High Fibroblast Growth Factor 23 Levels Associated With Low Hemoglobin Levels in Patients With Chronic Kidney Disease Stages 3 and 4

Tsai, Ming-Hsien; Leu, Jyh-Gang; Fang, Yu-Wei; Liou, Hung-Hsiang

doi:10.1097/md.0000000000003049

Cited by 34 publications

(35 citation statements)

References 43 publications

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“…At present, no association has been reported between high FGF23 levels and renal anemia according to animal or clinical studies. However, an observational study of 53 CKD patients showed that high FGF23 levels are negatively correlated with hemoglobin levels (42).…”

Section: Discussionmentioning

confidence: 98%

Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia

et al. 2018

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Severe anemia and iron deficiency are common complications in chronic kidney disease. The cause of renal anemia is multifactorial and includes decreased erythropoietin (Epo) production, iron deficiency, and inflammation, and it is currently treated with injections of synthetic Epo. However, the use of recombinant Epo has several adverse effects. We previously reported that high fibroblast growth factor 23 (FGF23) levels in mice are associated with decreased red blood cell production, whereas genetic inactivation of Fgf23 results in expansion of the erythroid lineage. The present study is the first to show that high FGF23 levels in a mouse model of renal failure contribute to renal anemia, and inhibiting FGF23 signaling stimulates erythropoiesis and abolishes anemia and iron deficiency. Moreover, we show that inhibition of FGF23 signaling significantly decreases erythroid cell apoptosis and influences the commitment of hematopoietic stem cells toward the erythroid linage. Furthermore, we show that blocking FGF23 signaling attenuates inflammation, resulting in increased serum iron and ferritin levels. Our data clearly demonstrate that elevated FGF23 is a causative factor in the development of renal anemia and iron deficiency, and importantly, blocking FGF23 signaling represents a novel approach to stimulate erythropoiesis and possibly improve survival for millions of chronic kidney disease patients worldwide.-Agoro, R., Montagna, A., Goetz, R., Aligbe, O., Singh, G., Coe, L. M., Mohammadi, M., Rivella, S., Sitara, D. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia.

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Section: Discussionmentioning

confidence: 98%

Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia

et al. 2018

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“…It has already been elegantly shown that iron deficiency by itself may cause the changes of the production and secretion of FGF23 [21, 40]. IV iron supplementation in the healthy population could provide information on the actual impact of iron without the confounding effect of anemia.…”

Section: Discussionmentioning

confidence: 99%

Associations Between Intravenous Iron, Inflammation and FGF23 in Non-Dialysis Patients with Chronic Kidney Disease Stages 3-5

Muras-Szwedziak¹,

Nowicki²

2018

Kidney Blood Press Res

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Background/Aims: Both iron deficiency and chronic inflammation are highly prevalent in patients with chronic kidney disease (CKD). The effect of intravenous iron infusion on mineral metabolism in CKD may be modified by inflammation. Intravenous iron theraphy may reduce peripheral degradation, secretion, clearence of iFGF23 and lead to hypophosphatemia. The aim of the study was to evaluate the effect of intravenous iron on mineral metabolism in CKD patients. Methods: 35 non-dialysis patients with CKD stages 3-5. received 100 mg/24h of ferric oxide saccharated solution for 5 days. Serum calcium (Ca), phosphorus (P), parathormone (PTH), intact-FGF23 (iFGF23), C-terminal-FGF23 (cFGF23), bone alkaline phosphatase (BAP) and high-sensitive CRP were assessed on day 1 and 3 at baseline and 2 hours after each dose administration and once on day 6. Plasma iFGF23 and cFGF23, as well as serum BAP were measured with ELISA and other parameters with standard automated laboratory methods. Results: Serum iFGF23 increased after iv iron on day 1 and 6 (from 268.9±446.5 to 326.3±529.9 on day 1; p=0.05 and to 451.4±601 pg/mL on day 6; p=0.03). cFGF23 was reduced only on day 1 (from 654.3±441.3 to 473.6±414 RU/mL; p=0.016). P concentration decreased significantly two hours after the first iron infusion (from 1.69±0.5 to 1.54±0.35 mmol/l; p=0.003). In following days the changes of cFGF23, P and of other calcium-phosphate metabolism were not significant. Serum CRP correlated neither with iFGF-23 nor cFGF-23. Conclusion: Intravenous iron supplementation may only transiently affect the production and degradation of FGF23 resulting in hypophosphatemia at the commencement of iron therapy. Chronic low-grade inflammation does not seem to play a role in that mechanism.

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“…2). This finding encompasses an important issue because FGF23 could cause the suppression of RAS due to systemic volume expansion and subsequently decrease plasma aldosterone levels [95]. In contrast, a positive correlation between FGF23 and aldosterone concentrations is also reported in patients with CKD and heart failure [96].…”

Section: Fgf23 and Sodium In Ckdmentioning

confidence: 67%

“…Because of the nature of iron loss during hemodialysis sessions, the use of this type of phosphate binders appears reasonable in such condition since iron is dissociated from the binders and then absorbed in part from the intestine. Of note, iron deficiency and the subsequent anemia are associated with the elevation in plasma FGF23 concentrations [95,[144][145][146][147] and the upregulation of bone FGF23 mRNA expression (Table 4) [147,148]. An in vitro study also shows that osteocytes in the medium containing low iron produce greater FGF23 mRNA expression [149].…”

Section: Ckd Ratsmentioning

confidence: 93%

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

Hayashi

Suzuki²,

Sakamaki

et al. 2018

Ren Replace Ther

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Cardiac hypertrophy is a life-threatening disorder and is frequently observed in patients with chronic kidney disease (CKD). Much attention has been focused on the derangement in hormonal factors, including aldosterone and FGF23, as novel causes of cardiac hypertrophy in CKD. Plasma aldosterone concentrations are elevated as renal function declines. Although aldosterone antagonists are available for the treatment of hypertension with cardiac hypertrophy, concern remains regarding the possible occurrence of serious hyperkalemia. Alternatively, certain types of calcium channel blockers suppress aldosterone synthesis or exert blocking action for mineralocorticoid receptors and could halt the progression of cardiac dysfunction. Recently, FGF23 is shown to be elevated as CKD progresses and may be responsible for the development of cardiac hypertrophy and heart failure. Furthermore, FGF23 not only inhibits the renal expression of angiotensin converting enzyme 2 but also enhances renin gene transcription, both of which could accelerate renin-angiotensin-aldosterone system. Although the increase in serum phosphate concentrations is a pivotal stimulus for FGF23 production, recent studies suggest that reduced iron status and elevated aldosterone levels, frequently seen in patients with CKD or on dialysis, might also contribute to the elevation in serum FGF23 levels. Conversely, phosphate binders and appropriate iron status could reduce serum FGF23, potentially leading to the alleviation of cardiac hypertrophy and heart failure. In conclusion, novel therapeutic strategies associated with aldosterone and FGF23 may confer a benefit in the management of cardiac disorders in CKD.

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High Fibroblast Growth Factor 23 Levels Associated With Low Hemoglobin Levels in Patients With Chronic Kidney Disease Stages 3 and 4

Cited by 34 publications

References 43 publications

Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia

Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia

Associations Between Intravenous Iron, Inflammation and FGF23 in Non-Dialysis Patients with Chronic Kidney Disease Stages 3-5

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

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