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

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-induced AKI. Key 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. Conclusion and Implications: 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. Here we provide a panel of metabolites to guide future clinical studies of cisplatin-induced AKI and provide insight into potential mechanisms behind cisplatin nephrotoxicity.

Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity and Nephrotoxicity

“…We began by examining the nephrotoxic effects of cisplatin in our mouse model, which had been developed for ototoxicity (60). Consistent with observations in other mouse models of cisplatininduced nephrotoxicity (83,(119)(120)(121)(122)(123)(124), our three-cycle cisplatin administration protocol resulted in elevated plasma levels of BUN and NGAL, indicating kidney dysfunction and injury (Figure 7A-B).…”

Pharmacometabolomics in Drug Disposition, Toxicity, and Precision Medicine

“…In mice administered cisplatin, untargeted metabolomics has been used to identify biomarkers that can identify AKI earlier in treatment than the conventional biomarker serum creatinine. 26 metabolites were identified that could be used to identify kidney damage prior to alterations in serum creatinine levels (Lim et al, 2023a). Cisplatin treatment caused changes in several metabolites associated with mitochondrial function, which is consistent with the known mechanisms of cisplatin's nephrotoxicity (Miller et al, 2010) For example, L-carnitine concentration was found to be increased in both urine and plasma following cisplatin administration.…”