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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 plays an important role in the prevention and treatment of acute rejection after renal transplantation. In the meantime, it has been reported that it can inhibit the proliferation and migration of vascular smooth muscle cells and prevent and treat chronic rejection and chronic renal allograft nephropathy. However, The specific mechanism is not clear. Objective: To investigate the effect of sirolimus on the expression of transforming growth factor and vascular endothelial growth factor in renal tissue of chronic allograft nephropathy. Methods: 60 primary renal allograft recipients with primary nephropathy were randomly divided into two groups: 30 in the sirolimus group and 30 in the azathioprine group, respectively, with sirolimus + cyclosporin A + Purine + cyclosporine A + hormone treatment, sirolimus first dose of 6mg, 2 weeks 2mg / d, 2 weeks to 1.0 ~ 2.0mg / d, cyclosporin A 5.0 ~ 7.0mg / d, Azathioprine 50 ~ 100mg / d, hormone 15 ~ 20mg / d. At 2 years after surgery, the kidneys were biopsied. The expressions of TGF-β1 and VEGF were observed. The liver function, serum creatinine concentration, incidence of acute rejection and human / kidney survival were observed. RESULTS AND CONCLUSION: After 2 years of follow-up, the cyclosporine dose in sirolimus group was significantly lower than that in azathioprine group at 1, 3, and 12 months after operation. However, the trough value of cyclosporine A No significant difference in concentration. In the azathioprine group, the expression of TGF-β1 mainly distributed in the proximal convoluted tubules, partially in the glomerular and interstitial blood vessels. Most of the transplanted renal tubules were found in the proximal convoluted tubules with linear distribution in the brush border and some in the Positive expression. Some patients glomerular visceral epithelial cells were segmental positive expression. Occasionally positive endothelial cells and mesangial expression. In the sirolimus group, the expression of TGF-β1 in the proximal tubule was significantly decreased, while there was no significant change in the glomerular and interstitial blood vessels. In the azathioprine group, the expression of VEGF mainly found in the glomerular visceral epithelial cells. Some cases were also found in the endothelial cells and mesangial cells. The interstitial blood vessels were positive and mainly distributed in the endothelium. Sirolimus group, glomerular, interstitial vascular staining were significantly reduced. Compared with azathioprine group, the survival rate of human / kidney in sirolimus group was high, and the expression of transforming growth factor-β1 and vascular endothelial growth factor in transplanted renal tissue was significantly decreased. The results showed that sirolimus could reduce the expression of transforming growth factor β1 and vascular endothelial growth factor (VEGF) in renal transplant recipients, slow down the progress of chronic allograft nephropathy and prolong the survival of renal allografts.