Fibroblast growth-factor 23 and vitamin D are associated with iron deficiency and anemia in children with chronic kidney disease.
Humans
Child
Child, Preschool
Adolescent
Young Adult
Adult
Cross-Sectional Studies
Anemia
Renal Insufficiency, Chronic
Iron
Vitamin D
Ferritins
Minerals
/ metabolism
Iron Deficiencies
Hemoglobins
/ metabolism
Fibroblasts
/ metabolism
Vitamin D Deficiency
/ complications
Anemia, Iron-Deficiency
/ diagnosis
Chronic kidney disease
FGF23
Hemoglobin
Klotho
Transferrin saturation
Vitamin D
Journal
Pediatric nephrology (Berlin, Germany)
ISSN: 1432-198X
Titre abrégé: Pediatr Nephrol
Pays: Germany
ID NLM: 8708728
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
21
06
2022
accepted:
02
02
2023
revised:
02
02
2023
medline:
2
8
2023
pubmed:
3
3
2023
entrez:
2
3
2023
Statut:
ppublish
Résumé
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). 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 m 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). 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. A higher resolution version of the Graphical abstract is available as Supplementary information.
Sections du résumé
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 m
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. A higher resolution version of the Graphical abstract is available as Supplementary information.
Identifiants
pubmed: 36862253
doi: 10.1007/s00467-023-05903-3
pii: 10.1007/s00467-023-05903-3
doi:
Substances chimiques
Iron
E1UOL152H7
Vitamin D
1406-16-2
Ferritins
9007-73-2
Minerals
0
Hemoglobins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2771-2779Informations de copyright
© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.
Références
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
pubmed: 20464428
doi: 10.1007/s00467-010-1538-6
Babitt JL, Lin HY (2012) Mechanisms of anemia in CKD. J Am Soc Nephrol 23:1631–1634
pubmed: 22935483
pmcid: 3458456
doi: 10.1681/ASN.2011111078
Patino E, Akchurin O (2022) Erythropoiesis-independent effects of iron in chronic kidney disease. Pediatr Nephrol 37:777–788
pubmed: 34244852
doi: 10.1007/s00467-021-05191-9
Atkinson MA, Furth SL (2011) Anemia in children with chronic kidney disease. Nat Rev Nephrol 7:635–641
pubmed: 21894183
pmcid: 5739031
doi: 10.1038/nrneph.2011.115
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
pubmed: 34422722
pmcid: 8378583
doi: 10.3389/fped.2021.696942
Leifheit-Nestler M, Haffner D (2021) How FGF23 shapes multiple organs in chronic kidney disease. Mol Cell Pediatr 8:12
pubmed: 34536161
pmcid: 8449753
doi: 10.1186/s40348-021-00123-x
Babitt JL, Sitara D (2019) Crosstalk between FGF23, iron, erythropoietin, and inflammation in kidney disease. Curr Opin Nephrol Hypertens 28:304–310
pubmed: 31145704
pmcid: 6693648
doi: 10.1097/MNH.0000000000000514
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
pubmed: 34504604
pmcid: 8393509
doi: 10.3892/etm.2021.10593
Wheeler JA, Clinkenbeard EL (2019) Regulation of fibroblast growth factor 23 by iron, EPO, and HIF. Curr Mol Biol Rep 5:8–17
pubmed: 31218207
pmcid: 6582956
doi: 10.1007/s40610-019-0110-9
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
pubmed: 26535997
pmcid: 4854810
doi: 10.1038/ki.2015.290
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
pubmed: 24509850
pmcid: 3975025
doi: 10.1074/jbc.M113.527150
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
pubmed: 29481308
pmcid: 5998980
doi: 10.1096/fj.201700667R
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
pubmed: 34339746
pmcid: 8608725
doi: 10.1016/j.kint.2021.07.013
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
pubmed: 29740119
pmcid: 5940871
doi: 10.1038/s41598-018-25439-z
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
pubmed: 33462793
doi: 10.1007/s12011-021-02598-1
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
pubmed: 26986127
doi: 10.1097/MD.0000000000003049
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
pubmed: 28784656
pmcid: 5672973
doi: 10.2215/CJN.03950417
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
pubmed: 32823844
pmcid: 7463779
doi: 10.3390/jcm9082640
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
pubmed: 33903951
pmcid: 8448905
doi: 10.1007/s00467-021-05081-0
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
pubmed: 19158356
pmcid: 2653687
doi: 10.1681/ASN.2008030287
Eleftheriadis T, Liakopoulos V, Antoniadi G, Stefanidis I (2010) Which is the best way for estimating transferrin saturation? Ren Fail 32:1022–1023
pubmed: 20722575
doi: 10.3109/0886022X.2010.502609
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
pubmed: 22854645
doi: 10.1038/ki.2012.270
Janus J, Moerschel SK (2010) Evaluation of anemia in children. Am Fam Physician 81:1462–1471
pubmed: 20540485
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
pubmed: 29451472
doi: 10.5414/CN109132
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
pubmed: 35612637
doi: 10.1007/s10157-022-02238-5
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
pubmed: 34775773
doi: 10.21037/apm-21-1943
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
pubmed: 24412515
pmcid: 3936331
doi: 10.1016/j.ajpath.2013.11.016
Park MY, Le Henaff C, Sitara D (2022) Administration of α-Klotho does not rescue renal anemia in mice. Front Pediatr 10:924915
pubmed: 35813388
pmcid: 9259788
doi: 10.3389/fped.2022.924915
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
pubmed: 14694273
doi: 10.1159/000074837
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
pubmed: 24204002
doi: 10.1681/ASN.2013040355
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
pubmed: 30008129
pmcid: 6528819
doi: 10.1007/s00467-018-4020-5
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
pubmed: 20130525
doi: 10.1038/ki.2009.551
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
pubmed: 32013954
pmcid: 6998164
doi: 10.1186/s12937-020-0526-3
Andıran N, Çelik N, Akça H, Doğan G (2012) Vitamin D deficiency in children and adolescents. J Clin Res Pediatr Endocrinol 4:25–29
pubmed: 22394709
pmcid: 3316459
doi: 10.4274/jcrpe.574
Dusso AS, Puche RC (1985) The effect of 1 alpha, 25-dihydroxycholecalciferol on iron metabolism. Blut 51:103–108
pubmed: 3849315
doi: 10.1007/BF00320118
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
pubmed: 25295189
pmcid: 4177080
doi: 10.1155/2014/602034
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
pubmed: 26394828
doi: 10.1016/j.nefro.2015.06.025
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
pubmed: 23573815
doi: 10.1111/bjh.12311
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
pubmed: 11427634
doi: 10.1093/ndt/16.7.1416
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
pubmed: 12425487
doi: 10.5414/CNP58363
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
pubmed: 30007314
doi: 10.1093/ndt/gfy189
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
pubmed: 28818868
pmcid: 5664401
doi: 10.3324/haematol.2017.167882
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
pubmed: 28475601
pmcid: 5419608
doi: 10.1371/journal.pone.0176984
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: 29744352
pmcid: 5878890