Erythropoiesis stimulating agents are associated with serum fibroblast growth factor 23 metabolism in patients on hemodialysis

Honda, Hirokazu; Tanaka, Kenji; Michihata, Tetsuo; Shibagaki, Keigo; Yuza, Toshitaka; Hirao, Keiichi; Tomosugi, Naohisa; Ganz, Tomas; Higashimoto, Yuichiro

doi:10.1093/ckj/sfaa042

Cited by 4 publications

(9 citation statements)

References 29 publications

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“…Therefore, a vicious cycle between increased FGF23 levels and impaired iron metabolism via hepcidin production might be suspected in HD patients whose serum levels of FGF23 are extremely persistently elevated. Several clinical studies have suggested a close relationship between high FGF23 levels and iron metabolism disorder as both have been reported in CKD patients [22,24].…”

Section: Discussionmentioning

confidence: 92%

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Serum Intact and Total Fibroblast Growth Factor 23 Levels and Iron-related Parameters in Hemodialysis Patients

Tanaka¹

2022

J Clin Med Res

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Objective: Fibroblast growth factor (FGF)23 suppresses erythropoiesis and is implicated in iron metabolism. It was investigated whether high levels of FGF23 was associated with hepcidin levels of iron metabolism markers in hemodialysis patients. Methods: The serum hepcidin, erythroferrone, and intact-FGF23 or total-FGF23 level as well as iron-related parameters at pre-dialysis in 70 hemodialysis (HD) patients was measured and performed a regression analysis. Results: Each measurement for FGF23, including the intact-/total-FGF23 ratio, correlated strongly with both serum inorganic phosphate and calcium-phosphate product concentrations. Serum hepcidin levels showed a positive correlation with TSAT or serum ferritin concentration. In addition, a negative correlation was found between serum of hepcidin and erythroferrone levels, but no correlation was found between FGF23-related measurements and serum hepcidin levels. Both serum FGF23 levels and erythroferrone levels correlated with erythropoietin-stimulating agent treatment. Conclusion: It was strongly suggested that both serum phosphate concentrations and calcium-phosphate products were associated with FGF23 production in HD patients. As previously reported, the association between hepcidin and iron metabolism markers was reconfirmed, but a simple linear relationship between hepcidin and FGF23 was not observed even after adjusting FGF23. However, a significant negative correlation between erythroferrone and serum hepcidin levels was confirmed in HD patients.

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Section: Discussionmentioning

confidence: 92%

“…In contrast, Farrow et al first reported the induction of FGF23 expression with iron deficiency in an experimental model [9]. Similar clinical observational studies indicating a possible implication of FGF23 with functional iron deficiency in HD patients have also been published [10,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 84%

Serum Intact and Total Fibroblast Growth Factor 23 Levels and Iron-related Parameters in Hemodialysis Patients

Tanaka¹

2022

J Clin Med Res

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“…ACE I/D polymorphism genetic testing could be predictive and guide patient triage and treatment decision making as individuals with the DD genotype are predisposed to a more severe COVID-19 disease course[ 59 ]. Research evidence supports the notion that endogenously[ 109 , 112 ] and exogenously increased EPO levels[ 123 ] could break the vicious circle of persistent ACE D allele augmented Ang II stimulation on PAI-1, IL-6 and FGF23 by both synergistic and individual inhibition[ 21 , 122 , 123 , 127 , 134 ]. Whenever the administration of rhEPO is not possible due to contraindications or heightened prothrombotic risk, EPO derivatives can coax EPO’s tissue-protective activity via its TPR for therapeutic use without the risks attributed to EPO’s hematological actions[ 10 , 14 , 134 ].…”

Section: Therapeutic Considerationsmentioning

confidence: 83%

“…EPO’s inhibitory effect on PAI-1 and subsequently FGF23 may well have contributed to the patient’s recovery and further studies are planned to investigate the potentially favorable rhEPO effect in severe COVID-19[ 124 - 126 ]. Human data show that both endogenous and exogenous EPO influence FGF23 levels via alterations of the ratio of active to inactive FGF23 in favor of its inactive form, thus attenuating effects of bioactive intact FGF23 levels and explain EPO’s protective effects[ 118 , 127 ]. At present, no study has been reported that investigated FGF23 levels in COVID-19.…”

Section: The Ace D Allele / Dd Genotype and Epo Interplay: Implications For Covid-19mentioning

confidence: 99%

Age and genotype dependent erythropoietin protection in COVID-19

Papadopoulos

Sutheesophon

Manipalviratn³

et al. 2021

WJSC

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Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a “bait” for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

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“…Clinkenbeard et al confirmed that recombinant human EPO (rHuEPO), a short-acting ESA, might induce the expression of bone FGF-23 production in vivo and increase serum intact FGF-23 levels in patients with anemia 11 . The effect of long-acting ESA on FGF-23 metabolism might differ from that of rHuEPO and could increase cleavage of FGF, decreasing intact FGF-23 and increasing C-terminal FGF-23 due to hepcidin-25 suppression 12 . HIF-PH inhibitors also increased FGF-23 due to EPO production, but the increased levels of FGF-23 were quite low compared with those with EPO treatment 7 .…”

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confidence: 99%

Changes of biomarkers for erythropoiesis, iron metabolism, and FGF23 by supplementation with roxadustat in patients on hemodialysis

Yoshida

Saito

Shibagaki³

et al. 2023

Sci Rep

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This study aimed to confirm changes in biomarkers of erythropoiesis and iron metabolism and serum fibroblast growth factor 23 (FGF-23) during darbepoetin-α treatment and then switching to the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat. A total of 28 patients on hemodialysis who received weekly doses of darbepoetin-α were switched to roxadustat. Biomarkers for erythropoiesis and iron metabolism and intact and C-terminal FGF-23 were measured in blood samples collected before the HD session on days − 7 (darbepoetin-α injection), − 4, and − 2, and days 0 (switch to roxadustat treatment, three times weekly), 3, 5, 7, 14, 21, and 28. Erythropoietin and erythroferrone levels were elevated on day − 4 by darbepoetin-α injection and decreased to baseline levels at day 0. Levels of erythropoietin were not significantly increased by roxadustat supplementation, but erythroferrone levels were continuously elevated, similar to darbepoetin-α treatment. Hepcidin-25 and total iron binding capacity were significantly decreased or increased in patients treated with roxadustat compared with darbepoetin-α. Changes of intact and C-terminal FGF-23 levels were parallel to changes of phosphate levels during roxadustat treatment. However, the actual and percentage changes of intact FGF-23 and C-terminal FGF-23 in patients with low ferritin levels were greater than those in patients with high ferritin levels. Roxadustat might stimulate erythropoiesis by increasing iron usage through hepcidin-25, which was suppressed by erythroferrone in the physiological erythropoietin condition. Changes of intact FGF-23 and C-terminal FGF-23 levels might be affected by roxadustat in patients on hemodialysis, especially those with a low-iron condition.

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Erythropoiesis stimulating agents are associated with serum fibroblast growth factor 23 metabolism in patients on hemodialysis

Cited by 4 publications

References 29 publications

Serum Intact and Total Fibroblast Growth Factor 23 Levels and Iron-related Parameters in Hemodialysis Patients

Serum Intact and Total Fibroblast Growth Factor 23 Levels and Iron-related Parameters in Hemodialysis Patients

Age and genotype dependent erythropoietin protection in COVID-19

Changes of biomarkers for erythropoiesis, iron metabolism, and FGF23 by supplementation with roxadustat in patients on hemodialysis

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