title: Sirolimus: a current perspective.
abstract: Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. The compound was documented in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids vs. azathioprine or placebo comparators. Furthermore, studies utilizing cyclosporine withdrawal documented a long-term benefit on renal function of chronic sirolimus therapy, albeit with a modestly enhanced incidence of acute rejection episodes. Although this application may be useful in selected cases, we believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy, while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients, as well as exerts myelosuppressive effects, which are augmented by concomitant therapy with azathioprine or, particularly, with mycophenolate mofetil. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury. Therefore, sirolimus proffers a potent and unique platform for new immunosuppressive strategies in organ transplantation.
authors.affiliation: The University of Texas Medical School at Houston, Department of Surgery, Division of Immunology and Organ Transplantation, 6431 Fannin, Suite 6.240, Houston, TX 77030, USA.
authors.forename: Yarkin K
authors.initials: YK
authors.lastname: Yakupoglu
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D002986:Clinical Trials as Topic; D016903:Drug Monitoring; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation; D020123:Sirolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus