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Updated: May 19, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by
Alison H Harrill1, Kristina D Desmet, Kristina K Wolf
1The Hamner Institutes for Health Sciences, Hamner-University of North Carolina Institute for Drug Safety Sciences, Durham, North Carolina 27709, USA. aharrill@thehamner.org
Abstract:
DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next-in-class compounds for renal injury.
Insights
DB289, an African sleeping sickness drug, caused kidney injury in mice. This study used a mouse diversity panel to identify sensitive strains and potential biomarkers for predicting drug toxicity.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Background:
- DB289 was the first oral drug effective against African trypanosomiasis.
- Clinical trials noted mild liver toxicity but severe kidney injury, which was not predicted by preclinical studies.
Purpose of the Study:
- To determine if a mouse diversity panel (MDP) could detect DB289's kidney toxicity.
- To identify sensitive mouse strains and potential kidney injury biomarkers for DB289.
Main Methods:
- 34 genetically diverse mouse strains were treated with DB289 or vehicle for 10 days.
- Renal biomarkers (blood urea nitrogen, serum creatinine) and urine kidney injury molecule-1 (KIM-1) were measured.
- Genome-wide association studies identified genes potentially involved in DB289-induced kidney injury.
Main Results:
- Elevated urine KIM-1 levels were observed in sensitive mouse strains, indicating kidney injury.
- Renal injury biomarkers were elevated independently of liver injury markers (ALT).
- Genes related to lipid metabolism, oxidative stress, and cytokine release were associated with KIM-1 elevations.
Conclusions:
- The MDP effectively predicted DB289's kidney safety liability.
- Urine KIM-1 is a potential biomarker for drug-induced kidney injury.
- Sensitive mouse strains can aid in screening future drug candidates for renal toxicity.
