Mycophenolate mofetil and sirolimus combination in renal transplantation

Mycophenolate mofetil (MMF) and sirolimus (SRL) are potent non-nephrotoxic xenobiotic immunosuppressants. Their complementary properties may provide the rationale for their combination in induction and maintenance regimens. MMF, a reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH) acts as an antiproliferative drug; and SRL, an mTOR (mammalian target of rapamycin) inhibitor, inhibits cell proliferation driven by growth factors. Early experiences with the use of the SRL, MMF and steroid combination yielded insufficient prophylaxis of acute rejection. However, the introduction of induction therapy with mono- or polyclonal antilymphocyte antibodies to the SRL-MMF and steroid combination brings an efficient acute rejection prophylaxis, while improving renal function and/or reducing of chronic allograft nephropathy (CAN). However, adverse events related to the use of this drug combination (mainly haematological and surgery-related) result in a high rate of discontinuations in some trials, which may hamper the potential benefits of this calcineurin-inhibitor (CNI)-free strategy. Also, currently under investigation is whether in long-term immunosuppression, in MMF-treated patients, CNIs can be replaced by SRL to avoid and/or halt progression of chronic nephropathy and to improve graft survival. However, some authors reported a high proportion of patients with oral ulcers and proteinuria after switching to SRL. In short, refining the use of MMF and SRL may provide a better risk/benefit ratio to pave the way towards non-nephrotoxic immunosuppression.