Circulating Levels of Fibroblast Growth Factor 23 Selective for C-Terminal (FGF23-CT) in Hemodialysis Patients
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Abstract
Background: In hemodialysis patients, fibroblast growth factor 23 (FGF23) has reportedly been associated with the development of cardiovascular complications and a high risk of mortality. Our objective here was to study the cleavage characteristics of FGF23 in hemodialysis patients.
Methods: This study design is a cross-sectional observational investigation of three facilities without intervention. To assess FGF23 concentrations, we obtained plasma samples from 97 hemodialysis patients before the hemodialysis session and from 16 healthy volunteers. We measured the FGF23 C-terminal fragment and intact FGF23 concentrations by using a commercial enzyme-linked immunosorbent assay.
Results: Serum levels of the FGF23 C-terminal fragment were 189 ± 121 ng/mL in healthy volunteers and 306 ± 206 ng/mL in hemodialysis patients. The ratios of intact FGF23 to total FGF23 were 0.03 ± 0.03 in healthy volunteers and 0.44 ± 0.28 in hemodialysis patients. The ratios were positively correlated with levels of inorganic phosphate in hemodialysis patients (p < 0.001, r < 0.52).
Conclusion: We measured actual levels of the serum FGF23 C-terminal fragment in hemodialysis patients by using a new commercial kit for the first time. The ratio of intact FGF23 to total FGF23 was lower in healthy controls than the ratio in hemodialysis patients. The cleavage percentage of FGF23 was considerably higher in both groups of subjects than previously thought. We suggest that hyperphosphatemia in hemodialysis patients was associated with impaired cleavage of FGF23.
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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 Jun 15;305(23):2432-9. doi: 10.1001/jama.2011.826. PMID: 21673295; PMCID: PMC3124770.
Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008 Aug 7;359(6):584-92. doi: 10.1056/NEJMoa0706130. PMID: 18687639; PMCID: PMC2890264.
Komaba H, Fuller DS, Taniguchi M, Yamamoto S, Nomura T, Zhao J, Bieber BA, Robinson BM, Pisoni RL, Fukagawa M. Fibroblast Growth Factor 23 and Mortality Among Prevalent Hemodialysis Patients in the Japan Dialysis Outcomes and Practice Patterns Study. Kidney Int Rep. 2020 Aug 20;5(11):1956-1964. doi: 10.1016/j.ekir.2020.08.013. PMID: 33163716; PMCID: PMC7609896.
Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab. 2012 Sep;97(9):3357-65. doi: 10.1210/jc.2012-1811. Epub 2012 Jun 11. PMID: 22689697.
Tanaka K, Motomiya Y, Kaneko Y, Higashimoto Y, Yoneda T. Serum intact and total fibroblast growth factor 23 levels and iron-related parameters in hemodialysis patients. J Clin Med Res. 2022; 4(5):1–18. https://doi.org/10.37191/Mapsci-2582-4333-4(5)-124.
Shinzato T, Nakai S, Fujita Y, Takai I, Morita H, Nakane K, Maeda K. Determination of Kt/V and protein catabolic rate using pre- and postdialysis blood urea nitrogen concentrations. Nephron. 1994;67(3):280-90. doi: 10.1159/000187980. PMID: 7936017.
Bhattacharyya N, Wiench M, Dumitrescu C, Connolly BM, Bugge TH, Patel HV, Gafni RI, Cherman N, Cho M, Hager GL, Collins MT. Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res. 2012 May;27(5):1132-41. doi: 10.1002/jbmr.1546. PMID: 22247037; PMCID: PMC7448291.
van Vuren AJ, Gaillard CAJM, Eisenga MF, van Wijk R, van Beers EJ. The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research. Front Physiol. 2019 Mar 26;10:304. doi: 10.3389/fphys.2019.00304. PMID: 30971944; PMCID: PMC6443968.
Huang X, Jiang Y, Xia W. FGF23 and Phosphate Wasting Disorders. Bone Res. 2013 Jun 28;1(2):120-32. doi: 10.4248/BR201302002. PMID: 26273497; PMCID: PMC4472102.
Luo Y, Ye S, Li X, Lu W. Emerging Structure-Function Paradigm of Endocrine FGFs in Metabolic Diseases. Trends Pharmacol Sci. 2019 Feb;40(2):142-153. doi: 10.1016/j.tips.2018.12.002. Epub 2019 Jan 4. PMID: 30616873.
Al Rifai O, Susan-Resiga D, Essalmani R, Creemers JWM, Seidah NG, Ferron M. In Vivo Analysis of the Contribution of Proprotein Convertases to the Processing of FGF23. Front Endocrinol (Lausanne). 2021 Jun 4;12:690681. doi: 10.3389/fendo.2021.690681. PMID: 34149625; PMCID: PMC8213403.
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016 Jan;89(1):135-46. doi: 10.1038/ki.2015.290. Epub 2016 Jan 4. PMID: 26535997; PMCID: PMC4854810.
Francis C, David V. Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens. 2016 Jul;25(4):325-32. doi: 10.1097/MNH.0000000000000232. PMID: 27191351; PMCID: PMC5016608.
Takashi Y, Kosako H, Sawatsubashi S, Kinoshita Y, Ito N, Tsoumpra MK, Nangaku M, Abe M, Matsuhisa M, Kato S, Matsumoto T, Fukumoto S. Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11418-11427. doi: 10.1073/pnas.1815166116. Epub 2019 May 16. PMID: 31097591; PMCID: PMC6561303.
Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, Koller A, Nizet V, White KE, Dixon JE. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5520-5. doi: 10.1073/pnas.1402218111. Epub 2014 Mar 26. PMID: 24706917; PMCID: PMC3992636.
Chefetz I, Kohno K, Izumi H, Uitto J, Richard G, Sprecher E. GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity. Biochim Biophys Acta. 2009 Jan;1792(1):61-7. doi: 10.1016/j.bbadis.2008.09.016. Epub 2008 Oct 11. PMID: 18976705; PMCID: PMC3169302.
Higashimoto Y, Tanaka K, Matsui T, Sakaguchi T, Yamagishi S-I, Motomiya Y. Fibroblast growth factor 23 contributes to regulation of hepcidin/ferroportin axis. Austin J Pharmacol Ther. 2020; 8(1):1118. https://austinpublishinggroup.com/pharmacology-therapeutics/fulltext/ajpt-v8-id1118.pdf.
Souvenir R, Flores JJ, Ostrowski RP, Manaenko A, Duris K, Tang J. Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia. Transl Stroke Res. 2014 Feb;5(1):118-27. doi: 10.1007/s12975-013-0312-z. Epub 2013 Nov 27. PMID: 24323731; PMCID: PMC3946340.
Kuro-O M. Klotho and endocrine fibroblast growth factors: markers of chronic kidney disease progression and cardiovascular complications? Nephrol Dial Transplant. 2019 Jan 1;34(1):15-21. doi: 10.1093/ndt/gfy126. PMID: 29800324.
Bär L, Stournaras C, Lang F, Föller M. Regulation of fibroblast growth factor 23 (FGF23) in health and disease. FEBS Lett. 2019 Aug;593(15):1879-1900. doi: 10.1002/1873-3468.13494. Epub 2019 Jul 5. PMID: 31199502.