1 Department of Safety Assessment, Genentech, A Member of the Roche Group, South San Francisco, CA, USA.
2 Janssen Research & Development, LLC, San Diego, CA, USA.
Int J Toxicol. 2019 Jan/Feb;38(1):12-22. doi: 10.1177/1091581818819791. Epub 2019 Jan 23.
Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there seems to be no standardized normalization method for analyzing these urinary biomarkers, as some users normalize with urinary creatinine (uCr), urine volume (uVol), or leave biomarker un-normalized. More recently, urinary cystatin C is also emerging as a urinary biomarker normalizer, given some of its characteristics as a glomerular filtration marker. The purpose of this study was to identify an optimal drug-induced kidney injury biomarker normalization method that can be adopted more uniformly in the field. To this end, we compared the variability of uVol, urinary cystatin C, and Cr in healthy rats; we evaluated the sensitivity of the renal biomarkers to renal injury after normalization with uVol, uCr, and cystatin C in rats with cisplatin-induced renal injury. We showed that, over time, uCr was less variable than urinary cystatin C and uVol. When the renal biomarkers were normalized with the 3 normalizing end points, the biomarkers showed (1) least variability following normalization with Cr in healthy animals and (2) poor sensitivity when normalized with urinary cystatin C in animals with renal injury. Overall, the results suggested that uCr is better than urinary cystatin C and uVol for normalizing renal biomarkers in rats under controlled preclinical conditions. To our knowledge, this is the first report that compared the variability of uVol, cystatin C, and Cr in the context of renal biomarkers' normalization.
最近，在大鼠中已经鉴定和确定了新的尿蛋白生物标志物，用于药物开发研究中早期检测肾脏损伤。然而，对于分析这些尿生物标志物似乎没有标准化的归一化方法，因为有些用户使用尿肌酐 (uCr)、尿体积 (uVol) 或不进行生物标志物归一化进行归一化。最近，由于其作为肾小球滤过标志物的一些特征，尿胱抑素 C 也作为尿生物标志物归一化剂出现。本研究的目的是确定一种更统一的药物诱导肾损伤生物标志物归一化方法，可以在该领域更广泛地采用。为此，我们比较了健康大鼠中 uVol、尿胱抑素 C 和 Cr 的变异性；我们评估了在顺铂诱导的肾损伤大鼠中，用 uVol、uCr 和胱抑素 C 归一化后，肾生物标志物对肾损伤的敏感性。结果表明，随着时间的推移，uCr 比尿胱抑素 C 和 uVol 的变异性更小。当用 3 个归一化终点对肾生物标志物进行归一化时，标志物表现出：(1) 在健康动物中用 Cr 归一化时变异性最小；(2) 在肾损伤动物中用尿胱抑素 C 归一化时敏感性差。总体而言，结果表明，在控制的临床前条件下，uCr 比尿胱抑素 C 和 uVol 更适合大鼠肾生物标志物的归一化。据我们所知，这是首次在肾生物标志物归一化背景下比较 uVol、胱抑素 C 和 Cr 的变异性的报告。
