Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease

J Am Heart Assoc. 2019 Aug 20;8(16):e011130. doi: 10.1161/JAHA.118.011130. Epub 2019 Aug 17.


Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.

Keywords: chronic kidney disease; erythropoietin; fibroblast growth factor.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anemia / blood
  • Anemia / complications
  • Anemia / drug therapy*
  • Erythropoietin / therapeutic use*
  • Female
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / blood*
  • Heart Failure / blood*
  • Heart Failure / complications
  • Hematinics / therapeutic use*
  • Hemoglobins / metabolism
  • Humans
  • Male
  • Peptide Fragments / blood*
  • Recombinant Proteins / therapeutic use
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / complications
  • Treatment Outcome


  • FGF23 protein, human
  • Hematinics
  • Hemoglobins
  • Peptide Fragments
  • Recombinant Proteins
  • epoetin beta
  • Erythropoietin
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23

Associated data

  • ClinicalTrials.gov/NCT00356733