Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors.
The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.
Nashan
Björn
B
Multi Organ Transplant Program, QEII Health Sciences Centre, Dalhousie University, VG Site, 1278 Tower Road 6S-202 Victoria Building, B3H 2Y9, Halifax, Nova Scotia, Canada. bjorn.nashan@cdha.nshealth.ca
D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation; D011494:Protein Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin