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Abstract
Sirolimus (Rapamune®, Wyeth-Ayerst, Madison, NJ) is a new, potent, immunosuppressant that is emerging as a foundation for long-term immunosuppressive therapy in renal transplantation. The drug acts during both co-stimulatory activation and cytokine-driven pathways via a unique mechanism: inhibition of a multifunctional serine-threonine kinase, mammalian target of rapamycin (mTOR). Although there is no a priori reason to assume it, sirolimus displays a synergistic interaction to enhance the efficacy of cyclosporin A (CsA). In trials wherein the concentrations of CsA and sirolimus were tightly controlled, rates of acute rejection episodes were ≤ 10%, despite markedly reduced exposures to each agent. In pivotal multi-centre blinded dose-controlled trials, the rates of acute rejection episodes within 12 months following administration of 2 or 5 mg/day sirolimus in combination with CsA and steroids were reduced to 19 and 14%, respectively. Since the inhibitory effect of sirolimus disables virtually all responses to cytokine mediators due to the widespread involvement of mTOR in multiple signalling pathways, the agent is likely also to retard proliferation of endothelial and vascular smooth muscle cells, an important component of the immuno-obliterative processes associated with chronic rejection. The advantages of this unique therapeutic action combined with an intrinsic lack of nephrotoxicity are counterbalanced by myelosuppressive and hyperlipidaemic side effects. Ongoing studies are assessing whether the long-term benefits of sirolimus to permit reduction in exposure to or elimination of calcineurin inhibitors ameliorate the progression of chronic nephropathy, the condition that erodes long-term renal transplant survival.
