Clinical and Experimental Nephrology

, Volume 22, Issue 4, pp 789–796 | Cite as

Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency

  • Akira Iguchi
  • Suguru Yamamoto
  • Mihoko Yamazaki
  • Kazuyuki Tasaki
  • Yasushi Suzuki
  • Junichiro James Kazama
  • Ichiei Narita
Original Article



In patients with normophosphatemia with chronic kidney disease (CKD), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) increase urinary phosphate excretion while maintaining serum phosphate within the normal range. Recent reports have shown that, in this stage, phosphate binders do not decrease serum FGF23 and PTH levels. Iron deficiency promotes transcription of FGF23 and iron-supplementation for iron deficiency decreases serum FGF23 levels. We hypothesized that ferric citrate hydrate, an iron-based phosphate binder, will decrease serum FGF23 levels in patients with non-dialysis-dependent CKD with normophosphatemia and iron deficiency.


This was a single-center, randomized, open-label interventional study. The inclusion criteria were as follows: (1) eGFR < 45 mL/min/1.73 m2, (2) normophosphatemia, (3) iron deficiency. Patients were assigned to the following groups: ferric citrate hydrate (FCH)-group, sodium ferrous citrate (SFC)-group, and control-group. After 12 weeks of intervention, we evaluated serum FGF23 levels and CKD-mineral bone disorder markers.


There were 17 patients in the FCH-group, 14 in the SFC-group, and 9 in the control-group. The serum ferritin levels increased in the FCH-group and SFC-group compared with baseline. Serum FGF23 levels were unchanged; the change in the FCH-group was from 52.91 RU/mL (42.48–72.91) to 40.00 RU/mL (30.30–58.13) (P = 0.1764). However, in the FCH-group, serum PTH levels significantly decreased compared with baseline, from 68.00 pg/mL (49.00–141.00) to 60.00 pg/mL (44.00–144.00) (P = 0.0101).


Iron-based phosphate binder did not decrease serum FGF23 levels, but decreased serum PTH levels.


FGF23 PTH Ferric citrate hydrate Iron deficiency Normophosphatemia 


Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Human and animal rights (with IRB approval number)

The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and was approved by the human research committee at our institution (authorization No. E15-16).

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009; 113:S1–130.Google Scholar
  2. 2.
    Fukagawa M, Yokoyama K, Koiwa F, Taniguchi M, Shoji T, Kazama JJ, Komaba H, Ando R, Kakuta T, Fujii H, Nakayama M, Shibagaki Y, Fukumoto S, Fujii N, Hattori M, Ashida A, Iseki K, Shigematsu T, Tsukamoto Y, Tsubakihara Y, Tomo T, Hirakata H, Akizawa T. CKD-MBD Guideline Working Group.; Japanese Society for Dialysis Therapy. Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder. Ther Apher Dial. 2013; 17:247–88.CrossRefPubMedGoogle Scholar
  3. 3.
    Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79:1370–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutiérrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M. Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305:2432–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, Ritz E, Kronenberg F; MMKD Study Group., Kuen E, König P, Kraatz G, Mann JF, Müller GA, Köhler H, Riegler P. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007;18:2600–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int. 2008;73:1296–302.CrossRefPubMedGoogle Scholar
  7. 7.
    Sprague SM, Abboud H, Qiu P, Dauphin M, Zhang P, Finn W. Lanthanum carbonate reduces phosphorus burden in patients with CKD stages 3 and 4: a randomized trial. Clin J Am Soc Nephrol. 2009;4:178–85.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ketteler M, Rix M, Fan S, Pritchard N, Oestergaard O, Chasan-Taber S, Heaton J, Duggal A, Kalra PA. Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008;3:1125–30.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yokoyama K, Hirakata H, Akiba T, Fukagawa M, Nakayama M, Sawada K, Kumagai Y, Block GA. Ferric citrate hydrate for the treatment of hyperphosphatemia in nondialysis-dependent CKD. Clin J Am Soc Nephrol. 2014;9:543–52.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, Jorgetti V, Canziani ME, Moysés RM. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010;5:286–91.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gonzalez-Parra E, Gonzalez-Casaus ML, Galán A, Martinez-Calero A, Navas V, Rodriguez M, Ortiz A. Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients. Nephrol Dial Transplant. 2011;26:2567–71.CrossRefPubMedGoogle Scholar
  12. 12.
    Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, Allison MA, Asplin J, Smits G, Hoofnagle AN, Kooienga L, Thadhani R, Mannstadt M, Wolf M, Chertow GM. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol. 2012;23:1407–15.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Di Iorio B, Di Micco L, Torraca S, Sirico ML, Russo L, Pota A, Mirenghi F, Russo D. Acute effects of very-low-protein diet on FGF23 levels: a randomized study. Clin J Am Soc Nephrol. 2012;7:581–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Chue CD, Townend JN, Moody WE, Zehnder D, Wall NA, Harper L, Edwards NC, Steeds RP, Ferro CJ. Cardiovascular effects of sevelamer in stage 3 CKD. J Am Soc Nephrol. 2013;24:842–52.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Seifert ME1, de las Fuentes L, Rothstein M, Dietzen DJ, Bierhals AJ, Cheng SC, Ross W, Windus D, Dávila-Román VG, Hruska KA. Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease. Am J Nephrol. 2013;38:158–67. doi: Epub 2013 Aug 7.CrossRefPubMedGoogle Scholar
  16. 16.
    Isakova T, Barchi-Chung A, Enfield G, Smith K, Vargas G, Houston J, Xie H, Wahl P, Schiavenato E, Dosch A, Gutiérrez OM, Diego J, Lenz O, Contreras G, Mendez A, Weiner RB, Wolf M. Effects of dietary phosphate restriction and phosphate binders on FGF23 levels in CKD. Clin J Am Soc Nephrol. 2013;8:1009–18. Epub 2013 Mar 7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ureña-Torres P, Prié D, Keddad K, Preston P, Wilde P, Wan H, Copley JB. Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial. BMC Nephrol. 2014;15:71. Scholar
  18. 18.
    Schouten BJ1, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94:2332–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Takeda Y, Komaba H, Goto S, Fujii H, Umezu M, Hasegawa H, Fujimori A, Nishioka M, Nishi S, Fukagawa M. Effect of intravenous saccharated ferric oxide on serum FGF23 and mineral metabolism in hemodialysis patients. Am J Nephrol. 2011;33:421–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013 28: 1793–803.CrossRefPubMedGoogle Scholar
  21. 21.
    Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. Clin Endocrinol Metab. 2011;96:3541–9.CrossRefGoogle Scholar
  22. 22.
    Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens. 2014;23:411–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yokoyama K, Hirakata H, Akiba T, Fukagawa M, Nakayama M, Sawada K, Kumagai Y, Block GA. Ferric citrate hydrate for the treatment of hyperphosphatemia in nondialysisdependent CKD. Clin J Am Soc Nephrol. 2014;9:543–52.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Block GA, Fishbane S, Rodriguez M, Smits G, Shemesh S, Pergola PE, Wolf M, Chertow GM. A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD Stages 3–5. Am J Kidney Dis. 2015;65:728–36.CrossRefPubMedGoogle Scholar
  25. 25.
    Iguchi A, Kazama JJ, Yamamoto S, Yoshita K, Watanabe Y, Iino N, Narita I. Administration of ferric citrate hydrate decreases circulating fgf23 levels independently of serum phosphate levels in hemodialysis patients with iron deficiency. Nephron. 2015;131:161–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Heinrich HC. Intestinal absorption of 59Fe from neutron-activated commercial oral iron(III)-citrate and iron(III)-hydroxide-polymaltose complexes in man. Arzneimittelforschung. 1987;37:105–7.PubMedGoogle Scholar
  27. 27.
    Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int. 2012;82:737–47.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zoccali C, Mallamaci F. Moderator’s view: Phosphate binders in chronic kidney disease patients: a clear ‘No’ at the moment, but stay tuned. Nephrol Dial Transplant. 2016;31:196–9.PubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2017

Authors and Affiliations

  1. 1.Division of Nephrology and RheumatologySaiseikai Niigata Daini HospitalNiigataJapan
  2. 2.Department of Internel MedicineNagaoka Red-Cross HospitalNagaokaJapan
  3. 3.Division of Blood Purification TherapyNiigata University Medical and Dental HospitalNiigataJapan
  4. 4.Department of Nephrology and HypertensionFukushima Medical UniversityFukushimaJapan
  5. 5.Division of Clinical Nephrology and RheumatologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan

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