High Incidence of Rejection Episodes and Poor Tolerance of Sirolimus in a Protocol With Early Steroid Withdrawal and Calcineurin Inhibitor–Free Maintenance Therapy in Renal Transplantation: Experiences of a Randomized Prospective Single-Center Study F. Burkhalter, T. Oettl, B. Descoeudres, A. Bachmann, L. Guerke, M.J. Mihatsch, M. Dickenmann, and J. Steiger ABSTRACT Immunosuppressive maintenance therapy after kidney transplantation leads to various undesired side effects such as calcineurin inhibitor (CNI)–associated nephrotoxicity or elevated cardiovascular risk due to posttransplantation diabetes and hypertension. These effects show negative impacts on long–term allograft function as well as patient morbidity and mortality. Therefore, we used an immunosuppressive regimen with early corticoste- roid withdrawal (ESW), maintenance therapy containing tacrolimus, sirolimus (SRL), and mycophenolate sodium for 3 months followed by a prospective randomized trial comparing a CNI free versus a low-dose CNI therapy. The primary endpoint was 6-month graft function. Among 75 patients, ESW was performed after 4 days in 65 patients. Over the following 3 months before randomization to CNI-free maintenance therapy, we experi- enced a high number (25%) of SRL discontinuations due to adverse events, including leukopenia, anemia, arthritis, and pneumonitis. In addition there were significantly more allograft rejection episodes in the CNI-free group (P = .017) during the study period leading to a switch from SRL to a CNI. Despite the higher rate of rejection episodes in the CNI-free groups, glomerular filtration rates (GFR) at 6 months were comparable between the study groups (P = .25). After 1 year only 9.2% (6/65) of all patients treated with SRL remained on this drug. Conclusion, there was an unacceptably high rate of SRL intolerance using an ESW and CNI-free immunosuppressive regimen combined with a significantly higher rate of rejection episodes. K IDNEY transplant success has increased over the last decade with rejection rates of 10 –20% and 1 year survival rates of 95% or 90% after living or cadaveric donations, respectively. Current posttransplantation immu- nosuppression usually includes steroids, a calcineurin inhib- itor (CNI) and an antiproliferative agent like mycophenolie acid. The first agents have major caveats. The most unde- sired effect of a CNI is nephrotoxicity with interstitial fibrosis, arterial hyalinosis, and glomerulosclerosis, 1 leading to negative impacts on long-term kidney function and graft loss. Other side effects include hypertension, hyperurice- mia, and dyslipidemia for cyclosporine and posttransplan- tation diabetes mellitus for tacrolimus. Steroids which are used since the first days after transplantation, show various undesired effects like diabetes mellitus, dyslipidemia, obe- sity, and osteoporosis. Many of these side effects increase the cardiovascular risk, which has become the leading cause of graft loss in the initial years posttransplantation. 2 With steady increase in 1-year graft survival, the focus after kidney transplantation must shift from “just” prevent- ing rejection to increasing long-term graft and patient From the Clinic for Transplant Immunology and Nephrology (F.B., T.O., B.D., M.D., J.S.), Department of Urology (A.B.), Department of Vascular Surgery (L.G.), and Department of Pathology (M.J.M.), University Hospital Basel, Basel, Switzer- land. F. Burkhalter and T. Oettl contributed as first authors. Address reprint requests to Felix Burkhalter, MD, Clinic for Transplant Immunology and Nepherology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: fburkhalter@uhbs.ch © 2012 by Elsevier Inc. All rights reserved. 0041-1345/–see front matter 360 Park Avenue South, New York, NY 10010-1710 http://dx.doi.org/10.1016/j.transproceed.2012.07.142 Transplantation Proceedings, 44, 2961–2965 (2012) 2961