Evaluation of nefrotoxicity by tacrolimus and micophenolate mofetil associated with kidney ischemia and reperfusion: experimental study in rats

ABSTRACT Objective: to evaluate the renal toxicity caused by tacrolimus and mycophenolate mofetil (MMF) in a single kidney ischemia and reperfusion model. Method: experimental study using Wistar rats, submitted to right nephrectomy and left renal ischemia for 20 minutes, separated into groups in the postoperative period (PO): 1) Control (nonoperated); 2) Sham (operated, without PO drug); 3) TAC0.1, TAC1 and TAC10, tacrolimus administered PO at doses of 0.1mg/kg, 1mg/kg and 10mg/kg via gavage, respectively; 4) MMF, administered mycophenolate mofetil 20mg/kg; 5) MMF/TAC1 and MMF/TAC0.5, with an association of mycophenolate mofetil 20mg/kg and tacrolimus 1mg/kg and 0.5mg/kg, respectively. They were killed on the 14th PO and the kidney was removed for tissue oxidative stress analysis, by the dosage of reduced glutathione (GSH), lipoperoxidation (LPO) and protein carbonylation (PCO), and histological analysis by glomerular stereology (Glomerular volume density, Numerical density glomerular and mean glomerular volume). Renal function was evaluated by the measurement of serum creatinine and urea. Results: both drugs caused alterations in renal function, and the toxicity of tacrolimus was dose-dependent. Subacute toxicity did not show significant glomerular histological changes, and there was renal and compensatory glomerular hypertrophy in all groups except TAC10. Conclusion: Both drugs cause changes in renal function. Glomerular morphometry and stereology showed negative interference of immunosuppressants during compensatory glomerular hypertrophy.

摘要 研究目的：评估他克莫司（tacrolimus）与吗替麦考酚酯（mycophenolate mofetil，MMF）在单侧肾脏缺血再灌注模型中引发的肾毒性。方法：本研究为实验研究，选用Wistar大鼠，行右侧肾切除术并对左侧肾脏实施20分钟缺血处理，术后按如下分组进行干预：1）对照组（未行任何手术）；2）假手术组（行手术操作，但术后未给予药物）；3）TAC0.1、TAC1及TAC10组：分别通过灌胃给予他克莫司，剂量依次为0.1mg/kg、1mg/kg及10mg/kg；4）MMF组：给予20mg/kg的吗替麦考酚酯；5）MMF/TAC1与MMF/TAC0.5组：联合给予20mg/kg吗替麦考酚酯与1mg/kg、0.5mg/kg他克莫司。于术后第14天处死大鼠，摘取肾脏开展组织氧化应激分析，通过检测还原型谷胱甘肽（reduced glutathione，GSH）、脂质过氧化（lipoperoxidation，LPO）及蛋白质羰基化（protein carbonylation，PCO）水平，并通过肾小球体视学分析（含肾小球体密度、肾小球数密度及平均肾小球体积）完成组织病理学检测。同时通过检测血清肌酐与尿素水平评估肾功能。结果：两种药物均可引发肾功能异常，且他克莫司的肾毒性呈剂量依赖性。亚急性毒性未引发显著的肾小球组织病理学改变，除TAC10组外，其余各组均出现肾脏代偿性肾小球肥大。结论：两种药物均可导致肾功能发生改变。肾小球形态计量学与体视学分析显示，免疫抑制剂对代偿性肾小球肥大存在负向干预作用。