Essay 8 Relationship between Acute and Chronic Rejection

Abhinav Humar and Arthur J. Matas Supported by NIH DK13083

With the evolution of immunosuppressive protocols and the improvement in posttransplant care, acute rejection is now only rarely a cause of graft loss. Chronic rejection and death with function have become the predominant causes. Thus, current clinical research focuses on decreasing the incidence of both of these events.

Two major hypotheses attempt to explain pathogenesis of chronic rejection. The first hypothesis is that nonimmunologic factors are primary. Proponents feel that if a kidney with a limited nephron mass (relative to recipient size) is transplanted, hyperfiltration of the remaining nephrons occurs, and that this hyperfiltration results in further renal damage. The second hypothesis is that chronic rejection results mainly from immunologic injury. Proponents note that most of patients with chronic rejection have had a previous acute rejection episode.

These two hypotheses are not necessarily contradictory. There may be a final common pathway for renal injury. Rejection may act by limiting nephron mass, which results in hyperfiltration of the remaining nephrons. (Alternatively, rejection may be an important prognostic factor because acute and chronic rejection have associated underlying immunologic injury, because acute rejection continues to smolder after treatment, or because an acute rejection episode sets off a cytokine cascade that continues to have effects after treatment.)

Arguments for and against both hypotheses exist (reviewed in 1), but a major argument against nonimmunologic factors playing a predominant role is that chronic rejection occurs in extrarenal transplants (where hyperfiltration cannot be implicated) and the histologic picture of chronic rejection in extrarenal transplants is similar to that in renal transplants. We recently analyzed our kidney transplant population to study the relative role of immunologic and nonimmunologic factors. In our analysis, we excluded our recipients with graft loss due to death with function, technical failure, primary nonfunction, and recurrent disease— leaving a group of 1,987 recipients with potentially both immunologic and nonimmunologic graft loss.2 For this group, 10-year graft survival was 72%. We then repeated the analysis, this time also excluding recipients who had had acute rejection episodes; presumably graft loss in the remaining group (n=1,128) would be primarily due to nonimmunologic causes. Importantly, overall 10-year graft

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