Sirolimus is a novel
immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing
mammalian target of rapamycin protein kinase.
Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the
therapy of
glomerulonephritis, autoimmunity,
cystic renal diseases and
renal cancer is under investigation. Because
sirolimus does not share the vasomotor renal adverse effects exhibited by
calcineurin inhibitors, it has been designated a 'non-nephrotoxic
drug'. However, clinical reports suggest that, under some circumstances,
sirolimus is associated with
proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of
sirolimus-associated
proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following
calcineurin inhibitor withdrawal. It has also been suggested that
sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with
sirolimus (such as in
delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of
sirolimus on the kidney, the use of
sirolimus in appropriate patient populations, close monitoring of
proteinuria and renal function, use of
angiotensin-converting enzyme inhibitors or
angiotensin II receptor blockers if
proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using
sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.