Sirolimus, a macrocylic
lactone, blocks T-cell activation by a mechanism of action distinct from
calcineurin inhibitors (CNIs). Therefore, it may be expected that
sirolimus would display a safety profile without the vasomotor form of nephrotoxicity characteristic of CNIs. Initial studies in rodent models and in
psoriasis patients showed that
sirolimus alone did not impair renal function. Subsequently, two pivotal, randomized double dummy, phase III trials in human
renal transplantation demonstrated that
sirolimus exacerbated the nephrotoxicity of full doses of CNIs. Both pharmacokinetic and pharmacodynamic mechanisms have been implicated in the pathogenesis of this disorder. Subsequent experience has shown that
cyclosporin A dose reduction, elimination, or avoidance mitigates these effects, particularly in patients distant from the transplant procedure. However, there is concern about recovery from
ischemia-reperfusion injury. Animal models suggesting that
sirolimus may delay recovery in this setting have been supported by non-randomized experiences at single centers, which have observed an increased incidence of
delayed graft function among
sirolimus-treated recipients. In contrast, large single- and multi-center studies have not confirmed this finding; impaired renal recovery has been observed in only occasional instances. Thus, present data indicate that
sirolimus does not impair the function of an uninjured kidney, but whether the
drug acts alone or potentiates conditions that delay recovery after ischemic injury remains to be established by large randomized trials specifically targeted to recipients at high risk for this complication.