FGF23 is associated with mortality in older individuals

Background:  

Fibroblast growth factor 23 (FGF23) is a key regulator of Vitamin D and phosphate metabolism. Preclinical studies have linked FGF23 with left ventricular hypertrophy. In a recent large prospective study, researchers identified that biologically active intact FGF23 is independently associated with all-cause and cardiovascular mortality. This finding opens the possibility for consideration of trials targeting FGF23 lowering in community-living individuals, as are being evaluated in other study populations. Read more

Fibroblast growth factor 23 (FGF23) is a 251 amino acid (AA) protein mainly produced by bone cells and functions as a central endocrine hormone regulating phosphate balance. The full-length protein comprises 251 AA including a 24 AA signal peptide. A proportion of FG23 is proteolytically processed between arginine179 and serine180 to generate N-terminal and C-terminal fragments. Therefore, the major forms of FGF23 present in human circulation are hormonally intact FGF23 and inactive N-terminal and C-terminal fragments. Depending on the epitope specificity of the antibodies utilized in commercial FGF23 assays, quantification of circulating FGF23 is based on two distinct approaches: Intact FGF23 (iFGF23) assays utilize a capture antibody that flanks the proteolytic cleavage site of FGF23, thus measuring exclusively biologically active intact FGF23 (AA 25 –251).  By contrast, C-terminal FGF23 (cFGF23) assays detect both c-terminal inactive fragments of FGF23 (AA 180-251) as well as the biologically active intact FGF23. The epitopes of the antibodies utilized in these assays lie within the c-terminal region of FGF23.

Most of the existing epidemiological studies on the association of FGF23 with clinical events related to mortality, cardiovascular disease and inflammation, measured FGF23 with a C-terminal FGF23 assay that detects both the biologically active intact hormone (iFGF23) as well as the inactive C-terminal fragments (cFGF23). These studies were performed both in the general population and in patients with kidney disease. Newer research however demonstrates that iron deficiency and inflammation induce FGF23 cleavage, increasing mainly cFGF23 degradation fragment levels whereas iFGF23 levels remain mostly unchanged.  Thus, it remains uncertain if the observed clinical associations are related to the biologically intact FGF23 hormone or if the effects of iron and inflammation on cFGF23 levels, influence the findings.

To closer evaluate the relationship of active FGF23 and its biological functions, a group of researchers recently investigated its association with mortality in a large prospective cohort of community-dwelling well-functioning older adults. The study published by Sharma et al.  included 2,763 individuals between 70-79 years who were followed up for more than 8 years. The results of the study indicate that intact FGF23 is independently associated with all-cause and cardiovascular mortality in community-living older individuals.  The authors concluded that the association seems to be restricted to certain death sub-types, in particular cardiovascular disease.  In summary, the findings suggest that the associations of FGF23 with the clinical outcomes are specific and provide insights into the biological mechanisms of FGF23. 

Click here to read full text: FGF23 and Cause-Specific Mortality in Community-Living Individuals-The Health, Aging, and Body Composition Study. Sharma S et al., 2021. Am Geriatr Soc, 69(3):711-717.

Abstract

Objectives: Fibroblast growth factor (FGF)-23 is a key regulator of mineral metabolism and has been linked with left ventricular hypertrophy in animal models. Most existing epidemiologic studies evaluated a C-terminal FGF23 assay which measures both the intact (active) hormone and inactive fragments. The relationship of intact FGF23 with cause-specific mortality is unknown.

Design: Prospective analyses of data from Health, Aging, & Body Composition (HABC) study

Setting: Community-living adults aged 70–79 years with longitudinal follow up.

Participants: 2763 older adults who participated in the HABC study

Measurements: Plasma intact FGF23 levels were measured from samples drawn in 2000 and 2001, and participants were followed through 2012. Mortality and its causes were determined by an adjudication committee. Associations of FGF23 with all-cause and cause-specific mortality were evaluated using Cox proportional hazards models adjusted for demographics, prevalent cardiovascular disease (CVD) and its risk factors, and kidney function.

Results: Median baseline intact FGF23 was 47 (IQR 37, 60) pg/ml and mean estimated glomerular filtration rate (eGFR) was 72 ± 18 ml/min/1.73m². During 8.3 years (median) follow-up, there were 821 deaths. In adjusted analysis, each two-fold higher FGF23 was associated with risk for all-cause mortality (HR 1.24 [95% CI 1.12, 1.37]). When evaluating cause-specific mortality, higher FGF23 was associated with cardiovascular mortality (HR 1.31 [95% CI 1.11, 1.54]), but not significantly with cancer (HR 1.01 [95% CI 0.83, 1.23]), gastrointestinal bleed (HR 2.49 [95% CI 0.86, 7.21]), and kidney failure (HR 1.25 [95% CI 0.77, 2.03]), dementia (HR 0.84 [95% CI 0.56, 1.26]), sepsis (HR 0.73 [95% CI 0.31, 1.73]) or pulmonary disease related mortality (HR 1.40 [95% CI 0.87, 2.27]).

Conclusion: Although higher intact FGF23 concentrations are associated with all-cause mortality in community-living individuals, the association appears limited to certain death sub-types, particularly CVD. Future studies are needed to evaluate potential mechanisms linking FGF23 concentrations with specific causes of death.

Did you know? 

Intact and c-terminal FGF23 can reliably be measured by ELISA in human serum and plasma with Biomedica’s fully validated kits. Only 50 µl of sample volume is required. The kits incorporate characterized epitope mapped antibodies and ready to use standards and controls. The assay range is optimized for clinical samples.

Biomedica´s Intact FGF23 and C-terminal FGF23 ELISA kits

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Literature:

C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. Chu C, Elitok S, Zeng S, Xiong Y, Hocher CF, Hasan AA, Krämer BK, Hocher B. BMC Nephrol. 2021 Apr 8;22(1):125. doi: 10.1186/s12882-021-02329-7. PMID: 33832449; PMCID: PMC8033679.

FGF23 and Cause-Specific Mortality in Community-Living Individuals-The Health, Aging, and Body Composition Study. Sharma S, Katz R, Dubin RF, Drew DA, Gutierrez OM, Shlipak MG, Sarnak MJ, Ix JH. J Am Geriatr Soc. 2021 Mar;69(3):711-717. doi: 10.1111/jgs.16910. Epub 2020 Nov 10. PMID: 33170519; PMCID: PMC8175094.

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes? Sharma S, Katz R, Bullen AL, Chaves PHM, de Leeuw PW, Kroon AA, Houben AJHM, Shlipak MG, Ix JH. J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4875–85. doi: 10.1210/clinem/dgaa665. PMID: 32951052; PMCID: PMC7571450.

FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Edmonston D, Wolf M. Nat Rev Nephrol. 2020 Jan;16(1):7-19. doi: 10.1038/s41581-019-0189-5. Epub 2019 Sep 13. PMID: 31519999.

Renal and extrarenal effects of fibroblast growth factor 23. Vervloet M. Nat Rev Nephrol. 2019 Feb;15(2):109-120. doi: 10.1038/s41581-018-0087-2. PMID: 30514976.

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator? Stöhr R, Schuh A, Heine GH, Brandenburg V. Front Endocrinol (Lausanne). 2018 Jun 27;9:351. doi: 10.3389/fendo.2018.00351. Erratum in: Front Endocrinol (Lausanne). 2018 Jul 18;9:422. PMID: 30013515; PMCID: PMC6036253.

Physiological Actions of Fibroblast Growth Factor-23. Front Endocrinol (Lausanne). Erben RG. 2018 May 28;9:267. doi: 10.3389/fendo.2018.00267. PMID: 29892265; PMCID: PMC5985418.

Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Wolf M, White KE. Curr Opin Nephrol Hypertens. 2014 Jul;23(4):411-9. doi: 10.1097/01.mnh.0000447020.74593.6f. PMID: 24867675; PMCID: PMC4322859.

Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study. Beben T, Ix JH, Shlipak MG, Sarnak MJ, Fried LF, Hoofnagle AN, Chonchol M, Kestenbaum BR, de Boer IH, Rifkin DE. J Am Geriatr Soc. 2016 Feb;64(2):270-6. doi: 10.1111/jgs.13951. PMID: 26889836; PMCID: PMC5510331.

Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M. Kidney Int. 2016 Jan;89(1):135-46. doi: 10.1038/ki.2015.290. Epub 2016 Jan 4. PMID: 26535997; PMCID: PMC4854810.

Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: a meta-analysis of prospective cohort studies. Xiao Y, Luo X, Huang W, Zhang J, Peng C. Int J Cardiol. 2014 Jul 1;174(3):824-8. doi: 10.1016/j.ijcard.2014.04.138. Epub 2014 Apr 22. PMID: 24820751.

Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Ärnlöv J, Carlsson AC, Sundström J, Ingelsson E, Larsson A, Lind L, Larsson TE. Kidney Int. 2013 Jan;83(1):160-6. doi: 10.1038/ki.2012.327. Epub 2012 Sep 5. PMID: 22951890.