Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice

Hanudel, Mark R.; Chua, Kristine J.; Rappaport, Maxime; Gabayan, Victoria; Valore, Erika V.; Goltzman, David; Ganz, Tomas; Nemeth, Elizabeta; Salusky, Isidro B.

doi:10.1152/ajprenal.00281.2016

Cited by 59 publications

(56 citation statements)

References 49 publications

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“…In animal models of CKD, it has been shown that ID stimulates FGF23 production but also upregulates cleavage, which leads to increased levels of circulating cFGF23, but normal levels of iFGF23. 9,27,28 In humans, Wolf and colleagues showed that ID anemia is associated with normal iFGF23 but markedly elevated cFGF23 levels to an extent that is only seen in advanced CKD or in hereditary diseases of FGF23 overproduction. 14 Moreover, rapid correction of ID with different intravenous iron preparations reduced cFGF23 levels by approximately 80% within 24 hours, 14 consistent with ID as an important stimulus for elevated cFGF23 levels.…”

Section: Discussionmentioning

confidence: 99%

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

Eisenga¹,

Londen²,

Leaf

et al. 2017

JASN

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Iron deficiency (ID) is independently associated with an increased risk of death in renal transplant recipients (RTRs). ID promotes production and cleavage of intact fibroblast growth factor 23 (iFGF23) into C-terminal fibroblast growth factor 23 (cFGF23), elevated levels of which are also prospectively associated with adverse outcomes. We hypothesized that in RTRs, the relationship between ID and mortality is mediated by FGF23. We measured plasma iFGF23 and cFGF23 levels in 700 stable RTRs at a median of 5.4 years after transplant. RTRs with ID had median (interquartile range) cFGF23 concentrations higher than those of RTRs without ID (223 [131-361] versus 124 [88-180] RU/ml; <0.001), whereas iFGF23 concentrations were similar between groups. In multivariable-adjusted Cox regression analyses, ID associated with increased mortality (81 events; hazard ratio, 1.95; 95% confidence interval, 1.22 to 3.10; <0.01). However, this association lost significance after additional adjustment for cFGF23 levels (hazard ratio, 1.45; 95% confidence interval, 0.87 to 2.51; =0.15). In further mediation analysis, cFGF23 explained 46% of the association between ID and mortality, whereas iFGF23 did not mediate this association. In conclusion, we found that cFGF23 levels are increased in iron-deficient RTRs and that the underlying biologic process driving production and cleavage of iFGF23, or alternatively the increased level of cFGF23 fragments, probably is an important mediator of the association between ID and mortality. Our results underline the strong relationship between iron and FGF23 physiology, and provide a potential mechanism explaining the relationship between ID and adverse outcome in RTRs.

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Section: Discussionmentioning

confidence: 99%

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

Eisenga¹,

Londen²,

Leaf

et al. 2017

JASN

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“…Hypoxia, anaemia and iron deficiency are frequent sequelae in CKD . They were all identified as stimuli of FGF23 production . Iron deficiency not only increases FGF23 transcription but also its cleavage .…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

“…They were all identified as stimuli of FGF23 production . Iron deficiency not only increases FGF23 transcription but also its cleavage . Interestingly, iron supplementation has been shown to increase or decrease FGF23 , possibly depending on whether the supplementation stronger affects FGF23 transcription or cleavage.…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age‐associated diseases, mainly as a result of hyperphosphataemia‐dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.

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“…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: 99%

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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Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice

Cited by 59 publications

References 49 publications

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

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

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