FGF23 and EPO resistance in hemodialysis patients

Fibroblast growth factor 23 (FGF23) plays a key role in mineral and bone disorders related to chronic kidney disease (CKD). Elevated FGF23 levels are linked to a higher risk of anemia in non-hemodialysis CKD and in patients undergoing hemodialysis. Researchers have identified a strong relationship between FGF23 and erythropoietin (EPO) resistance in hemodialysis (HD) patients. FGF23 is now recognized not only as a regulator of mineral metabolism but also as a direct inhibitor of erythropoiesis and a contributor to resistance against erythropoiesis-stimulating agents (ESAs) (1-3). 

Background:

-Erythropoietin (EPO) is a hormone produced mainly by the kidneys that regulates the production of red blood cells in the bone marrow, helping to maintain proper oxygen levels in the blood.

-Erythropoiesis-stimulating agents (ESAs) are medications that mimic the action of erythropoietin to stimulate the production of red blood cells in the bone marrow. They are commonly used to treat anemia, especially in patients with chronic kidney disease.

-High Fibroblast growth factor 23 (FGF23) levels are common in hemodialysis patients, mainly due to phosphate buildup from reduced kidney function.

 

FGF23 and EPO resistance in hemodialysis patients

A recent study by Hamano N. et al., explores the complex relationship between Fibroblast Growth Factor 23 (FGF23), endogenous erythropoietin (EPO), and the response to erythropoiesis-stimulating agents (ESAs) in hemodialysis patients. The research highlights how elevated FGF23 levels may influence erythropoietin production and resistance, impacting anemia management in chronic kidney disease (4).

FGF23 was measured in a cohort of 654 maintenance hemodialysis patients using the FGF23 ELISA assays from Biomedica.

FGF23 (C-terminal), cat. no. BI-20702 and FGF23 intact ELISA, cat. no. BI-20700 

• RELIABLE – validated following international quality guidelines
• CITED in over 80 publications
• EASY – 8 standards and 2 controls included
• For SERUM & PLASMA samples

 

Key findings:

-Elevated levels of FGF23 are associated with reduced natural EPO production.

-Higher ESA dose was associated with higher FGF23 levels measured by both intact and C-terminal assays.

-High FGF23 levels may contribute to erythropoietin resistance, making anemia harder to treat.

-Insights from the study may lead to new strategies to manage ESA resistance and enhance patient outcomes.

 

Fibroblast Growth Factor 23, Endogenous Erythropoietin, Erythropoiesis-Stimulating Agents, and Erythropoietin Resistance in Hemodialysis Patients. Hamano N et al., Am J Nephrol. 2025.

Abstract

Introduction: Recent experimental studies have reported that fibroblast growth factor 23 (FGF23) inhibits erythropoiesis by suppressing erythropoietin (EPO) production and downregulating the EPO receptor. Conversely, either endogenous or exogenous EPO has been shown to stimulate FGF23 production. However, little is known about the relationships between FGF23, erythropoiesis-stimulating agent (ESA) treatment, ESA resistance, and endogenous EPO in hemodialysis patients.

Methods: We analyzed cross-sectional data from a cohort of 654 maintenance hemodialysis patients. We examined the associations of intact or C-terminal FGF23 with ESA treatment, ESA resistance index (ERI), hemoglobin, C-reactive protein, and endogenous EPO levels using linear regression models. EPO was measured only in patients not receiving ESAs.

Results: A total of 458 patients (70%) were treated with ESAs. The median EPO concentration in non-ESA users was 7.8 (interquartile range, 5.3-14.4) mIU/mL. The median levels of intact and C-terminal FGF23 were 1,598 (interquartile range, 548-4,586) pg/mL and 38.7 (interquartile range, 14.0-127.6) pmol/L, respectively, in non-ESA users and 1,955 (interquartile range, 573-5,264) pg/mL and 41.4 (interquartile range, 13.9-116.8) pmol/L, respectively, in ESA users. After adjustment for potential confounders, higher ESA dose was associated with higher FGF23 levels measured by both intact and C-terminal assays. Higher C-terminal FGF23 was also associated with higher ERI, lower hemoglobin, and higher endogenous EPO, but no such associations were observed for intact FGF23 levels.

Conclusions: Both intact and C-terminal FGF23 showed similar associations with ESA dose, but they showed different patterns of association with other parameters related to anemia. Further research is needed to elucidate the mechanisms underlying these different associations.

 

 

 

Literature

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3. The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans. Bielesz B, Reiter T, Hammerle FP, Winnicki W, Bojic M, Gleiss A, Kieweg H, Ratzinger F, Sunder-Plassmann G, Marculescu R. J Clin Med. 2020 Aug 14;9(8):2640. doi: 10.3390/jcm9082640. PMID: 32823844; PMCID: PMC7463779.
4. Fibroblast Growth Factor 23, Endogenous Erythropoietin, Erythropoiesis-Stimulating Agents, and Erythropoietin Resistance in Hemodialysis Patients. Hamano N, Komaba H, Tanaka H, Takahashi H, Takahashi Y, Hyodo T, Hida M, Suga T, Wada T, Kakuta T, Fukagawa M, Komaba H. Am J Nephrol. 2025;56(4):403-411. doi: 10.1159/000543506. Epub 2025 Feb 20. PMID: 39978330.