Skip to main content
SpringerLink
Log in

Fibroblast growth-factor 23 and vitamin D are associated with iron deficiency and anemia in children with chronic kidney disease

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

This cross-sectional study investigates the association of fibroblast growth-factor 23 (FGF23) and other bone mineral parameters with iron status and anemia in pediatric chronic kidney disease (CKD).

Methods

Serum calcium, phosphorus, 25-hydroxyvitamin D (25(OH)D), intact parathormone, c-terminal FGF23, a-Klotho, iron (Fe), ferritin, unsaturated iron-binding capacity, and hemoglobin (Hb) were measured in 53 patients from 5 to 19 years old with GFR < 60 mL/min/1.73 m2. Transferrin saturation (TSAT) was calculated.

Results

Absolute (ferritin ≤ 100 ng/mL, TSAT ≤ 20%) and functional iron deficiency (ferritin > 100 ng/mL, TSAT ≤ 20%) were observed in 32% and 7.5% of patients, respectively. In CKD stages 3–4 (36 patients), lnFGF23 and 25(OH)D were correlated with Fe (rs =  − 0.418, p = 0.012 and rs = 0.467, p = 0.005) and TSAT (rs =  − 0.357, p = 0.035 and rs = 0.487, p = 0.003) but not to ferritin. In this patient group, lnFGF23 and 25(OH)D were correlated with Hb z-score (rs =  − 0.649, p < 0.001 and rs = 0.358, p = 0.035). No correlation was detected between lnKlotho and iron parameters. In CKD stages 3–4, in multivariate backward logistic regression analysis, including bone mineral parameters, CKD stage, patient age, and daily alphacalcidol dose as covariates, lnFGF23 and 25(OH)D were associated with low TSΑΤ (15 patients) (OR 6.348, 95% CI 1.106–36.419, and OR 0.619, 95% CI 0.429–0.894, respectively); lnFGF23 was associated with low Hb (10 patients) (OR 5.747, 95% CI 1.270–26.005); while the association between 25(OH)D and low Hb did not reach statistical significance (OR 0.818, 95% CI 0.637–1.050).

Conclusions

In pediatric CKD stages 3–4, iron deficiency and anemia are associated with increased FGF23, independently of Klotho. Vitamin D deficiency might contribute to iron deficiency in this population.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Atkinson MA, Martz K, Warady BA, Neu AM (2010) Risk for anemia in pediatric chronic kidney disease patients: a report of NAPRTCS. Pediatr Nephrol 25:1699–1706

    Article  PubMed  Google Scholar 

  2. Babitt JL, Lin HY (2012) Mechanisms of anemia in CKD. J Am Soc Nephrol 23:1631–1634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Patino E, Akchurin O (2022) Erythropoiesis-independent effects of iron in chronic kidney disease. Pediatr Nephrol 37:777–788

    Article  PubMed  Google Scholar 

  4. Atkinson MA, Furth SL (2011) Anemia in children with chronic kidney disease. Nat Rev Nephrol 7:635–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Karava V, Christoforidis A, Kondou A, Dotis J, Printza N (2021) Update on the crosstalk between adipose tissue and mineral balance in general population and chronic kidney disease. Front Pediatr 9:696942

    Article  PubMed  PubMed Central  Google Scholar 

  6. Leifheit-Nestler M, Haffner D (2021) How FGF23 shapes multiple organs in chronic kidney disease. Mol Cell Pediatr 8:12

    Article  PubMed  PubMed Central  Google Scholar 

  7. Babitt JL, Sitara D (2019) Crosstalk between FGF23, iron, erythropoietin, and inflammation in kidney disease. Curr Opin Nephrol Hypertens 28:304–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang R, Wang SY, Yang F, Ma S, Lu X, Kan C, Zhang JB (2021) Crosstalk of fibroblast growth factor 23 and anemia-related factors during the development and progression of CKD (Review). Exp Ther Med 22:1159

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wheeler JA, Clinkenbeard EL (2019) Regulation of fibroblast growth factor 23 by iron, EPO, and HIF. Curr Mol Biol Rep 5:8–17

    Article  PubMed  PubMed Central  Google Scholar 

  10. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Coe LM, Madathil SV, Casu C, Lanske B, Rivella S, Sitara D (2014) FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J Biol Chem 289:9795–9810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Agoro R, Montagna A, Goetz R, Aligbe O, Singh G, Coe LM, Mohammadi M, Rivella S, Sitara D (2018) Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. FASEB J 32:3752–3764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mehta RC, Cho ME, Cai X, Lee J, Chen J, He J, Flack J, Shafi T, Saraf SL, David V, Feldman HI, Isakova T, Wolf M, CRIC Study Investigators (2021) Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease. Kidney Int 100:1292–1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nam KH, Kim H, An SY, Lee M, Cha MU, Park JT, Yoo TH, Lee KB, Kim YH, Sung SA, Lee J, Kang SW, Choi KH, Ahn C, Han SH (2018) Circulating fibroblast growth factor-23 levels are associated with an increased risk of anemia development in patients with nondialysis chronic kidney disease. Sci Rep 8:7294

    Article  PubMed  PubMed Central  Google Scholar 

  15. Abu-Zaid A, Magzoub D, Aldehami MA, Behiry AA, Bhagavathula AS, Hajji R (2021) The effect of iron supplementation on FGF23 in chronic kidney disease patients: a systematic review and time-response meta-analysis. Biol Trace Elem Res 199:4516–4524

    Article  CAS  PubMed  Google Scholar 

  16. Tsai MH, Leu JG, Fang YW, Liou HH (2016) High fibroblast growth factor 23 levels associated with low hemoglobin levels in patients with chronic kidney disease stages 3 and 4. Medicine (Baltimore) 95:e3049

    Article  CAS  PubMed  Google Scholar 

  17. Mehta R, Cai X, Hodakowski A, Lee J, Leonard M, Ricardo A, Chen J, Hamm L, Sondheimer J, Dobre M, David V, Yang W, Go A, Kusek JW, Feldman H, Wolf M, Isakova T, CRIC Study Investigators (2017) Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clin J Am Soc Nephrol 12:1795–1803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bielesz B, Reiter T, Hammerle FP, Winnicki W, Bojic M, Gleiss A, Kieweg H, Ratzinger F, Sunder-Plassmann G, Marculescu R (2020) The role of iron and erythropoietin in the association of fibroblast growth factor 23 with anemia in chronic kidney disease in humans. J Clin Med 9:2640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Limm-Chan B, Wesseling-Perry K, Pearl MH, Jung G, Tsai-Chambers E, Weng PL, Hanudel MR (2021) Associations among erythropoietic, iron-related, and FGF23 parameters in pediatric kidney transplant recipients. Pediatr Nephrol 36:3241–3249

    Article  PubMed  PubMed Central  Google Scholar 

  20. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  21. Eleftheriadis T, Liakopoulos V, Antoniadi G, Stefanidis I (2010) Which is the best way for estimating transferrin saturation? Ren Fail 32:1022–1023

    Article  PubMed  Google Scholar 

  22. Drüeke TB, Parfrey PS (2012) Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s). Kidney Int 82:952–960

    Article  PubMed  Google Scholar 

  23. Janus J, Moerschel SK (2010) Evaluation of anemia in children. Am Fam Physician 81:1462–1471

    PubMed  Google Scholar 

  24. Goyal KK, Saha A, Sahi PK, Kaur M, Dubey NK, Goyal P, Upadhayay AD (2018) Hepcidin and proinflammatory markers in children with chronic kidney disease: a case-control study. Clin Nephrol 89:363–370

    Article  CAS  PubMed  Google Scholar 

  25. Yamamura-Miyazaki N, Michigami T, Ozono K, Yamamoto K, Hasuike Y (2022) Factors associated with 1-year changes in serum fibroblast growth factor 23 levels in pediatric patients with chronic kidney disease. Clin Exp Nephrol 26:1014–1021

    Article  CAS  PubMed  Google Scholar 

  26. Zhao SJ, Wang ZX, Chen L, Wang FX, Kong LD (2022) Effect of different phosphate binders on fibroblast growth factor 23 levels in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Ann Palliat Med 11:1264–1277

    Article  PubMed  Google Scholar 

  27. Vadakke Madathil S, Coe LM, Casu C, Sitara D (2014) Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis. Am J Pathol 184:827–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Park MY, Le Henaff C, Sitara D (2022) Administration of α-Klotho does not rescue renal anemia in mice. Front Pediatr 10:924915

    Article  PubMed  PubMed Central  Google Scholar 

  29. Aucella F, Scalzulli RP, Gatta G, Vigilante M, Carella AM, Stallone C (2003) Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure. A synergistic effect with r-HuEpo. Nephron Clin Pract 95:c121–c127

    Article  CAS  PubMed  Google Scholar 

  30. Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K, Nayak A, Wesseling-Perry K, Westerman M, Hollis BW, Salusky IB, Hewison M (2014) Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol 25:564–572

    Article  CAS  PubMed  Google Scholar 

  31. Altemose KE, Kumar J, Portale AA, Warady BA, Furth SL, Fadrowski JJ, Atkinson MA (2018) Vitamin D insufficiency, hemoglobin, and anemia in children with chronic kidney disease. Pediatr Nephrol 33:2131–2136

    Article  PubMed  PubMed Central  Google Scholar 

  32. Patel NM, Gutiérrez OM, Andress DL, Coyne DW, Levin A, Wolf M (2010) Vitamin D deficiency and anemia in early chronic kidney disease. Kidney Int 77:715–720

    Article  CAS  PubMed  Google Scholar 

  33. Arabi SM, Ranjbar G, Bahrami LS, Vafa M, Norouzy A (2020) The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analysis. Nutr J 19:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Andıran N, Çelik N, Akça H, Doğan G (2012) Vitamin D deficiency in children and adolescents. J Clin Res Pediatr Endocrinol 4:25–29

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dusso AS, Puche RC (1985) The effect of 1 alpha, 25-dihydroxycholecalciferol on iron metabolism. Blut 51:103–108

    Article  CAS  PubMed  Google Scholar 

  36. Akalin N, Okuturlar Y, Harmankaya O, Gedıkbaşi A, Sezıklı S, Koçak Yücel S (2014) Prognostic importance of fibroblast growth factor-23 in dialysis patients. Int J Nephrol 2014:602034

    Article  PubMed  PubMed Central  Google Scholar 

  37. Eser B, Yayar O, Buyukbakkal M, Erdogan B, Ercan Z, Merhametsiz O, Haspulat A, Oğuz EG, Dogan İ, Canbakan B, Ayli MD (2015) Fibroblast growth factor is associated to left ventricular mass index, anemia and low values of transferrin saturation. Nefrologia 35:465–472

    Article  PubMed  Google Scholar 

  38. Thomas DW, Hinchliffe RF, Briggs C, Macdougall IC, Littlewood T, Cavill I (2013) Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 161:639–648

    Article  CAS  PubMed  Google Scholar 

  39. Tessitore N, Solero GP, Lippi G, Bassi A, Faccini GB, Bedogna V, Gammaro L, Brocco G, Restivo G, Bernich P, Lupo A, Maschio G (2001) The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 16:1416–1423

    Article  CAS  PubMed  Google Scholar 

  40. Chiang WC, Tsai TJ, Chen YM, Lin SL, Hsieh BS (2002) Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients. Clin Nephrol 58:363–369

    Article  CAS  PubMed  Google Scholar 

  41. Hanudel MR, Eisenga MF, Rappaport M, Chua K, Qiao B, Jung G, Gabayan V, Gales B, Ramos G, de Jong MA, van Zanden JJ, de Borst MH, Bakker SJL, Nemeth E, Salusky IB, Gaillard CAJM, Ganz T (2019) Effects of erythropoietin on fibroblast growth factor 23 in mice and humans. Nephrol Dial Transplant 34:2057–2065

    Article  CAS  PubMed  Google Scholar 

  42. Clinkenbeard EL, Hanudel MR, Stayrook KR, Appaiah HN, Farrow EG, Cass TA, Summers LJ, Ip CS, Hum JM, Thomas JC, Ivan M, Richine BM, Chan RJ, Clemens TL, Schipani E, Sabbagh Y, Xu L, Srour EF, Alvarez MB, Kacena MA, Salusky IB, Ganz T, Nemeth E, White KE (2017) Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica 102:e427–e430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Honda H, Michihata T, Shishido K, Takahashi K, Takahashi G, Hosaka N, Ikeda M, Sanada D, Shibata T (2017) High fibroblast growth factor 23 levels are associated with decreased ferritin levels and increased intravenous iron doses in hemodialysis patients. PLoS One 12:e0176984

    Article  PubMed  PubMed Central  Google Scholar 

  44. Dignass A, Farrag K, Stein J (2018) Limitations of serum ferritin in diagnosing iron deficiency in inflammatory conditions. Int J Chronic Dis 2018:9394060

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Nephrology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 54642, Thessaloniki, Greece

    Vasiliki Karava, John Dotis, Antonia Kondou & Nikoleta Printza

  2. Pediatric Endocrinology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Athanasios Christoforidis

  3. Pediatric Immunology and Rheumatology Referral Center, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Anna Taparkou & Evangelia Farmaki

  4. Pediatric Hematology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Marina Economou

Authors
  1. Vasiliki Karava
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Dotis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonia Kondou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Athanasios Christoforidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Taparkou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Evangelia Farmaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marina Economou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nikoleta Printza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vasiliki Karava.

Ethics declarations

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Graphical Abstract (PPTX 165 kb)

Supplementary file2 (DOCX 36 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karava, V., Dotis, J., Kondou, A. et al. Fibroblast growth-factor 23 and vitamin D are associated with iron deficiency and anemia in children with chronic kidney disease. Pediatr Nephrol 38, 2771–2779 (2023). https://doi.org/10.1007/s00467-023-05903-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-023-05903-3

Keywords

Search

Navigation