ABSTRACT
Background and Purpose: Cisplatin-induced nephrotoxicity
manifests as acute kidney injury (AKI) in approximately one third of
patients receiving cisplatin therapy. Current measures of AKI are
inadequate in detecting AKI prior to significant renal injury, and
better biomarkers are needed for early diagnosis of cisplatin-induced
AKI.
Experimental Approach: C57BL/6 and FVB/N mice were treated with
a single intraperitoneal injection of cisplatin (15 mg
kg-1) or saline. Plasma, urine, and kidney samples
were collected prior to cisplatin injection and 24-, 48-, 72-, and
96-hours following cisplatin injection. Untargeted metabolomics was
employed using liquid chromatography-mass spectrometry to identify early
diagnostic biomarkers for cisplatin-induced AKI.
Key Results: There was clear metabolic discrimination between
saline and cisplatin-treated mice at all timepoints (day 1 to day 4). In
total, 26 plasma, urine, and kidney metabolites were identified as
exhibiting early alterations following cisplatin treatment. Several of
the metabolites showing early alterations were associated with
mitochondrial function and energetics, including intermediates of the
tricarboxylic acid cycle, regulators of mitochondrial function and
indicators of fatty acid β-oxidation dysfunction. Furthermore, several
metabolites were derived from the gut microbiome.
Conclusion and Implications: Our results highlight the
detrimental effects of cisplatin on mitochondrial function and
demonstrate potential involvement of the gut microbiome in the
pathophysiology of cisplatin-induced AKI. Here we provide a panel of
metabolites to guide future clinical studies of cisplatin-induced AKI
and provide insight into potential mechanisms behind cisplatin
nephrotoxicity.
Keywords: Metabolomics, cisplatin, nephrotoxicity, acute kidney
injury, biomarkers