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

Abstract

Background: Fibroblast growth factor-23 (FGF23) and α-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 α-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 α-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 α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-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 α-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 α-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 α-klotho under the condition of serum P and Hb were maintained.

Trial registration: ASTRIO study ( UMIN000019176 , registered at UMIN Clinical Trials Registry on October 1, 2015).

Keywords: ASTRIO study; FGF23; Ferric citrate hydrate; Hemodialysis; iron-based phosphate binder; α-Klotho.

Fig. 1

Study design. Hemodialysis patients receiving one or more non-iron-based phosphate binders and an erythropoiesis-stimulating agent (ESA) for at least 4 weeks before study registration were enrolled. Evaluation was carried out at week 0 (baseline), week 12, week 24, and at study discontinuation. End-of-treatment was at week 24 or discontinuation, whichever was earlier

Fig. 2

Flow of patients throughout the ASTRIO study

Fig. 3

Time-course changes in levels of biomarkers. Changes in (a) intact fibroblast growth factor-23 (FGF23), (b) C-terminal FGF23, and (c) α-klotho. Data are presented as means and upper and lower limits of the 95% confidence interval. FC, ferric citrate hydrate; EOT, end of treatment

Fig. 4

Time-course changes in difference from baseline to end-of-treatment (EOT) in levels of biomarkers. Changes in (a) intact fibroblast growth factor-23 (FGF23), (b) C-terminal FGF23, and (c) α-klotho. The asterisk in panel (b) designates a statistically significant difference between the control and FC groups (p = 0.04). Data are presented as means and upper and lower limits of the 95% confidence interval. FC, ferric citrate hydrate

Fig. 5

Association between baseline α-klotho levels and intact or C-terminal fibroblast growth factor 23 (FGF23). (a) α-klotho vs. intact-FGF23 (i-FGF23) in the ferric citrate hydrate (FC) group; b) α-klotho vs. i-FGF23 in the control group; (c) α-klotho vs. C-terminal-FGF23 (c-FGF23) in the FC group; and (d) α-klotho vs. c-FGF23 in the control group. FGF23 values were log-converted. r, Pearson’s correlation coefficient

Fig. 6

Association of change from baseline between α-klotho and intact or C-terminal fibroblast growth factor-23 (FGF23). (a) α-klotho vs. intact FGF23 (i-FGF23) in the ferric citrate hydrate (FC) group; (b) α-klotho vs. i-FGF23 in the control group; (c) α-klotho vs. C-terminal-FGF23 (c-FGF23) in the FC group; and (d) α-klotho vs. c-FGF23 in the control group. FGF23 values were log-converted. r, Pearson’s correlation coefficient