治疗剂量他克莫司对大鼠肾脏病理及超微结构变化的影响  

Nephrotoxicity of tacrolimus and preventive effect of diltiazem： experiment with rats

作　　者：陈业辉[1] 梁颜笑[3] 陈林强[2] 路艳蒙[5] 梁健健[4] 张静[3] 邱江[6] 谢克基[1] 胡建波[1] 钟惟德[1] 王斌[1] 陈立中[6] 郑克立[6] 

机构地区：[1]广州市第一人民医院泌尿外科,510180 [2]广州市第一人民医院检验科,510180 [3]广州市第一人民医院病理科,510180 [4]广州市第一人民医院药剂科,510180 [5]南方医科大学电镜室 [6]中山大学附属第一医院泌尿外科肾移植

出　　处：《中华医学杂志》2009年第10期704-708,共5页National Medical Journal of China

基　　金：基金项目：广东省自然科学基金（06301011）;广东省医学科学技术研究基金（B2006123）;广州市医药卫生科技重点项目基金（2008-ZDi-07）

摘　　要：目的探讨肾移植术后首剂治疗剂量他克莫司（FKS06）对大鼠肾脏组织和肾脏细胞超微结构的影响，以及地尔硫革（Dil）对FKS06肾毒性的防治作用。方法按公式将肾移植术后FKS06、环孢素A（CsA）和Dil的首剂治疗剂量换算成大鼠的治疗剂量。SD大鼠2，4只随机分成对照组、CsA组（25mg·kg-1·d-1）、FK506组（0．8mg·kg-1·d-1）和FK506＋Dil组（0．8mg·kg-1·d-1及8mg·kg-1·d-1），用药4周后建立起各组大鼠肾毒性模型。观察各组大鼠的肾功能指标、肾组织的病理改变（HE染色、PAS染色和MASSON染色）、电子显微镜下肾脏细胞内超微结构的改变。结果CsA组与FKS06组出现明显的血肌酐上升（36．0±2．6）、（34．2±4．5）μmol／L，对照组为（29．2±3．4）μmol／L；肌酐清除率下降（0．63±0．45）、（0．58±0．39）ml·min-1·100g-1，而对照组、FKS06＋Dil组为（1．55±0．91）、（1．024-0．62）ml·min-1·100g-1。两组均可观察到明显的肾小管细胞浊肿及空泡变性，并且出现不同程度的肾内小动脉玻璃样变、肾小管间质纤维化、肾小球足细胞融合、肾小管上皮细胞线粒体肿胀空泡化等病变。FKS06＋Dil组上述各项指标的变化有所减轻或接近正常。结论肾移植术后首剂治疗剂量FKS06与CsA一样，均可引起大鼠肾脏组织和肾脏细胞超微结构出现病理改变。地尔硫革可以减轻FKS06对肾脏组织和细胞的病理损害。Objective To study the nephrotoxicity tacrolimus （FKS06） at the therapeutic dose the preventive effect of dihiazem （Dil）, a calcium antagonist against the FKS06-induced pathological changes. Methods 24 Sprague-Dawley male rats were randomly divided into 4 equal groups ： cyclosporine A （CsA） group, undergoing treatment of CsA at the therapeutic dose after kidney transplantation （25 mg ·kg-1· d-1） for 4 weeks, FKS06 group treated with FKS06 （0.8 mg ·kg-1· d-1 ）, FKS06 ＋ Dil group treated withFKS06 （0.8 mg ·kg-1· d-1） and Dil at the dose of 8 mg ·kg-1· d-1, and control group. Four weeks later body weight was measured and 24 h urine sample was collected. Then the rats were killed. Their kidneys underwent light and transmission electron microscopy. Results The body weight ad weight gain, and the weights of both kidney of the CsA group were all significantly lower than those of the other 3 groups （ all P 〈 0.05 ）, and there were not significant differences in there parameters among the other 3 groups. The serum creatinine levels of the FKS06 and CsA groups were （ 36.0 ± 2.6 ） and （ 34.2± 4.5 ）μmol/L respectively, both significantly higher than those of the FK506 ＋ Dil and control groups [ （28.5 ±2.1 ） and （29.2 ± 3. 428）μmol/L respectively, all P 〈 0.05）, however, there was no significant difference between the FK506 ＋ Dil and control groups. The creatinine clearance rate of the FKS06 and CsA groups were （0.63 ±0.45） and （0.58±0.39）ml ·min-1 · 100 g-1 respectively, significantly lower than those of the FK506 ＋ Dil and control groups [ （ 1.55 ±0.91 ） and （ 1.02 ± 0.62） ml· min - 1 · 100 g - 1 respectively, all P 〈 0.05 ]. Pathological examination showed epithelial cell cloudy swelling and vacuolization and interstitial fibrosis in the renal tubules, mitochondria swelling and vaeuolization in renal tubular epithelial cells, renal arteriole hyalinization, and foot cell conjugation glomerulus, mitoehondria swelling and vaeuo

关 键 词：地尔硫革 病理学 他克莫司 肾毒性 超微结构 

分 类 号：R686[医药卫生—骨科学]