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

Abstract

BackgroundIn 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 ResultsIn 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).ConclusionsExogenous 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.

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

“…Generally, endogenous EPO levels are elevated during early-stage CKD (94), exogenous EPO is typically administered to patients with late-stage CKD due to the presence of renal anemia, and FGF23 cleavage may decrease as renal function declines (95,96). iFGF23 is considered the bioactive form, and high cFGF23 expression is associated with poor prognosis in patients with CKD (17,69). Future studies are required to determine the biological activities of the C-terminal fragments of FGF23.…”

“…Notably, these observed effects were independent of iron status. Studies on patients with chronic heart failure and CKD have reported that exogenous EPO injections markedly increase cFGF23 expression (69,70). The potential reasons for these differences may be attributed to the differences in renal functions of patients and/or the dose of rhEPO used.…”

Anemia of cardiorenal syndrome

“…100 In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study in patients with CRAS, epoetin-b for 50 weeks led to significant increases in Hb and hematocrit levels compared with standard care. 101 However, significant increases in C-terminal fibroblast growth factor 23 were also observed with epoetin-b therapy, which were positively associated with an increased risk of mortality, providing a possible mechanism for the increased CV risk. 101 Consistent with the limited data regarding the use of ESAs in patients with CRAS, and lack of recommendation for their use in HF, 79 real-world data suggest that a relatively low proportion of patients with CRAS (10%) are prescribed ESA therapy, with previous iron therapy and more severe CKD being predictors of initiating ESA therapy.…”

Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference

“…However, in CKD, where FGF23 cleavage is impaired, iron deficiency, ESAs, and inflammation increase iFGF23. The relative amounts of circulating iFGF23 and cFGF23 are impacted not only by iron status, inflammation, ESA use, and the presence of CKD, but also by the iron formulation administered (Table 4 [90][91][92][93][94][95][96][97] ). Indeed, certain i.v.…”