西罗莫司对慢性移植肾肾病肾组织转化生长因子β1和血管内皮生长因子表达的影响(英文)

Influence of sirolimus on transforming growth factor-beta 1 and vascular endothelial growth factor expression in chronic allograft nephropathy

背景:西罗莫司对肾移植术后急性排斥反应的防治产生重要作用,同时,有研究发现它可抑制血管平滑肌细胞的增殖和迁徙,对慢性排斥反应以及慢性移植肾肾病产生防治作用,但具体的机制尚不清楚。目的:探讨西罗莫司对慢性移植肾肾病肾组织转化生长因子和血管内皮生长因子表达的影响。方法:选择原发性肾病首次尸肾移植者60例,随机分为两组:西罗莫司组和硫唑嘌呤组各30例,分别采用西罗莫司+环孢素A+激素,硫唑嘌呤+环孢素A+激素治疗,西罗莫司首次负荷剂量为6mg,2周内2mg/d,2周后改为1.0～2.0mg/d,环孢素A为5.0～7.0mg/d,硫唑嘌呤为50～100mg/d,激素为15～20mg/d。术后2年时,对移植肾进行活检。观察移植肾组织转化生长因子β1和血管内皮生长因子表达情况,并观察肝功能、血肌酐浓度、急性排斥反应发生率、人/肾存活率。结果与结论:随访2年,西罗莫司组于术后1,3,12个月的环孢素剂量明显低于硫唑嘌呤组,但是两组之间的血环孢素A的谷值浓度没有明显差异。硫唑嘌呤组中,转化生长因子β1表达主要分布于近曲小管,部分可见肾小球以及间质血管;大部分移植肾组织近曲小管呈阳性表达,线型分布于刷状缘,部分呈阳性表达。部分患者肾小球脏层上皮细胞呈节段性阳性表达。内皮细胞及系膜偶见阳性表达。西罗莫司组中,转化生长因子β1在近曲小管的表达则明显减弱,肾小球和间质血管无明显改变。硫唑嘌呤组中血管内皮生长因子表达主要见于肾小球脏层上皮细胞,部分病例也可见于内皮细胞及系膜细胞,间质血管呈阳性表达,主要分布于内皮层。西罗莫司组,肾小球、间质血管染色均明显减少。与硫唑嘌呤组比较,西罗莫司组人/肾存活率高、移植肾组织转化生长因子β1和血管内皮生长因子表达明显降低。结果表明,西罗莫司可降低移植肾组织转化生长因子β1和血管内皮生长因子表达,减缓慢性移植肾肾病的进展,延长移植肾存活时间。

BACKGROUND：Sirolimus（SRL） has a very important effect on preventing and treating acute rejection in renal transplantation.Moreover,it is a potent inhibitor of smooth muscle cell proliferation and migration,and may play a role in preventing chronic rejection and chronic allograft nephropathy.However,the precise mechanism remains unclear.OBJECTIVE：To explore the influence of SRL on transforming growth factor-beta 1（TFG-β1） and vascular endothelial growth factor（VEGF） expression in chronic allograft nephropathy.METHODS：A total of 60 renal allograft recipients were randomly divided into SRL group,treated by SRL＋ cyclosporine A（CsA） ＋prednisone（Pred）,and Azathioprine（Aza） group,treated by Aza ＋CsA＋Pred.SRL was 6 mg and 2 mg per day in 2 weeks,and changed to 1.0-2.0 mg per day after 2 weeks;CsA was 5.0-7.0 mg per day;Aza was 50-100 mg per day,and Pred was 15-20 mg per day.After two years,the pathological changes of the allografts,serum creatinine of the recipients,distribution of TGF-β1 and VEGF,and hepatic function were observed.RESULTS AND CONCLUSION：The patients were followed-up for 2 years.CsA dose was significantly lower in SRL group than Aza group at 1,3,12 months postoperatively,but there were no differences in blood plasma CsA C0 concentration between two groups.In Aza group,TFG-β1 was expressed mostly in proximal convoluted tubule,also in glomerulus and interstitial blood vessel.Majority of tissues expressed TFG-β1 in proximal convoluted tubule,and presented at brush border in line.Some tissues expressed TFG-β1 in glomerular splanchnoderm epithelial cells.Additionally,little TFG-β1 was observed in endothelial cells and intercapillary cells.In SRL group,there was significant decreasing staining in proximal convoluted tubule,but there were no differences in glomerulus and blood vessel.In Aza group,VEGF was expressed mostly in glomerular splanchnoderm epithelial cells,and some in endothelial cells and intercapillary cells.VEGF was positively expressed in interstitial vessel,especially in endothelial layer.There was significant decreasing staining in SRL group glomerulus and blood vessel.Compared with Aza group,patient/kidney survival was high,but VEGF and TFG-β1 expression was significantly decreased.Results from the study showed that SRL decreased VEGF and TFG-β1 expression in renal graft,delayed progression of chronic allograft nephropathy,and prolonged survival of allografts.