Cyclosporine elimination in the presence of TOR inhibitors: Effects on renal function, acute rejection, and safety

Sirolimus in combination with cyclosporine reduces the incidence of acute r ejection in renal transplant recipients when administered in double- or tri ple-therapy immunosuppressive regimens. Sirolimus administered as primary t herapy has a beneficial effect on renal function, and the frequency of reje ction episodes is similar to that of primary immunosuppression with cyclosp orine. A strategy that may result in a more benign immunologic course with a substantially beneficial effect on renal function is to administer siroli mus and a calcineurin inhibitor early after transplantation, thereby promot ing immunologic adaptation, and then to withdraw the calcineurin inhibitor at some point after transplantation to prevent nephrotoxicity. This article examines the results of this approach in recent studies that evaluated the effect of cyclosporine withdrawal on renal function, acute rejection, and safety in patients treated with sirolimus. Two open-label randomized trials of cyclosporine withdrawal were conducted in the United States, Canada, Eu rope, and Australia. In one of the studies, graft survival, patient surviva l, and the incidence of acute rejection at 6 months posttransplantation wer e not statistically significantly different between the patients receiving cyclosporine and the group that had undergone cyclosporine withdrawal. Furt hermore, significantly better renal function was observed in the patients w ho underwent cyclosporine withdrawal compared with patients who continued t o receive full-dose cyclosporine. These studies indicate that cyclosporine withdrawal has a beneficial effect on renal function without a significant increase in the incidence of acute rejection episodes. (C) 2001 by the Nati onal Kidney Foundation, Inc.