Potential urinary biomarkers of nephrotoxicity in cyclophosphamide-treated rats investigated by NMR-based metabolic profiling.

The anticancer-drug cyclophosphamide (CP) is known to have nephrotoxicity. The aim of this study was to identify urinary biomarkers indicating CP-induced nephrotoxicity. We investigated the urine metabolic profiles using nuclear magnetic resonance spectrometry of rats administered with single high-doses of CP (0, 30, and 100 mg/kg body weight) and daily low-doses over a 4-week period (0, 1, 3, and 10 mg/kg body weight). Among 18 identified urinary metabolites, 2-oxoglutarate, citrate, hippurate, formate, valine, and alanine for short-term and 2-oxoglutarate, citrate, hippurate, isoleucine, leucine, allantoin, valine, and lysine for long-term were selected as potential biomarkers. Pathway-enrichment analysis suggested that the urinary metabolism of CP is related to valine, leucine, and isoleucine biosynthesis; taurine and hypotaurine metabolism; glyoxylate and dicarboxylate metabolism; citrate cycle; and alanine, aspartate, and glutamate metabolism, with high pathway impact. The potential biomarkers obtained in this study could be used to monitor CP-induced nephrotoxicity relative to dose and treatment time.