Modern approaches to combining sirolimus with calcineurin inhibitors

Routine renal transplantation maintenance immunosuppression at the University of Nebraska Medical Center consists of rabbit anti-thymocyte globulin (rATG) induction with early steroid withdrawal followed by maintenance with sirolimus and tacrolimus, a regimen we have used with >900 patients. Induction consists of 6 mg/kg rATG in 4 doses of 1.5 mg/kg each on days 0, 2, 4, and 6. Prednisone is used only in association with rATG administration. Maintenance agents are introduced gradually depending on renal function. Since April 2004, we have been conducting a prospective, randomized trial of this regimen versus 2 modifications: administering the rATG induction dose (6 mg/kg) in a single infusion over 24 hours; and, after 6 months, replacing tacrolimus with mycophenolate mofetil (MMF) in half of the study subjects. This study has shown several benefits of single-dose rATG induction, including significantly improved early graft function with both living and deceased donor kidneys and improved 2- to 12-month function in deceased donor organs (P = .026). Single-dose lymphocyte counts return to baseline sooner (2.2 vs 15.3 years; P < .05) without increased rejection (1 year; 8.5% single vs 12.5% divided; P = NS), and single-dose induction reduces chronic allograft nephropathy at 1 year (P = .05). Preliminary results of replacing tacrolimus with MMF show immediately improved renal function (months 1 and 2; P = .02 and .05; months 1-6, P = .058) without increased rejection.