Metabolomics for the identification of early biomarkers of nephrotoxicity in a mouse model of cisplatin-induced acute kidney injury

Yong Jin Lim; Nicholas C Tonial; Emily D Hartjes; Aaron Haig; Thomas J Velenosi; Bradley L Urquhart

doi:10.1016/j.biopha.2023.114787

Metabolomics for the identification of early biomarkers of nephrotoxicity in a mouse model of cisplatin-induced acute kidney injury

Biomed Pharmacother. 2023 Jul:163:114787. doi: 10.1016/j.biopha.2023.114787. Epub 2023 Apr 29.

Authors

Yong Jin Lim¹, Nicholas C Tonial¹, Emily D Hartjes¹, Aaron Haig², Thomas J Velenosi³, Bradley L Urquhart⁴

Affiliations

¹ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
² Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
³ Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Division of Nephrology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada. Electronic address: Brad.Urquhart@schulich.uwo.ca.

PMID: 37126930
DOI: 10.1016/j.biopha.2023.114787

Abstract

Background and purpose: Cisplatin-induced nephrotoxicity manifests as acute kidney injury (AKI) in approximately one third of patients receiving cisplatin therapy. Current measures of AKI are inadequate in detecting AKI prior to significant renal injury, and better biomarkers are needed for early diagnosis of cisplatin-induced AKI.

Experimental approach: C57BL/6 and FVB/N mice were treated with a single intraperitoneal injection of cisplatin (15 mg kg^-1) or saline. Plasma, urine, and kidney samples were collected prior to cisplatin injection and 24-, 48-, 72-, and 96-hours following cisplatin injection. Untargeted metabolomics was employed using liquid chromatography-mass spectrometry to identify early diagnostic biomarkers for cisplatin nephrotoxicity.

Principal results: There was clear metabolic discrimination between saline and cisplatin-treated mice at all timepoints (day 1 to day 4). In total, 26 plasma, urine, and kidney metabolites were identified as exhibiting early alterations following cisplatin treatment. Several of the metabolites showing early alterations were associated with mitochondrial function and energetics, including intermediates of the tricarboxylic acid cycle, regulators of mitochondrial function and indicators of fatty acid β-oxidation dysfunction. Furthermore, several metabolites were derived from the gut microbiome.

Major conclusions: Our results highlight the detrimental effects of cisplatin on mitochondrial function and demonstrate potential involvement of the gut microbiome in the pathophysiology of cisplatin-induced AKI. We provide a panel of metabolites to guide future clinical studies of cisplatin-induced AKI and provide insight into potential mechanisms behind cisplatin nephrotoxicity.

Keywords: Acute kidney injury; Biomarkers; Cisplatin; Cisplatin (PubChem CID, 5460033); Metabolomics; Nephrotoxicity.

MeSH terms

Acute Kidney Injury* / chemically induced
Acute Kidney Injury* / diagnosis
Animals
Biomarkers / metabolism
Cisplatin* / toxicity
Kidney
Metabolomics
Mice
Mice, Inbred C57BL

Substances

Biomarkers
Cisplatin