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The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans.

ABSTRACT: Anemia in chronic kidney disease (CKD) is an almost universal complication of this condition. Fibroblast growth factor 23 (FGF23), a key-player in mineral metabolism, is reportedly associated with anemia and hemoglobin levels in non-dialysis CKD patients. Here, we sought to further characterize this association while taking into account the biologically active, intact fraction of FGF23, iron metabolism, and erythropoietin (EPO). Hemoglobin, EPO, iron, and mineral metabolism parameters, including both intact and c-terminal-FGF23 (iFGF23 and cFGF23, respectively) were measured cross-sectionally in 225 non-dialysis CKD patients (stage 1-5, median eGFR: 30 mL/min./1.73m2) not on erythropoiesis stimulating agents or intravenous iron therapy. Statistical analysis was performed by multiple linear regression. After adjustment for eGFR and other important confounders, only cFGF23 but not iFGF23 was significantly associated with hemoglobin levels and this association was largely accounted for by iron metabolism parameters. cFGF23 but not iFGF23 was also associated with mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), again in dependence on iron metabolism parameters. Similarly, EPO concentrations were associated with cFGF23 but not iFGF23, but their contribution to the association of cFGF23 with hemoglobin levels was marginal. In pre-dialysis CKD patients, the observed association of FGF23 with hemoglobin seems to be restricted to cFGF23 and largely explained by the iron status.

SUBMITTER: Bielesz B

PROVIDER: S-EPMC7463779 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans.

Bielesz Bernhard B Reiter Thomas T Hammerle Fabian Peter FP Winnicki Wolfgang W Bojic Marija M Gleiss Andreas A Kieweg Heidi H Ratzinger Franz F Sunder-Plassmann Gere G Marculescu Rodrig R

Journal of clinical medicine 20200814 8

Anemia in chronic kidney disease (CKD) is an almost universal complication of this condition. Fibroblast growth factor 23 (FGF23), a key-player in mineral metabolism, is reportedly associated with anemia and hemoglobin levels in non-dialysis CKD patients. Here, we sought to further characterize this association while taking into account the biologically active, intact fraction of FGF23, iron metabolism, and erythropoietin (EPO). Hemoglobin, EPO, iron, and mineral metabolism parameters, including ...[more]

PMID: 32823844

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Project description:Background and objectivesAnemia is an early complication of CKD that is associated with increased morbidity and mortality. Prior data show associations between abnormal mineral metabolism markers and decreased erythropoiesis. However, few studies have investigated elevated fibroblast growth factor 23 as a risk factor for the development of anemia in patients with CKD.Design, setting, participants, & measurementsWe conducted a prospective cohort study of 3869 individuals with mild to severe CKD enrolled in the Chronic Renal Insufficiency Cohort Study between 2003 and 2008 and followed through 2013. We hypothesized that elevated baseline fibroblast growth factor 23 levels are associated with prevalent anemia, decline in hemoglobin over time, and development of incident anemia, defined as serum hemoglobin level <13 g/dl in men, serum hemoglobin level <12 g/dl in women, or use of erythropoietin stimulating agents.ResultsIn the 1872 of 3869 individuals who had prevalent anemia at baseline, mean age was 58 (11) years old, and mean eGFR was 39 (13) ml/min per 1.73 m2. Higher levels of fibroblast growth factor 23 were significantly associated with prevalent anemia (odds ratio per 1-SD increase in natural log-transformed fibroblast growth factor 23, 1.39; 95% confidence interval, 1.26 to 1.52), decline in hemoglobin over 4 years, and risk of incident anemia (hazard ratio per 1-SD increase in natural log-transformed fibroblast growth factor 23, 1.13; 95% confidence interval, 1.04 to 1.24; quartile 4 versus quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.19 to 2.11) independent of demographic characteristics, cardiovascular disease risk factors, CKD-specific factors, and other mineral metabolism markers. The results of our prospective analyses remained unchanged after additional adjustment for time-varying eGFR.ConclusionsElevated fibroblast growth factor 23 is associated with prevalent anemia, change in hemoglobin over time, and development of anemia. Future studies are needed to elucidate the mechanisms for these associations.

Project description:BackgroundEmerging 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 findingsWe 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 attributable to an increase in iFGF23 or in C-terminal FGF23 fragments.Conclusions and relevanceIn this study, we found that functional iron deficiency and higher EPO levels were each associated with an increased risk of death in the general population. Our findings suggest that FGF23 could be involved in the association between functional iron deficiency and increased EPO levels and death. Investigation of strategies aimed at correcting iron deficiency and reducing FGF23 levels is warranted.

Dataset Information

The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans.

Publications

The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans.

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