Sirolimus

The introduction of new immunosuppression drugs in the 1990s resulted in marked reduction in acute rejection but had no appreciable impact on long-term graft survival. A major impediment to the improvement of long-term outcome has been attributed to the inexorable and progressive nephrotoxicity associated with the use of calcineurin inhibitors (CNI).With the introduction of sirolimus in transplantation, it was hoped that its lack of nephrotoxicity in animal models would be translated in humans to improve immunosuppression with minimal effect on renal function. However, the results of the US Multicenter Trial with cyclosporine and sirolimus revealed that sirolimus-treated patients had significantly higher serum creatinine values at 6 and 12 mo despite a significant reduction in acute rejection rates (1). Further investigations proposed a pharmacokinetic interaction between sirolimus and cyclosporine to enhance tissue concentration of cyclosporine, augmenting its inherent nephrotoxic potential rather than a direct nephrotoxic effect of sirolimus (2). This clinical finding led to trials of sirolimus with cyclosporine minimization or withdrawal to address this combination-induced toxicity (3).Another twist in the story occurred when reports of sirolimus causing the prolonged recovery of delayed graft function after renal transplantation were published (4,5). The initial belief in the renal transplant community that sirolimus was not nephrotoxic led to its use in …