Immunosuppression Minimization and Avoidance Protocols: When Less Is Not More

Kidney transplantation is well established as the best treatment option for end-stage kidney disease. It confers not only a better quality of life but also a significant survival advantage compared to dialysis. However, despite significant improvement in short-term kidney transplant graft survival over the past three decades, long-term graft survival remains suboptimal. Concerns about the possible contribution of chronic calcineurin inhibitor (CNI) nephrotoxicity to late allograft failure and other serious adverse effects of currently used immunosuppressive agents (especially corticosteroids) have led to increasing interest in developing regimens which may better preserve kidney allograft function and minimize other immunosuppression-related problems without increasing the risk of rejection. The availability of newer immunosuppressive agents has provided the opportunity to formulate such regimens. Approaches to this end include minimization, withdrawal, or avoidance of corticosteroids and CNIs. Currently, replacement of a CNI with a mammalian target of rapamycin inhibitor while continuing mycophenolate and discontinuation of corticosteroids within the first post-transplant week is being increasingly utilized. Belatacept-based, CNI-free immunosuppression is an emerging alternative approach to avoiding CNI-mediated nephrotoxicity. We also discuss the evolution, results, and pros and cons of corticosteroid- and CNI minimization protocols. Recent studies suggest that chronic alloimmune damage rather than chronic CNI nephrotoxicity is the major contributor to late kidney allograft failure. The implications of this finding for the use of CNI minimization protocols are also discussed.