Urinary Untargeted Metabolomics Identifies Tryptophan-Nicotinamide Pathway Disturbance as an Early Biomarker of Vancomycin-Induced Acute Kidney Injury

Background: Vancomycin is widely used for treating Gram-positive infections but frequently causes acute kidney injury (AKI), especially in critically ill and postoperative patients. Early detection of vancomycin-induced AKI (VI-AKI) remains challenging due to the low sensitivity of traditional markers. This study aimed to identify urinary metabolic signatures associated with early VI-AKI using untargeted metabolomics. Methods: A total of 60 patients receiving intravenous vancomycin therapy were prospectively enrolled. According to KDIGO criteria, 30 patients developed AKI within 7 days (VI-AKI group) and 30 remained without AKI (control group). Urine samples were collected at baseline (before vancomycin) and at 24 hours after treatment initiation. Samples were analyzed by UHPLC-MS/MS-based untargeted metabolomics. Multivariate analysis (OPLS-DA) and pathway enrichment were performed. Results: A total of 108 differential urinary metabolites were identified (VIP>1.5, p<0.05). The tryptophan-nicotinamide pathway was the most significantly perturbed. Compared with controls, VI-AKI patients showed significantly decreased urinary levels of tryptophan and serotonin, accompanied by elevated levels of kynurenine, quinolinic acid, and nicotinamide (all p<0.01). Notably, changes in the kynurenine/tryptophan ratio and nicotinamide/tryptophan ratio were detectable as early as 24 hours, prior to the rise of serum creatinine. A combined panel of three metabolites (kynurenine, quinolinic acid, and nicotinamide) predicted VI-AKI with an area under the curve (AUC) of 0.93 (95% CI: 0.87–0.98). Conclusions: Urinary untargeted metabolomics reveals that disturbance of the tryptophan-nicotinamide pathway is an early metabolic signature of vancomycin-induced AKI. This panel may serve as a sensitive, non-invasive early warning biomarker to guide vancomycin dosing and prevent renal injury.