Prolonged Effects of Everolimus on Wound Healing in Experimental Intestinal Anastomoses

Abstract

Introduction: Everolimus (EVL) was approved as immunosuppressive drug in 2005 but almost all clinical trials before approval were in combination with Cyclosporin A (CyA), for that reason experience in conversion with calcineurin inhibitor (CNI) elimination was very limited. We report the combined experience of two renal transplant centres in conversion of stable transplant patients from a CNI-based regimen to an EVE-based regimen for different indications. Patients and methods: Between Mar/05 and Dec/07 155 patients were converted from a CNI to EVL with rapid and complete elimination of CNI (98 patients in HCM and 57 in HUMV). All patients were converted in the same way (Initial dose between 2 and 4 mg/day of EVL divided in two doses and half dose of CNI until EVL through level in the desired range and then suspension). EVL through levels were measured at 4 and 8 days after initiation and then monthly up to three months and every three months thereafter. Results: Indications for conversion were: Chronic allograft nephropathy/CNI nephrotoxicity (36.8%), malignant neoplasm (29.0%), cardiovascular disease (16.8%), and other reasons in 13.5% of patients. In 6 patients (3.9%) conversion was performed as a preventive strategy in the fi rst year postransplant in order to minimize the long-term CNI toxic effects. Two thirds of patients were males. Mean age at conversion was 55.8±12.6y and median time from transplant to conversion was 78 months (range 3-286m). Approximately the same proportion of patients were under CyA and Tacrolimus. Mean initial dose was 2.94±0.7 mg/ day and mean through levels at four days were 9±5.4 ng/mL (range: 1.8-28.5). In 92.4% this fi rst level was over 3 ng/mL and in 78.6 over 5 ng/mL. Mean time to CNI complete elimination was 5 days (p25-75 4-8 days). EVL had to be prematurely eliminated in 33 patients (21.3%) due to drug intolerance/toxicity (8.9%), poor graft evolution (5.1%), severe infection (1.9%) or other reasons (5.2%). Among drug toxicity, dermal eruption (3.2%) and non-infectious pneumonitis (2.6%) were the most frequent reasons for EVL withdrawal. Median time for EVL suspension in this subgroup was 3.7 months (p25-75 1.4-11.1m). Among poor graft evolution the reasons were proteinuria (2.6%), deterioration of renal function (1.9%) and acute rejection (0.6%). Renal function was analyzed in the 87 patients with a functioning graft and continuing on EVL at twelve months postconversion. Creatinine clearance (Cockcroft-Gault formula) signifi cantly improved at six months (57.0±21.4 vs 59.9±23.4 mL/min; p=0.001) but that difference decreased at 12 months (58.3±22.9mL/min; p=0.15) Conclusions: Conversion to EVL with complete suspension of CNI is a safe procedure in terms of risk of graft rejection. Approximately 10% of patients do not tolerate EVL due to drug toxicity and in an additional 10% of it must be eliminated for different reasons, specially poor graft evolution. This might be reduced with a more adequate selection of candidates. Progressive deterioration of renal function before co...