摘要目的 探讨肾移植术后首剂治疗剂量他克莫司(FK506)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FK506肾毒性的防治作用.方法 按公式将肾移植术后FK506、环孢素A(CsA)和Dil的首剂治疗剂最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(25 mg·kg-1·d-1)、FK506组(0.8 mg·kg-1·d-1)和FK506+Dil组(0.8 mg·kg-1·d1及8 mg·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-1·100 g-1,而对照组、FK506+Dil组为(1.55±0.91)、(1.02±0.62)ml·min-1·100 g-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.FK506+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FK506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FK506对肾脏组织和细胞的病理损害.

abstractsObjective To study the nephrotoxicity tacrolimus (FK506) at the therapeutic dose the preventive effect of diltiazem (Dil), a calcium antagonist against the FK506-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, FK506 group treated with FK506 (0.8 mg·kg1·d-1), FK506 + Dil group treated with FK506 (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 FK506 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 FK506 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 vaeuolization and interstitial fibrosis in the renal tubules, mitochondria swelling and vacuolization in renal tubular epithelial cells, renal arteriole hyalinization, and foot cell conjugation glomerulus, mitochondria swelling and vacuolization in the FK506 and CsA groups, and such changes were relatively mild in the FK506 + Dil group. Conclusion FK506 at renal transplantation therapeutic dose, as well as CsA, induces pathological changes in renal tissues and ultrastructural organization. Dil is able to prevent FK506-induced these pathological changes.