Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses

Abstract

Background: Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), ferric citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation.

Methods: We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with ferric citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT).

Results: We analyzed a total of 117 and 115 ferric citrate-treated and placebo-treated patients, respectively. At 16 weeks, ferric citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms.

Conclusions: Ferric citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.

Keywords: FGF23; ferric citrate; iron-deficiency anemia; nondialysis-dependent chronic kidney disease; serum phosphate.

FIGURE 1

Structural equation model specification for path analyses.

FIGURE 2

Mean trajectories of serum phosphate during 16 weeks by treatment (ferric citrate versus placebo) estimated at (A) baseline serum phosphate tertiles (ferric citrate curves), (B) baseline serum phosphate tertiles (placebo curves), (C) baseline eGFR level–CKD stage (ferric citrate curves) and (D) baseline eGFR level–CKD stage (placebo curves). Data are LSM (SE) serum phosphate estimates derived from a mixed-effects model for repeated measures analysis with fixed-effects terms for treatment (ferric citrate versus placebo), baseline covariate, visit, treatment × visit interaction, treatment × covariate interaction and treatment × visit × covariate interaction. ^aP = 0.006 versus placebo. ^bP = 0.438 versus placebo. ^cP = 0.236 versus placebo. ^dNormal laboratory reference range of serum phosphate. ^eP = 0.013 versus placebo. ^fP = 0.020 versus placebo. ^gP = 0.566 versus placebo. BL, baseline; SE, standard error; SP, serum phosphate.

FIGURE 3

Serum phosphate (SP) concentrations after dose increases of ferric citrate (FC) by baseline phosphate tertile (FC-treated patients only). For each tertile color coded as shown in the legend, circles indicate individual patient serum phosphate concentrations and the lines indicate the mixed-model regression line of best fit. ^aP = 0.013 versus lowest tertile slope. ^bP < 0.001 versus lowest tertile slope. ^cP < 0.001 versus middle tertile slope. ^dNormal laboratory reference range of SP. BL, baseline.

FIGURE 4

Path analyses exploring the change in serum phosphate and TSAT at 14 weeks as mediators of ferric citrate (FC)-induced reduction in (A) cFGF23 at 16 weeks and (B) iFGF23 at 16 weeks. ^•P < 0.10, *P < 0.05, **P < 0.01, ***P < 0.001. Obs, observed value analysis; RFI, random forest imputation analysis.