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Review
. 2024 Aug 5;13(4):tfae119.
doi: 10.1093/toxres/tfae119. eCollection 2024 Aug.

Drug-induced kidney injury: challenges and opportunities

Skylar Connor  1 , Ruth A Roberts  2   3 , Weida Tong  1
Affiliations
Review

Drug-induced kidney injury: challenges and opportunities

Skylar Connor et al. Toxicol Res (Camb). .

Abstract

Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%-26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development.

Keywords: DIKI; drug discovery; kidney injury; nephrotoxicity; renal injury.

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Figures

Fig. 1
Fig. 1
A) Incidence of preclinical and clinical failures due to renal injury. B) Incidence of project closure due to renal injury by therapy area. See Cook et al. 2014 for original data.
Fig. 2
Fig. 2
The potential application of biomarkers of DIKI during drug discovery and development. TS: Target selection; LG&LO: Lead generation and lead optimization; CD: Candidate drugs; DIKI: Drug-induced kidney injury; GLP: Good laboratory practice.
See this image and copyright information in PMC

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