunosuppressive regimens tested in this population for the prevention and control of post-transplantation deterioration of renal function. Copyright © 2013 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.
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Kim, Manbok, E-mail: email@example.com [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Cogle, Christopher R. [Department of Hematology/Oncology, University of Florida, Gainesville, FL 32610 (United States); McFadden, Grant [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)
Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.
Rejeição de transplantes de córnea: tratamento tópico vs. pulsoterapia - resultados de 10 anos Corneal allograft rejection: topical treatment vs. pulsed intravenous methylprednisolone - ten years' result
Dácio Carvalho Costa
Full Text Available OBJETIVOS: Avaliar a eficácia da associação de pulsoterapia com 500 mg de metilprednisolona intravenosa ao acetato de prednisolona 1% tópico no tratamento do primeiro episódio de rejeição endotelial de transplantes de córnea. MÉTODOS: Estudo caso-controle retrospectivo com 81 sujeitos que apresentaram o primeiro episódio de rejeição endotelial e submetidos à terapia nos primeiros quinze dias dos sintomas. RESULTADOS: 67 sujeitos foram tratados com acetato de prednisolona 1% tópico de 1 em 1 hora e pulsoterapia com 500 mg de metilprednisolona intravenosa no dia do diagnóstico e 14 sujeitos foram submetidos apenas ao tratamento com acetato de prednisolona 1% tópico formando o grupo controle. Dos 67 sujeitos submetidos a corticoterapia venosa e tópica, 41 (61,19% evoluíram satisfatoriamente e 26 (38,8% apresentaram falência endotelial. Dos 14 sujeitos submetidos apenas à corticoterapia tópica, 4 (28,57% evoluíram com enxerto transparente e os 10 restantes (71,43% com falência endotelial. O teste do qui-quadrado apontou maior taxa de sucesso (pPURPOSE: To evaluate the efficacy of intravenous 500 mg methylprednisolone in addition to topical treatment with 1% prednisolone in the treatment of the first episode of corneal endothelial rejection in patients that were submitted to corneal allograft transplantation. METHODS: Retrospective case-control study with 81 patients that presented the first episode of corneal endothelial rejection and were treated within the first 15 days of the onset of symptoms. RESULTS: 67 patients were treated with 1% topical prednisolone acetate and pulsed intravenous methylprednisolone 500 mg at the diagnosis of corneal allograft rejection. Fourteen patients were submitted to topical treatment only, thus forming the control group. Forty-one of 67 patients (61.2% that were submitted to pulsed steroid had good outcome and 26 (38.8% presented corneal graft failure while only 4 of 14 patients (28.57% that
Halperin, E.C.; Knechtle, S.J.; Harland, R.C.; Yamaguchi, Yasua; Sontag, M.; Bollinger, R.R.; Duke Univ., Durham, NC
Xenogeneic transplantation (XT) is the transplantation of organs or tissues from a member of one species to a member of another. Mammalian species frequently have circulating antibody which is directed against the foreign organ irrespective of known prior antigen exposure. This antibody may lead to hyperacute rejection once it ensues so efforts must be directed towards eliminating the pre-existing antibody. In those species in which hyperacute rejection of xenografts does not occur, cell-mediated refection, similar to allograft rejection, may occur. It is in the prevention of this latter form of refection that radiation is most likely to be beneficial in XT. Both total lymphoid irradiation (TLI) and selective lyphoid irradiation (LSI) have been investigated for use in conjunction with XT. TLI has contributed to the prolongation of pancreatic islet-cell xenografts from hamsters to rats. TLI has also markedly prolonged the survival of cardiac transplants from hamsters to rats. A more modest prolongation of graft survival has been seen with the use of TLI in rabbit-to-rat exchanges. Therapy with TLI, cyclosporine, and splenectomy has markedly prolonged the survival of liver transplants from hamsters to rats, and preliminary data suggest that TLI may contribute to the prolongation of graft survival in the transplantation of hearts from monkeys to baboons. SLI appears to have prolonged graft survival, when used in conjunction with anti-lymphocyte globulin, in hamster-to-rat cardiac graft exchanges. The current state of knowledge of the use of irradiaiton in experimental XT is reviewed. (author). 38 refs.; 1 fig.; 5 tabs
Ali H Dalloul
Full Text Available Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after one year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of tolerant vs effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic
Georgiou, H.M.; Bellgrau, D.
Bio-Breeding rat T lymphocytes proliferate poorly in response to alloantigen. Transplantation of Bio-Breeding rats with fetal thymus tissue from diabetes resistant rats leads to an improvement in the T cell proliferative response, but only if the thymus contains bone marrow-derived, radiation-resistant thymic antigen presenting cells of the diabetes-resistant phenotype. The current study provides evidence that thymus transplantation leading to the restoration of Bio-Breeding T cell proliferative function can also significantly reduce the incidence of insulitis and prevent the development of diabetes. It appears that a defect in the bone marrow-derived thymic APC population contributes to an abnormal maturation of Bio-Breeding T lymphocytes which in turn predisposes animals to insulitis and diabetic disease
van Kampen, C. A.; Versteeg-van der Voort Maarschalk, M. F.; Roelen, D. L.; ten Berge, I. J.; Claas, F. H.
BACKGROUND: Previous studies showed that graft rejection is often associated with the presence of primed cytotoxic T cells (CTLs) with a high avidity for donor cells. Similar high avidity CTLs have been found in individuals who have formed IgG anti-HLA antibodies. The presence of such CTLs to a
Coleman, Miranda; Jessup, Claire F.; Bridge, Jennifer A.
Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge in ...... responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells.......Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge...... in islet transplantation, and this will extend to application of personalized approaches using stem cell–derived replacement β-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β-cells. Here, we show that transfer of bone marrow encoding cognate...
Thomas H Waid
Full Text Available Thomas H Waid1, John S Thompson1, Maria Siemionow2, Stephen A Brown1 1Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA; 2Cleveland Clinic, Cleveland, Ohio, USAAbstract: T10B9.1A-31/MEDI-500 is a nonmitogenic immunoglobulin M kappa murine monoclonal antibody (mAb directed against the alpha-beta (αβ heterodimer of the T-lymphocyte receptor complex. The hybridoma was first produced by fusing spleen cells from BALB/C mice immunized with human peripheral blood T-lymphocytes with SP2/O-Ag14 mutant myeloma cells. The mAb is produced and purified using multistep ion exchange and molecular sieve chromatography protocols. T10B9 has been used successfully to treat acute cellular rejection in renal transplantation and as an immunosuppression induction agent in heart and simultaneous kidney-pancreas transplantation. Because T10B9 is nonmitogenic and causes minimal cytokine release, both treatment of rejection and induction of immunosuppression were accomplished with significantly fewer and milder untoward effects (cytokine release syndrome than its comparator OKT3. Since T10B9 is directed against the αβ heterodimer of the CD3 epitope, it spares the gamma delta (γδ region. These gamma delta (γδ T cells have a unique role in the immune response controlling many serious human diseases and perhaps facilitating the development of immunologic tolerance. T10B9 has a relatively short duration of action, depleting T cells for only 10 to 14 days, unlike the protracted depletion seen with thymoglobulin and Campath-1H. There is no B-lymphocyte depletion with T10B9 as there is with both of the aforementioned reagents. The lack of prolonged lymphocyte depletion may account for less infection observed with T10B9 treatment.Keywords: T10B9.1A-31, γδ T-cell, monoclonal antibody, Campath-1H, thymoglobulin, OKT3
Di Ianni, Mauro; Falzetti, Franca; Carotti, Alessandra; Terenzi, Adelmo; Castellino, Flora; Bonifacio, Elisabetta; Del Papa, Beatrice; Zei, Tiziana; Ostini, Roberta Iacucci; Cecchini, Debora; Aloisi, Teresa; Perruccio, Katia; Ruggeri, Loredana; Balucani, Chiara; Pierini, Antonio; Sportoletti, Paolo; Aristei, Cynthia; Falini, Brunangelo; Reisner, Yair; Velardi, Andrea; Aversa, Franco; Martelli, Massimo F
Hastening posttransplantation immune reconstitution is a key challenge in human leukocyte antigen (HLA)-haploidentical hematopoietic stem-cell transplantation (HSCT). In experimental models of mismatched HSCT, T-regulatory cells (Tregs) when co-infused with conventional T cells (Tcons) favored posttransplantation immune reconstitution and prevented lethal graft-versus-host disease (GVHD). In the present study, we evaluated the impact of early infusion of Tregs, followed by Tcons, on GVHD prevention and immunologic reconstitution in 28 patients with high-risk hematologic malignancies who underwent HLA-haploidentical HSCT. We show for the first time in humans that adoptive transfer of Tregs prevented GVHD in the absence of any posttransplantation immunosuppression, promoted lymphoid reconstitution, improved immunity to opportunistic pathogens, and did not weaken the graft-versus-leukemia effect. This study provides evidence that Tregs are a conserved mechanism in humans.
Lin, Chih-Che; Yong, Chee-Chien; Chen, Chao-Long
The shortage of organ donors mandates the use of liver allograft from anti-HBc(+) donors, especially in areas highly endemic for hepatitis B virus (HBV) infection. The incidence of de novo hepatitis B infection (DNH) is over 30%-70% among recipients of hepatitis B core antibody (HBcAb) (+) grafts without any prophylaxis after liver transplantation (LT). Systematic reviews showed that prophylactic therapy [lamivudine and/or hepatitits B immunoglobulin (HBIG)] dramatically reduces the probability of DNH. However, there are limited studies regarding the effects of active immunization to prevent DNH, and the role of active vaccination is not well-defined. This review focuses on the feasibility and efficacy of pre- and post-LT HBV vaccination to prevent DNH in HBsAg(-) recipient using HBcAb(+) grafts. The presence of HBsAb in combination with lamivudine or HBIG results in lower incidence of DNH and may reduce the requirement of HBIG. There was a trend towards decreasing incidence of DNH with higher titers of HBsAb. High titers of HBsAb (> 1000 IU/L) achieved after repeated vaccination could eliminate the necessity for additional antiviral prophylaxis in pediatric recipients. In summary, active vaccination with adequate HBsAb titer is a feasible, cost-effective strategy to prevent DNH in recipients of HBcAb(+) grafts. HBV vaccination is advised for candidates on waiting list and for recipients after withdrawal of steroids and onset of low dose immunosuppression after transplantation. PMID:26494965
Wissing, Karl Martin; Pipeleers, Lissa
The prevalence of the metabolic syndrome in dialysis patients is high and further increases after transplantation due to weight gain and the detrimental metabolic effects of immunosuppressive drugs. Corticosteroids cause insulin resistance, hyperlipidemia, abnormal glucose metabolism and arterial hypertension. The calcineurin inhibitor tacrolimus is diabetogenic by inhibiting insulin secretion, whereas cyclosporine causes hypertension and increases cholesterol levels. Mtor antagonists are responsible for hyperlipidemia and abnormal glucose metabolism by mechanisms that also implicate insulin resistance. The metabolic syndrome in transplant recipients has numerous detrimental effects such as increasing the risk of new onset diabetes, cardiovascular disease events and patient death. In addition, it has also been linked with accelerated loss of graft function, proteinuria and ultimately graft loss. Prevention and management of the metabolic syndrome are based on increasing physical activity, promotion of weight loss and control of cardiovascular risk factors. Bariatric surgery before or after renal transplantation in patients with body mass index >35 kg/m(2) is an option but its long term effects on graft and patient survival have not been investigated. Steroid withdrawal and replacement of tacrolimus with cyclosporine facilitate control of diabetes, whereas replacement of cyclosporine and mtor antagonists can improve hyperlipidemia. The new costimulation inhibitor belatacept has potent immunosuppressive properties without metabolic adverse effects and will be an important component of immunosuppressive regimens with better metabolic risk profile. Medical treatment of cardiovascular risk factors has to take potential drug interactions with immunosuppressive medication and drug accumulation due to renal insufficiency into account. Copyright © 2014 Elsevier Inc. All rights reserved.
Engberg, Henriette; Wehberg, Sonja; Bistrup, Claus
BACKGROUND: Kidney recipients receive immunosuppression to prevent graft rejection, and long-term outcomes such as post-transplant cancer and mortality may vary according to the different protocols of immunosuppression. METHODS: A national register-based historical cohort study was conducted......, the Danish National Cancer Registry and the Danish National Patient Register were used. A historical cohort of 1450 kidney recipients transplanted in 1995-2005 was followed up with respect to post-transplant cancer and death until 31 December 2011. RESULTS: Compared with Center 1 the adjusted post...... to examine whether post-transplant cancer and all-cause mortality differed between Danish renal transplantation centres using standard immunosuppressive protocols including steroids (Centres 2, 3, 4) or a steroid-free protocol (Centre 1). The Danish Nephrology Registry, the Danish Civil Registration System...
Full Text Available Rejection has always been one of the most important cause of late renal graft dysfunction. Aim of the study was to analyze the prevalence of different clinico-pathological variants of rejection that cause late graft dysfunction, and evaluate their impact on long-term outcome. Materials and methods. This is a retrospective study that analyzed 294 needle core biopsy specimens from 265 renal transplant recipients with late (48,8 ± 46,1 months after transplantation allograft dysfunction caused by late acute rejection (LAR, n = 193 or chronic rejection (CR, n = 78 or both (n = 23. C4d staining was performed by immunofl uorescence (IF on frozen sections using a standard protocol. Results. Peritubular capillary C4d deposition was identifi ed in 36% samples with acute rejection and in 62% cases of chronic rejection (including 67% cases of transplant glomerulopathy, and 50% – of isolated chronic vasculopathy. 5-year graft survival for LAR vs CR vs their combination was 47, 13 and 25%, respectively. The outcome of C4d– LAR was (p < 0,01 better than of C4d+ acute rejection: at 60 months graft survival for diffuse C4d+ vs C4d− was 33% vs 53%, respectively. In cases of chronic rejection C4d+ vs C4d– it was not statistically signifi cant (34% vs 36%. Conclusion. In long-term allograft biopsy C4d positivity is more haracteristic for chronic rejection than for acute rejection. Only diffuse C4d staining affects the outcome. C4d– positivity is associated with worse allograft survival in cases of late acute rejection, but not in cases of chronic rejection.
Wisgerhof, Hermina Christina
The risk of (skin) cancer is highly increased in organ-transplant recipients who are kept on immunesuppressive drugs to prevent graft rejection. This thesis dealt with the epidemiologic aspects and risk factors for cancer focused on cutaneous squamous cell carcinoma and basal cell carcinoma.
Full Text Available Karen L Hardinger, Daniel Sunderland, Jennifer A Wiederrich Division of Pharmacy Practice and Administration, School of Pharmacy, University of Missouri–Kansas City, Kansas City, MO, USA Background: Belatacept is a novel immunosuppressive therapy designed to improve clinical outcomes associated with kidney transplant recipients while minimizing use of calcineurin inhibitors (CNIs. Methods: We searched for clinical trials related to administration of belatacept to kidney transplant patients compared to various immunosuppression regimens, as well as for studies that utilized data from belatacept trials to validate new surrogate measures. The purpose of this review is to consolidate the published evidence of belatacept’s effectiveness and safety in renal transplant recipients to better elucidate its place in clinical practice. Results: Analysis of the results from the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppressive Trial (BENEFIT study, a de novo trial that compared cyclosporine (CsA-based therapy to belatacept-based therapy in standard criteria donors, found a significant difference in mean estimated glomerular filtration rate (eGFR of 13–15 mL/min/1.73 m2 and 23–27 mL/min/1.73 m2 at 1 year and 7 years, respectively. The BENEFIT-EXT study was similarly designed with the exception that it included extended criteria donors. Renal function improved significantly for the more intensive belatacept group in all years of the BENEFIT-EXT study; however, it was not significant in the less intensive group until 5 years after transplant. Belatacept regimens resulted in lower blood pressure, cholesterol levels, and incidence of new-onset diabetes after transplant compared to CsA-based regimens. Results from conversion of CNIs to belatacept therapy, dual therapy of belatacept with sirolimus, and belatacept with corticosteroid avoidance therapy are also included in this article. Conclusion: The evidence reviewed in
Full Text Available Viruses are among the most common causes of opportunistic infection after transplantation. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses have also affected outcomes. In some cases, preventive measures such as pretransplant screening, prophylactic antiviral therapy, or posttransplant viral monitoring may limit the impact of these infections. Recent advances in laboratory monitoring and antiviral therapy have improved outcomes. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections. This paper will summarize the major viral infections seen following transplant and discuss strategies for prevention and management of these potential pathogens.
Gouw, ASH; van den Heuvel, MC; van den Berg, AP; Slooff, NJH; de Jong, KP; Poppema, S
Background. Chronic rejection (CR) in liver allografts shows a rapid onset and progressive course, leading to graft failure within the first year after transplantation. Most cases are preceded by episodes of acute cellular rejection (AR), but histological features predictive for the transition
Nedbálková, Marta; Svojanovský, Jan; Trnavský, Karel; Kuman, Milan; Jarkovský, Jiří; Karpíšek, Michal; Souček, Miroslav
Metabolic syndrome is a risk factor for cardiovascular diseases. Higher risk of the metabolic syndrome and its components in patients after kidney transplantation is caused by immunosuppressive therapy. THE AIM OF OUR STUDY was to evaluate the prevalence of the metabolic syndrome and its components in kidney transplant recipients and to analyse their influence on allograft function and albuminuria. In the study we monitored 69 patients after cadaveric kidney transplantation. The prevalence of the meta-bolic syndrome was 61.3 % 3 years after kidney transplantation. The prevalence of new onset diabetes mellitus after transplantation was 27 % and that of abdominal obesity 59.7 % of patients. The age of kidney transplant recipients with the metabolic syndrome was higher than of these without it, but not statistically significant. The age of kidney transplant recipients with new onset diabetes mellitus after transplantation was significantly higher, 54.0 (35.0; 69.0) years, than in patients without it, 45.5 (27.0; 60.0) years, OR (95% IS) 1.116 (1.031; 1.207), p = 0.006.The number of components of the metabolic syndrome was negatively correlated with the graft function (rs -0,275, p = 0,031). In patients with impaired renal function with estimated glomerular filtration (using MDRD equation) metabolic syndrome and hypertriglyceridaemia was significantly higher. Chronic allograft dysfunction was predicted by donor age, delayed allograft function, rejection, low level of HDL-cholesterol, hypertriglyceridaemia and hyperuricaemia. Hyperuricaemia was the only significant predictor of allograft dysfunction independently of the presence of delayed allograft function, rejection episodes and donor age. The metabolic syndrome, elevation of apolipoprotein B and nonHDL-cholesterol and increased systolic blood pressure were associated with albuminuria. Higher levels of apolipoprotein B and total cholesterol were independent predictors of increased albumin-creatinine ratio. Obesity
Dimensão fractal na quantificação do grau de rejeição celular miocárdica pós-transplante cardíaco Fractal dimension in quantifying the degree of myocardial cellular rejection after cardiac transplantation
Roberto Douglas Moreira
Full Text Available INTRODUÇÃO: O termo "fractal" é derivado do latim fractus, que significa "irregular" ou "quebrado", considerando a estrutura observada como tendo uma dimensão não-inteira. Há muitos estudos que empregaram a Dimensão Fractal (DF como uma ferramenta de diagnóstico. Um dos métodos mais comuns para o seu estudo é a "Box-plot counting" (Método de contagem de caixas. OBJETIVO: O objetivo do estudo foi tentar estabelecer a contribuição da DF na quantificação da rejeição celular miocárdica após o transplante cardíaco. MÉTODOS: Imagens microscópicas digitalizadas foram capturadas na resolução 800x600 (aumento de 100x. A DF foi calculada com auxílio do "software ImageJ", com adaptações. A classificação dos graus de rejeição foi de acordo com a "Sociedade Internacional de Transplante Cardíaco e Pulmonar" (ISHLT 2004. O relatório final do grau de rejeição foi confirmado e redefinido após exaustiva revisão das lâminas por um patologista experiente externo. No total, 658 lâminas foram avaliadas, com a seguinte distribuição entre os graus de rejeição (R: 335 (0R, 214 (1R, 70 (2R, 39 (3R. Os dados foram analisados estatisticamente com os testes Kruskal-Wallis e curvas ROC sendo considerados significantes valores de P INTRODUCTION: The term "Fractal" is derived from the Latin fractus meaning "irregular" or "broken" considering the observed structure with a non-integer dimension. There are many studies which employed the Fractal Dimension (FD as a diagnostic tool. One of the most common methods for its study is the "Box Counting Method". OBJECTIVE: The aim of the present study was to try to establish the contribution of FD in the quantification of myocardial cellular rejection after cardiac transplantation. METHODS: Microscopic digital images were captured at 800x600 resolution (magnification 100x. FD was calculated with the aid of "ImageJ software" with adaptations. The classification of the degrees of rejection was in
Alfonzo, Jorge P
This article describes the background, beginnings, development, evolution and outcomes of kidney transplantation in Cuba. Nephrology as a medical specialty in Cuba began in 1962 and was formalized in 1966. Conditions were created to implement renal replacement therapy (including transplants), bring nephrology care to the entire country and train human resources who would assume this responsibility, making Cuba one of the first countries with a comprehensive program for renal patient care. After three unsuccessful cadaveric-donor kidney transplantations in 1968-69, the ensuing history of kidney transplantation can be summarized in the following three stages. 1970-1975: In January 1970, cadaveric-donor kidney transplantation began at the Nephrology Institute. That year, 17 kidney transplantations were performed; four of these patients lived with functional kidneys for 15-25 years; 10-year graft survival was 23.5% (Kaplan-Meier survival curve); HLA typing began in 1974. By December 1975, 170 grafts had been done in three hospitals. 1976-1985: Seven transplantation centers performed 893 grafts during this period. HLA-DR typing was introduced in 1976 and the National Histocompatibility Laboratory Network was founded in 1978. The first related living-donor kidney transplantation was done in 1979. 1986-2011: The National Kidney Transplantation Coordinating Center and the National Kidney Transplantation Program were created in 1986; the first combined kidney-pancreas transplantation was performed the same year. In 1990, cyclosporine and the Cuban monoclonal antibody IOR-T3 were introduced for immunosuppression to prevent rejection, as were other Cuban products (hepatitis B vaccine and recombinant human erythropoietin) for transplant patients. By December 2011, the cumulative number of transplants was 4636 (384 from related living donors). With over 40 years of experience, kidney transplantation is now well established in Cuba; it is free and universally accessible, on the
Iversen, Martin; Nilsson, Folke; Sipponen, Jorma
. Abbreviated AUC (AUC(0-4)) was measured at 7 days and 3 months. Primary outcome was C2 relation to the frequency of acute cellular rejection (ACR) needing treatment and possible decline in measured glomerular filtration rate (mGFR). Recipients were divided into lower, middle and upper third C2 groups based...... monitoring, but should be further explored in thoracic organ recipients. METHODS: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by C0 and blood was collected for analysis of C2 retrospectively...... on 2-week post-operative values (tertiles T1 to T3). RESULTS: C2 was the most robust substitute for AUC(0-4) in the group of patients studied. For lung, but not heart, recipients there were differences in mean number of ACRs (p = 0.05), incidence of any rejections (p = 0.04), mean number of any...
Full Text Available Abstract: Infections with Hepatitis viruses B and C pose major problems both short and long term respectively after HSCT. The key to prevention for Hepatitis B disease remains vaccination for HBV-naïve patients and judicial use of anti-viral therapy in both pre- and post-transplant settings for HBV-infected patients. HBsAg positive grafts to HBV-naïve recipients result in transmission of the virus in about 50%. The newer anti-viral agents have enabled effective treatment of post-transplant patients who might be lamivudine-resistant or might develop so. Selecting a previously infected donor who has high titres of surface antibody for HBsAg positive patients gives the best chance for immunological clearance. The most challenging aspect of preventing HBV reactivation remains the duration of anti-viral therapy and timing of its withdrawal as most reactivations and often fatal ones occur after this period. Hepatitis C, on the other hand affects long-term survival with early onset of fibrosis and cirrhosis. Early effect of Hepatitis C virus on the immune system remains conjectural. The standard combination therapy seems to be effective, but data on this front remains sparse, as in the case of the use of newer antiviral agents. HSCT from HCV infected grafts result in more consistent transmission of the virus and pre-donation treatment of donors should be undertaken to render them non-viremic, if possible. The current understanding and recommendations regarding prevention and management of these infections in HSCT recipients are discussed.
Song, Tu-Run; Rao, Zheng-Sheng; Qiu, Yang; Liu, Jin-Peng; Huang, Zhong-Li; Wang, Xian-Ding; Lin, Tao
Previous studies regarding the prevention of BK viremia following renal transplantation with fluoroquinolone have yielded conflicting results. The purpose of this systematic review was to examine the evidence regarding the efficacy of fluoroquinolone in preventing BK polyomavirus infection following renal transplantation. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for research articles published prior to January 2015 using keywords such as "fluoroquinolone," "BK viremia," and "renal transplantation." We extracted all types of study published in English. The primary outcome was BK viremia and viruria at 1 year post-transplantation. Secondary outcomes were BK virus-associated nephropathy (BKVN), graft failure, and fluoroquinolone-resistant infection. We identified eight trials, including a total of 1477 participants with a mean duration of fluoroquinolone prophylaxis of >1 month. At 1 year, fluoroquinolone prophylaxis was not associated with a decreased incidence of BK viremia [risk ratio (RR), 0.84; 95% confidence interval (95% CI), 0.58-1.20). No significant differences in BKVN (RR, 0.88; 95% CI, 0.37-2.11), risk of graft failure due to BKVN (RR, 0.68; 95% CI, 0.29-1.59), or fluoroquinolone-resistant infection (RR, 1.08; 95% CI, 0.64-1.83) were observed between the fluoroquinolone prophylaxis and control groups. The results of this study suggest that fluoroquinolone is ineffective in preventing BK polyomavirus infection following renal transplantation. Copyright © 2016. Published by Elsevier Taiwan.
Radhakrishnan, Kavita; Chi, Aileen; Quan, David J; Roberts, John P; Terrault, Norah A
Hepatitis B immune globulin (HBIG) has been an integral component of prophylaxis against hepatitis B virus (HBV) recurrence in liver transplantation (LT) recipients, but HBIG is costly and inconvenient to administer, prompting consideration of alternative regimens. In this retrospective cohort, we report on the success of antiviral therapy combined with a short course (in hospital only) HBIG in liver transplant recipients with HBV DNA less than 100 IU/mL pre-LT. A total of 42 hepatitis B surface antigen (HBsAg) positive, human immunodeficiency virus and hepatitis D virus-negative patients with pretransplant HBV DNA undetectable to 100 IU/mL who received HBIG 5000 IU in anhepatic phase and daily for 5 days together with nucleos(t)ide analogues indefinitely yielded 1- and 3-year cumulative incidences of recurrence, defined by positive serum HBsAg, of 2.9% (upper 95% confidence interval, 19%). One patient had HBV viremia 16 months post-LT without detectable HBsAg. Both patients with either HBsAg positivity or viremia had recurrent hepatocellular carcinoma diagnosed within a month of detection. Post-LT survival was 98% and 94% at 1 and 5 years, respectively. We conclude that a very short course of HBIG combined with long-term antiviral therapy is highly effective in preventing HBV recurrence and should be the preferred strategy for LT recipients with undetectable or low-level viremia at time of LT.
van Geel, Björn M; Poll-The, Bwee Tien; Verrips, Aad; Boelens, Jaap-Jan; Kemp, Stephan; Engelen, Marc
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder. Male patients develop adrenocortical insufficiency (80 % before 18 years), a chronic myelopathy (adrenomyeloneuropathy (AMN); all in adulthood), or progressive cerebral demyelination (cerebral ALD; 40 % before 18 years). Cerebral ALD is treated with haematopoetic cell transplantation (HCT). It is unknown if AMN still develops in patients with X-ALD that underwent HCT for cerebral ALD in childhood. A retrospective observational study was performed by selecting all adult patients with X-ALD in our cohort that underwent HCT in childhood. This retrospective study found that three out of five patients in our cohort who underwent HCT in childhood developed signs of myelopathy in adulthood. These data suggest that HCT for cerebral ALD in childhood does not prevent the onset of AMN in X-ALD in adulthood.
Full Text Available We present a case report of a 59-year-old man, who received a blood group identical living unrelated kidney graft. This was his second kidney transplantation. Pretransplant T-cell crossmatch resulted negative. B-cell crossmatch, which is not considered a strict contraindication for transplantation, resulted positive. During surgery no abnormalities occurred. Four hours after the transplantation diuresis suddenly decreased. In an immediately performed relaparotomy the transplanted kidney showed signs of hyperacute rejection and had to be removed. Pathological examination was consistent with hyperacute rejection. Depositions of IgM or IgG antibodies were not present in pathologic evaluation of the rejected kidney, suggesting that no irregular endothelial specific antibodies had been involved in the rejection. We recommend examining more closely recipients of second allografts, considering not only a positive T-cell crossmatch but also a positive B-cell crossmatch as exclusion criteria for transplantation.
Raber-Durlacher, J. E.; Abraham-Inpijn, L.; van Leeuwen, E. F.; Lustig, K. H.; van Winkelhoff, A. J.
Oral complications cause morbidity and mortality in patients, undergoing allogeneic or autologous bone-marrow transplantation. The clinical features and the pathogenesis of the oral sequelae of bone marrow ablative therapy and graft-versus-host disease are discussed. In addition, a preventive oral
Marcos V. Silva
Full Text Available Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients.
Storb, R.; Santos, G.W.
Bone marrow transplantation has been increasingly used to treat patients with severe combined immunodeficiency diseases, severe aplastic anemia, and malignant hematologic diseases, especially leukemia. At the Workshop a number of problems were discussed, e.g., conditioning regimens aimed at overcoming the problem of marrow graft rejection and reducing the incidence of recurrent leukemia, prevention of graft-versus-host disease (GVHD), possible mechanisms involved in stable graft-host tolerance, graft-versus-leukemia effect in mice, and finally, the possible use of autologous marrow transplantation.
Full Text Available Scedosporium spp. are saprobic fungi that cause serious infections in immunocompromised hosts and in near-drowning victims. Solid organ transplant recipients are at increased risk of scedosporiosis as they require aggressive immunosuppression to prevent allograft rejection. We present a case of disseminated Scedosporium apiospermum infection occurring in the recipient of a combined kidney and liver transplantation whose organs were donated by a near-drowning victim and review the literature of scedosporiosis in solid organ transplantation.
Shin, B C; Chung, J H; Kim, H L
Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy. One side effect of MMF is bone marrow toxicity, including leukopenia, which may necessitate drug withdrawal. We report 2 patients who underwent kidney transplantation and developed leukopenia while receiving MMF and safely switched to sirolimus. A 35-year-old woman underwent deceased donor kidney transplantation. She received basiliximab, tacrolimus, MMF, and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/μL. A 44-year-old women underwent deceased donor kidney transplantation and received basiliximab, tacrolimus, MMF, valganciclovir, and a corticosteroid. On POD 88, her WBC count was 1320/μL. MMF was switched to sirolimus, resulting in recovery of WBC count without rejection. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient. Copyright © 2013. Published by Elsevier Inc.
Wang, J; Yao, M; Xu, J-h; Shu, B; Wang, Y-j; Cui, X-j
We conducted a systematic review of randomized controlled trials (RCTs) of bisphosphonates for the prevention of osteopenia in kidney-transplant recipients. Bisphosphonates improved bone mineral density at the lumbar spine and femoral neck after 12 months. However, additional well-designed RCTs are required to determine the optimal treatment strategy. Osteopenic-osteoporotic syndrome is a bone complication of renal transplantation. Bisphosphonates, calcitonin, and vitamin D analogs may be used to prevent or treat osteoporosis or bone loss after renal transplantation. However, there is currently no widely recognized strategy for the prevention of corticosteroid-induced osteoporosis. This study aims to assess the available evidence to guide the targeted use of bisphosphonates for reducing osteoporosis and bone loss in renal-transplant recipients. We searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE for randomized controlled trials of bisphosphonates for osteoporosis or bone loss after renal transplantation. A total of 352 abstracts were identified, of which 55 were considered for evaluation and 9 were included in the final analysis. The primary outcome measure was change in the bone mineral density (BMD) of the lumbar spine and femoral neck after 12 months. Data extraction was performed independently by two investigators. BMD at the lumbar spine was improved after treatment with bisphosphonates [9 trials; 418 patients; weighted mean difference (WMD), 0.61; 95 % confidence interval (CI), 0.16-1.06]. Eight trials (406 patients) that reported changes in BMD at the femoral neck also showed improved outcomes after treatment with bisphosphonates (WMD, 0.06; 95 % CI, 0.03-0.09). Bisphosphonates improve BMD at the lumbar spine and femoral neck after 12 months in renal-transplant recipients.
Nagarkatti, Mitzi; Rieder, Sadiye Amcaoglu; Hegde, Venkatesh; Kanada, Shunsuke; Nagarkatti, Prakash
Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties. While significant clinical and experimental data on the use of cannabinoids as anti-inflammatory agents exist in many autoimmune disease settings, virtually no studies have been performed on their potential role in transplant rejection. Here we suggest a theoretical role for the use of cannabinoids in preventing allograft rejection. While the psychotropic properties of CB1 agonists limit their clinical use, CB2 agonists may offer a new avenue to selectively target immune cells involved in allograft rejection. Moreover, development of mixed CB1/CB2 agonists that cannot cross the blood-brain barrier may help prevent their undesired psychotropic properties. In addition, manipulation of endocannabinoids in vivo by activating their biosynthesis and inhibiting cellular uptake and metabolism may offer yet another pathway to regulate immune response during allograft rejection. PMID:20591510
Full Text Available
Abstract: Infections with Hepatitis viruses B and C pose major problems both short and long term respectively after HSCT. The key to prevention for Hepatitis B disease remains vaccination for HBV-naïve patients and judicial use of anti-viral therapy in both pre- and post-transplant settings for HBV-infected patients. HBsAg positive grafts to HBV-naïve recipients result in transmission of the virus in about 50%. The newer anti-viral agents have enabled effective treatment of post-transplant patients who might be lamivudine-resistant or might develop so. Selecting a previously infected donor who has high titres of surface antibody for HBsAg positive patients gives the best chance for immunological clearance. The most challenging aspect of preventing HBV reactivation remains the duration of anti-viral therapy and timing of its withdrawal as most reactivations and often fatal ones occur after this period. Hepatitis C, on the other hand affects long-term survival with early onset of fibrosis and cirrhosis. Early effect of Hepatitis C virus on the immune system remains conjectural. The standard combination therapy seems to be effective, but data on this front remains sparse, as in the case of the use of newer antiviral agents. HSCT from HCV infected grafts result in more consistent transmission of the virus and pre-donation treatment of donors should be undertaken to render them non-viremic, if possible. The current understanding and recommendations regarding prevention and management of these infections in HSCT recipients are discussed.
Daly, Kevin P; Chakravarti, Sujata B; Tresler, Margaret; Naftel, David C; Blume, Elizabeth D; Dipchand, Anne I; Almond, Christopher S
Sudden death is a well-recognized complication of heart transplantation. Little is known about the incidence and risk factors for sudden death after transplant in children. The purpose of this study was to determine the incidence of and risk factors for sudden death. This retrospective multicenter cohort study used the Pediatric Heart Transplant Study Group (PHTS) database, an event-driven registry of children aged heart transplantation between 1993 and 2007. Standard Kaplan-Meier and parametric analyses were used for survival analysis. Multivariate analysis in the hazard-function domain was used to identify risk factors for sudden death after transplant. Of 604 deaths in 2,491 children who underwent heart transplantation, 94 (16%) were classified as sudden. Freedom from sudden death was 97% at 5 years, and the hazard for sudden death remained constant over time at 0.01 deaths/year. Multivariate risk factors associated with sudden death included black race (hazard ratio [HR], 2.6; p transplant (HR, 1.8; p = 0.008), older age (HR, 1.4/10 years of age; p = 0.03), and an increased number of rejection episodes in the first post-transplant year (HR, 1.6/episode; p = 0.03). Sudden death accounts for 1 in 6 deaths after heart transplant in children. Older recipient age, recurrent rejection within the first year, black race, and UNOS status 2 at listing were associated with sudden death. Patients with 1 or more of these risk factors may benefit from primary prevention efforts. Copyright Â© 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society.
Alfred, Arun; Taylor, Peter C; Dignan, Fiona; El-Ghariani, Khaled; Griffin, James; Gennery, Andrew R; Bonney, Denise; Das-Gupta, Emma; Lawson, Sarah; Malladi, Ram K; Douglas, Kenneth W; Maher, Tracey; Guest, Julie; Hartlett, Laura; Fisher, Andrew J; Child, Fiona; Scarisbrick, Julia J
Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP. The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS ® machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults. © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.
Joseph Y Kim
Full Text Available Immune prophylaxis and treatment of transplanted tissue rejection act indiscriminately, risking serious infections and malignancies. Although animal data suggest that cellular immune responses causing rejection may be rather narrow and predictable based on genetic background, there are only limited data regarding the clonal breadth of anti-donor responses in humans after allogeneic organ transplantation. We evaluated the graft-infiltrating CD8+ T lymphocytes in skin punch biopsies of a transplanted hand over 178 days. Profiling of T cell receptor (TCR variable gene usage and size distribution of the infiltrating cells revealed marked skewing of the TCR repertoire indicating oligoclonality, but relatively normal distributions in the blood. Although sampling limitation prevented complete assessment of the TCR repertoire, sequencing further identified 11 TCR clonal expansions that persisted through varying degrees of clinical rejection and immunosuppressive therapy. These 11 clones were limited to three TCR beta chain variable (BV gene families. Overall, these data indicate significant oligoclonality and likely restricted BV gene usage of alloreactive CD8+ T lymphocytes, and suggest that changes in rejection status are more due to varying regulation of their activity or number rather than shifts in the clonal populations in the transplanted organ. Given that controlled animal models produce predictable BV usage in T lymphocytes mediating rejection, understanding the determinants of TCR gene usage associated with rejection in humans may have application in specifically targeted immunotherapy.
Terasaki, Paul I
The humoral theory states that antibodies cause the rejection of allografts. From 1917 to 1929, extensive efforts were made to produce antibodies against tumors. It was finally realized that the antibodies were produced against the transplant antigens present on transplantable tumors, not against the tumor-specific antigens. To get around this problem, inbred mouse strains were developed, leading to identification of the transplant antigens determined by the H-2 locus of mice. The antibodies were hemagglutinating and cytotoxic antibodies. The analogous human leukocyte antigen system was established by analysis of lymphocytotoxic alloantibodies that were made by pregnant women, directed against mismatched antigens of the fetus. The human leukocyte antigen antibodies were then found to cause hyperacute rejection, acute rejection, and chronic rejection of kidneys. Antibodies appeared in almost all patients after rejection of kidneys. With Luminex single antigen bead technology, donor-specific antibodies could be identified before rise in serum creatinine and graft failure. Antibodies were shown to be predictive of subsequent graft failure in kidney, heart, and lung transplants: patients without antibodies had superior 4-year graft survival compared with those who did have antibodies. New evidence that antibodies are also associated with chronic failure has appeared for liver and islet transplants. Four studies have now shown that removal or reduction of antibodies result in higher graft survival. If removal of antibodies prevents chronic graft failure, final validation of the humoral theory can be achieved.
Demir, Z; Frange, P; Lacaille, F
Vaccination is an effective strategy to decrease infections in transplant recipients. Children after intestinal transplantation carry a high risk of infection due to increased immunosuppression. In a series of 22 children after intestinal transplantation, we studied the vaccination schedules and the antibodies against vaccine-preventable diseases before transplantation, and at one and five yr after transplantation. We reviewed whether the vaccination schedules were complete, and we analysed the factors that may influence serological immunity and the incidence of disease in patients with deficient immunity. All patients completed the recommended vaccination schedules for DTaP-IPV and HBV. After transplantation, the negative antibodies against vaccine-preventable diseases were mostly related to an antirejection therapy: for DTaP-IPV: four of four patients with no antibody had been treated for rejection, for HBV: two of five, HAV: three of four, MMR: three of seven, and VZV: three of four. A post-transplantation varicella infection was followed by acute rejection, with probability for a relationship between both events. We observed 50% of varicella cases in unvaccinated children, highlighting the importance of pretransplant vaccination. Waning immunogenicity mediated by antibodies against vaccine-preventable disease after transplantation indicated a need for boosters. The recommendations should be regularly enforced, as the reliance on routine immunizations schedules is not adequate in immunocompromised patients. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Graaf, Ymke Grete Leontien de
Skin carcinomas develop at a high rate in organ-transplant recipients who are kept on immune suppressive drugs to prevent graft rejection. The present study dealt with a broad range of aspects of this elevated carcinoma risk, starting from the earliest oncogenic events to the ultimate therapy.
... in Edmonton, Canada, reported their findings in the New England Journal of Medicine . Their transplant protocol, known as the Edmonton protocol, has since been adapted by transplant centers around the world and continues ... new combination of immunosuppressive medications, also called anti-rejection ...
Chong, Pearlie P; Avery, Robin K
Vaccine-preventable diseases, especially influenza, varicella, herpes zoster, and invasive pneumococcal infections, continue to lead to significant morbidity and mortality in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. We highlight guideline recommendations for the use of key vaccines in SOT and HSCT recipients and to review the latest evidence and developments in the field. Physicians should vaccinate individuals with end-stage organ disease, as vaccine seroresponse rates are higher pretransplantation. Most live attenuated vaccines continue to be contraindicated post-transplantation, but there are emerging safety profile and efficacy data to support the use of specific live attenuated vaccines, such as measles, mumps, and rubella in pediatric liver or kidney transplant recipients who are on low-level maintenance immunosuppression and without recent history of allograft rejection. An inactivated subunit varicella zoster virus vaccine is currently awaiting US Food and Drug Administration approval. While we await the safety profile and efficacy data of this subunit vaccine in transplant recipients, it will likely benefit immunocompromised individuals, including transplant recipients, because the live attenuated herpes zoster vaccine is currently contraindicated in transplant recipients and transplantation candidates receiving immunosuppression. There is currently no evidence that vaccines lead to allograft rejection in SOT recipients. Household contacts of SOT and HSCT recipients should be vaccinated per the Advisory Committee on Immunization Practices schedule and recommendations. Immunizations remain underutilized in transplantation patients. Although efficacy of vaccines in SOT and HSCT may be suboptimal, partial protection is preferred over no protection. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.
Full Text Available Introduction and Aims. Post-transplant tuberculosis (TB is a problem in successful long-term outcome of renal transplantation recipients. Our objective was to describe the pattern and risk factors of TB infection and the prognosis in our transplant recipients. Patients and Methods. This study was a retrospective review of the records of 491 renal transplant recipients in our hospital during the period from January 1986 to December 2009. The demographic data, transplant characteristics, clinical manifestations, diagnostic criteria, treatment protocol, and long-term outcome of this cohort of patients were analyzed. Results. 16 patients (3,2% developed post-transplant TB with a mean age of 32,5 ± 12,7 (range: 13–60 years and a mean post-transplant period of 36,6months (range: 12,3 months–15,9 years. The forms of the diseases were pulmonary in 10/16 (62,6%, disseminated in 3/16 (18,7%, and extrapulmonary in 3/16 (18,7%. Graft dysfunction was observed in 7 cases (43,7% with tissue-proof acute rejection in 3 cases and loss of the graft in 4 cases. Hepatotoxicity developed in 3 patients (18,7% during treatment. Recurrences were observed in 4 cases after early stop of treatment. Two patients (12.5% died. Conclusion. Extra pulmonary and disseminated tuberculosis were observed in third of our patients. More than 9months of treatment may be necessary to prevent recurrence.
Ecocardiografia por Doppler tecidual no diagnóstico de rejeição após transplante cardíaco Ecocardiografía con Doppler tisular en el diagnóstico de rechazo después de transplante cardíaco Tissue doppler echocardiography in the diagnosis of heart transplantation rejection
Marcos Valério Coimbra Resende
,3%, especificidad de 73,8% (p = 0,001. En el análisis multivariado, la a'LAT (p = 0,001, a'SEP (p = 0,002, relación e'/a' LAT (p = 0,006, relación e'Mitral/e'LAT (p = 0,014, SINF (p = 0,009 fueron predictores de RC > 3A. Obtuvimos un escore con sensibilidad de 88,2%, precisión de 79,6%, y valor predictivo negativo de 92.9% para diagnosticar RC > 3A . El Doppler convencional (flujo mitral y pulmonar venoso no fue relevante para predecir la RC > 3A. CONCLUSIÓN: El estudio de IDT agregó información diagnóstica para predecir RC > 3A cuando fue comparado al Doppler convencional. El modelo basado en IDT puede volverse un método en potencial para detectar RC > 3A después de TC.BACKGROUND: Endomyocardial biopsy (EMB is the gold standard method for the diagnosis of cellular rejection (CR after heart transplantation (HT. OBJECTIVE: To test the hypothesis that tissue Doppler imaging (TDI could detect CR > 3A and add diagnostic information compared to conventional Doppler. METHODS: Fifty-four HT patients underwent 129 EMB and a TDI echocardiographic study within 24 hours. We compared HT patients with CR > 3A versus HT patients with CR 3A in 39/129 (30.2% EMB. The best isolated predictor for CR diagnosis was a'LAT, with a sensitivity of 76.3%, specificity of 73.8% (p = 0.001. In the multivariate analysis, a'LAT (p = 0.001, a'SEP (p = 0.002, e'/a' LAT ratio (p = 0.006, e'Mitral/ e'LAT ratio (p = 0.014, SINF (p = 0.009 predicted CR > 3A. We obtained a score with a sensitivity of 88.2%, accuracy of 79.6% and negative predictive value of 92.9% to diagnose CR > 3A. Conventional Doppler (mitral and pulmonary venous flow was not relevant to predict CR > 3A. CONCLUSION: TDI added diagnostic information to predict CR > 3A compared to conventional Doppler. A TDI-based model could become a potential method to detect CR > 3A after Heart Transplantation.
Ladrière, M; Bibes, B; Rabaud, C; Delaby, P; May, T; Canton, P
Leukemeia and lymphoproliferative disease are associated with a high risk of varicela-zoster virus (VZV) infection. Although infrequent, visceral involvement can be fatal. We report two cases of patients presenting severe VZV infection after bone marrow transplantation. The first patient was a 42-year old man who received an allogeneic bone marrow transplantation for chronic myelogenous leukemia. A severe graft-versus-host reaction occurred. Three months after discontinuing VZV prophylaxis, VZV transverse myelitis was diagnosed, leading to death despite prompt treatment with acyclovir. The second patient was a 42-year-old woman treated with autologous bone marrow transplantation for lymphoma. She developed acute viral pancreatitis one month after discontinuing VZV prophylaxis. Recovery was achieved with intravenous treatment. These two cases illustrate the potential gravity of VZV infection after bone marrow transplantation. These observations point to the need for revisiting the duration of VZV prophylaxis.
Full Text Available Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy.
Mahendra, Ankit; Peyron, Ivan; Dollinger, Cécile; Gilardin, Laurent; Sharma, Meenu; Wootla, Bharath; Padiolleau-Lefevre, Séverine; Friboulet, Alain; Boquet, Didier; Legendre, Christophe; Kaveri, Srinivas V.
Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy. PMID:23967092
Full Text Available Vascularized composite allotransplantation (VCA is an effective treatment option for patients suffering from limb loss or severe disfigurement. However, postoperative courses of VCA recipients have been complicated by skin rejection, and long-term immunosuppression remains a necessity for allograft survival. To widen the scope of this quality-of-life improving procedure minimization of immunosuppression in order to limit risks and side effects is needed. In some aspects, the molecular mechanisms and dynamics of skin allograft rejection seem similar to inflammatory skin conditions. T cells are key players in skin rejection and are recruited to the skin via activation of adhesion molecules, cytokines, and chemokines. Blocking these molecules has not only shown success in the treatment of inflammatory dermatoses, but also prolonged graft survival in various models of solid organ transplantation. In addition to T cell recruitment, ectopic lymphoid structures within the allograft associated with chronic rejection in solid organ transplantation might contribute to the strong alloimmune response towards the skin. Selectively targeting the molecules involved offers exciting novel therapeutic options in the prevention and treatment of skin rejection after VCA.
The bachelor theses attend to people with diabetes mellitus Type 1 and patients after pancreas transplantation. The first chapters of theoretical part deal with pancreas anatomy, matter of disorder, its medication, belated complications, movement and nutrition connected with diabetes. The last chapter of this part is about pancreas transplantation. The practical part shows importance of education and knowledge of diabetics. It deals with life quality of diabetics who undergo pancreas transpla...
Avaliação do peptídeo natriurético tipo B no diagnóstico de rejeição após transplante cardíaco pediátrico Evaluación del péptido natriurético tipo B en el diagnóstico de rechazo tras transplante cardiaco pediátrico B-type natriuretic peptide assessment in the diagnosis of rejection after pediatric heart transplant
Cristina de Sylos
agudo diagnosticado por biopsia endomiocárdica en pacientes del grupo de transplante cardiaco pediátrico. MÉTODOS:Se recolectaron 50 muestras de BNP de 33 niños en postoperatorio de transplante cardiaco, y se analizaron datos como edad, sexo, color, grupo sanguíneo, cuadro inmunológico, tiempo de evolución tras el transplante, clase funcional, inmunosupresión utilizada y número de rechazos. RESULTADOS:Se seleccionaron a 33 niños con edad promedio de 10,13 años, predominio del sexo femenino (54% y de color blanca (78%. Al momento de la dosificación de BNP, el tiempo promedio de transplante fue de 4,25 años. La biopsia endomiocárdica diagnosticó nueve rechazos en ocho pacientes (27%, de ellos tres presentaron grado 3A, cinco grado 2 y uno rechazo humoral. Ya al momento de la biopsia, la mayoría de los pacientes se encontraba asintomática. El nivel sérico de BNP tuvo como promedio, 77,18 pg/ml; 144,22 pg/ml en el grupo con rechazo y 62,46 pg/ml en el grupo sin rechazo, con p = 0,02. CONCLUSIÓN: Niños asintomáticos pueden presentar rechazo agudo en el postoperatorio de transplante cardiaco. El nivel sérico de BNP presentó diferencia estadísticamente significante en el grupo con rechazo, lo que lo convierte en posible método adicional en el diagnóstico de rechazo cardiaco.BACKGROUND: Rejection is one of the major causes of mortality following pediatric heart transplant. B-type natriuretic peptide (BNP has been studied as a method for the diagnosis of acute rejection, especially in adult patients undergoing heart transplant. OBJECTIVE: To correlate serum BNP levels with acute rejection as diagnosed by endomyocardial biopsy in patients of the pediatric heart transplant group. METHODS: A total of 50 BNP samples were collected from 33 children in the postoperative period of heart transplant, and data on age, gender, skin color, blood group, immune panel, follow-up time after transplant, functional class, immunosuppressive regimen used and number of
NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: Report from the Committee on Prevention of Relapse Following Allogeneic Cell Transplantation for Hematological Malignancies
Alyea, Edwin P.; DeAngelo, Daniel J.; Moldrem, Jeffrey; Pagel, John M.; Przepiorka, Donna; Riddell, Stan; Sadelin, Michel; Young, James W.; Giralt, Sergio; Bishop, Michael
Prevention of relapse after allogeneic hematopoietic stem cell transplantation is the most likely approach to improve survival of patients treated for hematologic malignancies. Herein we review the limits of currently available transplant therapies and the innovative strategies being developed to overcome resistance to therapy or to fill therapeutic modalities not currently available. These novel strategies include nonimmunologic therapies, such as targeted preparative regimens and posttransplant drug therapy, as well as immunologic interventions, including graft engineering, donor lymphocyte infusions, T cell engineering, vaccination and dendritic cell-based approaches. Several aspects of the biology of the malignant cells as well as the host have been identified that obviate success of even these newer strategies. To maximize the potential for success, we recommend pursuing research to develop additional targeted therapies to be used in the preparative regimen or as maintenance post-transplant, better characterize the T-cell and dendritic cells subsets involved in graft-versus-host disease and the graft-versus-leukemia/tumor effect, identify strategies for timing immunologic or nonimmunologic therapies to eliminate the noncycling cancer stem cell, identify more targets for immunotherapies, develop new vaccines that will not be limited by HLA, and develop methods to identify population at very high risk for relapse in order to accelerate clinical development and avoid toxicity in patients not at risk for relapse. PMID:20580849
Yang Hong; Zhao Deshan
Radionuclide renal imaging and plasma clearance methods can quickly quantitate renal blood flow and function in renal transplants. They can diagnose acute tubular necrosis and rejection, renal scar, surgical complications such as urine leaks, obstruction and renal artery stenosis after renal transplants. At the same time they can assess the therapy effect of renal transplant complications and can also predict renal transplant survival from early post-operative function studies
Klaassen, Gerald; Zelle, Dorien M; Navis, Gerjan J; Dijkema, Desie; Bemelman, Frederike J; Bakker, Stephan J L; Corpeleijn, Eva
BACKGROUND: Low physical activity and reduced physical functioning are common after renal transplantation, resulting in a reduced quality of life. Another common post-transplantation complication is poor cardio-metabolic health, which plays a main role in long-term outcomes in renal transplant
Catherine Van Der Straeten
Full Text Available Meniscal tears are common knee injuries. Meniscal allograft transplantation (MAT has been advocated to alleviate symptoms and delay osteoarthritis (OA after meniscectomy. We investigated (1 the long-term outcome of MAT as a treatment of symptomatic meniscectomy, (2 most important factors affecting survivorship and (3 OA progression.From 1989 till 2013, 329 MAT were performed in 313 patients. Clinical and radiographic results and MAT survival were evaluated retrospectively. Failure was defined as conversion to knee arthroplasty (KA or total removal of the MAT.Mean age at surgery was 33 years (15-57; 60% were males. No-to-mild cartilage damage was found in 156 cases, moderate-to-severe damage in 130. Simultaneous procedures in 118 patients included cartilage procedures, osteotomy or ACL-reconstruction. At a mean follow-up of 6.8 years (0.2-24.3years, 5 patients were deceased and 48 lost (14.6%, 186 MAT were in situ (56.5% whilst 90 (27.4% had been removed, including 63 converted to a KA (19.2%. Cumulative allograft survivorship was 15.1% (95% CI:13.9-16.3 at 24.0 years. In patients <35 years at surgery, survival was significantly better (24.1% compared to ≥35 years (8.0% (p = 0.017. In knees with no-to-mild cartilage damage more allografts survived (43.0% compared to moderate-to-severe damage (6.6% (p = 0.003. Simultaneous osteotomy significantly deteriorated survival (0% at 24.0 years (p = 0.010. 61% of patients underwent at least one additional surgery (1-11 for clinical symptoms after MAT. Consecutive radiographs showed significant OA progression at a mean of 3.8 years (p<0.0001. Incremental Kellgren-Lawrence grade was +1,1 grade per 1000 days (2,7yrs.MAT did not delay or prevent tibiofemoral OA progression. 19.2% were converted to a knee prosthesis at a mean of 10.3 years. Patients younger than 35 with no-to-mild cartilage damage may benefit from MAT for relief of symptoms (survivorship 51.9% at 20.2 years, but patients and healthcare payers
Full Text Available Total body irradiation is used in conjunction with chemotherapy as a conditioning regimen in the treatment of many disease such as leukemia, myelodysplastic syndrome, aplastic anemia, multiple myeloma and lymphoma prior to the hematopoetic stem cell transplantation. The main purposes of the hematopoetic stem cell transplantation are eradication of the recipient bone marrow and any residual cancer cells, creation of space in the receipient bone marrow for donor hematopoetic stem cells, and immunosuppression to prevent rejection of donor stem cells in the case of an allotransplant. [Archives Medical Review Journal 2014; 23(3.000: 398-410
DeFilipp, Z; Duarte, RF; Snowden, JA; Majhail, NS; Greenfield, DM; Miranda, JL; Arat, M; Baker, KS; Burns, LJ; Duncan, CN; Gilleece, M; Hale, GA; Hamadani, M; Hamilton, BK; Hogan, WJ; Hsu, JW; Inamoto, Y; Kamble, RT; LupoStanghellini, MT; Malone, AK; McCarthy, P; Mohty, M; Norkin, M; Paplham, P; Ramanathan, M; Richart, JM; Salooja, N; Schouten, HC; Schoemans, H; Seber, A; Steinberg, A; Wirk, BM; Wood, WA; Battiwalla, M; Flowers, MED; Savani, BN; Shawon, BE
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31–49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. PMID:27548466
Shrestha, Badri Man
The immune system recognises a transplanted kidney as foreign body and mounts immune response through cellular and humoral mechanisms leading to acute or chronic rejection, which ultimately results in graft loss. Over the last five decades, there have been significant advances in the understanding of the immune responses to transplanted organs in both experimental and clinical transplant settings. Modulation of the immune response by using immunosuppressive agents has led to successful outcomes after kidney transplantation. The paper provides an overview of the general organisation and function of human immune system, immune response to kidney transplantation, and the current practice of immunosuppressive therapy in kidney transplantation in the United Kingdom.
Kim, H; Cheigh, J S; Ham, H W
The formation of urinary tract stones following renal transplantation is a rare complication. The clinical features of stones after transplantation differ from those of non-transplant patients. Renal colic or pain is usually absent and rarely resembles acute rejection. We retrospectively studied 849 consecutive kidney transplant patients in The Rogosin Institute/The Weill-Cornell Medical Center, New York who were transplanted between 1980 and 1997 and had functioning grafts for more than 3 months, to determine the incidence of stone formation, composition, risk factors and patient outcome. At our center, urinary stones were diagnosed in 15 patients (1.8%) of 849 functioning renal grafts for 3 or more months. Of the 15 patients, 10 were males and 5 were females in their third and fourth decade. Eight patients received their transplant from living donors and 7 from cadaveric donors. The stones were first diagnosed between 3 and 109 months after transplantation (mean 17.8 months) and 5 patients had recurrent episodes. The stones were located in the bladder in 11 cases (73.3%), transplanted kidney in 3 cases and in multiple sites in one case. The size of stones varied from 3.4 mm to 40 mm (mean 12 mm). The composition of stones was a mixed form of calcium oxalate and calcium phosphate in 5 cases and 4 patients had infected stones consisting of struvite or mixed form of struvite and calcium phosphate. Factors predisposing to stone formation included tertiary hyperparathyroidism (n = 8), hypercalciuria (n = 5), recurrent urinary tract infection (n = 5), hypocitraturia (n = 4), and obstructive uropathy (n = 2). Many cases had more than one risk factor. Clinically, painless hematuria was observed in 6 patients and dysuria without bacteriuria in 5 patients. None had renal colic or severe pain at any time. There were no changes in graft function at diagnosis and after removal of stones. Five patients passed stones spontaneously and 8 patients underwent cystoscopy for stone
BACKGROUND: Renal transplantation remains the preferred method of renal replacement therapy in terms of patient survival, quality of life and cost. However, patients have a high risk of complications ranging from rejection episodes, infection and cancer, amongst others. AIMS AND METHODS: In this study, we sought to determine the long-term health outcomes and preventive health measures undertaken for the 1,536 living renal transplant patients in Ireland using a self-reported questionnaire. Outcomes were divided into categories, namely, general health information, allograft-related information, immunosuppression-related complications and preventive health measures. RESULTS: The results demonstrate a high rate of cardiovascular, neoplastic and infectious complications in our transplant patients. Moreover, preventive health measures are often not undertaken by patients and lifestyle choices can be poor. CONCLUSIONS: This study highlights the work needed by the transplantation community to improve patient education, adjust immunosuppression where necessary and aggressively manage patient risk factors.
Williams, Allison; Low, Jac Kee; Manias, Elizabeth; Crawford, Kimberley
To obtain an understanding of how health professionals support the kidney transplant patient to take their medications as prescribed long term. Kidney transplantation requires stringent adherence to complex medication regimens to prevent graft rejection and to maintain general well-being. Medication nonadherence is common in kidney transplantation, emerging in the first few months post-transplantation, leading to poor patient outcomes. Exploratory qualitative design. Five focus groups were conducted with a total of seven renal nurse transplant coordinators, two renal transplant nurse unit managers, seven nephrologists, seven pharmacists, four social workers, and one consumer representative representing all five hospitals offering adult kidney transplantation in Victoria, Australia in 2014. The views of two general practitioners who were unable to attend the focus groups were incorporated into the data set. All data underwent thematic analysis. Analysis revealed that adherence was a collective responsibility involving the whole of the transplant team and the patient via education blitz in hospital, identifying and managing nonadherence, promotion of self-advocacy, and the partnership between the patient and health professional. Patients were directed how to take their complex medications to be self-empowered, yet the partnership between the patient and health professional limited the patient's voice. Although medication adherence was a collective responsibility, communication was often one-way chiefly as a result of staffing and time constraints, hindering effective partnerships necessary for medication adherence. Expert skills in communication and adherence counselling are necessary to identify barriers affecting medication adherence. Patients need to be systematically screened, prepared and supported long-term within an accommodating healthcare system for the reality of caring for their transplanted kidney. Kidney transplant recipients require systematic
Slavcev, Antonij; Brozova, Jitka; Slatinska, Janka; Sekerkova, Zuzana; Honsova, Eva; Skibova, Jelena; Striz, Ilja; Viklicky, Ondrej
The B-cell activating factor (BAFF) cytokine has important functions for the survival and maturation of B lymphocytes, which implies that this cytokine might play a role in the development of antibody-mediated rejection (AMR) after kidney transplantation. In our study, we compared the concentrations of the soluble BAFF cytokine in kidney graft recipients with AMR and patients without rejection with the goal of testing the hypothesis whether BAFF level measurement might be useful as a diagnostic marker of AMR. The study included a cohort of 19 high-risk patients with diagnosed AMR and 17 control patients free of rejection. BAFF was measured in all patients before transplantation, during the rejection episodes, and three months after transplantation in patients free of rejection using the Luminex technique. Before transplantation, the serum concentrations of BAFF in patients with AMR and kidney recipients without rejection did not significantly differ. After transplantation, however, BAFF levels were significantly lower in patients with AMR and also in patients with concurrent humoral and cellular rejection compared with patients without rejection (p BAFF and the production of donor-specific antibodies (DSA) before and after transplantation. Patients experiencing AMR and simultaneous cellular and AMR had significantly lower concentrations of BAFF in comparison with patients free of rejection.
Análise da rejeição nos pacientes transplantados por anemia aplástica severa condicionados com ciclofosfamida ou a associação desta ao bussulfano Analysis of rejection in transplanted patients suffering severe aplastic anemia conditioned with cyclophosphamide alone or associated with busulfan
Lídice C. Lenz e Silva
Full Text Available O transplante de medula óssea é um tratamento eficaz para pacientes com anemia aplástica severa (AAS e é a modalidade terapêutica de escolha para pacientes jovens com doador aparentado HLA idêntico. A rejeição é uma importante complicação do transplante de medula, que, independentemente do tipo de tratamento imunossupressor pré e pós-transplante, ocorre em 55% a 60% dos pacientes. O serviço de TMO da Universidade Federal do Paraná (UFPR acumula a experiência de 178 casos de AAS transplantados no período de 1993 a 2001, usando como condicionamento tanto a ciclofosfamida (CFA como a combinação desta ao bussulfano (CFA + BU. Dentre eles, 39 apresentaram rejeição ou falha de pega. Dos pacientes condicionados com ciclofosfamida, 24 (46% apresentaram rejeição, sendo 3 (6% com falha primária de pega (FPP e 21 (40% com pega transitória (PT. Entre os pacientes condicionados com BU+CFA, 15 (12% apresentaram rejeição, sendo 4 (3% com FPP e 11 (9% com pega transitória. Os pacientes condicionados com ciclofosfamida (200 mg/kg que apresentaram rejeição tiveram uma sobrevida global alta (aproximadamente 80%, pois conseguiram ser resgatados por um novo transplante ou pelo tratamento imunossupressor com ciclosporina. A sobrevida dos pacientes politransfundidos condicionados com a associação de ciclofosfamida e bussulfano foi de aproximadamente 35%.Bone marrow transplantation is an effective therapy for severe aplastic anemia and is generally considered the preferable treatment for young patients who have an HLA (Human Leukocyte Antigen identical sibling donor. Recent studies report 55% to 80% extended survival. Graft failure owing to rejection or others causes remains an important life-threatening complication following allogeneic bone marrow transplantation for aplastic anemia. It occurs in 55% to 60% of patients receiving HLA identical transplants, using different immunosuppressive therapies before and after transplant. The BMT
Lee, K W; Lee, D S; Lee, H H; Kim, S J; Joh, J W; Seo, J M; Choe, Y H; Lee, S K
Hepatitis B virus (HBV) prophylaxis is necessary to prevent de novo hepatitis B infection from HbcAb-positive donors. However, which protocol is more effective is somewhat controversial. Also, it is uncertain whether it is necessary to administer HBV prophylaxis for HbsAb-positive recipients. This study attempted to determine whether it is necessary to administer HBV prophylaxis for HbsAb-positive patients and to evaluate the efficacy of an HBIG monotherapy protocol. From May 1996 to July 2001, among 128 donors examined for HbcAb, 58 donors (45.3%) were HbcAb-positive. Eighteen HbcAb-positive grafts were transplanted to HbsAg-negative recipients. The 4 patients who died of unrelated causes were excluded from this study. Of 14 study cases, 12 recipients were HbsAb-positive, and 2 were HbsAb-naive. Prior to late 1998, we used HBV vaccination only for de novo infection prophylaxis. However, starting from December 1998, HBIG was administered from the time of the liver transplantation regardless of HBsAb positivity. The overall rate of de novo HBV infections from HbcAb-positive donors was 21.4% (3 of 14). All 3 recipients without HBIG prophylaxis presented with de novo HBV infections. Two were HbsAb-positive preoperatively. No de novo HBV infections occurred among recipients with HBIG prophylaxis. Therefore, it is essential to administer HBV prophylaxis even for vaccinated HbsAb-positive patients. HBIG monotherapy is effective to prevent de novo hepatitis B infections from HbcAb-positive donors in living donor liver transplantation.
Full Text Available Physeal cartilage is known to have poor self-repair capacity after injury. Evaluation of the ability of cultured mesenchymal stem cells to repair damaged physis is the topic of current research. In 10 immature New Zealand white rabbits autogenous mesenchymal stem cells were transplanted into a iatrogenic physeal defect in a lateral portion of the distal growth plate of the right femur. The same defect without stem cells transplantation in the left femoral distal physis served as a control. In our study, we used our own technique of implantation of MSCs with a newly modified gel scaffold (New Composite Hyaluronate/Collagen Type I/Fibrin Scaffold. The rabbits were euthanized 4 months after transplantation. Bone length discrepancy and valgus deformity were measured from femoral radiographs. Healing of the defect was investigated histologically. The ability of mesenchymal stem cells to survive and promote cartilage healing in the physeal defect was assessed by immunofluorescence. Average difference in femur length measured from surgery to euthanasia (4 months was 0.61 ± 0.19 cm after preventive transplantation of MSCs in the right femur, but only 0.11 ± 0.07 cm in the left femur. Average angular (valgus deformity of the right femur with MSCs preventively transplanted to iatrogenically damaged distal femoral physis was 1.2 ± 0.72 °. Valgus deformity in the left femur was 5.4 ± 2.5 °. Prophylactic transplantation of autogenous mesenchymal stem cells to iatrogenically damaged distal growth plate of the rabbit femur prevented a bone bridge formation and resulted in healing of the physeal defect with hyaline cartilage. Immunofluorescence examination showed that the chondrocytes newly formed in growth zone are the result of implanted MSCs differentiation. Femur growth in traumatized physis was maintained even after transplantation of autogenous MSCs. As compared with the opposite femur (with physeal defect but without transplanted MSCs, the bone
Rosenblatt, E.; Gocheva-Petkova, L.
Each year, hundreds of cancer patients in Bulgaria receive bone marrow transplants as treatment for haematological malignancies such as leukaemia, lymphoma and multiple myeloma, or for solid tumours such as neuroblastoma, one of the more common cancers in infancy. To undergo a bone marrow transplant, patients must first go through a preparatory process that conditions the body for the transplant. This involves a special radiotherapy technique called total body irradiation (TBI). TBI helps to make space for the transplanted marrow, destroys any malignant cells that may be left in the bone marrow after chemotherapy and suppresses the immune system to help prevent rejection of the transplant. To avoid complications, patients must also receive irradiated cellular blood components during the preparatory process. The IAEA assisted medical professionals in Bulgaria in optimizing bone marrow transplants by providing the equipment and building the capabilities necessary to carry out TBI. The IAEA also offered very specialized radiotherapy training to the medical staff, including blood irradiation.
Penninga, Luit; Møller, Christian H; Penninga, Ida Elisabeth Irene
Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted organ rejection, and life-long immunosuppression is necessary. Clear evidence is essential to identify an optimal, safe...... and effective immunosuppressive treatment strategy for lung transplant recipients. Consensus has not yet been achieved concerning use of immunosuppressive antibodies against T-cells for induction following lung transplantation....
Full Text Available Pulmonary complications after liver transplantation (LT often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LT-associated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 μM for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG and quarter-size grafts (QSG, respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5–18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1β mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-for-size LT.
Prop, J.; Nieuwenhuis, P.; Wildevuur, C.R.
To find out to what extent rejection of lungs differs from that of other organs, functional rejection of lung allografts was studied in five combinations of inbred rat strains. Rejection could be monitored accurately by perfusion scintigraphy, and equally well by chest roentgenography. The rejection of lung grafts was found to proceed remarkably fast, when compared with heart grafts, in combinations with strong RT1-incompatibilities. This accelerated rejection pattern could be converted into rejection at a normal pace by pretreatment of the donor with 10 Gy roentgen irradiation one day before transplantation. Donor pretreatment depleted the lung graft's bronchus-associated lymphoid tissue (BALT) of lymphocytes. When grafts were depleted of all other passenger cells as well--by retransplantation from a cyclosporine-treated intermediate host--they showed an even more reduced immunogenicity, probably because of the loss of donor-type dendritic cells. These results indicate that lymphocytes from the BALT of lung grafts are capable of accelerating the rejection response
Full Text Available Clinical islet transplantation is a -cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the -cells regenerative capacity of stem cells.
Eunice G John
Full Text Available Hypertension after pediatric renal transplant is a common and important risk factor for graft loss and patient survival. The mechanism of post kidney transplant hypertension is complex and multifactorial. Control of blood pressure in renal transplant patients is important but often times blood pressures remain uncontrolled. The management of hypertension and obesity in pediatric kidney transplant patients is based on the pathophysiology. Compared to the general pediatric hypertensive population, special attention needs to be focused on the additional impact of immunosuppressive medications side effects and interactions, recurrent disease, and donor and recipient comorbidities such as obesity on blood pressure control with thoughtful consideration of the risk of graft failure. In general, there is a need for prospective studies in pediatric kidney transplant patients to understand the pathophysiology of hypertension and obesity and the appropriate approach to achieve a balance between the primary need to avoid rejection and the need to lower blood pressure and prevent obesity.
Yuh, W.T.C.; Wiese, J.A.; Abu-Yousef, M.M.; Rezai, K.; Sato, Y.; Kao, S.C.S.; Hunsicker, L.G.; Corry, R.J.
Forty-two MR studies, 162 radionuclide scintigraphic studies, and 57 sonographic studies were performed on 15 pancreatic transplant patients for evaluation of suspected graft rejection. The results of these studies were correlated with clinical presentations, laboratory data, and pathologic specimens when available. Radionuclide studies provide excellent information for estimating graft size and for evaluation of perfusion. Sonography is valuable for evaluation of the gland texture and peripancreatic abnormalities. MR provides useful information regarding parenchymal changes in rejection and response of the graft to treatment. These three imaging modalities are therefore complementary in the evaluation of pancreatic transplantation
Wolden, Suzanne L.; Tate, David J.; Hunt, Sharon A.; Strober, Samuel; Hoppe, Richard T.
Purpose: To evaluate the short and long term effects of total lymphoid irradiation (TLI) in the treatment of allograft rejection in cardiac transplant patients. Materials and Methods: From 1986 to 1995, 48 courses of TLI were delivered to 47 patients who had received cardiac transplants at Stanford University. In 38 cases, TLI was administered for chronic, intractable allograft rejection despite conventional anti-rejection therapy, including corticosteroids, azathioprine, cyclosporine, OKT3, DHPG, RATG, and methotrexate. Ten patients received TLI prophylactically, beginning radiation between 5 and 16 days after heart transplantation. The prescribed radiation dose was 800 cGy given in 80 cGy fractions twice weekly to all major lymph node regions using mantle and inverted Y fields. Patients continued to receive all medications except azathioprine which was held during TLI to prevent severe marrow suppression. All patients were closely monitored for episodes of rejection, infection, prednisone requirements, blood counts, and complications of treatment. Post-irradiation follow up ranged from 6 months to 9.1 years with a mean of 3.1 years. Results: The actual mean dose of radiation was 730 cGy delivered over a mean of 39 calendar days. Fifty six percent of patients required treatment delay or abbreviation because of thrombocytopenia, leukopenia, infection, or unrelated problems. In patients treated for intractable rejection, the frequency of rejection dropped from 0.46 episodes/patient/month before radiation to 0.14 episodes/patient/month during TLI (p 3 during TLI (p = 0.01) and remained low at 167.6 cells/mm 3 2-4 months after treatment (p = 0.05). CD8+ lymphocytes also decreased during treatment from 233.2 to 65.8 cells/mm 3 (p = 0.003) but rose significantly above normal to 381.3 cells/mm 3 2-4 months after TLI (p 0.05). Thus, the ratio of helper/suppresser T-cells was chronically decreased. Infection rates were not significantly different before, during or after
Rinehart, Matthew; Hochard, Erica; Rockey, Michelle; Abhyankar, Sunil; Ganguly, Siddhartha; Lin, Tara; McGuirk, Joseph; Shune, Leyla; Singh, Anurag; Aljitawi, Omar
Cytomegalovirus (CMV) causes significant morbidity and mortality in CMV seropositive patients undergoing umbilical cord blood transplants (UCBT). Our study aimed to describe the incidence of CMV reactivation and burden of disease, as well as the tolerability of an intensive prevention strategy as compared to historical prevention. This was a retrospective chart review of 33 CMV seropositive patients that underwent UCBT. The intensive prevention strategy in UCBT consisted of ganciclovir 5mg/kg/d intravenously or valganciclovir 900mg by mouth daily initiated at the beginning of the conditioning regimen until Day -2. Then from Day -1 to Day +100, patients received valacyclovir 2g by mouth three times daily, and from Day +101 to Day +365, acyclovir 800mg by mouth twice daily. Historical standard prevention was acyclovir 800mg by mouth twice daily initiated at the beginning of the conditioning regimen until Day +365. Thirty-three patients were included from 2008 to 2014. There were no differences in the adverse effects experienced between the two regimens (p=.4). CMV reactivation occurred significantly later with intensive prevention (p=.003). The median CMV viral titer at reactivation was lower in the intensive versus the historic prevention (1,800copies/mL and 2,700copies/mL, respectively), but was not significantly different. CMV disease occurred significantly less often in the intensive group (p=.039). The results from this study indicate that the intensive prevention strategy was well tolerated, significantly delayed CMV reactivation, and patients had less CMV disease. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.
Dehghani, S M; Shahramian, I; Afshari, M; Bahmanyar, M; Ataollahi, M; Sargazi, A
Acute cellular rejection (ACR), a reversible process, can affect the graft survival. To evaluate the relation between ACR and clinical factors in recipients of allograft liver transplantation. 47 recipients of liver were consecutively enrolled in a retrospective study. Their information were retrieved from their medical records and analyzed. Of the 47 recipients, 38 (81%) experienced acute rejection during 24 months of the transplantation. None of the studied factors for occurring transplant rejection, i.e ., blood groups, sex, age, familial history of disease, receiving drugs and blood products, type of donor, Child score, and Child class, was not found to be significant. During a limited follow-up period, we did not find any association between ACR and suspected risk factors.
Jung, Ji-Won; Overgaard, Nana H; Burke, Michael T
Patients receiving immunosuppression to prevent organ transplant rejection are at a greatly increased risk of developing nonmelanoma skin cancer. In recent years a correlation has been identified between the class of immunosuppressant that these patients receive and their subsequent cancer risk; ...
Human polyclonal anti-hepatitis B surface antigen immunoglobulin reduces the frequency of acute rejection after liver transplantation for chronic hepatitis B A imunoglobulina policlonal humana anti-antígeno de superfície da hepatite B reduz a freqüência da rejeição aguda após transplante de fígado
Claudia Alves COUTO
Full Text Available BACKGROUND: Use of polyclonal anti-hepatitis B surface antigen immunoglobulin (HBIg has been shown to reduce hepatitis B virus (HBV recurrence after liver transplantation (LT and to decrease the frequency of acute cellular rejection (ACR. However, the protective role of HBIg against ACR remains controversial, since HBV infection has been also associated with a lower incidence of ACR. AIM: To assess the relationship between HBIg immunoprophylaxis and the incidence of rejection after LT. METHODS: 260 patients (158 males, 43 ± 14 years old submitted to LT were retrospectively evaluated and divided into three groups, according to the presence of HBsAg and the use of HBIg. Group I was comprised of HBsAg-positive patients (n = 12 that received HBIg for more than 6 months. Group II was comprised of HBsAg-positive patients that historically have not received HBIg or have been treated irregularly for less than 3 months (n = 10. Group III was composed of 238 HBsAg-negative subjects that have not received HBIg. RESULTS: HBIg-treated patients (group I had significantly less ACR episodes, when compared to group II and III. No differences between groups II and III were observed. CONCLUSIONS: Long-term HBIg administration contributes independently to reduce the number of ACR episodes after LT.INTRODUÇÃO: O emprego da imunoglobulina policlonal anti-antígeno de superfície da hepatite B (HBIg tem reduzido a recorrência da hepatite B após transplante hepático (TH, assim como também a freqüência de rejeição celular aguda (RCA. No entanto, o papel protetor da HBIg contra a RCA permanece controverso, pois a própria infecção por vírus B foi também associada a menor incidência de RCA. OBJETIVOS: Verificar a relação entre HBIg e a freqüência de RCA após TH. MÉTODOS: 260 pacientes (158 do sexo masculino, com 43 ± 14 anos submetidos a TH foram avaliados, retrospectivamente, e divididos em três grupos de acordo com a presença de AgHBs e uso de
Al-Wedaie, Fatima; Farid, Eman; Tabbara, Khaled; El-Agroudy, Amgad E; Al-Ghareeb, Sumaya M
Studying regulatory T cells in kidney allograft acceptance versus chronic rejection may help in the understanding of more mechanisms of immune tolerance and, in the future, may enable clinicians to induce immune tolerance and decrease the use of immunosuppressive drugs. The aim of the current study was to evaluate regulatory T cells in kidney transplant patients with stable graft versus transplant with biopsy-proven chronic rejection. The 3 groups that were studied included: kidney transplanted patients with no rejection episodes (n = 43); transplanted patients with biopsy-proven renal rejection (n = 27); and healthy age-matched nontransplanted individuals as controls (n = 42).The percentage of regulatory T cells (CD4+CD25+Foxp3+) in blood was determined by flow cytometry. The regulatory T cell percentage was significantly lower in chronic rejection patients than control or stable graft groups. No significant difference was observed in regulatory T cell percentage between the stable graft and control groups. In the stable graft group, patients on rapamycin had a significantly higher regulatory T cell percentage than patients on cyclosporine. No effect of donor type, infection, or duration after transplant was observed on regulatory T cell percentage. The results of the current study are consistent with previous studies addressing the function of regulatory T cells in inducing immunotolerance after kidney transplant. Considering the established role of regulatory T cells in graft maintenance and our observation of high regulatory T cell percentage in patients receiving rapamycin than cyclosporine, we recommend including rapamycin when possible in immunosuppressive protocols. The findings from the current study on the chronic rejection group support ongoing research of having treatment with regulatory T cells, which may constitute a novel, efficient antirejection therapy in the future.
Hongwei, Chen; Zhang, Liang; Maoping, Li; Yong, Zhang; Chengyou, Du; Dewei, Li
Portal vein thrombosis (PVT) is a common complication following splenectomy in patients with liver cirrhosis and portal hypertension, which also brings difficulties to future possible liver transplantation. This paper retrospectively analyzes the preventive effect of combined anatomic splenectomy and early anticoagulant therapy on post-splenectomy portal vein thrombosis in patients with portal hypertension. We retrospectively analyzed 136 patients who underwent splenectomy at our hospital between January 2010 and December 2013 due to liver cirrhosis and portal hypertension. Patient conditions, such as coagulation function, splenic and portal vein thrombosis, intra-abdominal hemorrhage, pancreatic leakage and intra-abdominal infections, are observed postoperatively. Despite the presence of liver cirrhosis and portal hypertension in patients, early postoperative anticoagulant therapy has no significant impact on coagulation function and intra-abdominal hemorrhage of these patients (p > 0.05). Anatomic splenectomy can reduce the occurrence of complications such as postoperative bleeding, pancreatic leakage and intra-abdominal infections (p splenectomy and early postoperative anticoagulant therapy can reduce post-splenectomy portal vein thrombosis in patients with portal hypertension, and is conducive to the future liver transplantation therapy may be needed by the patients.
Dehghani, S. M.; Shahramian, I.; Afshari, M.; Bahmanyar, M.; Ataollahi, M.; Sargazi, A.
Background: Acute cellular rejection (ACR) has a reversible effect on graft and its survival. Objective: To evaluate the relation between ACR and clinical factors in recipients of liver transplant allografts. Methods: 47 consecutive liver recipients were retrospectively studied. Their data were extracted from records and analyzed. Results: 38 (81%) of the 47 recipients experienced ACR during a 24-month follow-up. The rate of rejection was associated with none of the studied factors—recipient’...
Full Text Available Solid organ transplantation is the treatment of choice for patients with end-stage organ dysfunction. Despite improvements in short-term outcome, long-term outcome is suboptimal due to the increased morbidity and mortality associated with the toxicity of immunosuppressive regimens and chronic rejection (1–5. As such, the attention of the transplant community has focused on the development of novel therapeutic strategies to achieve allograft tolerance, a state whereby the immune system of the recipient can be re-educated to accept the allograft, averting the need for long-term immunosuppression. Indeed, reports of “operational” tolerance, whereby the recipient is off all immunosuppressive drugs and maintaining good graft function, is well documented in the literature for both liver and kidney transplantations (6–8. However, this phenomenon is rare and in the setting of liver transplantation has been shown to occur late after transplantation, with the majority of patients maintained on life-long immunosupression to prevent allograft rejection (9. As such, significant research has focused on immune regulation in the context of organ transplantation with regulatory T cells (Tregs identified as cells holding considerable promise in this endeavor. This review will provide a brief introduction to human Tregs, their phenotypic and functional characterization and focuses on our experience to date at the clinical translation of Treg immunotherapy in the setting of solid organ transplantation.
Flotats, A.; Carrio, I.
Effective noninvasive evaluation of acute and chronic allograft rejection remains an important challenge in patients with cardiac transplantation. Radionuclide studies have demonstrated utility because of their ease of use, giving relevant information about the pathophysiology of the transplanted heart, along with valuable diagnostic and prognostic indicators. This article focuses on reviewing the pathophysiological changes of the transplanted heart and implications for radionuclide studies. (author)
Scholten, Eduard Maximiliaan
After successful renal transplantation a gradual decline of renal function can be detected about 40 % of the transplant recipients. The histological substrate for this condition is chronic allograft nephropathy (CAN). Nephrotoxicity of immunosuppressive drugs and rejection mechanisms, due to
Mahesh, Balakrishnan; Leong, Hon-Sing; McCormack, Ann; Sarathchandra, Padmini; Holder, Angela; Rose, Marlene L
Autoimmune responses to vimentin occur after solid organ transplantation, but their pathogenic effects are unclear. The aim of these studies was to investigate the effects of vimentin preimmunization on allogeneic and isografted hearts in a murine transplant model. Immunization of C57BL/6 mice with murine vimentin in complete Freund's adjuvant resulted in anti-vimentin antibodies and vimentin-reactive Th-1 cells. Transplantation of 129/sv hearts into vimentin-immunized C57BL/6 recipients resulted in accelerated rejection (8.4 +/- 1.5 days; n = 18), compared with hen egg lysozyme-immunized C57BL/6 (13.3 +/- 2.2 days; n = 10; P rejection, shown by the fact that vimentin-immunized B-cell-deficient IgH6 mice did not show accelerated rejection of 129/sv allografts, but rejection was restored by adoptive transfer of serum containing anti-vimentin antibodies. Eluates from donor hearts placed in vimentin/complete Freund's adjuvant recipients contained anti-vimentin antibodies, shown by Western blotting. Confocal imaging of rejected hearts de-monstrated presence of vimentin and C3d on apoptosed leukocytes, endothelial cells, and platelet/leukocyte conjugates. These results demonstrate that autoantibodies to vimentin, in conjunction with the alloimmune response, have a pathogenic role in allograft rejection.
Guzzetta, P C; Stolar, C H; Potter, B M; Broadman, L; Ruley, E J
Patients with end-stage renal disease who develop hypersplenism, patients with mild neutropenia, and those patients whose WBC fails to increase in response to cortisol administration will develop significant neutropenia following transplantation with routine doses of azathioprine. This "intolerance" of azathioprine mandates a reduction in the dose of azathioprine often resulting in allograft rejection. Splenectomy will prevent azathioprine-induced neutropenia, but the hazards of splenectomy in these immunosuppressed patients have led to attempts to salvage at least part of the spleen. Partial splenic ablation by embolization has been utilized in adults prior to transplantation to prevent azathioprine-induced neutropenia while preserving the spleen's protective mechanisms against infection. Eight children in our series of transplant candidates required a reduction of splenic function to prevent azathioprine induced neutropenia. One child had a functioning renal allograft but had recurrent neutropenia limiting the azathioprine dose. Partial splenic embolization was attempted in four children and was initially successful in two. Both patients later developed recurrent neutropenia and needed partial splenectomy. The two patients in whom partial splenic embolization was unsuccessful and five further patients in whom embolization was not attempted also underwent partial splenectomy. Approximately 75% to 80% of the spleen was resected. Six children have since undergone renal transplantation and one child had a transplant with chronic rejection at the time of partial splenectomy. Routine doses of azathioprine have been used in these children with no episodes of neutropenia or sepsis observed. We recommend partial splenectomy in those children requiring renal transplantation who are at risk for development of azathioprine induced neutropenia.
Shrestha, Shailendra; Kanellis, John; Korman, Tony; Polkinghorne, Kevan R; Brown, Fiona; Yii, Ming; Kerr, Peter G; Mulley, William
Nocardia infections are an uncommon but important cause of morbidity and mortality in renal transplant recipients. The present study was carried out to determine the spectrum of Nocardia infections in a renal transplant centre in Australia. A retrospective chart analysis of all renal transplants performed from 2008 to 2014 was conducted to identify cases of culture proven Nocardia infection. The clinical course for each patient with nocardiosis was examined. Four of the 543 renal transplants patients developed Nocardia infection within 2 to 13 months post-transplant. All patients were judged at high immunological risk of rejection pre-transplant and had received multiple sessions of plasmaphoeresis and intravenous immunoglobulin before the onset of the infection. Two patients presented with pulmonary nocardiosis and two with cerebral abscesses. One case of pulmonary nocardiosis was complicated by pulmonary aspergillosis and the other by cytomegalovirus pneumonia. All four patients improved with combination antibiotic therapy guided by drug susceptibility testing. At the time of Nocardia infection all four patients were receiving primary prophylaxis with trimethoprim/sulphamethoxazole (TMP/SMX) 160/800 mg, twice weekly. Plasmaphoeresis may be risk factor for Nocardia infection and need further study. Nocardia infection may coexist with other opportunistic infections. Identification of the Nocardia species and drug susceptibility testing is essential in guiding the effective management of patients with Nocardia. Intermittent TMP-SMX (one double strength tablet, twice a week) appears insufficient to prevent Nocardia infection in renal transplant recipients. © 2015 Asian Pacific Society of Nephrology.
Rozenberg, S; Bourgeois, P
Heart transplantation is an effective means of treating irreversible heart failure in selected patients. Preventing organ rejection requires immunosuppressor treatment with corticosteroids, azathioprine and/or cyclosporine. Bone and joint complications are frequent and increase overall morbidity directly related to anti-rejection therapy. Corticosteroids favour osteopenia which can be detected by measurement of bone density. The risks include spontaneous wedge fractures of the spine and aseptic necrosis. The frequency of complications has been reduced with the use of cyclosporine allowing a reduction in corticosteroids. Raised serum urate levels and increased risk of gout can be induced by cyclosporine. The gout in these patients has a particular course since it appears rapidly after only a few months of hyperuricaemia. Several joints may be involved with production of tophi. Treatment is particularly difficult. Its frequency increases after heart transplantation compared with other organs which can be explained by the more prevalent prescription of diuretics which further aggravate urate secretion. These complications cause further discomfort in transplant recipients.
National Aeronautics and Space Administration — Develop advanced technologies to enable a variable heat rejection Thermal Control System (TCS) capable of operating through a wide range of thermal environments...
Gansbeke, D. Van; Segebarth, C.; Toussaint, C.
MR appearance of the kidney transplant is evaluated on a series of 80 examinations performed on a supraconductive unit operating at 0.5 T. Normal function kidneys displayed a clearly delineated corticomedullary differentiation (CMD); the ratio between the thickness of cortex and medulla didn't exceed 0.6. The same appearance was observed in non complicated acute tubular necrosis. Complete loss of CMD was the major finding in acute rejection (74% of the cases), but it was not specific as it was also observed in chronic rejection and in acute glomerulonephritis. Cortex thickening was helpful for the detection of rejected transplants with visible CMD. The sensitivity of MR in the detection of acute rejection was 94%. Specificity of MR findings for acute rejection depended on the transplant age: it varied from 100% for examinations performed during the first 3 months after transplantation, to less than 50% for examinations of the second year [fr
Anna K Kraus
Full Text Available DNAX accessory protein-1 (DNAM-1, CD226 is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental.
Lin, Su-Yueh; Fetzer, Susan J; Lee, Po-Chang; Chen, Ching-Huey
This study examined health promotion behaviours of kidney transplant recipients, 1-5 years after transplant and identified the risk factors predicting non-adherence to post-transplant recommendations. Non-adherence to health care recommendations and health promotion behaviours is one of the top three reasons for graft loss following kidney transplantation. A cross-sectional study. Kidney transplant recipients (n=101) in southern Taiwan completed a self reported survey, the Kidney Transplant Health Promotion Behavior and Healthcare Provider Support survey. Kidney transplant patients had better adherence with medication and least adherence with regular exercise health promotion behaviours. Age, post kidney transplant time, health care provider support and financial satisfaction accounted for 37·2% of the explained variance in monitoring and management for rejection and infection. Marital status, post kidney transplant time and gender accounted for 16·2% of the explained variance in infection prevention. Age was the sole predictor of exercise (odds ratio=1·08, p=0·025). Health promotion behaviours declined with time and perceived healthcare provider support decreased at the third (p=0·04) post kidney transplant year. In this study, young, single, males were identified as requiring specific strategies to improve post kidney transplant health promotion behaviours. The need for health promotion must be continually reinforce by healthcare providers throughout the lifespan of a kidney transplant recipient. Understanding the changes of health behaviours of post kidney transplant recipients and their risk factors, healthcare providers can be more aware of the needs of patients in maintaining health promotion behaviours. © 2011 Blackwell Publishing Ltd.
Tonsho, Makoto; Michel, Sebastian; Ahmed, Zain; Alessandrini, Alessandro; Madsen, Joren C
There has been significant progress in the field of heart transplantation over the last 45 years. The 1-yr survival rates following heart transplantation have improved from 30% in the 1970s to almost 90% in the 2000s. However, there has been little change in long-term outcomes. This is mainly due to chronic rejection, malignancy, and the detrimental side effects of chronic immunosuppression. In addition, over the last decade, new challenges have arisen such as increasingly complicated recipients and antibody-mediated rejection. Most, if not all, of these obstacles to long-term survival could be prevented or ameliorated by the induction of transplant tolerance wherein the recipient's immune system is persuaded not to mount a damaging immune response against donor antigens, thus eliminating the need for chronic immunosuppression. However, the heart, as opposed to other allografts like kidneys, appears to be a tolerance-resistant organ. Understanding why organs like kidneys and livers are prone to tolerance induction, whereas others like hearts and lungs are tolerance-resistant, could aid in our attempts to achieve long-term, immunosuppression-free survival in human heart transplant recipients. It could also advance the field of pig-to-human xenotransplantation, which, if successful, would eliminate the organ shortage problem. Of course, there are alternative futures to the field of heart transplantation that may include the application of total mechanical support, stem cells, or bioengineered whole organs. Which modality will be the first to reach the ultimate goal of achieving unlimited, long-term, circulatory support with minimal risk to longevity or lifestyle is unknown, but significant progress in being made in each of these areas.
Tonsho, Makoto; Michel, Sebastian; Ahmed, Zain; Alessandrini, Alessandro; Madsen, Joren C.
There has been significant progress in the field of heart transplantation over the last 45 years. The 1-yr survival rates following heart transplantation have improved from 30% in the 1970s to almost 90% in the 2000s. However, there has been little change in long-term outcomes. This is mainly due to chronic rejection, malignancy, and the detrimental side effects of chronic immunosuppression. In addition, over the last decade, new challenges have arisen such as increasingly complicated recipients and antibody-mediated rejection. Most, if not all, of these obstacles to long-term survival could be prevented or ameliorated by the induction of transplant tolerance wherein the recipient’s immune system is persuaded not to mount a damaging immune response against donor antigens, thus eliminating the need for chronic immunosuppression. However, the heart, as opposed to other allografts like kidneys, appears to be a tolerance-resistant organ. Understanding why organs like kidneys and livers are prone to tolerance induction, whereas others like hearts and lungs are tolerance-resistant, could aid in our attempts to achieve long-term, immunosuppression-free survival in human heart transplant recipients. It could also advance the field of pig-to-human xenotransplantation, which, if successful, would eliminate the organ shortage problem. Of course, there are alternative futures to the field of heart transplantation that may include the application of total mechanical support, stem cells, or bioengineered whole organs. Which modality will be the first to reach the ultimate goal of achieving unlimited, long-term, circulatory support with minimal risk to longevity or lifestyle is unknown, but significant progress in being made in each of these areas. PMID:24789875
Wilson, M.A.; Mehta, R.C.; Perlman, S.B.; Servilla, K.; Sollinger, H.W.; Deierhoi, M.H.; Belzer, F.O.
All 470 scans on 132 consecutive renal transplantation patients were reviewed. Scan patterns identified included acute tubular necrosis and conventional rejection. A new pattern, donor specific rejection (DSR), was identified in 24 of 42 patients on the living related donor specific transfusion (DST) protocol. This was characterized by good perfusion and extraction but significant renal stasis of tracer. This pattern was unique to the DST recipients and improved with antirejection therapy. The clinical features (incidence, temporal onset) and severity (duration, serum creatinines) are compared in these patient populations. DSR occurs more frequently than conventional rejection but is a milder process
Rutzky, Lynne P.
Type I insulin-dependent diabetes mellitus (IDDM) remains a major cause of morbidity and mortality in both pediatric and adult populations, despite significant advances in medical management. While insulin therapy treats symptoms of acute diabetes, it fails to prevent chronic complications such as microvascular disease, blindness, neuropathy, and chronic renal failure. Strict control of blood glucose concentrations delays but does not prevent the onset and progression of secondary complications. Although, whole pancreas transplantation restores physiological blood glucose levels, a continuous process of allograft rejection causes vascular and exocrine-related complications. Recent advances in methods for isolation and purification of pancreatic islets make transplantation of islet allografts an attractive alternative to whole pancreas transplantation. However, immunosuppressive drugs are necessary to prevent rejection of islet allografts and many of these drugs are known to be toxic to the islets. Since auto-transplants of isolated islets following total pancreatectomy survive and function in vivo, it is apparent that a major obstacle to successful clinical islet transplantation is the immunogenicity of the islet allografts.
Soulen, R.L.; Fraser, C.D.; Hutchins, G.M.; Baumgartner, W.A.; Reitz, B.A.
Serial MR images and endomyocardial biopsy specimens of heterotopic cervical cardiac allotransplants were obtained in six dogs during 2 weeks of immunosuppression followed by 1 week without such therapy. A surface coil and gated spin-echo technique were used. Myocardial intensity (MI) measurements and histopathologic interpretations were performed independently. All six dogs showed a decrease in MI between their first and second MR studies, while showing no rejection. One dog had no rejection and died; in five dogs studies gated to every other beat showed progressive increase in MI that correlated significantly with increasing rejection, though absolute MI values did not correlated with a specific biopsy score. Severe rejection also caused overt increase in myocardial mass. The MI in the early postoperative period may reflect reperfusion injury. Absolute intensity values cannot predict rejection. Serial studies in transplant patients may prove clinically useful
Full Text Available Thymoglobulin is a purified polyclonal immunoglobulin that has been used widely over the last decades in the prevention and treatment of rejection following renal transplantation. This immunoglobulin works against human thymocytes. Since thymoglobulin does not contain the nephrotoxic properties therefore it can be used in induction therapy especially in patients with higher risk of graft rejection such as patients who receive graft from cadavers. Recent research showed also its beneficial role in cross-match-positive transplantation, a role that is mediated through conjunction with inhibitors of terminal complement activation. This immunoglobulin has also been used for treatment of rejection following renal transplantation. Thymoglobulin can have various effects on various Immune system cells including T cells, B cells and also plasma cells. Thymoglobulin also affects the Tcell surface antigens, natural killer-cell antigens, B cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors. Diverse effects of thymoglobulin on the immune system includes: T cell depletion, induce apoptosis in B cell lineage and interference with dendritic cell functional properties. Thymoglobulin can cause acute complications, delayed complications as well as infectious complications. Acute reaction events includes: anaphylaxis, fever, chills, dyspnea, nausea, vomiting and diarrhea. Thymoglobulin also induces cytokine release syndrome manifested by high grade fevers and chills and treated by steroid therapy. Delayed reactions events usually present as serum sickness and infections. Infectious complications are more important and include cytomegalovirus (CMV infection, sepsis, candidiasis, herpes simplex and urinary infections. Thymoglobulin can also induce cytokine release syndrome. It has been thought that thymoglobulin increases the risk of post-transplant lymphoproliferative disorder (PTLD, however, debate still exists whether such an
Penninga, Luit; Wettergren, André; Wilson, Colin H
. OBJECTIVES: To assess the benefits and harms of T-cell specific antibody induction versus corticosteroid induction for prevention of acute rejection in liver transplant recipients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register...... to identify additional trials. SELECTION CRITERIA: We included all randomised clinical trials assessing immunosuppression with T-cell specific antibody induction versus corticosteroid induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should...... (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). MAIN RESULTS: We included 10 randomised trials with a total of 1589 liver transplant recipients, which studied the use of T-cell specific antibody induction versus...
Lucas Souto Nacif
Full Text Available OBJECTIVES: Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study. RESULTS: The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%, with a higher prevalence observed in male patients (68.18%. The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1±9.32 days and the mean Model for End-stage Liver Disease score was 26.18±4.28. There were five cases of acute cellular rejection (11.37% and 16 cases of infection (36.37%. The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (p<0.05. Patients with infections had a higher serum level of Tacrolimus (p = 0.012. The dose and presence of rejection were significantly different (p = 0.048 and the mean glomerular filtration rate was impaired in patients who underwent rejection compared with patients who did not undergo rejection (p = 0.0084. CONCLUSION: Blood Tacrolimus levels greater than 10 ng/ml were correlated with impaired renal function. Doses greater than 0.15 mg/kg/day were associated with the prevention of acute cellular rejection but predisposed patients to infectious disease.
Full Text Available Broncho-alveolar lavage is an important diagnostic instrument in lung transplantation. It can give insight into the mechanisms of acute and chronic rejection, but can also be of interest to explore the possible effects of new therapies. This has particularly been the case with azithromycin as add-on therapy for chronic rejection.Furthermore BAL after lung transplantation is important to differentiate between infection and rejection and the changes in the cellular profile may be of prognostic significance. Key-words: Broncho-alveolar lavage, lung transplantation, neutrophils
Lofgren, Eric T; Moehring, Rebekah W; Anderson, Deverick J; Weber, David J; Fefferman, Nina H
Fecal microbiota transplantation (FMT) has been suggested as a new treatment to manage Clostridium difficile infection (CDI). With use of a mathematical model of C. difficile within an intensive care unit (ICU), we examined the potential impact of routine FMT. A mathematical model of C. difficile transmission, supplemented with prospective cohort, surveillance, and billing data from hospitals in the southeastern United States. Cohort, surveillance, and billing data as well as data from the literature were used to construct a compartmental model of CDI within an ICU. Patients were defined as being in 1 of 6 potential health states: uncolonized and at low risk; uncolonized and at high risk; colonized and at low risk; colonized and at high risk; having CDI; or treated with FMT. The use of FMT to treat patients after CDI was associated with a statistically significant reduction in recurrence but not with a reduction in incident cases. Treatment after administration of high-risk medications, such as antibiotics, did not result in a decrease in recurrence but did result in a statistically significant difference in incident cases across treatment groups, although whether this difference was clinically relevant was questionable. Our study is a novel mathematical model that examines the effect of FMT on the prevention of recurrent and incident CDI. The routine use of FMT represents a promising approach to reduce complex recurrent cases, but a reduction in CDI incidence will require the use of other methods to prevent transmission.
Bloom, Roy D; Bromberg, Jonathan S; Poggio, Emilio D; Bunnapradist, Suphamai; Langone, Anthony J; Sood, Puneet; Matas, Arthur J; Mehta, Shikha; Mannon, Roslyn B; Sharfuddin, Asif; Fischbach, Bernard; Narayanan, Mohanram; Jordan, Stanley C; Cohen, David; Weir, Matthew R; Hiller, David; Prasad, Preethi; Woodward, Robert N; Grskovic, Marica; Sninsky, John J; Yee, James P; Brennan, Daniel C
Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls ( P =0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection. Copyright © 2017 by the American Society of Nephrology.
Here we report our experience with Tx for the last 25 years, specially our long experience of live related donor transplantation in children and adolescents with emphasis on technical issues in small children and pediatric patients with severe urologic malformations and bladder dysfunction. We′ll make special considerations on the improvement in short and long follow-up with the actual prevention and treatment of graft rejection, due to the new immunosuppressive agents and protocols.
Nassiri-Toosi, Mohssen; Kasraianfard, Amir; Ahmadinejad, Zahra; Dashti, Habibollah; Moini, Majıd; Najafi, Atabak; Salimi, Javad; Jafarian, Ali
Hepatitis B immunoglobulin prophylaxis in combination with antiviral drugs is recommended for prevention of hepatitis B virus reinfection after liver transplant. However, there is no consensus on a standard prophylactic method, and controversy exists over the duration, dose, and route of administration. We conducted a prospective study to evaluate the safety and effectiveness of intramuscular hepatitis B immunoglobulin in combination with lamivudine and/or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year for prevention of hepatitis B virus reinfection. Patients with hepatitis Brelated liver cirrhosis who had undergone primary liver transplants were enrolled. The prophylactic protocol involved intraoperative intramuscular hepatitis B immunoglobulin at 10 000 IU, tapering to 5000 IU daily for the first 6 days, weekly for a month, every 2 weeks for the next month, and monthly for a year after liver transplant, in combination with antiviral drugs. From January 2002 until March 2014, two hundred sixty-eight liver transplants were performed. Forty-four patients (16.4%) who underwent liver transplants due to hepatitis B-related liver failure were enrolled. Five patients had hepatocellular carcinoma; 20 had both hepatitis D and hepatitis B virus infection. The median age was 47 years (range, 26-59 y) with a median model for end stage liver disease score of 20. Thirty-three patients were men (76%). Sixty-one percent of patients were negative for hepatitis B virus DNA at the time of transplant. The median follow-up was 13.6 months (range, 0-142 mo). Only 1 patient (2.3%) experienced hepatitis B virus reinfection (at 44.7 months posttransplant), which was successfully treated with tenofovir. Five patients died (11.4%) during the follow-up from nonhepatitis B causes. Intramuscular hepatitis B immunoglobulin in combination with lamivudine or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year posttransplant may provide safe and cost
Full Text Available Abstract Background Inducing donor-specific tolerance in renal transplant patients could potentially prevent allograft rejection and calcineurin inhibitor nephrotoxicity. Combined kidney and hematopoietic stem cell transplant from an HLA-matched donor is an exploratory and promising therapy to induce immune tolerance. Investigtion of molecular mechanisms involved in the disease is needed to understand the potential process of cell therapy and develop strategies to prevent this immunologic rejection. Methods We enrolled nine patients in a clinical study in which cryopreserved donor hematopoietic stem cells were infused on days 2, 4, and 6 after kidney transplantation. One month post-transplant, 4 plasma samples were collected from combined transplants (C + Tx, and 8 plasma samples from patients with kidney transplantation alone (Tx. High abundance proteins in plasma were depleted and the two-dimensional liquid chromatography-tandem mass spectrometry coupled with iTRAQ labeling was utilized to identify the protein profiling between the two groups. Clusters of up- and down-regulated protein profiles were submitted to MetaCore for the construction of transcriptional factors and regulation networks. Results and Discussion Among the 179 identified proteins, 65 proteins were found in C + Tx with at least a 2-fold change as compared with Tx. A subset of proteins related to the complement and coagulation cascade, including complement C3a,complement C5a, precrusors to fibrinogen alpha and beta chains,was significantly downregulated in C + Tx. Meanwhile, Apolipoprotein-A1(ApoA1, ApoC1, ApoA2, ApoE, and ApoB were significantly lower in Tx compared to C + Tx. Gene ontology analysis showed that the dominant processes of differentially expressed proteins were associated with the inflammatory response and positive regulation of plasma lipoprotein particle remodeling. Conclusions Thus, our study provides new insight into the molecular events in
Conclusions: RVIs are associated with high morbidity and mortality among SOT and HSCT recipients. Management options are currently limited or lack strong clinical evidence. As community and nosocomial spread has been reported for all reviewed RVIs, strict adherence to infection control measures is key to preventing outbreaks.
Schousboe, Karoline; Titlestad, Kjell; Baudier, Francois
INTRODUCTION: Kidney transplantation is the optimal treatment for many patients with end-stage renal disease (ESRD). Due to shortage of donor kidneys in Denmark, there is a need to expand the possibilities for donation. At the Odense University Hospital (OUH), we have introduced ABO......-incompatible kidney transplantation. We used antigenspecific immunoadsorptions to remove blood group antibodies and anti-CD20 antibody (rituximab) to inhibit the antibody production. The aim of introducing the ABO-incompatible kidney transplantation at the OUH was to increase the rate of living donor kidney...... transplantation without increasing rejection or mortality rates. MATERIAL AND METHODS: Retrospective evaluation. Eleven patients received ABO-incompatible kidney transplantation. The patients were followed for 3-26 months. RESULTS: One patient had an antibody-mediated rejection, one patient suffered T...
Treister, Nathaniel; Nieder, Michael; Baggott, Christina; Olson, Ellen; Chen, Lu; Dang, Ha; Krailo, Mark; August, Amanda; Sung, Lillian
The primary objective was to determine whether topically administered Caphosol, rinsed orally four times daily at the initiation of conditioning, reduces the duration of severe oral mucositis (OM) compared with placebo among children and adolescents undergoing haematopoietic cell transplantation (HCT). This was a Children's Oncology Group multicentre randomised double-blinded placebo-controlled clinical trial. Patients between the ages of 4 and 21 years who were scheduled to undergo myeloablative HCT for any indication were randomised to Caphosol or placebo saline rinses four times daily from initiation of conditioning through day +20. Subjects were assessed daily for OM using the World Health Organisation (WHO) Oral Toxicity Scale, Mouth Pain Categorical Scale (0-10) and the Oral Mucositis Daily Questionnaire (OMDQ). The primary end point was duration of severe OM (WHO ⩾3). The study enrolled 220 participants with a median age of 13.7 years (range 4.0-21.9); 163 (74%) received allogeneic HCT. The mean (±s.d.) duration of severe OM was not reduced among Caphosol (4.5±5.0 days) vs placebo (4.5±4.8; P=0.99) recipients. The incidence of severe OM in the Caphosol and placebo arms was 63% (57 out of 91) and 68% (62 out of 91), respectively (P=0.44). There were no significant differences in any of the secondary end points between the groups. Caphosol did not reduce severe OM when compared with placebo among children and adolescents undergoing myeloablative HCT. Studies to identify effective interventions for OM are needed in this population.
Trabelsi, H; Néji, S; Sellami, H; Yaich, S; Cheikhrouhou, F; Guidara, R; Charffedine, K; Makni, F; Hachicha, J; Ayadi, A
Invasive fungal infections are a major complication and an important cause of morbidity and mortality among solid organ transplant recipients. Their diagnosis is difficult and their prognosis is often pejorative. The aim of this study was to report the cases of invasive fungal infections in renal transplant recipients in Habib Bourguiba Sfax university hospital and to identify the main fungal agents. It is a retrospective study of invasive fungal infections in renal transplant recipient reported in our hospital from January 1995 to February 2013. Invasive fungal infections were diagnosed in 11 cases (3.4%) among 321 renal transplant recipients. These infections included four cases of pneumocystosis, two cases of candidiasis, two cases of aspergillosis, two cases of cryptococcosis and one case of mucormycosis. There were six men and five women. The mean age was 37 years. The infection was late in 63% of cases (>3 months after transplantation). The prolonged corticosteroid and immunosuppressive therapy were the main risk factors (100%) followed by renal failure (45%), graft rejection (45%), broad spectrum antibiotics (45%), CMV infection (36%), neutropenia (36%) and dialysis (18%). The evolution under treatment was favourable only in two cases (18%). Invasive fungal infections are not common among kidney transplant recipients. However, they remain an important cause of morbidity and mortality in this group of patients. Prevention, early diagnosis and appropriate management are necessary to improve prognosis and reduce mortality rate. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
Pfitzmann, R; Müller, J; Grauhan, O; Hetzer, R
Measurements of intramyocardial impedance at high frequencies can indicate alterations in cell membranes and intracellular spaces during acute cardiac allograft rejection. Fifteen beagle dogs underwent heterotopic heart transplantation and were immunosuppressed with cyclosporine and methyl prednisolone (MP). Impedance was determined twice daily by means of four screw-in electrodes in the right and left ventricle. Transmyocardial biopsies and the intramyocardial electrogram (IMEG) were performed as reference methods. A total of 23 rejection episodes were induced. When acute rejection was recognized histologically and through IMEG readings, the animals were treated with a bolus of 125 mg of methyl prednisolone over 5 consecutive days. Treatment of rejection was controlled by biopsy and IMEG. All hearts showed a uniform decrease in impedance of about 28.3%+/-5.5% immediately after transplantation, which subsequently reached a stable plateau after 7 to 8 days. Impedance values then remained unchanged as long as rejection was absent. Biopsy findings of grades 1A to 1B (ISHLT) were accompanied by a statistically significant increase in impedance of 12.2%+/-2.5%; of grades 2 to 3A of 19.2%+/-3.2% and of grades 3B to 4 of 27.0%+/-2.9%. Sensitivity was 96%, specificity 91%. Successful treatment of rejection led to a decrease of impedance to the initial levels. The amount of increase in impedance of high frequencies is a method to stratify acute cardiac allograft rejection into grades like histologically grading. The effectiveness of rejection treatment can also be monitored through impedance measurement. The method is also applicable for telemetric rejection monitoring by means of an implantable device.
Full Text Available To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR and with cytomegalovirus (CMV infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score >37% = AR and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.
Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of relapse after transplantation.
Gress, Ronald E; Miller, Jeffrey S; Battiwalla, Minoo; Bishop, Michael R; Giralt, Sergio A; Hardy, Nancy M; Kröger, Nicolaus; Wayne, Alan S; Landau, Dan A; Wu, Catherine J
In the National Cancer Institute's Second Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Biology of Relapse discussed recent advances in understanding some of the host-, disease-, and transplantation-related contributions to relapse, emphasizing concepts with potential therapeutic implications. Relapse after hematopoietic stem cell transplantation (HSCT) represents tumor escape, from the cytotoxic effects of the conditioning regimen and from immunologic control mediated by reconstituted lymphocyte populations. Factors influencing the biology of the therapeutic graft-versus-malignancy (GVM) effect-and relapse-include conditioning regimen effects on lymphocyte populations and homeostasis, immunologic niches, and the tumor microenvironment; reconstitution of lymphocyte populations and establishment of functional immune competence; and genetic heterogeneity within the malignancy defining potential for clonal escape. Recent developments in T cell and natural killer cell homeostasis and reconstitution are reviewed, with implications for prevention and treatment of relapse, as is the application of modern genome sequencing to defining the biologic basis of GVM, clonal escape, and relapse after HSCT. Published by Elsevier Inc.
Scheffert, Jenna L; Raza, Kashif
Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over 6 years. Immunosuppressive regimens are employed to reduce the rate of rejection, and while protocols vary from center to center, conventional maintenance therapy consists of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agents [azathioprine (AZA), mycophenolate, sirolimus (srl), everolimus (evl)], and corticosteroids (CS). Roughly 50% of lung transplant centers also utilize induction therapy, with polyclonal antibody preparations [equine or rabbit anti-thymocyte globulin (ATG)], interleukin 2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab. This review summarizes these agents and the data surrounding their use in lung transplantation, as well as additional common and novel therapies in lung transplantation. Despite the progression of the management of lung transplant recipients, they continue to be at high risk of treatment-related complications, and poor graft and patient survival. Randomized clinical trials are needed to allow for the development of better agents, regimens and techniques to address above mentioned issues and reduce morbidity and mortality among lung transplant recipients.
Mitchell, A.B.; Meneley, D.
The objective of the present study was to establish a set of criteria (or Rejection Index) which could be used to decide whether a zirconium-2 1/2 w/o niobium pressure tube in a CANDU reactor should be removed from service due to in-service degradation. A critique of key issues associated with establishing a realistic rejection index was prepared. Areas of uncertainty in available information were identified and recommendations for further analysis and laboratory testing made. A Rejection Index based on the following limits has been recommended: 1) Limits related to design intent and normal operation: any garter spring must remain within the tolerance band specified for its design location; the annulus gas system must normally be operated in a circulating mode with a procedure in place for purging to prevent accumulation of deuterium. It must remain sensitive to leaks into any part of the systems; and pressure tube dimensions and distortions must be limited to maintain the fuel channels within the original design intent; 2) Limits related to defect tolerance: adequate time margins between occurrence of a leaking crack and unstable failure must be demonstrated for all fuel channels; long lap-type flaws are unacceptable; crack-like defects of any size are unacceptable; and score marks, frat marks and other defects with contoured profiles must fall below certain depth, length and stress intensity limits; and 3) Limits related to property degradation: at operating temperature each pressure tube must be demonstrated to have a critical length in excess of a stipulated value; the maximum equivalent hydrogen level in any pressure tube should not exceed a limit which should be defined taking into account the known history of that tube; the maximum equivalent hydrogen level in any rolled joint should not exceed a limit which is presently recommended as 200 ppm equivalent hydrogen; and the maximum diametral creep strain should be limited to less than 5%
Flávio Henrique Ferreira Galvão
to treat special cases of intestinal failure. AIM: This review highlights recent developments in the area of small bowel transplantation. MATERIAL AND METHODS: Over 600 reports on clinical and experimental small bowel transplantation were reviewed. Aspects concerning research development, different immunosuppressive strategies, patient and graft monitoring, and improvements in surgical techniques are discussed. RESULTS: About 700 small bowel transplantation were performed in 55 transplant centers, 44% intestine-liver, 41% isolated intestinal graft and 15% multivisceral transplantation. Rejection and infection are the main limitation of this procedure. Actual 5 years post transplantation graft survival of the total international experience is 46% for isolated intestinal graft, 43% for combined intestine-liver and nearly 30% for multivisceral transplantation. Higher graft and patient survival are seen at the more experienced centers. In a series of 165 intestinal transplantation at University of Pittsburgh, PA, USA, actuarial patient survival was reported to be over 75% at one year, 54% at 5 years and 42% at 10 years. Over 90% patients from Pittsburgh program resume an unrestricted oral diet. CONCLUSION: Small bowel transplantation has advanced from an experimental strategy to a feasible alternative for patients with permanent intestinal failure. Further refinements in graft acceptance, immunosuppressive regiments, infection management and prophylaxis, surgical techniques as well as appropriated patient referral and selection are crucial to improve outcomes.
Full Text Available We have utilized patients' own oral mucosa as a cell source for the fabrication of transplantable epithelial cell sheets to treat limbal stem cell deficiency and mucosal defects after endoscopic submucosal dissection of esophageal cancer. Because there are abundant microbiotas in the human oral cavity, the oral mucosa was sterilized and 40 μg/mL gentamicin and 0.27 μg/mL amphotericin B were added to the culture medium in our protocol. Although an oral surgeon carefully checked each patient's oral cavity and although candidiasis was not observed before taking the biopsy, contamination with Candida albicans (C. albicans was detected in the conditioned medium during cell sheet fabrication. After adding 1 μg/mL amphotericin B to the transportation medium during transport from Nagasaki University Hospital to Tokyo Women's Medical University, which are 1200 km apart, no proliferation of C. albicans was observed. These results indicated that the supplementation of transportation medium with antimycotics would be useful for preventing contamination with C. albicans derived from the oral mucosa without hampering cell proliferation.
Leventhal, Joseph R; Ildstad, Suzanne T
Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system in order to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for anti-rejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for anti-rejection drugs. Establishment of durable hematopoietic chimerism through hematopoietic stem cell transplantation (HSCT) has been shown in preclinical models and patients to lead to donor specific tolerance. However, the application HSCT is limited by the potential toxicity of conditioning regimens, the risk of graft versus host disease (GVHD) and the challenge of HLA mismatching. In this review we describe the clinical outcomes and science behind a CD8 + /TCR - facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to mismatched renal allografts while minimizing the risk of graft-versus-host GVHD and achieving avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients. Copyright © 2018 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Kawamura, K; Wada, H; Yamasaki, R; Ishihara, Y; Sakamoto, K; Ashizawa, M; Sato, M; Machishima, T; Terasako, K; Kimura, S I; Kikuchi, M; Nakasone, H; Yamazaki, R; Kanda, J; Kako, S; Tanihara, A; Nishida, J; Kanda, Y
Currently, acyclovir (ACV) at 1000 mg/day is widely used as prophylaxis in the early phase of hematopoietic stem cell transplant (HSCT) in Japan. However, low-dose ACV (200 mg/day) has been shown to prevent varicella zoster virus reactivation in the middle and late phases of HSCT. Therefore, in this study, we decreased the dose of ACV to 200 mg/day in the early phase after HSCT. We analyzed 93 consecutive herpes simplex virus (HSV)-seropositive patients who underwent allogeneic HSCT for the first time in our center between June 2007 and December 2011. Before August 2009, 38 patients received oral ACV at 1000 mg/day (ACV1000) until day 35 after HSCT, whereas 55 patients received oral ACV at 200 mg/day (ACV200) after September 2009. We compared the cumulative incidence of HSV infection in the 2 groups. Oral ACV was changed to intravenous administration because of intolerance in 66% and 45% of the patients in the ACV1000 and ACV200 groups, respectively (P = 0.060). The probability of severe stomatitis (Bearman grade II-III) was 76% and 60% in the ACV1000 and ACV200 groups, respectively (P = 0.12). The number of patients who developed HSV disease before day 100 after HSCT was 0 in the ACV1000 group and 2 in the ACV200 group, with a cumulative incidence of 3.6% (P = 0.43). HSV disease in the latter 2 patients was limited to the lips and tongue and was successfully treated with ACV or valacyclovir at a treatment dose. ACV at 200 mg/day appeared to be effective for preventing HSV disease in the early phase after HSCT. © 2013 John Wiley & Sons A/S.
Fuji, Shigeo; Kapp, Markus; Einsele, Hermann
Even though the overall outcome after allogeneic transplant has improved significantly in the last decades, late infectious diseases are still the most important causes of late morbidity and mortality. Here, impaired immune reconstitution and therapy of chronic graft-versus-host disease (GVHD) represent the major risk factors. In this review, we give a comprehensive overview of late infectious complications and summarize possible diagnostic and therapeutic interventions to prevent these complications. Copyright © 2012 Elsevier Inc. All rights reserved.
Full Text Available The goals of post-transplant management are to manage and treat postoperative complications, and develop a balanced long-term immunotherapy regimen that minimizes infection and side effects but controls rejection. While modern immunosuppressant regimes have reduced rates of graft loss due to rejection, they impart major risks for infection, growth failure, metabolic complications, and malignancy. There is significantly more post-transplant morbidity and mortality from infection than from rejection, particularly in infants. This has led to a trend toward minimization of immunosuppression, which is supported by evidence that some rejection facilitates graft tolerance and thus is not necessarily always harmful. Post-transplant complications are divided into those that occur in the first 3–12 months (“early”, and these are relatively common, and those occurring after 12 months (“late”, which are generally uncommon. Most “early” complications relate to surgical issues, and/or immunosuppression, most notably infection, vascular complications of the graft, and biliary leaks. Infection is the most common cause of post-transplant mortality. Rejection does occur but usually responds to treatment with steroid pulse dosing, and appears not to contribute to either graft or patient mortality. “Late” complications include biliary strictures, which are uncommon and generally respond to percutaneous biliary dilatation and stent procedures. Most late complications are primarily related to the effects of long-term immunosuppression, notably infections such as EBV and associated PTLD, and side effects of immunosuppression such as renal dysfunction, hypertension, and immune dysregulation.
Cui, Yufeng; Lu, Wei; Gao, Wei; Dong, Chong; Han, Chao; Liu, Yihe
To investigate the effect of active immunization on prevention of post-transplantation de novo hepatitis B virus (HBV) infection in patients receiving liver grafts from hepatitis B core antibody (HBcAb) positive donors. A retrospective analysis was conducted. Eighty-seven children undergoing liver transplantation from HBcAb positive donors admitted to Tianjin First Center Hospital from October 2012 to December 2016 were enrolled, and the data of donors and recipients were collected. The hepatitis B vaccine was given before operation for hepatitis B surface antibody (HBsAb) > 1 000 U/L; hepatitis B immunoglobulin (HBIG) 100 U/kg was given during the operation, in order to prevent children from HBV infected by obtaining passive immunity quickly, children with HBsAb HBcAb positive donor livers, 9 (10.3%) developed de novo HBV infection, which occurred in 16 (10, 25) months after liver transplantation. Among the 9 children with HBV infection, 7 children had HBsAb HBcAb positive donors with preventive treatment.
Avaliação da interferência da tolerância oral na rejeição do transplante de coração alogênico avascular na orelha de camundongo Evaluation of the interference of oral tolerance in the rejection of avascular allogeneic heart grafts to mouse ears
discovery of immune-suppressors permitted heart transplantation to be accepted as a widespread treatment for terminally ill patients, rejection, complications due to these drugs and the chronic vasculopathies continue to be majority problems. The search for alternatives to supplant these impediments by performing avascular allogeneic heart transplants from newborn BALB/C mice (24h old to the subcutaneous tissue of the ears of adult male C57BI/6J and C3H/HEJ mice to evaluate the interference of systemic oral tolerance on the rejection mechanisms are our main goal. METHOD: Adult, male C57BI/6 e C3H/HEJ were divided in two groups. The tolerant group received peanuts ad libitum for one week in the diet while the immune group continued to eat mouse chow. Both groups were immunized sc with 100mg of peanut extract. The transplanted newborn BALB/C hearts were deposited of into the subcutaneous tissue of the ears of tolerant and immune mice in the presence or not of concomitant immunization to peanut protein. RESULTS: We demonstrated that feeding proteins induces systemic tolerance since animals of both strains that ate the seeds before being immunized had lower systemic antibodies than immune animals. Tolerant C3H/HEJ mice with concomitant administration of the tolerogenic antigen presented a more preserved transplanted heart than all other groups. CONCLUSION: Although not homegeneously, the immunoregulatory mecanisms of oral tolerance modified the rejection process of alogenic avascular heart transplant to the ear of adult mice. As these mecanisms are not yet well understood more work needs to be done in this field.
Novitzky, D.; Bonioszczuk, J.; Cooper, D.K.C.; Isaacs, S.; Rose, A.G.; Smith, J.A.; Uys, C.J.; Barnard, C.N.; Fraser, R.
Radionuclide scanning of the donor left ventricle using technetium-99m-labelled red cells was used to monitor acute rejection after heterotopic heart transplantation and compared with histopathological evidence of rejection obtained at examination of an endomyocardial biopsy specimen. The ejection fraction and end-diastolic, end-systolic and stroke volumes were calculated at each examination; an equation was derived from these data to predict the degree of acute rejection, using histopathological examination of endomyocardial biopsy specimens as criteria of the presence and severity of rejection. A highly significant multiple correlation between radionuclide scanning parameters and endomyocardial biopsy was found. The advantages of non-invasive radionuclide scanning over the invasive procedure of endomyocardial biopsy are discussed
Ji Won Min
Full Text Available It is well known that pre-transplant B cell activating factor (BAFF levels are associated with the development of de novo anti-HLA antibodies and antibody mediated rejection post-transplant. However, the clinical significance of BAFF values at allograft rejection has not been determined. In this study, we investigated the clinical significance of pre-transplant BAFF level as well as post-transplant BAFF levels measured when indication biopsy was done. We checked for anti-HLA antibodies in 115 kidney transplant recipients who required allograft biopsy due to an increase in serum creatinine. With the same serum specimen, we measured BAFF levels, and in 78 of these patients, pre-transplant BAFF and anti-HLA antibody levels were detected as well. Patients in each group were divided into tertiles according to BAFF levels. We investigated the relationship between BAFF levels and the occurrence of anti-HLA antibodies. Pre-transplant BAFF levels showed significant association with pre-transplant sensitization, and also with early rejection (Tertile 3, 26.9% vs. Tertile 1, 11.5%; P<0.05. Post-transplant BAFF levels showed significant association with pre-transplant sensitization, but did not show association with anti-HLA antibodies and positive donor-specific antibodies at the time of biopsy. We did not find any association between post-transplant BAFF levels and allograft biopsy results, Banff scores and microvascular inflammation scores. In conclusion, pre-transplant BAFF levels are associated with pre-transplant sensitization and are useful in predicting allograft rejection. But post-transplant BAFF levels measured at the time of indication biopsy are not associated with the appearance of de novo HLA-DSA, allograft rejection, biopsy findings and other allograft outcomes.
Full Text Available Cyclosporine is the main immunosuppressive drug used for renal transplant reci-pients in order to prevent transplant rejection. Although the drug has increased the survival of patients and grafted organ, it has some side effects independent of its effect on the immune system. This study was done to evaluate the effect of cyclosporine on serum Mg level and its metabolic side effects in renal allograft patients. 157 (62 female and 95 male renal transplant recipients treated with cyclosporine to prevent transplant rejection were included in the study. Clinical and biochemical data along with cyclosporine levels was documented. Mean serum Mg level was 196 ± 0.31 mg/dL and mean serum cyclosporine level was 371 ± 192 µg/dL. Hypomagnesemia was detected in 16 (10.2% with a negative significant correlation with cyclosporine levels, serum creatinine, plasma LDL, fasting Blood sugar and uric acid. In conclusion according to the results of this study there is a significant correlation between cyclosporine and hypomagnesemia. Therefore, routine measurement of serum Mg and its treatment seems necessary to prevent its complications.
Gordon, A. M.; Briggs, J. D.; Bell, P. R. F.
The nitroblue tetrazolium (NBT) test has been evaluated as a means of differentiating episodes of infection and rejection in 10 cadaver kidney transplant recipients. Normal NBT values were observed during all 11 episodes of acute rejection. A significant elevation of the NBT score was encountered in six of eight episodes of infection after transplantation. A positive NBT result is useful additional evidence in favour of infection in patients in whom the differentiation of infection and rejection is proving difficult. PMID:4610010
Reversal of tolerance induced by transplantation of skin expressing the immunodominant T cell epitope of rat type II collagen entitles development of collagen-induced arthritis but not graft rejection
Bäcklund, Johan; Treschow, Alexandra; Firan, Mihail
Collagen-induced arthritis (CIA) is induced in H-2(q) mice after immunization with rat type II collagen (CII). The immunodominant T cell epitope on heterologous CII has been located to CII256-270. We have previously shown that TSC transgenic mice, which express the heterologous epitope in type I...... collagen (CI), e.g. in skin, are tolerized against rat CII and resistant to CIA. In this study we transplanted skin from TSC transgenic mice onto non-transgenic CIA-susceptible littermates to investigate whether introduction of this epitope to a naïve immune system would lead to T cell priming and graft...
Bailey, S.; Miller, Barbara J.; Cooper, E. L.
The oligochaete annelids Lumbricus terrestris and Eisenia foetida were used to demonstrate adoptive transfer of transplantation immunity. Eisenia grafts were used as sensitizing antigen and test grafts. Host Lumbricus injected with coelomic fluid containing coelomocytes from Lumbricus donors previously sensitized to Eisenia grafts rejected test grafts in an accelerated fashion. The rejection time was shorter and significantly different from that of worms injected with saline or coelomocytes from unsensitized worms. Coelomocytes resemble various vertebrate leucocytes and immunocytes and seem equivalent to a hypothetical invertebrate precursor wandering cell which recognizes and reacts to antigen. ImagesFIG. 1 PMID:5558033
Veighey, Kristin; MacAllister, Raymond
Ischemia-reperfusion injury is a composite of the injury sustained during a period of reduced or absent blood flow to a tissue or organ and the additional insult sustained on reperfusion, which limits the amount of tissue that can be salvaged. Ischemia-reperfusion injury is the predominant insult during kidney transplantation, contributing to graft dysfunction, increased rates of acute rejection, and reduced rejection-free graft survival. In this review, we discuss the potential therapeutic benefits of a cost-effective and low-risk intervention, ischemic preconditioning, and its potential for improving kidney function following transplantation.
Martelli, Massimo F; Di Ianni, Mauro; Ruggeri, Loredana; Falzetti, Franca; Carotti, Alessandra; Terenzi, Adelmo; Pierini, Antonio; Massei, Maria Speranza; Amico, Lucia; Urbani, Elena; Del Papa, Beatrice; Zei, Tiziana; Iacucci Ostini, Roberta; Cecchini, Debora; Tognellini, Rita; Reisner, Yair; Aversa, Franco; Falini, Brunangelo; Velardi, Andrea
Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow. © 2014 by The American Society of Hematology.
Phelan, Paul J
Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis.
Phelan, Paul J
Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis.
Wang, Weilin; Xu, Shaoyan; Ren, Zhigang; Jiang, Jianwen; Zheng, Shusen
The latest high-throughput sequencing technologies show that there are more than 1000 types of microbiota in the human gut. These microbes are not only important to maintain human health, but also closely related to the occurrence and development of various diseases. With the development of transplantation technologies, allogeneic transplantation has become an effective therapy for a variety of end-stage diseases. However, complications after transplantation still restrict its further development. Post-transplantation complications are closely associated with a host's immune system. There is also an interaction between a person's gut microbiota and immune system. Recently, animal and human studies have shown that gut microbial populations and diversity are altered after allogeneic transplantations, such as liver transplantation (LT), small bowel transplantation (SBT), kidney transplantation (KT) and hematopoietic stem cell transplantation (HTCT). Moreover, when complications, such as infection, rejection and graft versus host disease (GVHD) occur, gut microbial populations and diversity present a significant dysbiosis. Several animal and clinical studies have demonstrated that taking probiotics and prebiotics can effectively regulate gut microbiota and reduce the incidence of complications after transplantation. However, the role of intestinal decontamination in allogeneic transplantation is controversial. This paper reviews gut microbial status after transplantation and its relationship with complications. The role of intervention methods, including antibiotics, probiotics and prebiotics, in complications after transplantation are also discussed. Further research in this new field needs to determine the definite relationship between gut microbial dysbiosis and complications after transplantation. Additionally, further research examining gut microbial intervention methods to ameliorate complications after transplantation is warranted. A better understanding of the
Min, Ji Won; Kim, Kyoung Woon; Kim, Bo-Mi; Doh, Kyoung Chan; Choi, Min Seok; Choi, Bum Soon; Park, Cheol Whee; Yang, Chul Woo; Kim, Yong-Soo; Oh, Eun-Jee; Chung, Byung Ha
It is well known that pre-transplant B cell activating factor (BAFF) levels are associated with the development of de novo anti-HLA antibodies and antibody mediated rejection post-transplant. However, the clinical significance of BAFF values at allograft rejection has not been determined. In this study, we investigated the clinical significance of pre-transplant BAFF level as well as post-transplant BAFF levels measured when indication biopsy was done. We checked for anti-HLA antibodies in 115 kidney transplant recipients who required allograft biopsy due to an increase in serum creatinine. With the same serum specimen, we measured BAFF levels, and in 78 of these patients, pre-transplant BAFF and anti-HLA antibody levels were detected as well. Patients in each group were divided into tertiles according to BAFF levels. We investigated the relationship between BAFF levels and the occurrence of anti-HLA antibodies. Pre-transplant BAFF levels showed significant association with pre-transplant sensitization, and also with early rejection (Tertile 3, 26.9% vs. Tertile 1, 11.5%; PBAFF levels showed significant association with pre-transplant sensitization, but did not show association with anti-HLA antibodies and positive donor-specific antibodies at the time of biopsy. We did not find any association between post-transplant BAFF levels and allograft biopsy results, Banff scores and microvascular inflammation scores. In conclusion, pre-transplant BAFF levels are associated with pre-transplant sensitization and are useful in predicting allograft rejection. But post-transplant BAFF levels measured at the time of indication biopsy are not associated with the appearance of de novo HLA-DSA, allograft rejection, biopsy findings and other allograft outcomes.
Tapak, Leili; Hamidi, Omid; Amini, Payam; Poorolajal, Jalal
Kidney transplantation is the best renal replacement therapy for patients with end-stage renal disease. Several studies have attempted to identify predisposing factors of graft rejection; however, the results have been inconsistent. We aimed to identify prognostic factors associated with kidney transplant rejection using the artificial neural network (ANN) approach and to compare the results with those obtained by logistic regression (LR). The study used information regarding 378 patients who had undergone kidney transplantation from a retrospective study conducted in Hamadan, Western Iran, from 1994 to 2011. ANN was used to identify potential important risk factors for chronic nonreversible graft rejection. Recipients' age, creatinine level, cold ischemic time, and hemoglobin level at discharge were identified as the most important prognostic factors by ANN. The ANN model showed higher total accuracy (0.75 vs. 0.55 for LR), and the area under the ROC curve (0.88 vs. 0.75 for LR) was better than that obtained with LR. The results of this study indicate that the ANN model outperformed LR in the prediction of kidney transplantation failure. Therefore, this approach is a promising classifier for predicting graft failure to improve patients' survival and quality of life, and it should be further investigated for the prediction of other clinical outcomes.
Ashokkumar, Chethan; Soltys, Kyle; Mazariegos, George; Bond, Geoffrey; Higgs, Brandon W.; Ningappa, Mylarappa; Sun, Qing; Brown, Amanda; White, Jaimie; Levy, Samantha; Fazzolare, Tamara; Remaley, Lisa; Dirling, Katie; Harris, Patti; Hartle, Tara; Kachmar, Pam; Nicely, Megan; O'Toole, Lindsay; Boehm, Brittany; Jativa, Nicole; Stanley, Paula; Jaffe, Ronald; Ranganathan, Sarangarajan; Zeevi, Adriana; Sindhi, Rakesh
Background Allospecific CD154+T-cytotoxic memory cells (CD154+TcM) predict acute cellular rejection (ACR) after liver or intestine transplantation (LTx, ITx) in small cohorts of children and can enhance immunosuppression management, but await validation and clinical implementation. Methods To establish safety and probable benefit, CD154+TcM were measured in cryopreserved samples from 214 children 1 implies increased rejection-risk. Results Training and validation set subjects were demographically similar. Mean coefficient of test variation was <10% under several conditions. Logistic regression incorporating several confounding variables identified separate pre-transplant and post-transplant IR thresholds for prediction of rejection in respective training set samples. An IR ≥ 1.1 in post-transplant training samples, and IR ≥1.23 in pre-transplant training samples predicted LTx or ITx rejection in corresponding validation set samples in the 60-day post-sampling period with sensitivity, specificity, positive and negative predictive values of 84%, 80%, 64%, and 92%, respectively (AUC 0.792), and 57%, 89%, 78%, and 74%, respectively (AUC 0.848). No adverse events were encountered due to phlebotomy. Conclusions Allospecific CD154+T-cytotoxic memory cells predict acute cellular rejection after liver or intestine transplantation in children. Adjunctive use can enhance clinical outcomes. PMID:26950712
Aziz, Fahad; Penupolu, Sudheer; Xu, Xin; He, Jianxing
Lung transplantation is commonly used for patients with end-stage lung disease. However, there is continuing debate on the optimal operation for patients with chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Single-lung transplantation (SLT) provides equivalent short- and medium-term results compared with bilateral lung transplantation (BLT), but long-term survival appears slightly better in BLT recipients (especially in patients with COPD). The number of available organs for lung transplantation also influences the choice of operation. Recent developments suggest that the organ donor shortage is not as severe as previously thought, making BLT a possible alternative for more patients. Among the different complications, re-implantation edema, infection, rejection, and bronchial complications predominate. Chronic rejection, also called obliterative bronchiolitis syndrome, is a later complication which can be observed in about half of the patients. Improvement in graft survival depends greatly in improvement in prevention and management of complications. Despite such complications, graft survival in fibrosis patients is greater than spontaneous survival on the waiting list; idiopathic fibrosis is associated with the highest mortality on the waiting list. Patients should be referred early for the pre-transplantation work-up because individual prognosis is very difficult to predict.
Poropat, Goran; Giljaca, Vanja; Stimac, Davor
Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium and central vein...
Knosalla, C; Grauhan, O; Muller, J; Pfitzmann, R; Fietze, E; Cohnert, T; Volk, H D; Hetzer, R
The purpose of this study was to prove the reliability of intramyocardial electrogram (IMEG) recordings for diagnosis and treatment monitoring of (1) cellular and (2) humoral mediated allograft rejection after heart transplantation. Fifteen beagle dogs underwent heterotopic neck-heart transplantation. Eight of them were previously sensitized through several skin transplantations. IMEG recordings were performed daily. Donor-specific antibodies (IgG, IgM) were determinated in serum daily. Transmyocardial biopsies were performed every two days. In the sensitized group (group I) accelerated rejection occurred under triple drug immunosuppression with cyclosporine A, azathioprine, and cortisone on the fifth postoperative day (range: 4th-5th). All episodes were detected through IMEG diagnosis. In each case rejection could be treated successfully. In the cellular mediated group (group II), the average sensitivity for rejection diagnosis of a single lead was 24% for the unipolar and 42% for the bipolar leads. When the voltages of different leads were summed up the sensitivity rose to 36% (3 unipolar), 81% (3 bipolar) and 100% (all leads). During rejection therapy the IMEG recovered within 24-48 hours. The IMEG detects cellular and humoral mediated rejection early and with high reliability. The rejection-related changes of grade 2/3a rejection in IMEG seem to follow a Ofocal patternO similar to the histology. Therefore the recording of several, preferably bipolar, electrode configurations appears to enhance diagnostic reliability.
Full Text Available BACKGROUND: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs. Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. CONCLUSIONS: Our data show, for the first time, the efficacy of ES-derived CD45(+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.
Results of a 2-Arm, Phase 2 Clinical Trial Using Post-Transplantation Cyclophosphamide for the Prevention of Graft-Versus-Host Disease in Haploidentical Donor and Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation
Gaballa, Sameh; Ge, Isabell; Fakih, Riad El; Brammer, Jonathan E.; Kongtim, Piyanuch; Tomuleasa, Ciprian; Wang, Sa A.; Lee, Dean; Petropoulos, Demetrios; Cao, Kai; Rondon, Gabriela; Chen, Julianne; Hammerstrom, Aimee; Lombardi, Lindsey; Alatrash, Gheath; Korbling, Martin; Oran, Betul; Kebriaei, Partow; Ahmed, Sairah; Shah, Nina; Rezvani, Katayoun; Marin, David; Bashir, Qaiser; Alousi, Amin; Nieto, Yago; Qazilbash, Muzaffar; Hosing, Chitra; Popat, Uday; Shpall, Elizabeth J.; Khouri, Issa; Champlin, Richard E.; Ciurea, Stefan O.
BACKGROUND High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients. METHODS A parallel, 2-arm, nonrandomized phase 2 clinical trial was conducted of melphalan-based reduced-intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high-risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT. RESULTS The 1-year overall and progression-free survival rates were 70% and 60%, respectively, in the HAPLO arm and 60% and 47%, respectively, in the 9/10 MUD arm. The day +100 cumulative incidence of grade II to IV acute GVHD and grade III to IV acute GVHD was 28% and 3%, respectively, in the HAPLO arm and 33% and 13%, respectively, in the 9/10 MUD arm. The 2-year cumulative incidence of chronic GVHD was 24% in the HAPLO arm and 19% in the 9/10 MUD arm. The 1-year cumulative incidence of nonrelapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, and the 1-year relapse rate was 19% in the HAPLO arm and 25% in the 9/10 MUD arm. CONCLUSIONS Although this was a nonrandomized study and could not serve as a direct comparison between the 2 groups, the authors conclude that PTCy-based GVHD prophylaxis is effective for both HAPLO and 9/10 MUD SCTs. Prospective randomized trials will be required to compare the efficacies of alternative donor options for patients lacking HLA-matched donors. PMID:27404668
Ayduk, Özlem; Gyurak, Anett; Luerssen, Anna
Self-concept clarity (SCC) refers to the extent to which self-knowledge is clearly and confidently defined, internally consistent, and temporally stable. Research shows that SCC can be undermined by failures in valued goal domains. Because preventing rejection is an important self-relevant goal for people high in rejection sensitivity (RS), it is hypothesized here that failures to attain this goal would cause them to experience diminished SCC. Study 1, an experimental study, showed that high-RS people’s SCC was undermined following rejection but not following an aversive experience unrelated to rejection. Study 2, a daily diary study of couples in relationships, used occurrence of partner conflicts to operationalize rejection. Replicating the findings in Study 1, having a conflict on any given diary day predicted a greater reduction in the SCC of high- compared to low-RS people on the following day. The implications for understanding the conditions under which rejection negatively affects the self-concept are discussed. PMID:19713567
Kramer, C S M; Roelen, D L; Heidt, S; Claas, F H J
Transplantation of an human leukocyte antigen (HLA) mismatched graft can lead to the development of donor-specific antibodies (DSA), which can result in antibody mediated rejection and graft loss as well as complicate repeat transplantation. These DSA are induced by foreign epitopes present on the mismatched HLA antigens of the donor. However, not all epitopes appear to be equally effective in their ability to induce DSA. Understanding the characteristics of HLA epitopes is crucial for optimal epitope matching in clinical transplantation. In this review, the latest insights on HLA epitopes are described with a special focus on the definition of immunogenicity and antigenicity of HLA epitopes. Furthermore, the use of this knowledge to prevent HLA antibody formation and to select the optimal donor for sensitised transplant candidates will be discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Krishnan, Rahul; Alexander, Michael; Robles, Lourdes; Foster 3rd, Clarence E.; Lakey, Jonathan R.T.
Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues. PMID:25148368
Mittel, Aaron M; Wagener, Gebhard
Kidney transplants are the most common solid organ abdominal transplant and are occasionally performed simultaneously with pancreas transplants in diabetic patients. Preoperative evaluation of potential transplant recipients should focus on the potential for occult cardiovascular disease while also screening for other signs of end-organ dysfunction. Intraoperatively, it is of utmost importance to ensure adequate graft perfusion to limit the risk of postoperative graft dysfunction or rejection. Postoperative care of the kidney or pancreas transplant patient should focus on ensuring normalization of volume status, electrolyte concentrations, and glycemic control. Copyright © 2017 Elsevier Inc. All rights reserved.
Rodrigues, Luis Vaz; Gandara, Judit; Pires, João; Duarte, Raquel; Calvário, Fernando; Dominguez, Miguel; Carvalho, Aurora; Seca, Rui
We report on a patient diagnosed with disseminated (hepatic and pulmonary) tuberculosis in the context of immunosuppression following liver transplant. During the administration of anti-tuberculosis drugs an abrupt elevation of liver enzymes was detected leading us to suspect drug toxicity rather than graft rejection. Nevertheless, careful surveillance and adjustment of serum levels of immunosuppressant drugs permitted continuance of tuberculosis treatment with no further side effects.
Liu, Jin-Yu; You, Ru-Xu; Guo, Min; Zeng, Lu; Zhou, Pu; Zhu, Lan; Xu, Gang; Li, Juan; Liu, Dong
Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period.
Versele, Emmanuelle B; Van Laecke, Steven; Dhondt, Annemieke W; Verbeke, Francis; Vanholder, Raymond; Van Biesen, Wim; Nagler, Evi V
An estimated 60% of kidney transplant recipients have mineral bone disease and about 0.5% break their hip within the first year after transplantation. We conducted a systematic review of benefits and harms of bisphosphonates in kidney transplant recipients. We searched CENTRAL (Issue 5, 2015) for randomized controlled trials in all languages and screened the reference list of an earlier Cochrane review. One reviewer identified the trials, extracted all data, and assessed risk of bias. Meta-analysis used a random effects model, with results expressed as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). Bisphosphonates have uncertain effects on death (RR 0.45, CI 0.04-4.69) and vertebral fractures (RR 0.58, CI 0.24-1.43, I(2) 0%). Bisphosphonates moderately to importantly reduce the loss of vertebral bone mineral density (MD 5.98%, CI 3.77-8.18% change from baseline in g calcium/cm² at 12 months, I(2) 91%) and femoral bone mineral density (MD 5.57%, 3.12-8.01% change from baseline in g calcium/cm² at 12 months, I(2) 69%). At this stage, insufficient evidence exists to support routine use of bisphosphonates to reduce fracture risk after kidney transplantation. Data on important health outcomes are lacking, surrogate outcomes poorly reflect bone quality in kidney transplant recipients, and serious adverse events are not studied and reported systematically. © 2015 Steunstichting ESOT.
Manito, Nicolás; Delgado, Juan F; Crespo-Leiro, Maria G; González-Vílchez, Francisco; Almenar, Luis; Arizón, José M; Díaz, Beatriz; Fernández-Yáñez, Juan; Mirabet, Sònia; Palomo, Jesús; Rodríguez Lambert, José L; Roig, Eulàlia; Segovia, Javier
Proliferation signal inhibitors (PSIs), everolimus (EVL), and sirolimus are a group of immunosuppressor agents indicated for the prevention of acute rejection in adult heart transplant recipients. Proliferation signal inhibitors have a mechanism of action with both immunosuppressive and antiproliferative effects, representing an especially interesting treatment option for the prevention and management of some specific conditions in heart transplant population, such as graft vasculopathy or malignancies. Proliferation signal inhibitors have been observed to work synergistically with calcineurin inhibitors (CNIs). Data from clinical trials and from the growing clinical experience show that when administered concomitantly with CNIs, PSIs allow significant dose reductions of the latter without loss of efficacy, a fact that has been associated with stabilization or significant improvement in renal function in patients with CNI-induced nephrotoxicity. The purpose of this article was to review the current knowledge of the role of PSIs in heart transplantation to provide recommendations for the proper use of EVL in cardiac transplant recipients, including indications, treatment regimens, monitoring, and management of the adverse events. Copyright 2010 Elsevier Inc. All rights reserved.
El-Chemaly, Souheil; O’Brien, Kevin J.; Nathan, Steven D.; Weinhouse, Gerald L.; Goldberg, Hilary J.; Connors, Jean M.; Cui, Ye; Astor, Todd L.; Camp, Philip C.; Rosas, Ivan O.; Lemma, Merte; Speransky, Vladislav; Merideth, Melissa A.; Gahl, William A.
Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants. PMID:29547626
Warnecke, H; Schüler, S; Goetze, H J; Matheis, G; Süthoff, U; Müller, J; Tietze, U; Hetzer, R
Rejection after cardiac transplantation was monitored in nine patients by control of intramyocardial electrogram (IMEG) recordings transmitted by an implanted telemetric pacemaker. Under immunosuppression with cyclosporin A and prednisolone, 33 out of a total of 119 endomyocardial biopsy specimens showed moderate rejection (infiltrate with myocytolysis). Twenty-nine of these rejection episodes could be correctly predicted from IMEG recordings with a voltage drop above 15% used as a criterion (sensitivity 87.9%). Eighty-three of 86 negative biopsy results corresponded to negative IMEG results (specificity 96.5%). In this group of patients, amplitude of body surface electrocardiograms was not useful for the diagnosis of rejection because of the broad range of spontaneous variation. Control of IMEG voltage amplitude appears to be more accurate than body surface electrocardiogram amplitude in the detection of rejection episodes. Thus the onset of rejection during biopsy intervals is more readily detected and treatment is instituted earlier. The method is suitable for ambulatory patient monitoring by the patient's local physician.
Full Text Available Amit Sharma, Rajesh Ramanathan, Marc Posner, Robert A Fisher Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA Abstract: Pediatric kidney transplantation is the preferred treatment for children with end-stage renal disease. The most common indications for transplantation in children are renal developmental anomalies, obstructive uropathy, and focal segmental glomerulosclerosis. Living donor kidney transplants are often performed pre-emptively and offer excellent graft function. Policy changes in deceased-donor kidney allocation have increased the proportion of such transplants in pediatric recipients. Adequate pretransplant workup along with evaluation of urologic abnormalities is imperative in achieving good outcomes. Overall, patient and graft outcomes after kidney transplantation have improved, with five-year deceased donor and living donor graft survivals of 78.8% and 84.3%, respectively. Improvements in induction and maintenance immunosuppression have contributed to the gradual improvement in outcomes. Unique challenges in pediatric recipients include increased graft thrombosis, adverse growth, and abnormal development relating to immunosuppression, increased rejection due to nonadherence, increased susceptibility to opportunistic infections, and post-transplant malignancy. This review focuses on the current practices and outcomes in pediatric kidney transplantation in North America. We discuss the indications for transplantation, the evaluation process, some key surgical and immunologic considerations, and the common risk factors for graft dysfunction. Keywords: pediatric kidney transplantation, end-stage renal disease, dialysis, organ donors, immunosuppression
Al Otaibi, Torki; Ahmadpoor, Pedram; Allawi, Ali Abdulmajid Dyab; Habhab, Wael Taher; Khatami, Mohammad Reza; Nafar, Mohsen; Glotz, Denis
With an increased incidence of living-donor kidney transplants, in response to increasing unmet needs for renal transplant, a clear understanding of determinants of posttransplant outcomes is essential. The importance of delayed graft function in deceased-donor kidney transplant is now part of conventional medical wisdom, due to the large amount of evidence focused on this aspect. However, the same is not true for living-donor kidney transplant, partly due to lack of evidence on this crucial clinical question and partly due to lack of awareness about this issue. The current review aims to highlight the importance of delayed graft function as a crucial determinant of outcomes in living-donor kidney transplant. An exhaustive search of online medical databases was performed with appropriate search criteria to collect evidence about delayed graft function after living-donor kidney transplant, with a special focus on studies from the Middle East. Data on incidence, impact, risk factors, and possible prevention modalities of delayed graft function in patients undergoing living-donor kidney transplant are presented. A key finding of this review is that contemporary incidence rates reported from the Middle East are comparatively higher than those reported from outside the region. Although in absolute terms the incidence is lower than deceased donor kidney transplant, the effects of delayed graft function on graft rejection and graft and patient survival are sufficiently large to warrant the formulation of specific treatment protocols. Key to formulating prevention and treatment strategies is identifying discrete risk factors for delayed graft function. Although this evidence is scant, an overview has been provided. Further studies examining different aspects of delayed graft function incidence after living-donor kidney transplant are urgently needed to address a so far little known clinical question.
Gumabay, Franz Marie; Novak, Marta; Bansal, Aarushi; Mitchell, Margot; Famure, Olusegun; Kim, S Joseph; Mucsi, Istvan
The association between pre-transplant mental health concerns and non-adherence and post-transplant outcomes after kidney transplantation is not fully established. We examined the relationship between a pre-transplant history of mental health concerns and non-adherence and post-transplant outcomes among kidney transplant recipients. In this retrospective single center cohort study of adult kidney transplant recipients (n=955) the associations between the history of mental health concerns or non-adherence and the time from kidney transplant to biopsy proven acute rejection; death-censored graft failure and total graft failure were examined using Cox proportional hazards models. Mean (SD) age was 51 (13) years, 61% were male and 27% had a history of diabetes. Twenty-two and 11% of patients had mental health concerns and non-adherence, respectively. Fifteen percent of the patients had acute rejection, 5.6% had death-censored graft failure and 13.0% had total graft failure. The history of mental health concerns was not associated with acute rejection, death-censored graft failure or total graft failure. Patients with versus without a history of non-adherence tended to have higher cumulative incidence of acute rejection (23.3% [95% CI: 16.1, 33.2] vs. 13.6% [95% CI: 11.4, 16.2]) and death-censored graft failure (15.0% [95% CI: 6.9, 30.8] vs. 6.4% [95% CI: 4.7, 8.7]) (log rank p=0.052 and p=0.086, respectively). These trends were not significant after multivariable adjustment. In summary, a history of pre-transplant mental health concerns or non-adherence is not associated with adverse outcomes in patients who completed transplant workup and received a kidney transplant. Copyright © 2018 Elsevier Inc. All rights reserved.
Akoh, Jacob A
Access to organ transplantation depends on national circumstances, and is partly determined by the cost of health care, availability of transplant services, the level of technical capacity and the availability of organs. Commercial transplantation is estimated to account for 5%-10% (3500-7000) of kidney transplants performed annually throughout the world. This review is to determine the state and outcome of renal transplantation associated with transplant tourism (TT) and the key challenges with such transplantation. The stakeholders of commercial transplantation include: patients on the waiting lists in developed countries or not on any list in developing countries; dialysis funding bodies; middlemen, hosting transplant centres; organ-exporting countries; and organ vendors. TT and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection which cause major morbidity and mortality. There are ethical and medical concerns regarding the management of recipients of organs from vendors. The growing demand for transplantation, the perceived failure of altruistic donation in providing enough organs has led to calls for a legalised market in organ procurement or regulated trial in incentives for donation. Developing transplant services worldwide has many benefits - improving results of transplantation as they would be performed legally, increasing the donor pool and making TT unnecessary. Meanwhile there is a need to re-examine intrinsic attitudes to TT bearing in mind the cultural and economic realities of globalisation. Perhaps the World Health Organization in conjunction with The Transplantation Society would set up a working party of stakeholders to study this matter in greater detail and make recommendations.
Akoh, Jacob A
Access to organ transplantation depends on national circumstances, and is partly determined by the cost of health care, availability of transplant services, the level of technical capacity and the availability of organs. Commercial transplantation is estimated to account for 5%-10% (3500-7000) of kidney transplants performed annually throughout the world. This review is to determine the state and outcome of renal transplantation associated with transplant tourism (TT) and the key challenges with such transplantation. The stakeholders of commercial transplantation include: patients on the waiting lists in developed countries or not on any list in developing countries; dialysis funding bodies; middlemen, hosting transplant centres; organ-exporting countries; and organ vendors. TT and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection which cause major morbidity and mortality. There are ethical and medical concerns regarding the management of recipients of organs from vendors. The growing demand for transplantation, the perceived failure of altruistic donation in providing enough organs has led to calls for a legalised market in organ procurement or regulated trial in incentives for donation. Developing transplant services worldwide has many benefits - improving results of transplantation as they would be performed legally, increasing the donor pool and making TT unnecessary. Meanwhile there is a need to re-examine intrinsic attitudes to TT bearing in mind the cultural and economic realities of globalisation. Perhaps the World Health Organization in conjunction with The Transplantation Society would set up a working party of stakeholders to study this matter in greater detail and make recommendations. PMID:24175191
Marty, Francisco M; Ljungman, Per; Papanicolaou, Genovefa A; Winston, Drew J; Chemaly, Roy F; Strasfeld, Lynne; Young, Jo-Anne H; Rodriguez, Tulio; Maertens, Johan; Schmitt, Michael; Einsele, Hermann; Ferrant, Augustin; Lipton, Jeffrey H; Villano, Stephen A; Chen, Hongzi; Boeckh, Michael
, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. ViroPharma Incorporated. Copyright © 2011 Elsevier Ltd. All rights reserved.
Eisen, H.J.; Rosenbloom, M.; Laschinger, J.C.; Saffitz, J.E.; Cox, J.L.; Sobel, B.E.; Bolman, R.M. III; Bergmann, S.R.
Previous studies have demonstrated the feasibility of detecting canine heterotopic cardiac allograft rejection scintigraphically after administration of 111In lymphocytes. To determine whether the approach is capable of detecting rejection in orthotopic cardiac transplants in which labeled lymphocytes circulating in the blood pool may reduce sensitivity, the present study was performed in which canine orthotopic cardiac transplants were evaluated in vivo. Immunosuppression was maintained with cyclosporine A (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 2 wk after transplantation. Subsequently, therapy was tapered. Five successful allografts were evaluated scintigraphically every 3 days after administration of 100-350 microCi 111In autologous lymphocytes. Correction for labeled lymphocytes circulating in the blood pool, but not actively sequestered in the allografts was accomplished by administering 3-6 mCi 99mTc autologous erythrocytes and employing a previously validated blood-pool activity correction technique. Cardiac infiltration of labeled lymphocytes was quantified as percent indium excess (%IE), scintigraphically detectable 111In in the transplant compared with that in blood, and results were compared with those of concomitantly performed endomyocardial biopsy. Scintigraphic %IE for hearts not undergoing rejection manifest histologically was 0.7 +/- 0.4. Percent IE for rejecting hearts was 6.8 +/- 4.0 (p less than 0.05). Scintigraphy detected each episode of rejection detected by biopsy. Scintigraphic criteria for rejection (%IE greater than 2 s.d. above normal) were not manifest in any study in which biopsies did not show rejection. Since scintigraphic results with 111In-labeled lymphocytes were concordant with biopsy results in orthotopic cardiac transplants, noninvasive detection of graft rejection in patients should be attainable with the approach developed
Full Text Available Cytomegalovirus (CMV is a significant pathogen causing disease in renal transplant patients. The highest incidence of CMV disease occurs during the first 3 months post-transplant and is most problematic in CMV-naïve transplant recipients. In this study, we conducted a retrospective review of two databases, the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA and the National Hospital Morbidity Database, from the Australian Institute of Health and Welfare (AIHW, to examine CMV in renal transplant recipients. The first source looked at CMV serostatus at the time of transplantation and the second recorded hospital admissions for recipients with invasive CMV disease. From the ANZDATA registry, we obtained information from 13,530 renal transplants recipients from 1980 to 2004. Of these recipients, 7808 had a known CMV serostatus, of which 65.7% (5134/7808 had a positive sero antibody status and 34.2% (2674/7808 had a negative sero antibody status. In univariate analysis, factors significantly associated with renal rejection were being male, recipient age <50 years, being diabetic, being diagnosed with cancer at some point and having a positive EBV status. Positive CMV serostatus was not a contributing factor. Between 1993 and 2001 there were 1445 renal transplant recipients hospitalized in Australia with a diagnosis of CMV disease, of which 38% (554/1445 had CMV disease as a principal diagnoses. The average annual rate of admissions with any diagnosis was 3871 episodes per 100,000 people living with a functioning graft. Preventative strategies for CMV in renal transplant recipients should be a priority. New vaccines for CMV may soon be available and renal transplant recipients would be a suitable target group for vaccination.
Lorraine V. Alves
Full Text Available ABSTRACTIntroduction:The success of kidney transplantation depends on prevention of organ rejection by the recipient’s immune system, which recognizes alloantigens present in transplanted tissue. Human leukocyte antigen (HLA typing is one of the tests used in pre-renal transplantation and represents one of the most important factors for a successful procedure.Objective:The present study evaluated creatinine and cytokines plasma levels in kidney transplant patients according to pre-transplant HLA typing.Methods:We assessed 40 renal transplanted patients selected in two transplant centers in Belo Horizonte (MG.Results:Patients were distributed into three groups according to HLA compatibility and, through statistical analysis, the group with more than three matches (H3 was found to have significantly lower post-transplant creatinine levels, compared to groups with three or fewer matches (H2 and H1, respectively. The median plasma levels of cytokines interleukin 6 (IL-6, tumor necrosis factor alpha (TNF-α, and interleukin 10 (IL-10 were evaluated according to the number of matches. Pro-inflammatory cytokines (IL-6 and TNF-α were significantly higher in groups with lower HLA compatibility. On the other hand, the regulatory cytokine IL-10 had significantly higher plasma levels in the group with greater compatibility between donor and recipient.Conclusion:These findings allow us to infer that pre-transplant HLA typing of donors and recipients can influence post-transplant renal graft function and may contribute to the development and choice of new treatment strategies.
Lipshultz, Steven E.; Chandar, Jayanthi J.; Rusconi, Paolo G.; Fornoni, Alessia; Abitbol, Carolyn L.; Burke III, George W.; Zilleruelo, Gaston E.; Pham, Si M.; Perez, Elena E.; Karnik, Ruchika; Hunter, Juanita A.; Dauphin, Danielle D.; Wilkinson, James D.
In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children. Regarding pediatric cardiac transplantation, we discuss the mechanisms of cardiac transplant rejection, including the role of endomyocardial biopsy in detecting graft rejection and the role of biomarkers in detecting cardiac graft rejection, including biomarkers of inflammation, cardiomyocyte injury, or stress. We review cardiac allograft vasculopathy. We also address the role of genetic analyses, including genome-wide association studies, gene expression profiling using entities such as AlloMap®, and adenosine triphosphate release as a measure of immune function using the Cylex® ImmuKnow™ cell function assay. Finally, we identify future translational research directions in heart transplantation in children. PMID:24860861
Posadas Salas MA
Full Text Available Maria Aurora Posadas Salas, Titte R Srinivas Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA Abstract: Adherence to immunosuppression and minimizing variability in drug exposure are important considerations in preventing rejection and maximizing overall transplant outcomes. The availability of once-daily tacrolimus may confer potential benefit by simplifying immunosuppressive regimens, thereby improving medication adherence among transplant recipients. Pharmacokinetic studies in healthy normal volunteers and stable transplant recipients suggest that once-daily tacrolimus is bioequivalent to twice-daily tacrolimus. Efficacy studies suggest that once-daily tacrolimus is noninferior to twice-daily tacrolimus with a concentration-dependent rejection risk. The incidence of biopsy-proven acute rejection, graft survival, and patient survival are more or less comparable between the two tacrolimus formulations. Once-daily tacrolimus has also been reported to have favorable effects on blood pressure, lipid profile, and glucose tolerance. Once-daily tacrolimus may be a viable option to consider for de novo immunosuppression or for conversion from conventional tacrolimus. Keywords: pharmacokinetics, toxicity, immunosuppression, adherence
Zandberg, M; de Maar, EF; Hofker, HS; van der Heide, JJH; Rosati, S; van Son, WJ
A 37-year-old woman presented with malaise, upper abdominal pain and fever seven months after renal transplantation. She was seronegative for cytomegalovirus (CMV) and had received a kidney from a seropositive donor. She had received CMV prophylaxis (oral ganciclovir) for three months after
Full Text Available ObjectiveTo investigate the risk factors for non-anastomotic biliary stricture (NABS following liver transplantation. MethodsA retrospective analysis was performed on 175 patients who underwent liver transplantation from January 2004 to December 2010 to analyze the risk factors for NABS, which included sex, age, primary disease, blood type, T-tube placement, acute rejection, biliary tract infection, cytomegalovirus infection, Child-Pugh score, cold ischemia time, warm ischemia time, duration of anhepatic phase, and mean hepatic artery blood flow within one week after operation. These patients were divided into early group, who underwent operation from January 2004 to December 2006, and late group, who underwent operation from January 2007 to December 2010; each group was further divided into two subgroups according to whether they developed NABS. The risk factors for NABS were determined by univariate and multivariate logistic regression analyses. ResultsThe univariate logistic regression analysis showed that the risk factors for NABS were biliary tract infection, T-tube placement, and acute rejection in the early group (P＜0.05 and that acute rejection was the risk factor in the late group (P=0003. The multivariate logistic regression analysis showed that acute rejection was significantly associated with NABS in the early group (P=0.014. ConclusionThe risk factors for NABS following liver transplantation from January 2004 to December 2006; biliary tract infection and T-tube placement could be prevented by perioperative interventions, thus reducing the incidence of NABS. The incidence of acute rejection was reduced from January 2007 to December 2010, but it was still significantly associated with NABS.
Feldman, Amy G; Kempe, Allison; Beaty, Brenda L; Sundaram, Shikha S
Vaccination of pediatric liver transplant candidates and recipients represents an opportunity to decrease infectious complications following transplant. Although vaccine recommendations exist, studies have shown that many transplant candidates and recipients are under-immunized. The goals of this study were to assess among pediatric transplant hepatologists: (i) current immunization practices before and after transplantation, (ii) involvement of an ID physician in the transplant evaluation, and (iii) perceptions about vaccine safety and barriers to immunization. An 80-item e-mail survey of pediatric transplant hepatologists at centers in the United States and Canada participating in the SPLIT consortium was conducted from December 2014 to March 2015. The overall response rate was 80% (73/91), representing 97% (32/33) of SPLIT centers. Fifty percent of programs routinely involved an ID physician in the transplant evaluation. Administration of palivizumab was routinely considered by 48% of hepatologists pre-transplant and by 41% post-transplant. Live vaccines were recommended by 26% of hepatologists after transplant. About 10% of hepatologists reported concern that live vaccines after transplant could induce rejection. There is wide variation in immunization practices among transplant hepatologists. Specific evidence-based protocols are needed to guide immunization practices in transplant candidates and recipients. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Full Text Available Abstract Background The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11 have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. Results In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. Conclusions SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and
Nielsen, H; Sørensen, Flemming Brandt; Nielsen, B
Transplantation has become an accepted treatment of many cardiac end-stage diseases. Acute cellular rejection accounts for 15% to 20% of all graft failures. The first grading system of acute cellular rejection, the Stanford Classification, was introduced in 1979, and since then many other grading...
Scott, Victoria; Williams, Ryan J.; Levi, Daniel S.
Despite aggressive immunosuppressive therapy, pediatric orthotopic heart transplant (OHT) candidates with elevated pre-transplant panel reactive antibody (PRA) carry an increased risk of rejection and early graft failure following transplantation. This study has aimed to more specifically evaluate the outcomes of transplant candidates stratified by PRA values. Records of pediatric patients listed for OHT between April 2004 and July 2008 were reviewed (n = 101). Survival analysis was performed...
Papel do ecocardiograma na avaliação ventricular do coração transplantado versus rejeição cardíaca Role of echocardiography in the ventricular assessment of the transplanted heart versus heart rejection
Gabriel Antonio Stanisci Miguel
Full Text Available FUNDAMENTO: O Transplante Cardíaco (TC é uma alternativa para os indivíduos com doença cardíaca terminal. Na evolução pós-transplante, a ocorrência de episódios de Rejeição Cardíaca (RC é evento frequente que aumenta a morbimortalidade, sendo necessário o emprego de exame não invasivo com boa acurácia para seu diagnóstico, pois a Biópsia Endomiocárdica (BEM não é um procedimento isento de complicações. OBJETIVO: Comparar parâmetros obtidos com o princípio Doppler, entre os pacientes transplantados com RC (TX1 e os pacientes transplantados sem rejeição (TX0; utilizando como referência o Grupo Controle (GC e observando o comportamento da função sistodiastólica ventricular esquerda expressa por meio do Índice de Performance Miocárdica (IPM. MÉTODOS: Foram realizados ecocardiogramas transtorácicos no período de janeiro de 2006 a janeiro de 2008, para a avaliação prospectiva de 47 pacientes, subdivididos em GC (36,2%, TX0 (38,3% e TX1 (25,5%, comparando-se o IPM entre eles. Para a análise dos dados foram realizados os testes exato de Fisher e o não paramétrico de Kruskal-Wallis, ambos com nível de significância de 5%. RESULTADOS: Os grupos não diferiram em relação a idade, peso, altura e superfície corpórea. Quando comparado ao GC, TX0 e TX1 apresentaram alteração da função sistodiastólica ventricular esquerda, expressa como aumento do IPM, que foi mais intenso no TX1 [0,38 (0,29 - 0,44 X 0,47 (0,43 - 0,56 X 0,58 (0,52 - 0,74 p BACKGROUND: Heart transplantation is an alternative for individuals with end-stage heart disease. However, episodes of heart rejection (HR are frequent and increase morbidity and mortality, requiring the use of an accurate non-invasive exam for their diagnosis, since endomyocardial biopsy (EMB is not a complication-free procedure. OBJECTIVE: To compare the parameters obtained by use of Doppler echocardiography in a group of transplanted patients with HR (TX1 and another
Pooranfar, S; Shakoor, E; Shafahi, MJ; Salesi, M; Karimi, MH; Roozbeh, J; Hasheminasab, M
Background: Patients undergoing renal transplantation consume immunosuppressive drugs to prevent graft rejection. Cardiovascular complications and reduced quality of sleep are among the side effects of these drugs. Studies have indicated that the use of non-therapeutic methods such as exercise is important to reduce these complications. Objective: To evaluate the effect of a period of exercise training, as a non-therapeutic method, on quality and quantity of sleep and lipid profile in renal t...
Murphy J Mary
Full Text Available Abstract Adult bone marrow derived mesenchymal stem cells offer the potential to open a new frontier in medicine. Regenerative medicine aims to replace effete cells in a broad range of conditions associated with damaged cartilage, bone, muscle, tendon and ligament. However the normal process of immune rejection of mismatched allogeneic tissue would appear to prevent the realisation of such ambitions. In fact mesenchymal stem cells avoid allogeneic rejection in humans and in animal models. These finding are supported by in vitro co-culture studies. Three broad mechanisms contribute to this effect. Firstly, mesenchymal stem cells are hypoimmunogenic, often lacking MHC-II and costimulatory molecule expression. Secondly, these stem cells prevent T cell responses indirectly through modulation of dendritic cells and directly by disrupting NK as well as CD8+ and CD4+ T cell function. Thirdly, mesenchymal stem cells induce a suppressive local microenvironment through the production of prostaglandins and interleukin-10 as well as by the expression of indoleamine 2,3,-dioxygenase, which depletes the local milieu of tryptophan. Comparison is made to maternal tolerance of the fetal allograft, and contrasted with the immune evasion mechanisms of tumor cells. Mesenchymal stem cells are a highly regulated self-renewing population of cells with potent mechanisms to avoid allogeneic rejection.
Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.
Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony; Lechler, Robert; Lombardi, Giovanna
Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.
Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.
Full Text Available Type 1 diabetes mellitus (T1DM is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice