Metabolomic investigation of cisplatin-induced acute kidney injury in paediatric cancer patients.
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AIM: Cisplatin causes acute kidney injury (AKI) in approximately 46% of paediatric cancer patients who receive it. Serum creatinine (SCr) is a poor biomarker of cisplatin nephrotoxicity, because there is a delay between cisplatin infusion and SCr elevation. Accordingly, there is a need for predictive or early diagnostic biomarkers for cisplatin-induced nephrotoxicity that help determine AKI risk. METHODS: Samples from the Applying Biomarkers to Long-term Effects in Child and Adolescent Cancer Treatment (ABLE) study were used. Urine and serum from 86 patients were subjected to an exploratory untargeted metabolomics analysis. Urine and serum samples were collected prior to cisplatin, 24-48 h after cisplatin and 5-14 days after cisplatin. Liquid chromatography-mass spectrometry-based metabolomics was performed on serum and urine to identify predictive or early diagnostic biomarkers of cisplatin-induced AKI. RESULTS: Of the 86 patients included in this study, 34/86 (39.5%) were classified as having AKI based on SCr change from baseline. Overall, there was poor metabolomic discrimination of AKI vs. no-AKI. When patients were stratified by age (≤3 vs. >3 years old), discrimination was greatly improved. Urinary metabolites of the NAD+ synthesis pathway (kynurenine, 2-PY, 1-methlynicotinamide and quinolinate) were found to be significantly elevated in AKI patients compared to no-AKI patients. CONCLUSION: Urine metabolomic differences exist 24-48 h following cisplatin dosing in paediatric patients who develop AKI. Changes in metabolites involved in the NAD+ synthesis pathway may serve as early indicators of cisplatin-induced nephrotoxicity and may represent promising therapeutic interventions.