Everolimus and Minimization of Cyclosporine in Renal Transplantation: 24-Month Follow-Up of the EVEREST Study

Abstract

The association of cyclosporine A (CsA) with everolimus can exert synergistic effects on the alloimmune response. CsA inhibits the synthesis of interleukin-2 while everolimus inhibits the response to interleukin-2. Moreover, the interaction with CsA increases the bioavailability of everolimus (1). These data suggest that it is possible to reduce the doses of both drugs when given in combination. Previously, we reported the 1-year results of a randomized trial in 285 de novo renal transplants, 278 from deceased donors (2). Patients of group A received low-concentration CsA (C2 maintenance levels 350–500 ng/mL) plus everolimus (C0 levels 3–8 ng/mL), while patients of group B received very low-concentration CsA (C2 maintenance levels 150–300 ng/mL) and everolimus at higher target levels (C0 8–12 ng/mL). One-year graft survival rate was better in group B (98% vs. 90%; P=0.007). The mean serum creatinine levels at 1 year were, respectively, 1.51±0.55 mg/dL and 1.55±0.62 mg/dL. After the 1-year study was completed, 215 patients (110 in group A and 115 in group B) accepted to enter the extension study and to continue the study treatment up to 2 years. At 24 months, the mean everolimus dosages were 1.45±0.6 mg/day in group A (blood levels 6.17±2.1 ng/mL) and 2.24±1.1 mg/day in group B (blood levels 8.15±3.5 ng/mL), and the dosages of CsA were 1.62±0.5 mg/kg/day (C2 levels 407.6±159 ng/mL) and 1.38±0.7 mg/kg/day (C2 blood levels 330.7±159 ng/mL), respectively; the prednisone dosages were 5.14±1.28 mg/day in group A and 4.91±1.10 mg/day in group B. Four deaths (two in group A and two in group B) occurred within 6 months since transplantation; another patient of group A died after the first year because of myocardial infarction. Fifteen grafts were lost in group A and six in group B (P=0.043). In group A, only one graft was lost after the first year because of recurrent focal glomerular sclerosis. In group B, three failures occurred in the second year; two because of chronic rejection and one because of infection. The 24-month graft survival, including death as a cause of graft failure, was 87.4% in group A and 94.4% in group B (P=0.048). Acute rejection after the first year occurred in just one patient of group B. The cumulative probability of biopsy-proven rejection at 2 years was 15.0% in group A and 15.7% in group B. The mean levels of serum creatinine at 24 months were 1.45±0.5 mg/dL in group A and 1.52±0.7 mg/dL in group B (P=not significant [NS]). Mean glomerular filtration rate according to Nankivell et al. (3) was 65.8±19.7 mL/min in group A versus 61.8±22.0 mL/min in group B. The slopes of serum creatinine and glomerular filtration rate between 6 months and 2 years were practically flat (data not shown). At 24 months, systolic blood pressure was 135.6±16.1 mm Hg in group A and 135.8±18.8 mm Hg in group B; diastolic blood pressure was 81.2±9.8 mm Hg in group A versus 81.7±10.4 mm Hg in group B. Most patients were on antihypertensive medication. Mean hemoglobin levels were 13.1±1.6 g/dL in group A and 13.0±1.7 g/dL in group B. Plasma cholesterol levels were 228.0±41 mg/dL in group A and 235.1±54.5 mg/dL in group B (P=NS). Triglycerides levels were 193.3±84.9 mg/dL versus 224.4±120.6 mg/dL (P=NS). 3-hydroxy-3-methyl-glutaryl-Co (HMG-CoA) reductase inhibitors were administered in 83% of patients in both groups. Proteinuria more than 0.2 g/day occurred in 13 patients of group A (9.1%) and in 20 of group B (14.1%). The overall incidence of infections requiring hospitalization was similar in the two groups (10.5% in group A and 14.5% in group B). Diabetes was diagnosed in 7 (4.9%) patients in group A and in 13 patients (9.2%) in group B (P=NS). One patient (0.7%) in group A and three patients in group B (2.1%) developed nonmelanoma skin cancer. Twelve patients (four in group A and eight in group B) discontinued treatment because of adverse events after the first year (Table 1).TABLE 1: Adverse events leading to discontinuation of treatment between the first and the second yearFrom these results, it is possible to conclude that minimal doses of CsA in association with everolimus may offer excellent graft survival and stable renal function at 2 years. Claudio Ponticelli1 Maurizio Salvadori2 Maria Piera Scolari3 Franco Citterio4 Paolo Rigotti5 Antonella Veneziano6 Marta Bartezaghi6 on behalf of EVEREST Study 1Division of Nephrology Humanitas Scientific Institute Rozzano (Milano), Italy 2Division of Nephrology Careggi Hospital Firenze, Italy 3Renal Transplant Unit S. Orsola Malpighi University Hospital Bologna, Italy 4Department of Surgery Catholic University Hospital Roma, Italy 5Surgery Division Policlinic University Hospital Padova, Italy 6Medical Department Novartis Italy Origgio (Varese), Italy