雷帕霉素联合环孢素对肾移植患者长期存活的影响  

Combined regimen of rapamycin and ciclosporin in long-term follow-up in renal allograft recipients

作　　者：张政[1] 尚明花[1] 张渊[2] 范昱[3] 龚华[3] 刘皋林[2] 

机构地区：[1]上海交通大学附属第一人民医院肾内科,上海200080 [2]上海交通大学附属第一人民医院临床药理室,上海200080 [3]上海交通大学附属第一人民医院器官移植中心,上海200080

出　　处：《中国临床药学杂志》2008年第2期85-88,共4页Chinese Journal of Clinical Pharmacy

基　　金：上海市卫生局课题(局00433);上海市卫生局青年课题(局004Y17)

摘　　要：目的研究雷帕霉素(Rapa)联合环孢素(CsA)对移植肾患者长期存活的影响及机制。方法①40例肾移植患者,其中20例术后采用CsA和泼尼松(CsA组),20例采用Rapa联合CsA和泼尼松(Rapa组);随访5 a,分析临床和移植肾活检资料。②不同浓度Rapa干预CsA诱导的人脐静脉内皮细胞(ECV304),用3H-胸腺嘧啶核苷掺入法和3H-亮氨酸掺入法测定细胞DNA和蛋白质合成,免疫印迹(Western blot)检测细胞信号蛋白p70核糖体蛋白S6激酶(p70S6K)、细胞外信号调节激酶(ERK2)表达的变化。结果①Rapa组a 3和a 5 Ccr水平均低于CsA组(P<0.05);a 5移植肾活检组织学比较,Rapa组慢性指数(CI)比CsA组明显降低,分别为(4±0.6)vs(7±1.4),差异有统计学意义(P<0.05),其中移植肾血管病变降低最明显。②Rapa各浓度组与CsA组比较,均抑制血管内皮细胞DNA和蛋白质的合成,cpm值呈剂量依赖性下降。③R10组和R100组与C1000组比较p70S6K表达明显下降(P<0.05),而ERK2的表达在Rapa不同浓度组中均无明显变化。结论Rapa联合CsA的免疫抑制方案有利于移植肾长期存活,可能与降低CsA的肾毒性,尤其是抑制移植肾血管内皮细胞的增生,阻断PI3K-p70S6K信号通路有关。AIM To investigate the clinical efficacy and mechanism of a combined regimen with rapamycin（rapa） and ciclosporin（CsA） in the long-term follow-up after kidney transplantation. METHODS ①Forty consecutive kidney transplant recipients were initially treated with corticosteroids, CsA, and rapa. After 6 mo, patients were randomly assigned to either received the same treatment （group rapa） or to withdrew rapa and continued CsA （group CsA）. Twenty- seven patients underwent kidney graft biopsy 5 a after engraftment. Clinical data collected included serum creatinine （Scr） and creatinine clearance（Cockcroft-Gauh formula）, lipid profiles, complete blood counts and blood pressure. ② Human umbilical vein endothelial cells （ECV304） stimulated with CsA were treated with different doses of rapa. The cell proliferation was detected by ^3H-TdR incorporation and ^3H-leucine incorporation. Western blot was applied to assess protein expression of p70S6K and ERK2. RESULTS ①Patients treated with rapa showed a significantly better average of graft function than those without rapa after 5 a of kidney transplantation. Group rapa patients showed a significantly lower degree of chronic damage in all compartments at allograft biopsy 5 a after engraftment （ total histologic score, 4 ± 0.6 vs 7 ± 1.4 ; P 〈 0.05）. The difference was most prominent in the vascular compartment （ vascular score, 2.7 ± 0.5 vs 1.3± 0.4; P 〈 0.05） ②In cultured ECV304 cells, both 3H-TdR incorporation and ^3H-leucine incorporation were in dose dependently impressed by rapa. ③Rapa inhibited the activation of p70S6K（ P 〈 0.05）, without any effect on the expression of ERK2. CONCLUSION Patients treated with CsA in combination with Rapa would be benefit for allograft long-term survival due to reducing the lesion of CsA nephrotoxieity, especially for the proliferation of vascular endothelial cells, and blocking the signaling cascades PI3K-p70S6K may play the important role.

关 键 词：雷帕霉素 p70核糖体蛋白S6激酶 环孢素 小动脉病变 

分 类 号：R699.2[医药卫生—泌尿科学] R979.5[医药卫生—外科学]