Association between Serum Glycerol-3-Phosphate and Fibroblast Growth Factor-23 in Nondiabetic Patients on Hemodialysis

Background: Fibroblast growth factor-23 (FGF23) is a key regulator of mineral metabolism that is independently associated with mortality in patients with end-stage kidney disease (ESKD). Glycerol-3-phosphate (G3P), a byproduct of glycolysis that can be derived from injured kidneys, stimulates FGF23 production. We aimed to determine if serum G3P is associated with FGF23 levels in patients with ESKD and identify potential molecular pathways that mediate their relationship. Methods: We conducted a cross-sectional study of 99 non-diabetic patients with ESKD on hemodialysis. We utilized linear regression to examine the association between G3P terciles and log-transformed C-terminal FGF23 levels, adjusting for demographics, coronary artery disease, serum calcium, phosphorus, and parathyroid hormone. Mann-Whitney U tests compared 247 serum metabolite levels between the first and third FGF23 terciles; significant metabolites (p<0.01) were selected for pathway enrichment analyses. Top pathway scores were used in mediation analyses. Results: The median age of participants was 54 years (Interquartile Range (IQR): 44-63), 38% were women, 71% self-identified as Black, and 27% had coronary artery disease. Median FGF23 level was 777 (IQR 222-1,310) RU/mL. In adjusted analyses, compared with participants with the lowest G3P tercile, those with the highest G3P tercile had a 95% higher FGF23 level (95% Confidence Interval (CI): 6%, 260%, p=0.004). Of the 27 metabolites significantly associated with FGF23 levels, pathway enrichment analysis identified the pentose phosphate pathway as the top hit (impact score=0.33, false discovery rate-adjusted p-value= 0.01). The pentose phosphate pathway mediated the relationship between G3P and FGF23, resulting in a 62% change in the β coefficient. Conclusion: In nondiabetic patients with ESKD on hemodialysis, serum G3P positively correlated with serum C-terminal FGF23, and this relationship was mediated by the pentose phosphate pathway. Exploring the pentose phosphate pathway could yield critical mechanistic insights into the regulation of FGF23, enhancing our understanding of its broader biological functions.