Risk factors for chronic rejection in renal allograft recipients.
TL;DR: In this article, the authors found that acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection.
Abstract: Chronic rejection is a major barrier to long-term renal allograft survival. Cyclosporine, though effective at reducing graft loss to acute rejection, has had little impact on the incidence of chronic rejection. Between June 2, 1986 and January 22, 1991, 587 kidney-alone transplants (566 patients) were performed, and had been entered into our renal transplant database and had at least 1 year of follow-up: 103 with biopsy-proven chronic rejection (37 living-related donor, 66 cadaver) and 484 without chronic rejection (236 LRD 248 CAD). The 5-year patient survival was 84% for recipients with biopsy-proven chronic rejection vs. 89% without (P = .08). The 5-year graft survival was 31% for recipients with biopsy-proven chronic rejection vs. 81% without (P 50 years), gender, human leukocyte antigen matching, peak and transplant panel-reactive antibody, acute rejection episodes, infections (including cytomegalovirus, viral, and bacterial), donor age, and CsA dosage at 1 year ( or = 5 mg/kg). Logistic regression models were fit to the data using a forward stepwise selection procedure. In this analysis, risk factors included an acute rejection episode (P < .001), CsA dosage < 5 mg/kg/day at 1 year (P = .007), infection (P = .023), female gender (P = .042), and retransplant (P = .103). Individual analyses were done for CAD and LRD recipients. For both groups, important variables were acute rejection, infection, CsA dosage at 1 year, and age at transplant. In conclusion, acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection, suggesting that chronic rejection may be the result of inadequate immunosuppression (acute rejection episodes and low CsA dosage) or the production of inflammatory cytokines (infections).
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TL;DR: There has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors since 1988.
Abstract: Background The introduction of cyclosporine has resulted in improvement in the short-term outcome of renal transplantation, but its effect on the long-term survival of kidney transplants is not known. Methods We analyzed the influence of demographic characteristics (age, sex, and race), transplant-related variables (living or cadaveric donor, panel-reactive antibody titer, extent of HLA matching, and cold-ischemia time), and post-transplantation variables (presence or absence of acute rejection, delayed graft function, and therapy with mycophenolate mofetil and tacrolimus) on graft survival for all 93,934 renal transplantations performed in the United States between 1988 and 1996. A regression analysis adjusted for these variables was used to estimate the risk of graft failure within the first year and more than one year after transplantation. Results From 1988 to 1996, the one-year survival rate for grafts from living donors increased from 88.8 to 93.9 percent, and the rate for cadaveric grafts increased...
1,723 citations
TL;DR: This work analyzed data provided by the Scientific Registry of Transplant Recipients regarding all adult first renal transplants between 1995 and 2000 to investigate how acute rejection rates have evolved on a national level in the U.S and how this has impacted graft survival in the most recent era of kidney transplantation.
1,157 citations
University of Helsinki1, Churchill Hospital2, University of Western Ontario3, Hoffmann-La Roche4, Princess Alexandra Hospital5, Queen Elizabeth II Hospital6, University of Münster7, RMIT University8, Royal Prince Alfred Hospital9, University of Alberta10, Université de Montréal11, McMaster University12, Joseph Fourier University13, University of Zurich14, Beaumont Hospital15, Mario Negri Institute for Pharmacological Research16
TL;DR: MMF is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection.
Abstract: Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.
1,010 citations
TL;DR: Current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus and the purine-synthesis inhibitor mycophenolate mofetil are discussed, which inhibits the proliferation of T cells and B cells.
Abstract: This article provides a comprehensive, up-to-date review of methods to prevent early and late renal-allograft loss and to improve long-term outcomes in patients. The authors focus particular attention on the problem of late graft loss and discuss current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus, and the purine-synthesis inhibitor mycophenolate mofetil, which inhibits the proliferation of T cells and B cells.
830 citations
TL;DR: A role for peroxynitrite during development and progression of chronic rejection in human renal allografts is suggested, and inactivation of manganese superoxide dismutase by peroxlynitrite may represent a general mechanism that progressively increases the production of peroxysine nitration, leading to irreversible oxidative injury to mitochondria.
Abstract: Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation Activated cellular infiltrate produces high levels of both superoxide and nitric oxide These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 microM) decrease in enzymatic activity and concomitant increase in tyrosine nitration Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria
766 citations