1. INTRODUCTION
Cisplatin is a platinum-based chemotherapeutic agent used in the treatment of a wide variety of malignancies . Although cisplatin is highly effective and widely used, clinical usage of cisplatin is often limited by toxicity to non-cancerous tissues. The kidneys are especially sensitive to cisplatin toxicity, and as such, cisplatin-induced nephrotoxicity is the dose-limiting factor in cisplatin therapy . Cisplatin is primarily excreted by the kidneys, through both glomerular filtration and tubular secretion . Transporter-mediated uptake of cisplatin by tubular epithelial cells results in the renal accumulation of cisplatin, subsequent biotransformation into highly reactive thiol metabolites, and ultimately cell injury .
Cisplatin-induced nephrotoxicity manifests as acute kidney injury (AKI) in approximately one-third of patients . AKI is characterised by a rapid decline in kidney function and is associated with increased risk for chronic kidney disease, major cardiovascular events, and mortality . AKI is defined by the Kidney Disease Improving Global Outcomes (KDIGO) as a ≥ 1.5-fold increase in serum creatinine (SCr) versus baseline, or as an increase in SCr ≥ 26.5 µmol/L . Though SCr is used for clinical diagnosis of AKI, detectable changes in SCr only occur after substantial kidney injury and functional impairment . Earlier identification of nephrotoxicity is necessary to initiate nephroprotective interventions for cisplatin-induced AKI. The search for diagnostic/prognostic biomarkers of AKI has yielded the discovery of several serum and urinary protein biomarkers, including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, cystatin C, tissue inhibitor of metalloproteinase 2, and insulin-like growth factor binding protein 7 . However, these markers are not specific to AKI, nor are they specific for any one etiology of AKI. There is a consensus that the application of a panel of biomarkers is better suited for the early detection of AKI, evaluation of AKI severity/prognosis, and discrimination of AKI etiology, rather than the use of any one single biomarker .
In this study, we aimed to identify early biomarkers of cisplatin-induced AKI through metabolomics analysis of mouse plasma, kidney, and urine samples taken at multiple time points throughout AKI progression from two different strains of mice. We used C57BL/6 and FVB/N mice, with FVB/N mice having been reported to have higher susceptibility to cisplatin-induced AKI compared to C57BL/6 . To date, there have been few studies utilizing metabolomics in rodent models of cisplatin-induced AKI. Investigating metabolic alterations in all three of plasma, urine, and kidney tissue samples at multiple timepoints throughout AKI progression is needed to characterize biomarkers from treatment to establishment of AKI.