1 Pfizer Worldwide Research and Development, Drug Safety R&D, Cambridge, MA, USA.
Int J Toxicol. 2019 May/Jun;38(3):215-227. doi: 10.1177/1091581819831701. Epub 2019 Mar 7.
Anatomically, the kidneys are paired, bean-shaped (in most mammals), excretory organs that lie in the retroperitoneum. High blood flow to the kidneys, together with high oxygen consumption, makes them more vulnerable to exposure, via the circulation, and subsequent injury related to high concentrations of xenobiotics and chemicals. In preclinical drug development and safety assessment of new investigational drugs, changes in kidney structure and/or function following drug administration in experimental laboratory animals need to be put in context with interspecies differences in kidney functional anatomy, physiology, spontaneous pathologies, and toxicopathological responses to injury. In addition, translation to human relevance to avoid premature drug termination from development is vital. Thus, detection and characterization of kidney toxicity in preclinical species and human relevance will depend on the preclinical safety testing strategy and collective weight-of-evidence approach including new investigational drug mechanism of action (MOA), preclinical and clinical interspecies differences, and MOA relevance to humans. This review describes kidney macroscopic and microscopic functional anatomy, physiology, pathophysiology, toxicology, and drug-induced kidney toxicities in safety risk assessment and drug development.
从解剖学上讲，肾脏呈成对的、豆形（在大多数哺乳动物中），是位于腹膜后的排泄器官。由于肾脏的血液流量高，氧气消耗量大，因此它们更容易通过循环暴露于高浓度的外源性物质和化学物质，从而导致损伤。在新药的临床前药物开发和安全性评估中，需要将药物给药后实验动物的肾脏结构和/或功能变化与物种间肾脏功能解剖学、生理学、自发性病理学以及对损伤的毒理学反应的差异联系起来。此外，为了避免药物过早从开发中终止，将其转化为与人类的相关性至关重要。因此，在临床前物种和人类相关性中检测和表征肾脏毒性将取决于临床前安全性测试策略和综合证据方法，包括新的研究药物作用机制（MOA）、临床前和临床种间差异以及 MOA 与人类的相关性。本文综述了肾脏的宏观和微观功能解剖学、生理学、病理生理学、毒理学以及药物引起的肾脏毒性在安全性风险评估和药物开发中的作用。
