Toxicologic Pathology Forum Opinion Paper*: Recommendations for a Tiered Approach to Nonclinical Mechanistic...

Nephrotoxicity is one of the more common causes of attrition in nonclinical drug development. Like most tissues, the kidney has a limited number of ways of responding to toxicological insults from diverse mechanistic pathways, which can limit the ability to determine mechanisms of renal injury using the assays routinely performed in preclinical toxicologic studies. In situations where the renal injury is unusual in morphology or if a therapeutic margin is low, additional investigative techniques may be needed to identify a potential mechanism of toxicity in order to inform clinical risk assessment or establish human relevance and translatability of the toxicity. While routine microscopic evaluation can suggest a specific pathogenesis, understanding the mechanism of renal injury often requires additional hypothesis-driven investigations and specialized techniques to obtain the data necessary to identify a nephrotoxic mechanism. Nonclinical mechanistic investigations can be resource-intensive and often yield limited new information. Although there are multiple avenues to investigate renal toxicity, no single mechanistic study or prescriptive battery of tests will identify the pathophysiologic basis for every potential mechanism of renal injury. To aid the nonclinical investigator, we outline a tiered approach for prioritizing investigations to provide a rational and linear road map for the exploration of mechanisms of drug-induced kidney injury. [Box: see text].