环孢素A诱导的大鼠慢性肾毒性变化及与血药浓度的关系

摘要 目的 观察长期应用不同剂量环孢素A（CsA）诱导的大鼠肾毒性的变化，并分析其与血药浓度的关系。方法 SD大鼠随机分为4组：正常对照组，低盐对照组，30 mg/kg剂量组(CsA-L组)，60 mg/kg剂量组(CsA-H组)，于给药后第2和4周观察大鼠肾功能和肾组织形态学的变化。CsA血药浓度采用FPIA法测定。结果 与低盐对照组相比，药后第2周CsA-L组各指标无明显变化，CsA-H组尿量增多，尿蛋白降低，尿素氮（BUN）升高；药后第4周时，尿量呈减少趋势，肌酐（Crea）和BUN明显升高，且与CsA血药浓度呈显著正相关，病理表现为肾小管细胞空泡变性及小动脉和肾间质病变，CsA-H组各种变化较CsA-L组更为明显。各项检测指标在两个对照组间差异无统计学意义。结论 大鼠长期应用CsA可导致肾脏功能和组织学病变，且病变程度与用药时间和血药浓度有明显的相关性。

Relationship between chronic nephrotoxicity and blood cycloshporine A concentration

Abstract Objective To observe the renal changes of cyclosporine A (CsA)-induced nephrotoxicity by long-term using different dose of CsA in rats, and investigate the relationship between the changes and blood CsA concentration. Methods Male SD rats were randomized into 4 groups: normal diet control group, low-salt diet control group, CsA 30 mg/kg group (CsA-L group) and CsA 60 mg/kg group (CsA-H group). Renal function and morphological changes in renal tissue were observed at 2 and 4 weeks after treatment with CsA, respectively. The CsA concentration in blood was determined by FPIA method. Results Compared with low-salt diet control group, the renal changes in CsA-L group were not obvious at the 2nd weeks, the urine volume and the level of BUN were remarkably increased in CsA-H group. At the 4th weeks, the urine volume was decreased; the levels of Crea and BUN were significantly increased and showed a significant positive correlation with the blood CsA concentration. Morphologic changes consisted of vacuolization of renal tubular cells, hyalinization of small arterioles and the light renal interstitial fibrosis. All the injury changes in CsA-H group were more severe than those in CsA-L group. The parameters in two control groups had no statistical significance. Conclusion Long-term use of CsA in rats results in renal function and morphological changes, which correlated with time of used CsA and blood CsA concentration.