Higher Glycolysis in Circulating Leukocytes in Patients with CKD

Background: Increased expression of glycolytic enzymes in kidney tissue correlates with CKD progression in the subtotal nephrectomy murine model. There are also higher levels of inflammatory cytokines with worsening CKD. These proinflammatory cytokines promote glycolysis in human endothelial cell lines. It is unknown whether glycolysis is altered in the circulating immune cells of patients with CKD that's associated with the pro-inflammatory phenotype of these patients. Methods: We collected peripheral blood mononuclear cells from outpatients with CKD with eGFR <30 (n=37) and controls with normal kidney function (n=29) using ficoll high-density gradient leukoseparation. We identified pathways that were significantly different between groups using HALLMARK analysis. We also performed DEseq analysis for differentially expressed genes that met threshold fold change of 1.5 at false discovery rate of 0.1. Seahorse assays measured ATP production from leukocytes via glycolysis and non-glycolytic pathways. Results: The glycolytic pathway was significantly upregulated in the CKD group in unadjusted analysis; and remained significant even after adjusting for presence of diabetes, age, race and gender. We also found 7 differentially expressed genes in CKD leukocytes - 2 of them from the glycolytic pathways- IDH1 (Isocitrate dehydrogenase 1) and SLC16A3 (Solute carrier). There was higher ATP generation via glycolysis pathways in CKD leukocytes that positively correlated with patients’ serum CRP levels. Conclusion: There is overexpressed glycolytic pathway with differentially overexpressed genes of glycolytic pathways in the immune cells of patients with CKD. In addition, CKD leukocytes rely more on glycolysis for energy production that the controls which positively correlates with their proinflammatory burden.