PDF(Pubmed)
Abstract：
Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%-26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development.
摘要：
药物性肾损伤（DIKI）是一种常见的不良事件，与急性肾损伤相关，慢性肾病,和终末期肾衰竭.关于急性损伤的前瞻性队列研究表明，成年人群中的频率约为14％-26％，在儿科中引起了极大的关注，其中16％的频率归因于药物。在药物发现和开发中，肾损伤占临床前和临床失败的8%和9%，分别,影响多个治疗领域。目前,鉴定DIKI的标准生物标志物是血清肌酐和血尿素氮.然而,这两种标志物均缺乏在肾功能显著丧失之前检测肾毒性的敏感性和特异性.因此,迫切需要开发替代方法,以在早期药物发现中可靠地预测药物诱导的肾损伤(DIKI).在这篇文章中,我们讨论了DIKI的各个方面，以及如何在临床前模型和临床环境中对其进行评估，包括将动物数据转化为人类带来的挑战。然后，我们检查了美国食品和药物管理局（FDA）和欧洲药品管理局接受的尿液生物标志物，用于在临床前研究中以及在临床试验中逐案监测DIKI。我们还回顾了新的方法方法（NAMs），以及它们如何帮助开发DIKI的新型生物标志物，这些生物标志物可用于早期药物发现和开发。
