GlaxoSmithKline, King of Prussia, PA.
Pfizer, Groton, CT.
Semin Nephrol. 2019 Mar;39(2):190-201. doi: 10.1016/j.semnephrol.2018.12.007.
Drug-induced kidney toxicity is a significant contributor to acute kidney injury. Nephrotoxic drugs need to be identified during nonclinical testing to highlight potential risk translatable to the intended patient population. When nonclinical kidney toxicity signals arise, scientists and physicians affiliated with clinical trials need to be familiar with commonly encountered drug-induced perturbations in the kidney, terminology, and how these changes relate to clinical risk. Mechanistic and translational toxicologic studies beyond routine histopathology and clinical pathology approaches may be needed to elucidate the pathogenesis and human relevance to inform clinical risk assessment. Investigational studies may help elucidate specific sites of injury within the nephron, the presence of reactive metabolites, mechanisms of membrane transport or tissue distribution, potential drug-drug interactions, or the ability to recover function after drug withdrawal. Cutting-edge techniques such as in vitro alternative platforms, humanized animal models, translational imaging/microscopy or circulating/secretory biomarkers, omics platforms at the interface of genes, proteins, metabolites, or advanced molecular and biochemical approaches provide toxicologists and pathologists with a wide variety of potential experimental modalities to investigate mechanisms of kidney toxicity.
药物性肾毒性是急性肾损伤的一个重要原因。在非临床测试中需要识别肾毒性药物，以突出潜在的可转化为目标患者人群的风险。当出现非临床肾毒性信号时，参与临床试验的科学家和医生需要熟悉常见的药物引起的肾脏改变、术语，以及这些变化与临床风险的关系。除了常规组织病理学和临床病理学方法之外，可能还需要进行机制和转化毒理学研究，以阐明发病机制和对人类的相关性，从而为临床风险评估提供信息。研究性研究可能有助于阐明肾单位内的特定损伤部位、活性代谢物的存在、膜转运或组织分布的机制、潜在的药物相互作用，或在停药后恢复功能的能力。体外替代平台、人源化动物模型、转化成像/显微镜或循环/分泌生物标志物等前沿技术，以及基因、蛋白质、代谢物界面的组学平台，或先进的分子和生化方法，为毒理学家和病理学家提供了广泛的潜在实验方法，用于研究肾毒性的机制。
