Screening the novel serum metabolites of vancomycin-induced acute kidney injury mice based on integrated metabolomics and transcriptomics.

Abstract

Vancomycin-induced acute kidney injury (VANI-AKI) commonly occurs in critically ill patients. Current diagnosis relies on insensitive indicators such as serum creatinine (SCr) or oliguria, while the underlying molecular mechanisms remain unclear, hindering early detection and timely treatment. To identify novel metabolites and elucidate metabolic pathways disrupted by VAN exposure, we established mouse models of VANI-AKI at multiple time points to mimic various AKI stages through intraperitoneal injection of VAN. C57BL/6J female mice received either 400 mg per kg per day (clinically relevant dose) for 1 day, 2 days, 3 days and 4 days, and 1200 mg kg-1 (as the toxic dose) for 1 day. Kidney injury was assessed using SCr and blood urea nitrogen as biochemical indices, along with histopathology evaluated by H&E staining. Transcriptomic and metabolomic analyses revealed 3858 differentially expressed genes in kidney tissue and 73 altered endogenous metabolites in serum. The findings showed that amino acid metabolism, the tricarboxylic acid (TCA) cycle, and glycerophospholipid metabolism were significantly perturbed during VANI-AKI progression. Metabolites including p-cresol glucuronide, 2-hydroxyethanesulfonate, and kynurenic acid were promising biomarkers for early VANI-AKI diagnosis with AUC >0.95, whereas norepinephrine sulfate, glucuronic acid, and 4-pyridoxic acid emerged as potential markers for severe disease (with AUC 1.0 for each metabolite). These key metabolites were correlated closely with inflammatory responses, oxidative stress, and alterations in cell viability. The study provides valuable insights into the metabolic dysregulation during the onset and progression of VANI-AKI.