The combination of tacrolimus and mycophenolate mofetil (MMF) has proved to be a highly efficacious treatment for patients undergoing kidney transplantation, and is now the most commonly prescribed immunosuppressive regimen in Europe and the United States (1). The combination is well-tolerated by the patient, has reduced acute rejection to low levels and resulted in substantial improvement in short- and long-term graft survival outcomes (2).
Sirolimus (rapamycin, RAPA) was recently introduced as an adjunctive immunosuppressant for solid organ transplantation. Sirolimus binds to the same immunophilin (FKBP-12) as tacrolimus, but unlike tacrolimus, the sirolimus/FKBP complex does not attach to calcineurin, but rather to a different protein called mammalian target of rapamycin (mTOR) (3). The FKBP/RAPA/mTOR complex prevents the progression of the cell cycle from G1 to S in T cells by inhibiting cytokine-induced signal transduction pathways (4). Therefore, due to the complementary mechanism of action, sirolimus and tacrolimus act synergistically to create effective immunosuppression.
The tacrolimus-sirolimus combination was first tested in 32 recipients of liver, kidney or pancreas transplants, and resulted in a low rate of rejection and excellent graft function (5). In a small study of 11 kidney transplant patients treated with tacrolimus and low-dose sirolimus, the patients had good renal function after 1 year with no acute rejection episodes (6). Several larger studies published recently have reported that the combination of tacrolimus with sirolimus can achieve acute rejection rates of less than 10% (7–9). The overall safety profile of the tacrolimus-sirolimus regimen appears to be good, the main side effect of sirolimus appearing to be a dose-dependent increase in serum lipid levels (7,10,11).
The combination of tacrolimus with 2 mg sirolimus seems very effective in preventing acute rejection in kidney transplant patients, and clinical efficacy appears to start with sirolimus doses as low as 0.5 mg (7). To determine the optimal dose of sirolimus in combination with tacrolimus, we investigated the efficacy and safety of two regimens that combined tacrolimus with either 0.5 or 2 mg sirolimus, and compared these with a tacrolimus and MMF regimen that has proven efficacy in preventing acute rejection in kidney transplant patients. Here, we present the data from the largest multicenter study to compare these three different immunosuppressive regimens.