Diamond J R, Anderson S
Department of Pathology, harvard Medical School, Boston, Massachusetts.
Am J Pathol. 1990 Dec;137(6):1323-32.
Chronic aminonucleoside nephrosis is variably associated with tubulointerstitial damage, depending on the route and frequency of drug administration. Recently, different groups have shown this injurious tubulointerstitial process to be reversible, coinciding with the resolution of heavy proteinuria to normal values. The authors have previously shown that a single jugular intravenous administration of puromycin aminonucleoside (PA) to male Munich-Wistar rats produces a triphasic pattern of glomerular injury and proteinuria, which culminates in focal glomerulosclerosis 70 weeks after drug administration. The authors now report the later progression of the tubulointerstitial morphologic abnormalities associated with acute nephrosis (phase I), despite spontaneous resolution of glomerular injury during the intermediate period (phase II) in this model. Although treatment of rats with the angiotensin I converting enzyme inhibitor enalapril (50 mg/l drinking water) over the 70-week period did not affect the magnitude of proteinuria during the acute nephrotic phase, enalapril prevented the recurrence of proteinuria (phase III), as well as significantly reducing the severity of interstitial fibrosis, extent of tubular dilatation, and number of intratubular casts on semiquantitative scoring at the conclusion of the study. In addition, enalapril-treated rats had less low-molecular-weight protein excretion during the recurrent phase of proteinuria, suggesting a preservation of tubular functional capacity to reabsorb these proteins. In vitro cytotoxicity studies showed only the glomerular visceral epithelial cell to be sensitive to PA, in contrast with rat tubular epithelium and other cellular controls. Although the exact pathogenetic mechanism responsible for the development of the tubulointerstitial damage remains unknown, PA in vitro does not adversely affect rat tubular epithelium; there is however a clear correlation between the magnitude of recurrent proteinuria and the severity of tubulointerstitial morphologic abnormalities, as suggested by the beneficial effect of converting enzyme inhibition on both of these untoward processes.
慢性氨基核苷肾病与肾小管间质损伤的关联程度各异，这取决于给药途径和频率。最近，不同研究团队已表明这种损伤性的肾小管间质病变是可逆的，同时蛋白尿也会恢复到正常水平。作者之前曾表明，对雄性慕尼黑 - 威斯塔大鼠单次经颈静脉注射嘌呤霉素氨基核苷（PA）会产生肾小球损伤和蛋白尿的三相模式，在给药70周后会发展为局灶性肾小球硬化。作者现在报告，尽管在此模型的中期（第二阶段）肾小球损伤会自发缓解，但与急性肾病（第一阶段）相关的肾小管间质形态学异常仍会出现后期进展。虽然在70周期间用血管紧张素I转换酶抑制剂依那普利（50毫克/升饮用水）治疗大鼠，在急性肾病阶段并未影响蛋白尿的程度，但依那普利可预防蛋白尿复发（第三阶段），并且在研究结束时通过半定量评分显著降低了间质纤维化的严重程度、肾小管扩张的程度以及肾小管内管型的数量。此外，在蛋白尿复发阶段，接受依那普利治疗的大鼠低分子量蛋白排泄较少，这表明肾小管重吸收这些蛋白的功能能力得以保留。体外细胞毒性研究表明，与大鼠肾小管上皮细胞和其他细胞对照相比，只有肾小球脏层上皮细胞对PA敏感。尽管导致肾小管间质损伤的确切发病机制尚不清楚，PA在体外对大鼠肾小管上皮细胞并无不利影响；然而，正如转换酶抑制对这两个不良过程均有有益作用所表明的那样，复发性蛋白尿的程度与肾小管间质形态学异常的严重程度之间存在明显相关性。
