Zamlauski-Tucker M J, Morris M E, Springate J E
Department of Pediatrics, State University of New York at Buffalo 14214.
Toxicol Appl Pharmacol. 1994 Nov;129(1):170-5. doi: 10.1006/taap.1994.1241.
Renal proximal tubule dysfunction has been reported in patients treated with the chemotherapeutic agent ifosfamide. The present study investigated whether ifosfamide or its metabolites acrolein and chloroacetaldehyde would impair function in the isolated perfused rat kidney. Renal function was monitored before and after these chemicals were added to a modified Krebs-Ringer-bicarbonate perfusion medium containing 6.6 g/dl albumin and a mixture of substrates. No functional changes were observed when ifosfamide (470 microM) or acrolein (470 microM) was added to the perfusate. Addition of chloroacetaldehyde (210 microM) resulted in significant decreases in the fractional reabsorption of sodium (from 92 to 32%), glucose (from 97 to 46%), inorganic phosphate (from 88 to 22%), and inorganic sulfate (from 94 to 86%). There were no changes in glomerular filtration rate. PAH clearance also significantly decreased from 4.1 to 0.7 ml/min per gram of kidney weight, indicating impairment of proximal tubule organic acid secretion. This impairment was associated with a significant decline in the extraction ratio for PAH, suggesting abnormal PAH uptake at the basolateral membrane. These results show that chloroacetaldehyde causes generalized renal proximal tubule dysfunction and that it may be the ifosfamide metabolite responsible for nephrotoxic side effects.
已有报道称，接受化疗药物异环磷酰胺治疗的患者会出现肾近端小管功能障碍。本研究调查了异环磷酰胺及其代谢产物丙烯醛和氯乙醛是否会损害离体灌注大鼠肾脏的功能。在将这些化学物质添加到含有6.6 g/dl白蛋白和底物混合物的改良 Krebs-Ringer-碳酸氢盐灌注培养基之前和之后，监测肾功能。当向灌注液中添加异环磷酰胺（470 microM）或丙烯醛（470 microM）时，未观察到功能变化。添加氯乙醛（210 microM）导致钠的分数重吸收（从92%降至32%）、葡萄糖（从97%降至46%）、无机磷酸盐（从88%降至22%）和无机硫酸盐（从94%降至86%）显著降低。肾小球滤过率没有变化。每克肾脏重量的对氨基马尿酸清除率也从4.1显著降至0.7 ml/min，表明近端小管有机酸分泌受损。这种损害与对氨基马尿酸提取率的显著下降有关，提示基底外侧膜对氨基马尿酸摄取异常。这些结果表明，氯乙醛会导致广泛性肾近端小管功能障碍，并且它可能是异环磷酰胺导致肾毒性副作用的代谢产物。
