Sequential Quadruple Immunosuppression Including Sirolimus in Extended Criteria and Nonheartbeating Donor Kidney Transplantation Fritz Diekmann, Josep M. Campistol, Nu ´ria Saval, Alex Gutie ´rrez-Dalmau, Edgar M. Arellano, Marta Crespo, Esther Rossich, Nu ´ria Esforzado, Federico Cofa ´n, Marı ´a Jose ´ Ricart, Jose ´ Vicente Torregrosa, and Federico Oppenheimer The aim was to evaluate feasibility and safety of calcineurin inhibitor–free immunosuppression in high-risk donor kidney transplantation with sequential sirolimus introduction. Kidney transplant patients (n=76) with a donor aged 60 years, donor with acute renal failure, or a nonheartbeating donor were included. Immunosuppression consisted of antithymocyte globulin or basiliximab, mycophenolate mofetil, prednisone, and sequential introduction of sirolimus. One-year patient survival was 96.2% and 95.8%; graft survival was 94.2% and 91.7%; acute rejection rates were 21.2% and 12.4%; delayed graft function was 21.2% and 66.7%; and creatinine clearance was 5820 mL/min and 5621 mL/min for the brain-dead donor group and the nonheartbeating donor group, respectively. Most adverse events were infections, but also three lymphoceles, three urinary fistulas, three wound seromas. Sequential sirolimus introduction in high-risk donor kidney transplantation was found to lead to good patient and graft survival and incidence of acute rejection and delayed graft function. Keywords: Calcineurin inhibitor, Extended criteria donors, Nonheartbeating donors, Interleukin-2 receptor antago- nist, mTOR inhibitor, Mycophenolate mofetil, Proteinuria, Rapamycin, Sirolimus, Thymoglobulin. (Transplantation 2007;84: 429–432) T he use of kidneys from extended criteria (ECD) and non- heartbeating donors (NHBD) has become more frequent (1–3). They show a higher incidence of delayed graft function (DGF) (4–6), which itself is associated with a higher inci- dence of chronic allograft nephropathy (CAN) (7). Calcineurin inhibitor (CNI)-free immunosuppression may reduce the risk of DGF, improve recovery of renal func- tion after transplantation and reduce long-term conse- quences of drug-related nephrotoxicity. Sirolimus (SRL) does not possess CNI-like nephrotoxicity (8). So far, the de novo use of SRL had been associated with a higher than nor- mal incidence of wound healing problems (9, 10). Moreover, due to long plasma half-life SRL dosing has proven to be difficult, especially in the first postoperative days, when it is extremely important to achieve a trough concentration within the narrow therapeutic window to avoid acute rejection or side effects from overdosing. An induction agent facilitates a sequen- tial introduction of SRL five days after transplantation. The aim of this strategy is to reduce the risk of early SRL-associated wound healing problems and under- or overimmunosuppres- sion during the saturation phase of the drug. The objective of our study was to assess feasibility and potential benefit of a CNI-free protocol with sequential SRL introduction and antibody induction for kidney recipients who have a high risk of delayed graft function. All patients receiving a kidney transplant at our center between December 2002 and December 2004 with one of the following characteristics were included in the study: 1) donor aged 60 years, 2) donor with acute renal failure (serum creatinine 2.5 mg/dL and preimplantation biopsy with acute tubular necrosis), and 3) nonheartbeating donor (1 or 2 of the Maastricht criteria). Follow-up was 1 year. Patients with living donors and immunological high-risk patients were excluded from the study. All patients received mycophe- nolate mofetil (MMF) 2 g preoperatively and then 2 g/day until postoperative day (POD) 14, then 1.5 g/day until day 30, and 1 g/day thereafter, methylprednisolone 500 mg intraop- eratively, then prednisolone 0.5 mg/kg/day tapered to 20, 15 and 5 mg/day on POD 7, 30, and 90 respectively. SRL was introduced regardless of renal function at POD 5 starting with three consecutive doses of 6 mg/day, continuing with 3 mg/day. Target levels were 10 –15 ng/ml. All patients were treated with an induction agent: either antithymocyte globulin (ATG) 1.25 mg/day for seven days or 20 mg of basiliximab at day 0 and day 4. Generally, all NHBD patients were scheduled for ATG treatment. Patients receiv- ing an organ from a brain-dead donor (BDD) were scheduled for ATG treatment if they were under 60 years of age at time of transplantation. Cytomegalovirus (CMV) prophylaxis was performed for all patients who received ATG and for the other patients only if they were CMV-negative and received an organ from a CMV-positive donor. Prophylaxis consisted of either 2 weeks of intravenous ganciclovir (5 mg/kg/day, adjusted to renal function) and ten weeks of oral ganciclovir thereafter (until 2004), or of oral valganciclovir dosed according to renal func- tion for twelve weeks (starting in 2004). Patient and graft survival, incidence and duration of This study was funded in part by the Redes Tema ´ticas de Investigacio ´n cooperativa (V-2003-REDC03) and Marato ´ (TV3 TV 3610). Department of Nephrology and Renal Transplantation, Hospital Clı ´nic, Barcelona, Spain. Address correspondence to: Federico Oppenheimer, M.D., Department of Nephrology and Renal Transplantation, Hospital Clı ´nic, Villarroel, 170, E-08036 Barcelona, Spain. E-mail: oppen@clinic.ub.es Received 31 January 2007. Revision requested 4 April 2007. Accepted 27 April 2007. Copyright © 2007 by Lippincott Williams & Wilkins ISSN 0041-1337/07/8403-429 DOI: 10.1097/01.tp.0000269610.13590.52 Transplantation • Volume 84, Number 3, August 15, 2007 429