Department of Investigative Laboratory Sciences, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.
Nat Biotechnol. 2010 May;28(5):486-94. doi: 10.1038/nbt.1627.
The Predictive Safety Testing Consortium's first regulatory submission to qualify kidney safety biomarkers revealed two deficiencies. To address the need for biomarkers that monitor recovery from agent-induced renal damage, we scored changes in the levels of urinary biomarkers in rats during recovery from renal injury induced by exposure to carbapenem A or gentamicin. All biomarkers responded to histologic tubular toxicities to varied degrees and with different kinetics. After a recovery period, all biomarkers returned to levels approaching those observed in uninjured animals. We next addressed the need for a serum biomarker that reflects general kidney function regardless of the exact site of renal injury. Our assay for serum cystatin C is more sensitive and specific than serum creatinine (SCr) or blood urea nitrogen (BUN) in monitoring generalized renal function after exposure of rats to eight nephrotoxicants and two hepatotoxicants. This sensitive serum biomarker will enable testing of renal function in animal studies that do not involve urine collection.
预测安全测试联盟(Predictive Safety Testing Consortium)首次向监管机构提交的资格申请中,有两项缺陷。为了满足监测药物诱导肾损伤恢复的生物标志物的需求,我们对暴露于碳青霉烯 A 或庆大霉素引起肾损伤恢复过程中大鼠尿液生物标志物的水平变化进行了评分。所有生物标志物对组织学肾小管毒性都有不同程度和不同动力学的反应。恢复期后,所有生物标志物的水平都接近未受伤动物的水平。接下来,我们需要一种血清生物标志物来反映肾功能,而不管确切的肾损伤部位。我们的血清胱抑素 C 检测比血清肌酐(SCr)或血尿素氮(BUN)更敏感、更特异,可在大鼠接触八种肾毒性剂和两种肝毒性剂后监测全身性肾功能。这种敏感的血清生物标志物将使无需收集尿液的动物研究中的肾功能检测成为可能。