A study on establishment of a renal toxicity model using nephretomized rats

采用5/6肾切除大鼠建立肾毒性模型，依次观察5/6肾切除大鼠的生化指标和组织学变化。肾小球和小管功能指标肌酐清除率和电解质重吸收的变化分为三个阶段：肾切除术后第2 ~ 4周下降，第6 ~ 10周略有上升，此后再次下降。这些变化被认为与肾切除术后肾功能的改变有关：早期表现为肾单位明显减少引起的急性肾功能衰竭，中期表现为生理性代偿适应，晚期表现为慢性肾功能衰竭。结果表明，肌酐清除率、电解质重吸收等临床生化指标是区分5/6肾切除大鼠肾功能不同阶段的良好指标。此外，形态变化也被相似地划分为相同的阶段。为了研究肾毒性药物对肾切除大鼠的影响，我们检测了庆大霉素和嘌呤霉素。与假手术大鼠相比，庆大霉素治疗肾切除术大鼠肾小管病变在早期、中期和晚期均有生化和形态学上的恶化，尤其是在中期。相比之下，只有在肾切除大鼠中，在中期给予低剂量嘌呤霉素时，才能通过生化指标检测到肾小球毒性的增加。结果表明，某些生化指标在检测肾小球毒性方面可能比形态学检查更敏感。综上所述，我们的研究表明，5/6肾化大鼠是检测肾毒性的有效模型，而中期是检测肾毒性的更有效时间。

To establish a renal toxicity model using 5/6 nephretomized rats, changes of biochemical parameters and histological findings were sequentially investigated in 5/6 nephrectomized rats. Changes of creatinine clearance and electrolyte reabsorption, indicatorsforglomerular and tubaular functions, respectively, were divided into three stages : a reduction at weeks 2 to 4after nephrectomy, a slight increase from weeks 6 to 10, and a reduction again thereafter. These changes were considered to be correlated to alteration of renal function after nephrectomy : the early stage indicating acute renal failure caused by marked decrease of nephron units, the middle one showing physiological compensatory adaptation, and the late one being attributed to an onset of chromic renal failure, respectively. These results indicate that clinical biochemical parameters such as creatinine clearance and electolyte reabsorption are good indicators fo distinguish three stages of renal dysfunction in 5/6 nephrectomized rats. In addition, morphological canges were also divided similarly into same stages.To examine the effect of renal toxicants in nephrectomized rats, gentamycin and puromycin were tested. Gentamycin-induced tubular lesions worsened biochemically and morphologically in the nephrectomized rats treated when gentamycin was given at the early, middle or late stages, especially in the middle stage compared with those in the sham operated rats. In contrast, the increase in glomerular toxicity was only detectable in nephrectomized rats by biochemical indicators when low-dose puromycin wasgiven at the middle stage. The result suggests that some biochemical parameters may be morae sensitivethan morphological examinaation to detect glomerular toxicity.In conclusion, our study described above suggests that the 5/6 nephrecomized rat is a useful model for detection of renal toxicity and that the middle stage is a more effective time to detect it.