Screening for Early Biomarkers of Cisplatin-Induced Acute Kidney Injury in Rats Through Serum Metabolomics Technology.

ABSTRACT

OBJECTIVE: To systematically identify early biomarkers of cisplatin-induced acute kidney injury (AKI) in rats. STUDY DESIGN: An experimental study. Place and Duration of the Study Experimental Animal Laboratory of Lanzhou University, Gansu, China, and the Department of Pharmacy, The First Hospital of Lanzhou University, Gansu, China, from July 2022 to October 2023. METHODOLOGY: In this study, an AKI model was established by continuously injecting cisplatin into rats at a dose of 1 mg/kg once a day for control group and for 2, 3, 4, and 5 days to other four groups, respectively. Subsequently, rat plasma samples were collected for metabolomics analysis to identify early differentiated metabolites in the plasma prior to creatinine elevation. Furthermore, accurate HPLC-MS/MS methods were developed to validate the biomarker variation in other AKI models. RESULTS: The occurrence of time-dependent renal cortical injury and significant alterations of creatinine (Cr) concentration were observed on day-4 and 5, which demonstrated successful model construction. Sixty-six compounds changed on Day-2 while 61 compounds changed on Day-3. Eleven compounds with variable importance in projection (VIP) >1.5 and false discover rate (FDR) <0.2 were selected and identified by HPLC-MS/MS. Among these, N-acetylglutamine and citramalic acid changed earlier than serum creatinine (sCr) in the AKI model. CONCLUSION: N-acetylglutamine and citramalic acid may serve as early biomarker of cisplatin-induced AKI. KEY WORDS Acute kidney injury, Biomarker, Cisplatin, Metabolomics, LC-MS/MS, Rats.