Transplantation is the therapy of choice for patients with end stage kidney disease, but long-term allograft survival and function remain suboptimal, in part due to the adverse consequences of ischemia reperfusion (IR) injury. Evidence from animal models and from studies of human transplant recipients suggest that inflammation initiated by IR injury augments graft immunogenicity, thereby facilitating activation and amplification of pre- existing and de novo, graft-reactive, pathogenic T and B cell immunity, which together have negative long-term consequences for the allograft. Based on preclinical studies we hypothesize that TNF? is a crucial mediator of the posttransplant inflammation. The hypothesis predicts that early posttransplant TNF? blockade will dampen the vicious cycle of allograft inflammation and as a consequence confer a long-term protective effect on allograft function and survival. Building upon our previous CTOT experience in which we developed an operational infrastructure and an effective, multicenter consortium for performing clinical trials that provide mechanistic insight into risk for acute graft injury, we propose 3 specific aims:
Aim 1. To determine the impact of anti-TNF? mAb (infliximab), administered intraoperatively, on 2 year kidney allograft function. We will perform a multicenter clinical trial of 300 "high-risk" deceased donor kidney transplant recipients randomized 1:1 to induction therapy with rabbit anti-thymocyte globulin (ATG) alone as the control group, or ATG plus a single intra-operative dose of anti-TNF? mAb (infliximab) to inhibit early inflammation (experimental arm). The primary endpoint of the study will be estimated glomerular filtration rate (eGFR) at 2 years.
Aim 2. To define the utility of previously identified, noninvasive biomarkers as risk assessment, diagnostic, and predictive testing strategies for outcomes in higher risk recipients of deceased donor kidney allografts. In previous CTOT-funded work we developed, and standardized multiple biomarker testing strategies that function as risk assessment tools for low risk kidney transplant recipients Herein we will test and validate the panel of reactive T cell ELISPOT assay, urinary protein and molecular markers, and specific graft- and peripheral blood-derived gene panels to predict and diagnose incipient AR and 2-year graft dysfunction/failure.
Aim 3. To test the effects of induction therapy with ATG plus infliximab on the intensity of graft inflammation, donor reactive immunity and graft pathology. In these mechanistic studies we will determine the mechanisms through which the addition of infliximab impacts kidney transplant outcome. We will test the hypothesis that anti-TNF? dampens early inflammation within the allograft and synergizes with ATG to limit activation and reconstitution of donor reactive immunity, thereby preventing progressive graft fibrosis and preserving kidney function. TNF? blockade early posttransplant is an innovative approach that, if effective, has the potential to alter current treatment paradigms and improve transplant outcomes. The biomarker and mechanistic studies will be informative regardless of the outcome of the trial.
Although transplantation is the ideal therapy for kidney failure, long term function of the transplanted organ is suboptimal;half of kidney transplants from deceased donors fail by 11 years. In this application we propose an innovative strategy to prolong transplant survival by blocking TNFa with a drug called infliximab, which we hypothesize will dampen the immune response directed toward the transplant and as a consequence, improve long term graft survival and function and improve patient health. Accompanying studies will assess the utility of noninvasive testing strategies to predict long term graft outcome and wil determine why the intervention did or did work as expected.
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