Identification of Early Diagnostic and Predictive Biomarkers of Cisplatin-Induced Acute Kidney Injury Using Metabolomics
Abstract
Cisplatin is an effective chemotherapeutic agent used for the treatment of a wide variety of solid tumors and hematologic cancers. Despite its effectiveness, cisplatin is associated with several toxic effects to non-cancerous tissues. Nephrotoxicity is the main dose-limiting toxicity in cisplatin therapy, manifesting as acute kidney injury (AKI) in approximately one-third of patients receiving cisplatin. AKI is defined as an abrupt decline in kidney function and is associated with several short- and long-term adverse outcomes, including chronic kidney disease, cardiovascular disease, and mortality. AKI is currently diagnosed by increased serum creatinine (SCr) concentrations. However, SCr is a marker of functional impairment of the kidneys and is only elevated after significant kidney injury. Novel biomarkers are necessary for early diagnosis of cisplatin-induced AKI and to identify high risk patients prior to cisplatin therapy. Untargeted metabolomics was utilized to characterize the metabolic alterations induced by cisplatin in a mouse model of cisplatin-induced nephrotoxicity, an adult cohort of head and neck cancer patients receiving cisplatin, and a cohort of pediatric cancer patients receiving cisplatin. In our mouse model, we identified 26 metabolites that show early alterations following cisplatin administration, prior to elevations in plasma creatinine and histological evidence of kidney injury. Many of these metabolites were indicative of mitochondrial dysfunction or gut-derived metabolites. In the metabolomic investigations of adult and pediatric cancer patients, patients who developed AKI (AKI group) after cisplatin therapy were compared with patients who did not develop AKI (no AKI group) to identify metabolites that discriminate between AKI and no AKI patients. The central role of mitochondria in cisplatin nephrotoxicity was further reinforced in the adult cohort where we identified markers of fatty acid β-oxidation as predictive markers of cisplatin-induced AKI. Metabolomic investigation of the pediatric cohort revealed metabolites involved with de novo NAD+ synthesis were consistently elevated in the urine of AKI patients compared to no AKI patients. Metabolites identified as early diagnostic markers or predictive markers must be further validated in larger patient cohorts. Collectively, these results should be used to guide future targeted metabolomics investigations and experiments to test therapeutic interventions against cisplatin-induced AKI.