Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation.
A 10-year experience with the immunosuppressive drug rapamycin that begins in the laboratory then extends through multicentre trials in combination with cyclosporine in kidney transplant recipients, exploration of its use as a single agent and in combination with tacrolimus, and its potential in nonrenal organs is described. Rapamycin is a potent inhibitor of endothelial injury in rat aortic allografts. When added to full-dose cyclosporine it achieves low rejection rates, but it augments the nephrotoxicity and hyperlipidemia of cyclosporine. On the other hand, it allows discontinuation of calcineurin inhibitors in stable kidney and liver patients suffering from nephrotoxicity late posttransplant. At least in Caucasian patients, discontinuation of cyclosporine is possible as early as 3 months post-kidney transplant. In combination with low-dose tacrolimus, exceptionally low rates of rejection were seen in recipients of kidney, pancreas, and liver recipients with preservation of excellent renal function. These pilot studies have been confirmed in several single-centre and, more recently, multicentre trials in kidney and pancreas transplantation. The side-effect profile of hyperlipidemia, lymphocoeles, delayed wound healing, and possible liver effects are coming into focus, and ways of minimizing these problems being introduced. The lessons learned include the need for early adequate blood levels, the lack of correlation between dose and drug exposure, and the potency that allows marked dose reductions in calcineurin inhibitors and steroids.
Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada. Allan.macdonald@dal.ca
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D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology*; D023421:Models, Animal; D016035:Pancreas Transplantation / Q000276:immunology*; D051381:Rats; D020123:Sirolimus / Q000097:blood / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus