Effect of roxadustat on serum metabolome and lipidome in patients with end-stage renal disease and erythropoiesis-stimulating agent resistance

BACKGROUND: Roxadustat is a newly marketed hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia in patients with end-stage renal disease (ESRD). While clinical trials have demonstrated the therapeutic effects of roxadustat in patients with ESRD who are resistant to erythropoiesis-stimulating agents (ESAs), its metabolic effects are still unclear. METHODS: Thirty-two individuals with ESRD and ESA resistance from the Blood Purification Center of Dalian Municipal Central Hospital were included. A total of 96 fasting serum samples were obtained from participants before treatment with roxadustat, and after treatment for 15 and 30 days. Ultra-high performance liquid chromatography-mass spectrometry-based metabolomics and lipidomics strategies were applied to investigate the effects of roxadustat on serum metabolism. RESULTS: A total of 255 metabolites and 444 lipid molecular species were detected and quantified. Sphingolipids and phospholipids decreased significantly during treatment, possibly associated with changes in phospholipid and ceramide metabolism. Bile acid levels decreased and cholic acid/chenodeoxycholic acid increased, indicating changes in gut microbiota and bile acid metabolism. Amino acids also changed during the process of treatment. CONCLUSIONS: The present study showed sphingolipids, phospholipids, and bile acids were significantly altered, which may be associated with a changed metabolism caused by roxadustat. This approach provided a powerful tool for exploring the mechanisms of ESA resistance in ESRD patients and may represent a promising strategy for elucidating the complex therapeutic mechanisms of other drugs.