Upregulation of Lipid Metabolism and Tricarboxylic Acid (TCA) Cycle Pathways Marks Disease in Lupus Nephritis Based on Comprehensive Urine Metabolomics

Background: Lupus nephritis (LN) is a severe renal complication of systemic lupus erythematosus (SLE). Identifying metabolic biomarkers of active LN is essential for early diagnosis and for understanding disease pathogenesis. Methods: Urine samples from active LN, inactive LN and healthy controls (N=8 each) were subjected to comprehensive metabolomics using Metware Biotechnology’s Untargeted Plus Metabolomics platform. Results were normalized by creatinine and subjected to statistical and pathway enrichment analysis using MetaboAnalyst. Results: A total of 14275 metabolites were identified. 164 urine metabolites were significantly upregulated in active LN, and 346 were significantly down-regulated, compared to inactive LN (Fig. 1). 30 discriminatory urine biomarkers exhibited ROC AUC = 1. Dysregulated proteins in active LN urine were enriched for the following metabolic pathways: Glycerophospholipid metabolism (raw p = 0.017, impact = 0.145), Glycerolipid metabolism (raw p = 0.025, impact = 0.191), TCA cycle (raw p = 0.038, impact = 0.063) and Propanoate metabolism (raw p = 0.045, impact = 0.041) as summarized in Fig. 2(b). Conclusion: Active LN is marked by significant upregulation of glycerophospholipid, glycerolipid, and TCA cycle metabolic pathways, as viewed through the window of urine metabolomics. These could have originated from blood, renal parenchymal cells, or infiltrating immune cells, and this needs to be dissected out. Interestingly, we observed an overlap between key pathways implicated in our findings and dysregulated lipid metabolism in T cells during LN. These findings may yield additional biomarkers for LN diagnosis and provide deeper insight into the metabolic mechanisms driving progress of SLE to LN.