环孢素A转换为雷帕霉素对大鼠移植肾功能和组织学的作用

Effects of conversion from Cyclosporine A to Rapamycin on the function and histological structure of renal allograft in a rat transplantation model

目的:研究并比较环孢素A(CsA)转换为雷帕霉素(Rapa)与CsA持续使用对大鼠移植肾的长期作用。方法:建立大鼠慢性移植肾肾病模型并分组:CsA转换为Rapa组(第1组,n=10)、CsA持续使用组(第2组,n=10)、CsA撤离组(第3组,n=8)和控制对照组(第4组,n=8)予以安慰剂至第24周。另6只Lewis→Lewis同系移植作为同系移植组(T组)。每4周查24 h尿蛋白定量,24周时处死动物,获取移植肾标本行组织学和免疫组化研究并检测转换生长因子β1和血小板源性生长因子A链的表达。结果:对比控制对照组(第4组),CsA和Rapa的使用(第1,2,3组)均显著地降低了尿蛋白的排泄量;CsA转换为Rapa(第1组)较CsA的持续使用(第2组)进一步降低了尿蛋白的排泄,在第24周差异有统计学意义(P=0.006)。CsA和Rapa的使用(第1,2,3组)大体保护移植肾组织学破坏;而对比CsA持续使用或撤离(第2、3组),CsA转换为Rapa(第1组)则进一步地降低了移植肾组织学Banff评分、显著地减少了肾组织中浸润的炎性细胞数、TGF-β1和α-SMA的染色强度以及转换生长因子β1和血小板源性生长因子A链的mRNA的表达量。结论:CsA转换为Rapa减少了移植肾远期尿蛋白的排泄,减缓远期移植肾组织学的损害并下调了纤维相关基因的表达,可能改善临床移植肾的远期成功率。

Objective： To investigate the long-term outcomes of rat renal allograft with eyclosporine A （CsA） to Rapamycin（Rapa） conversion versus continuous use of CsA. Methods： Model of chronic allograft nephropathy was established in rats, which were then randomized into the following groups： Group 1 （CsA to Rapamycin conversion, n = 10 ） , Group 2 （ Continuous use of CsA, n = 10 ） , Group 3 （ CsA withdrawal, n = 8 ） and Group 4 （ Control group on placebo, n = 8 ）. An additional Group 5 （ n =- 6, isografl） underwent Lewis to Lewis syngeneic kidney graft. Every 4 weeks after transplantation, 24-hr urine was collected and measured for protein concentrations. At 24 week post transplantation, all rats were killed and the grafts were harvested for morphological and immunohistoehemical analysis as well as transforming growth factor-β1 （TGF-β1） and platelet derived growth factor-A chain expression. Results： Use of CsA or Rapa （Groups 1,2 and 3 ） significantly decreased the proteinuria as compared with the control group（ Group 4）. Conversion from CsA to Rapa（ Group 1 ） resulted in significantly decreased proteinuria at 24 week after transplantation compared to continuous use of CsA or withdrawal（ Groups 2 and 3 ） （ P = 0. 006 ）. Use of CsA or Rapa （ Groups 1,2 and 3 ） largely preserved the structure of allografts. Conversion from CsA to Rapamycin （ Group 1 ） resulted in significantly lower Banff sum score ,decreased inflammatory infiltration of graft tissue ,the intensity of TGF-β1 and α-SMA immunostaining,and lower mRNA expression of TGF-β1 and platelet derived growth factor-A chain compared to continuous use of CsA or withdrawal （Groups 2 and 3 ）. Conclusion： Conversion from CsA to Rapamycin reduces the long-term proteinuria, delays the progression of histological disorder, and down-regulates the fibrosis related gene in rat renal allograft, and therefore may improve the long-term outcome of clinical kidney transplantation.