Sirolimus: A ten-year perspective

Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. This immunosuppressive agent was studied in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids versus azathioprine or placebo comparators. Cyclosporine withdrawal studies documented a long-term benefit of chronic sirolimus therapy on renal function, albeit with a modestly enhanced incidence of acute rejection episodes. I believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients and exerts myelosuppressive effects. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury.