Dataset Information

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

ABSTRACT:

Background

Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models.

Methods

We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose.

Results

Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models.

Conclusion

EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

SUBMITTER: Hanudel MR

PROVIDER: S-EPMC6888066 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

Hanudel Mark R MR Eisenga Michele F MF Rappaport Maxime M Chua Kristine K Qiao Bo B Jung Grace G Gabayan Victoria V Gales Barbara B Ramos Georgina G de Jong Maarten A MA van Zanden Jelmer J JJ de Borst Martin H MH Bakker Stephan J L SJL Nemeth Elizabeta E Salusky Isidro B IB Gaillard Carlo A J M CAJM Ganz Tomas T

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20191201 12

<h4>Background</h4>Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models.<h4>Methods</h4>We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, wi ...[more]

PMID: 30007314

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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

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

Background

Methods

Results

Conclusion

Publications

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

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