Iron deficiency, elevated erythropoietin, fibroblast growth factor 23, and mortality in the general population of the Netherlands: A cohort study

Abstract

Background Emerging data in chronic kidney disease (CKD) patients suggest that iron deficiency and higher circulating levels of erythropoietin (EPO) stimulate the expression and concomitant cleavage of the osteocyte-derived, phosphate-regulating hormone fibroblast growth factor 23 (FGF23), a risk factor for premature mortality. To date, clinical implications of iron deficiency and high EPO levels in the general population, and the potential downstream role of FGF23, are unclear. Therefore, we aimed to determine the associations between iron deficiency and higher EPO levels with mortality, and the potential mediating role of FGF23, in a cohort of community-dwelling subjects. Methods and findings We analyzed 6,544 community-dwelling subjects (age 53 ± 12 years; 50% males) who participated in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study—a prospective population-based cohort study, of which we used the second survey (2001–2003)—and follow-up was performed for a median of 8 years. We measured circulating parameters of iron status, EPO levels, and plasma total FGF23 levels. Our primary outcome was all-cause mortality. In multivariable linear regression analyses, ferritin (ß = –0.43), transferrin saturation (TSAT) (ß = −0.17), hepcidin (ß = −0.36), soluble transferrin receptor (sTfR; ß = 0.33), and EPO (ß = 0.28) were associated with FGF23 level, independent of potential confounders. During median (interquartile range [IQR]) follow-up of 8.2 (7.7–8.8) years, 379 (6%) subjects died. In multivariable Cox regression analyses, lower levels of TSAT (hazard ratio [HR] per 1 standard deviation [SD], 0.84; 95% confidence interval [CI], 0.75–0.95; P = 0.004) and higher levels of sTfR (HR, 1.15; 95% CI 1.03–1.28; P = 0.01), EPO (HR, 1.17; 95% CI 1.05–1.29; P = 0.004), and FGF23 (HR, 1.20; 95% CI 1.10–1.32; P < 0.001) were each significantly associated with an increased risk of death, independent of potential confounders. Adjustment for FGF23 levels markedly attenuated the associations of TSAT (HR, 0.89; 95% CI 0.78–1.01; P = 0.06), sTfR (HR, 1.08; 95% CI 0.96–1.20; P = 0.19), and EPO (HR, 1.10; 95% CI 0.99–1.22; P = 0.08) with mortality. FGF23 remained associated with mortality (HR, 1.15; 95% CI 1.04–1.27; P = 0.008) after adjustment for TSAT, sTfR, and EPO levels. Mediation analysis indicated that FGF23 explained 31% of the association between TSAT and mortality; similarly, FGF23 explained 32% of the association between sTfR and mortality and 48% of the association between EPO and mortality (indirect effect P < 0.05 for all analyses). The main limitations of this study were the observational study design and the absence of data on intact FGF23 (iFGF23), precluding us from discerning whether the current results are at...

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population

“…FGF23 levels were measured in plasma EDTA samples with a human FGF23 ELISA (Quidel Corp, San Diego, CA), the details of which have been described elsewhere. 27 The intra‐assay and interassay coefficients of variation of the FGF23 ELISA were <5% and <16%, respectively, in blinded replicated samples. 28 The FGF23 measurement that we used in our current study is directed against 2 different epitopes within the C‐terminal part of the FGF23 molecule.…”

Fibroblast growth factor 23 and new-onset chronic kidney disease in the general population: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

“…Analysis of each individual component of the primary endpoint revealed that a higher FGF23 level was also associated with an increased risk of either a reduced eGFR or increased UAE. These associations were independent of established risk factors for CKD, including baseline albuminuria, and other markers of bone and mineral metabolism and iron parameters [ 13 ]. FGF23 was also associated with a higher risk of premature mortality in this general population–based cohort.…”

“…The data collection procedures of the PREVEND study have been described in detail elsewhere [ 12 , 13 ]. In brief, each examination consisted of two outpatient clinic visits separated by 2 weeks.…”

“…We measured serum cystatin C concentrations using the Gentian Cystatin C Immunoassay (Gentian, Moss, Norway) on a Roche Diagnostics modular auto-analyser. The cystatin C assay was calibrated using the standard supplied by the manufacturer, which is traceable to the International Federation of Clinical Chemistry Working Group for Standardization of Serum Cystatin C. Glomerular filtration rate (GFR) was estimated using the 2012 combined creatinine cystatin C-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [ 13 ].…”

Crosstalk of fibroblast growth factor 23 and anemia‑related factors during the development and progression of CKD (Review)

“…Molecular studies have reported that iron deficiency upregulates furin by stabilizing HIF1-α, which subsequently cleaves FGF23 into cFGF23 fragments (6,35,36). Furthermore, Eisenga et al (37) demonstrated that increased FGF23 levels mediate the association between iron deficiency and mortality. Iron deficiency, as a crucial determinant of FGF23 expression, can also occur during blood loss from trauma, surgery and bowel dysfunction (38,39).…”