Sirolimus Attenuates Chronic Allograft Nephropathy in an Experimental Rat Kidney Transplantation Model

Abstract

Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation. The use of calcineurin inhibitors is suggested to be a risk factor for the development of CAN. Thus, calcineurin-inhibitor-free immunosuppressive protocols are needed to improve long-term graft outcome. Sirolimus affects the immune response by interfering with postreceptor interleukin-2 signaling. Safety profile of sirolimus is different from that of calcineurin inhibitors. We investigated the long-term effects of sirolimus on kidney allografts and fibrogenic growth factor expression and compared it to cyclosporine A. Kidney transplantations were performed from DA to WF rats and syngenic controls were done between DA rats. Allograft recipients were immunosuppressed daily with sirolimus 2 p.o. or CsA 1.5 mg/kg s.c. In addition, sirolimus-treated animals were treated with cyclosporine 1.5 mg/kg s.c. for the first 7 days after transplantation. Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry. Histological changes were scored according to the chronic allograft damage index (CADI). No signs of CAN were seen in syngenic grafts, CADI 0.8 ± 0.2 (mean ± SEM). In cyclosporine-treated allografts moderate to intense chronic changes were seen; CADI 10.3 ± 0.6. Sirolimus significantly ameliorated the development of CAN compared to cyclosporine, CADI 3.0 ± 0.5 ( P < .05). Creatinine values of sirolimus-treated allografts were lower compared to the cyclosporine-treated allografts and were nearly similar to the syngenic grafts. Our results demonstrate that sirolimus attenuates the development of CAN and restores kidney function. Based on our findings, sirolimus improves the long-term kidney graft outcome.