Association of fibroblast growth factor 23 and alpha-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study

Background: Fibroblast growth factor-23 (FGF23) and alpha-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and alpha-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and alpha-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. Methods: The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and alpha-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and alpha-klotho were conducted. Results: Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p < 0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean +/- standard deviation (SD): - 0.2 +/- 0.8 log(e) pg/mL vs. 0.2 +/- 0.8 log(e) pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and alpha-klotho were not significantly different between the FC and control groups (mean +/- SD: - 0.1 +/- 0.8 log(e) pg/mL vs. 0.1 +/- 0.9 log(e) pg/mL; p = 0.33, and 2.0 +/- 91.5 pg/mL vs. - 8.9 +/- 145.3; p = 0.58, respectively). However, both forms of FGF23 and alpha-klotho were not significantly associated with each other in both groups. Conclusions: Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and alpha-klotho under the condition of serum P and Hb were maintained.