Improving tolerability of immunosuppressive regimens.

CNIs and corticosteroids are associated with adverse effects that can diminish quality of life and detrimentally affect long-term allograft and patient survival. Nephrotoxicity is the major side effect of CNI therapy. A search has been ongoing for improved immunosuppressive regimens that will provide adequate protection against acute allograft rejection, while decreasing the nephrotoxic and other effects associated with CNIs. This paper reviewed the immunosuppressive agent sirolimus as a potential new option in transplantation, focusing on its mechanism of action and clinical efficacy as well as potential antiproliferative and antineoplastic properties. The findings and lessons learned from key clinical studies in which sirolimus was used to augment or replace CNIs and/or corticosteroids were highlighted, and the importance of clinical pharmacokinetics and therapeutic drug monitoring in these regimens were discussed. Preliminary studies of combination therapy with sirolimus and tacrolimus in solid organ transplantation indicate that sirolimus/tacrolimus combination therapy may provide strong protection against acute rejection and diminish the nephrotoxicity associated with CNI-based therapy. Other studies suggest that sirolimus can be used as base immunosuppressive therapy, thereby completely avoiding the nephrotoxicity associated with CNI-based therapies, while continuing to provide powerful protection against rejection. With patients surviving longer with functional allografts, quality of life is becoming an increasing important clinical endpoint in transplantation. The studies reviewed here suggest that sirolimus might be used to improve quality of life significantly without increasing the risk of allograft rejection or shortening patient survival.