Ferric Citrate Decreases Fibroblast Growth Factor 23 and Improves Erythropoietin Responsiveness in Hemodialysis Patients

Abstract

Background: Serum phosphate and vitamin D receptor activator regulate fibroblast growth factor 23 (FGF23), and iron may modulate FGF23 metabolism. The aim of the present study was to elucidate the effects of ferric citrate hydrate and lanthanum carbohydrate on serum FGF23 levels in hemodialysis patients. Methods: This prospective, open-label, multicenter study enrolled 60 patients on hemodialysis treated with lanthanum carbonate. Patients were randomly assigned to 2 groups: those switching from lanthanum carbonate to ferric citrate hydrate (ferric citrate group, n = 30) or those continuing lanthanum carbonate (control group, n = 30). Patients were monitored for 24 weeks. Endpoints included changes in FGF23, phosphate, and the dose of erythropoiesis stimulating agent (ESA), erythropoietin responsiveness index (ERI), and adverse events. Results: FGF-23 levels were significantly lower in the ferric citrate group compared with the levels in the control group (change from baseline –6,160 vs. –1,118 pg/mL; p = 0.026). There were no significant changes in serum calcium, phosphate, and intact parathyroid hormone levels in either group. The ferric citrate group had significantly increased serum iron, ferritin, and transferrin saturation. Hemoglobin levels were significantly elevated, and the dose of ESA was significantly decreased in the ferric citrate group but not in the control group. ERI and the dose of intravenous saccharated ferric oxide were significantly lower in the ferric citrate group compared with those of the control group (p = 0.015 and p = 0.002). Conclusion: In patients on hemodialysis, 24-week treatment with ferric citrate hydrate resulted in significant reduction in FGF23 and ERI independently of serum phosphate level.

Regulation of Fibroblast Growth Factor 23 by Iron, EPO, and HIF

“…Ferric citrate acts similarly in that the efficacy in reducing serum phosphorus is superior to sevelamer (105) and also significantly improves iron parameters as measured by ferritin and transferrin saturation (106). In hemodialysis CKD patients, ferric citrate improved serum iron and hemoglobin, which was also associated with a reduction in serum FGF23 (107). In contrast, treatment with ferric citrate in non-dialysis CKD patients had a modest reduction in serum FGF23 that did not reach significance.…”

Mechanism of Action and Clinical Attributes of Auryxia® (Ferric Citrate)

“…In a Phase 3, 56-week, placebo- and active-controlled trial in patients with dialysis-dependent CKD, Auryxia (dosed and titrated to maintain serum phosphate control) significantly improved iron parameters compared with active controls (sevelamer carbonate and/or calcium acetate) as early as Week 12 (ferritin: mean difference of 281.8 ± 42.9 ng/mL at week 52, p < 0.001; TSAT: mean difference of 9.55% ± 1.58%, p < 0.001) [ 96 ]. Additionally, two studies have suggested that Auryxia may reduce the need for IV iron when used as a phosphate binder in patients with CKD treated with dialysis [ 72 , 96 , 97 ]. Lower percentages of patients required IV iron in the Auryxia group compared with an active control group at all time points over the 52-week active control period; at the end of this period, 85.4% and 69.0% of patients did not receive IV iron at week 52 in the Auryxia and active control groups, respectively ( p < 0.001) [ 96 ].…”

“…This was true both for the intact bioactive form of FGF23 (iFGF23) and for its carboxy-terminal cleavage product (cFGF23), whose biological activities are under investigation [ 106 ]. Similarly, an open-label Japanese study in patients on hemodialysis showed that treatment with Riona compared with lanthanum carbonate led to significantly lower levels of iFGF23, independent of phosphate levels (change from baseline in iFGF23: − 6160 vs − 1118 pg/mL, respectively; p = 0.026) [ 97 ]. Although this conjecture is still speculative, reduction of FGF23 levels could have a beneficial effect on the progression of CKD and cardiovascular disease.…”

Briefly Noted

“…In a prospective 24 week, randomize trial in 60 HD patients, replacing lanthanum carbonate with ferric citrate in 30 patients was associated with a significant fall in FGF‐23 (11 000 to 7240 pg/mL vs 10 850 to 11 160 pg/mL in the lanthanum controls). Levels of calcium, phosphate, and PTH did not change in the two groups …”

“…Levels of calcium, phosphate, and PTH did not change in the two groups. 16 A case control analysis of USRDS data found that the adjusted likelihood of withdrawal from dialysis was increased in older patients (OR 1.61 for ≥85 years vs 65-74 years) and with increased morbidity score (OR 12.1 for the highest vs lowest scores). Blacks, Asians, and Hispanics were far less likely to withdraw than whites (OR 0.36, 0.7, and 0.46, respectively); women also stopped dialysis more often than men (OR 1.07).…”