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.