Kidney Pathophysiology, Toxicology, and Drug-Induced Injury in Drug Development.

Abstract

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.