OUTCOMES Combined Use of Tacrolimus and Sirolimus in De Novo Renal Transplant Patients: Current Data D. Ribes, N. Kamar, L. Esposito, and L. Rostaing ABSTRACT The concomitant use of calcineurin inhibitors (CNIs) with mTOR inhibitors, that is, either sirolimus (SRL) or everolimus (ERL), in de novo renal transplant patients is still debated. Prescription of full doses of cyclosporine A (CsA) with either SRL or ERL in that population leads to impaired renal function and hyperlipidemia compared with a regimen using mycophenolate mofetil (MMF) with CsA. The current data for the use of SRL doses, ranging from 0.5 to 2 mg/d, or SRL troughs ranging from 8 to 12 ng/mL with conventional doses of tacrolimus, are associated with reduced renal function, higher blood pressure, and an increase in serum lipids compared with MMF/tacrolimus therapy. C URRENTLY, MANY immunosuppressive drugs are used to treat renal transplant patients. They target both T and B lymphocytes. Their combined use can act synergistically or additively. Until recently, immunosup- pression relied on anti-calcineurin agents, namely, cyclo- sporine (CsA) or tacrolimus. Recently, agents that target the mTOR protein, namely, sirolimus and everolimus, have been launched. Both tacrolimus and mTOR inhibi- tors have the same binding protein in the cytosol, the FK-binding protein 12 (FKBP12). Consequently, if CsA and mTOR inhibitors act synergistically, the concomitant use of tacrolimus and mTOR inhibitors may only be additive. 1 The main side effects of mTOR inhibitors are dyslipidemia and hematologic toxicities (e.g., anemia, leu- kopenia, and thrombopenia). Moreover, it has been dem- onstrated in both rats and humans that the concomitant use of CsA and sirolimus leads to impaired renal function, which may be harmful in the long term. 2,3 Hence, de novo renal transplant patients who receive CsA, sirolimus, and steroids for the first 3 months, and then have CsA discon- tinued show significantly improved renal function at 1 year posttransplantation compared with those for whom CsA was continued. The difference in renal function persists in the long term, and was associated with better histology. 3,4 Likewise, the concomitant use of full doses of CsA in de novo renal transplant patients, in addition to everolimus, was associ- ated with poorer renal function compared with patients who received CsA in addition to mycophenolate mofetil. 5 How- ever, if the dose of CsA was significantly decreased, the addition of everolimus was efficient as far as acute rejection was concerned, and renal function was excellent. 6 The conclusions are that (i) CsA should not be used in the long term in combination with sirolimus, and that (ii) low doses of CsA, in addition to everolimus, are efficient and safe in the long term. What are the data regarding the concomitant use of tacrolimus and mTOR inhibitors? To date, the only data available are those for the combined use of tacrolimus and sirolimus. It has been shown that there is a pharmaco- kinetic interaction between tacrolimus and sirolimus. Thus, in stable renal transplant patients on tacrolimus-based therapy, the addition of various doses of sirolimus (1, 2, or 5 mg/d), without changing the daily tacrolimus dose, led to a significant decrease in tacrolimus area under the curve (AUC) at 2 weeks after the introduction of sirolimus. 7 Likely, in de novo renal transplant patients receiving either nothing or daily doses of sirolimus at 0.5, 1, and 2 mg, in addition to tacrolimus-based immunosuppression, tacroli- mus AUCs were always higher among patients not taking sirolimus, both after the first dose of tacrolimus, and also at posttransplant weeks 2 and 12. 7 Conversely, tacrolimus has no effect on the pharmacokinetics of sirolimus. Therefore, in cases where sirolimus is added to a tacrolimus-based From the Multiorgan Transplant Unit, University Hospital, Toulouse, France. Address reprint requests to Lionel Rostaing, MD, PhD, Multi- organ Transplant Unit, University Hospital, CHU Rangueil, 1 av. J. Pouilhès, TSA 50032, 31059 Toulouse Cedex 9, France. E-mail: rostaing.l@chu-toulouse.fr © 2005 by Elsevier Inc. All rights reserved. 0041-1345/05/$–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2005.05.029 Transplantation Proceedings, 37, 2813–2816 (2005) 2813