sanofi-aventis, Alnwick, Northumberland, UK.
Toxicol Sci. 2011 Aug;122(2):235-52. doi: 10.1093/toxsci/kfr112. Epub 2011 May 18.
This study reports the evaluation of four urinary biomarkers of renal toxicity, α-glutathione-S-transferase (α-GST), μ-GST, clusterin, and renal papillary antigen-1 (RPA-1), in male Sprague-Dawley and Han-Wistar rats given cisplatin, gentamicin, or N-phenylanthranilic acid (NPAA). Kidney injury was diagnosed histopathologically, according to site/nature of renal injury, and graded for severity. The area under the receiver operating characteristic (ROC) curve was used to compare the diagnostic accuracy of each exploratory renal biomarker with traditional indicators of renal function and injury (blood urea nitrogen [BUN], serum creatinine [sCr] as well as urinary N-acetyl-β-D-glucosaminidase [NAG] and protein). These analyses showed that increased urinary α-GST was superior to BUN, sCr, and NAG for diagnosis of proximal tubular (PT) degeneration/necrosis. Paradoxically, urinary α-GST was decreased in the presence of collecting duct (CD) injury without PT injury (NPAA administration). RPA-1 demonstrated high specificity for CD injury, superior to all of the reference biomarkers. The clusterin response correlated well with tubular injury, whatever the location, particularly when regeneration was present (superior to all of the reference markers for cortical tubular regeneration). There was no conclusive evidence for the diagnostic utility of μ-GST. The data were submitted for qualification review by the European Medicines Agency and the US Food and Drug Administration. Both agencies concluded that the data justified the qualification of RPA-1 and increased the level of evidence for, and clarified the context of use of, the previously qualified clusterin for use in male rats. These biomarkers can be used in conjunction with traditional clinical chemistry markers and histopathology in Good Laboratory Practice rodent toxicology studies used to support renal safety studies in clinical trials. Qualification of α-GST must await further explanation of the differences in response to PT and CD injury.
本研究报告了对四种肾毒性生物标志物的评估，即α-谷胱甘肽-S-转移酶（α-GST）、μ-GST、簇集素和肾乳头抗原-1（RPA-1），这些标志物在雄性 Sprague-Dawley 和 Han-Wistar 大鼠中给予顺铂、庆大霉素或 N-苯丙氨酸（NPAA）后的情况。根据肾损伤的部位/性质，通过组织病理学诊断肾损伤，并对严重程度进行分级。受试者工作特征（ROC）曲线下面积用于比较每个探索性肾生物标志物与传统肾功能和损伤指标（血尿素氮[BUN]、血清肌酐[sCr]以及尿 N-乙酰-β-D-氨基葡萄糖苷酶[NAG]和蛋白质）的诊断准确性。这些分析表明，尿α-GST 对诊断近端肾小管（PT）变性/坏死的敏感性优于 BUN、sCr 和 NAG。矛盾的是，在没有 PT 损伤的情况下（NPAA 给药），尿α-GST 减少。RPA-1 对集合管（CD）损伤具有高特异性，优于所有参考生物标志物。簇集素反应与管状损伤密切相关，无论损伤部位如何，特别是在存在再生时（优于皮质管状再生的所有参考标志物）。μ-GST 的诊断效用没有确凿的证据。这些数据已提交给欧洲药品管理局和美国食品和药物管理局进行资格审查。这两个机构都得出结论，数据证明了 RPA-1 的资格，提高了之前合格的簇集素的证据水平，并澄清了其在雄性大鼠中的使用范围。这些生物标志物可与传统的临床化学标志物和组织病理学相结合，用于支持临床试验中的肾脏安全性研究的良好实验室规范啮齿动物毒理学研究。α-GST 的资格必须等待对其对 PT 和 CD 损伤反应的差异的进一步解释。
