Lifelong administration of multiple immunosuppressants is usually required to maintain function of a transplanted kidney. Selection of immunosuppressant agents has been geared toward preventing acute rejection and minimizing drug-induced side effects. In recent years, a number of new immunosuppressant agents have been approved for the prevention of acute rejection resulting in improved graft and patient survival, as well as improved function of the transplanted kidney. The opportunity to individualize immunosuppressant regimens based upon patient demographics and immunologic characteristics has expanded with the recent approval of sirolimus for prevention of acute rejection in renal transplant recipients.
Mechanism of Action
The mechanism of action of sirolimus is distinct from that of other commonly used immunosuppressants. Sirolimus and its O-alkylated analogue SDZ RAD bind to immunophilins known as FK 506 binding proteins (FKBP), specifically FKBP12. These sirolimus-FKBP complexes then bind to mammalian target of rapamycin, an intracellular enzyme that modulates lymphocyte cellular division and proliferation (Sehgal, 1998; Vasquez, 2000). While calcineurin inhibitors, like cyclosporine and tacrolimus, interfere with T-cell activation by blocking the production of interleukin-2 (IL-2), sirolimus predominantly inhibits T-cell proliferation by blocking T-cell responsiveness to IL-2. However, sirolimus does not block the IL-2 signals that lead to T-cell apoptosis, a process believed to be essential in the development of allograft tolerance. Additionally, sirolimus decreases immunoglobulin production by B-cells (American Society of Transplantation, 2000).
The safety and efficacy of sirolimus in combination with cyclosporine to prevent acute rejection of a transplanted kidney has been established in randomized, multicentered clinical studies. Combination immunosuppressant therapy of sirolimus, cyclosporine (at full or reduced dose), and steroids resulted in a lower incidence of biopsy proven rejection in kidney transplant recipients compared to transplant recipients who received cyclosporine, steroids, and placebo (Khan, Julian, Pescovitz, Vanrenterghem, & Neylan, 1999). In phase III clinical trials, cylosporine, corticosteroids, and either sirolimus (2 or 5 mg/day doses), azathriopine, or placebo were administered to 1,296 kidney transplant recipients. The incidence of acute rejection of the transplanted kidney was significantly lower among patients receiving sirolimus as part of their immunosuppressant regimen compared to those receiving azathriopine or placebo (Food and Drug Administration, 2000).
Although tacrolimus and sirolimus bind to the same immunophilin, their mechanism of action differs. The combination of tacrolimus and sirolimus is synergistic in pre-clinical models permitting the use of lower dosages of tacrolimus that may reduce or eliminate some of the adverse effects of tacrolimus. McAlister and colleagues (2000) reported only one episode of rejection, attributed to noncompliance, in 32 liver, kidney, and kidney-pancreas transplant recipients receiving a combination of sirolimus, low dose tacrolimus, and low dose steroid with early withdrawal for immunosuppression. Currently, studies are being conducted to determine the effect of tacrolimussirolimus combinations on kidney transplant graft function, patient and graft survival, and adverse effects.
Although current immunosuppressive regimens based upon cyclosporine or tacrolimus are very effective at reducing the incidence of acute rejection and preventing loss of the transplanted kidney from acute rejection, these drugs are known to compromise renal function. Subsequently, investigations comparing sirolimus...