Savikko J, von Willebrand E
Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland; Department of Surgery, Päijät-Häme Central Hospital, Lahti, Finland.
Transplant Proc. 2006 Oct;38(8):2699-700. doi: 10.1016/j.transproceed.2006.08.009.
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.
慢性移植肾肾病（CAN）是肾移植术后晚期移植肾丢失的主要原因。钙调神经磷酸酶抑制剂的使用被认为是CAN发生的一个危险因素。因此，需要无钙调神经磷酸酶抑制剂的免疫抑制方案来改善移植肾的长期预后。西罗莫司通过干扰受体后白细胞介素-2信号传导来影响免疫反应。西罗莫司的安全性与钙调神经磷酸酶抑制剂不同。我们研究了西罗莫司对肾移植的长期影响以及对促纤维化生长因子表达的影响，并将其与环孢素A进行比较。将DA大鼠的肾脏移植到WF大鼠体内，并在DA大鼠之间进行同基因对照。移植肾受体每天口服2mg西罗莫司或皮下注射1.5mg/kg环孢素A进行免疫抑制。此外，接受西罗莫司治疗的动物在移植后的前7天皮下注射1.5mg/kg环孢素。每周测量一次血清肌酐水平。移植后90天取出移植肾进行组织学和免疫组织化学检查。根据慢性移植肾损伤指数（CADI）对组织学变化进行评分。同基因移植肾未见CAN迹象，CADI为0.8±0.2（平均值±标准误）。在接受环孢素治疗的移植肾中可见中度至重度慢性改变；CADI为10.3±0.6。与环孢素相比，西罗莫司显著改善了CAN的发展，CADI为3.0±0.5（P<0.05）。接受西罗莫司治疗的移植肾的肌酐值低于接受环孢素治疗的移植肾，且与同基因移植肾几乎相似。我们的结果表明，西罗莫司可减轻CAN的发展并恢复肾功能。基于我们的研究结果，西罗莫司可改善移植肾的长期预后。
