Kidney Pathology and Investigative Nephrotoxicology Strategies Across Species

Abstract

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.

Keywords: Nephrotoxicity; drug development; kidney; mechanism; pharmaceuticals.