Observations regarding the use of sirolimus and tacrolimus in high-risk cadaveric renal transplantation

Background: Balancing the risk of acute rejection (AR) with drug-induced toxicities complicates the selection of the optimal immunosuppressive regimen, especially in the high-risk renal transplant recipient. This study was designed to determine the optimal dosage combinations of tacrolimus and sirolimus in a high-risk cadaveric renal transplant population. Methods: Primary cadaveric renal transplant recipients were randomly assigned to receive either standard tacrolimus (trough levels of 10-15 ng/mL) plus reduced sirolimus (trough levels of 5-10 ng/mL) (Group I) or to receive reduced tacrolimus (trough levels of 5-10 ng/mL) plus standard sirolimus (trough levels of 10-15 ng/mL) (Group II). All patients received Thymoglobulin induction and steroids. Results: Thirty-nine (16 in Group I and 23 in Group II) high-risk renal transplant recipients (100% cadaveric donors, 79% African-American recipients, and 59% delayed graft function) are the subjects of this report. At 6 months, the patient survival rate was 94 and 100% and the graft survival rate was 94 and 83% in Groups I and II, respectively. The incidence of biopsy-proven AR was 6 and 5% in Groups I and II, respectively. Eight patients (50%) in Group I required discontinuation of tacrolimus, seven because of biopsy-proven tacrolimus nephrotoxicity and one secondarily to interstitial pneumonitis. Wound complications were the most frequent adverse event reported in both groups. Conclusions: The combination of tacrolimus and sirolimus was associated with a low risk of AR in this cohort of high-risk renal transplant recipients. However, 50% of patients who received standard tacrolimus and reduced sirolimus combination had to be discontinued from the regimen because of biopsy-proven nephrotoxicity. These preliminary results provide evidence that sirolimus should not be added to tacrolimus without dosage adjustments. We have discontinued recruitment of patients to the standard tacrolimus and reduced sirolimus combination and we have tightened our criteria for selection of marginal donor kidneys with our high-risk renal transplant recipients.