Acute Rejection and Chronic Nephropathy: A Systematic Review of the Literature

Background. The risk of graft failure is the pivotal measure of effectiveness when evaluating immunosuppressive regimens for renal transplantation. However, to date most randomized trials of immunosuppressive therapy have had acute rejection as the primary endpoint for treatment comparisons. The objective here was to review the evidence relating acute rejection to renal graft function and graft survival. Methods. A systematic review of the published literature was undertaken. Studies were reviewed if they included the following: study populations of adults undergoing renal transplantation, endpoints of graft loss or survival, and quantitative data on the associations between acute rejection and graft function and survival. Results. Overall, 31 observational studies were included. The definition of acute rejection varied, and there was substantial heterogeneity in study design and methodology. In all but two studies, acute rejection was associated with an increased risk of graft loss-risk ratios ranged from 1.2 (no definition reported) to 10.5 (confirmed by biopsy and grade I Banff criteria). In addition, there was fairly strong evidence linking timing of acute rejection and graft survival and weaker evidence linking the number of episodes and graft survival. The heterogeneity between studies invalidated pooling of quantitative studies. Conclusions. The weight of the evidence indicates that occurrence, timing, and number of acute rejection episodes are associated with increased risk of graft loss. Less is known about the severity of rejection, which is important because many immunosuppressive regimens lessen severity. Quantifying these relationships is a priority if acute rejection continues to be a surrogate trial endpoint.