Pinches M, Betts C, Bickerton S, Burdett L, Thomas H, Derbyshire N, Jones H B, Moores M
Safety Assessment AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
Toxicol Pathol. 2012 Apr;40(3):522-33. doi: 10.1177/0192623311432438.
A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. We use two novel multiplex assays to quantify biomarker concentration in multiple urine collections made prior to and following administration of cisplatin, a common nephrotoxicant, to rats. We investigate the correlation of the magnitude of biomarker changes with the severity of histopathological observations and explore the relationship of these to both dose and sex. The novel biomarkers evaluated are urinary albumin, alpha glutathione s-transferase (α-GST), glutathione S-transferase-yb1 (GSTYb1), lipocalin-2, kidney injury molecule-1 (KIM-1), osteopontin, and renal papillary antigen 1 (RPA-1) and plasma cystatin C, alongside the traditional biomarkers of plasma urea, creatinine, and urinary n-acetyl-beta-d-glucosaminidase (NAG), total protein, and glucose. We show for all time points, and for almost all doses, that male rats consistently had either more severely graded or a higher incidence of histologically observed lesions than females; that changes in urinary glucose, total urinary protein, NAG, and the novel urinary biomarkers albumin, osteopontin, and KIM-1 are clearly temporally associated; and that changes are related to the severity of injury. We also found that receiver operating characteristic curve analysis and area under the curve are significantly higher than urea or creatinine for all new biomarkers except aGST, GSTYb1, cystatin c, and total protein in both sexes.
已经鉴定出多种新型尿液生物标志物，其中一些已部分具备用作大鼠肾损伤标志物的条件。我们使用两种新型多重检测方法来量化在给大鼠施用常见肾毒物顺铂之前和之后多次采集的尿液中生物标志物的浓度。我们研究生物标志物变化幅度与组织病理学观察结果严重程度之间的相关性，并探讨这些与剂量和性别的关系。所评估的新型生物标志物包括尿白蛋白、α-谷胱甘肽S-转移酶（α-GST）、谷胱甘肽S-转移酶-yb1（GSTYb1）、脂质运载蛋白-2、肾损伤分子-1（KIM-1）、骨桥蛋白和肾乳头抗原1（RPA-1）以及血浆胱抑素C，同时还有血浆尿素、肌酐以及尿N-乙酰-β-D-氨基葡萄糖苷酶（NAG）、总蛋白和葡萄糖等传统生物标志物。我们发现，在所有时间点以及几乎所有剂量下，雄性大鼠组织学观察到的损伤分级始终比雌性大鼠更严重或发生率更高；尿葡萄糖、尿总蛋白、NAG以及新型尿液生物标志物白蛋白、骨桥蛋白和KIM-1的变化在时间上明显相关；并且这些变化与损伤的严重程度有关。我们还发现，除了两性中的aGST、GSTYb1、胱抑素c和总蛋白外，所有新生物标志物的受试者工作特征曲线分析和曲线下面积均显著高于尿素或肌酐。
