Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease

Francis, CM; Courbon, Guillaume; Gerber, Claire; Neuburg, Samantha; Wang, Xueyan; Dussold, Corey; Capella, Maralee; Qi, Lixin; Isakova, Tamara; Mehta, Rupal; Martin, Aline; Wolf, Myles; David, Véronique

doi:10.1016/j.kint.2019.07.026

Cited by 51 publications

(63 citation statements)

References 58 publications

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“…Overall, ferric citrate slowed the progression of CKD and improved the survival of CKD mice. Interestingly, the protective effects of ferric citrate were higher when the Col4a3 knockout mice were treated in the early stages of CKD compared with a later onset of therapy [159]. If clinical trials can confirm findings of this animal study, ferric citrate and other non-calcium-phosphate binder represent promising drugs to improve cardiac and kidney function in CKD patients.…”

Section: Therapeutic Approaches To Inhibit Fgf23- and Phosphate-mementioning

confidence: 85%

“…Recent studies indicate beneficial effects of ferric citrate treatment for CKD patients [157,158,159]. Block et al showed in a placebo-controlled clinical trial in non-dialysis CKD patients that ferric citrate significantly reduces intact FGF23 and serum phosphate levels among patients with elevated baseline phosphate (≥4.5 mg/dL).…”

Section: Therapeutic Approaches To Inhibit Fgf23- and Phosphate-mementioning

confidence: 99%

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FGF23 and Phosphate–Cardiovascular Toxins in CKD

Vogt

Haffner

Leifheit-Nestler

2019

Toxins

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Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages of CKD, FGF23 prevents the increase of serum phosphate levels and thereby attenuates phosphate-induced vascular calcification, whereas in end-stage kidney disease, FGF23 fails to maintain phosphate homeostasis. Both hyperphosphatemia and elevated FGF23 levels promote the development of hypertension, vascular calcification, and left ventricular hypertrophy by distinct mechanisms. Therefore, FGF23 and phosphate are considered promising therapeutic targets to improve the cardiovascular outcome in CKD patients. Previous therapeutic strategies are based on dietary and pharmacological reduction of serum phosphate, and consequently FGF23 levels. However, clinical trials proving the effects on the cardiovascular outcome are lacking. Recent publications provide evidence for new promising therapeutic interventions, such as magnesium supplementation and direct targeting of phosphate and FGF receptors to prevent toxicity of FGF23 and hyperphosphatemia in CKD patients.

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Section: Therapeutic Approaches To Inhibit Fgf23- and Phosphate-mementioning

confidence: 85%

Section: Therapeutic Approaches To Inhibit Fgf23- and Phosphate-mementioning

confidence: 99%

FGF23 and Phosphate–Cardiovascular Toxins in CKD

Vogt

Haffner

Leifheit-Nestler

2019

Toxins

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“…Although this conjecture is still speculative, reduction of FGF23 levels could have a beneficial effect on the progression of CKD and cardiovascular disease. In mice treated with Auryxia, the concentrations of FGF23 decreased and CKD disease progression was slowed [ 107 ]. More definitive clinical trials will be needed to validate the hypothesis that ferric citrate slows CKD progression by lowering FGF23 [ 108 ].…”

Section: Clinical Characteristics Of Auryxiamentioning

confidence: 99%

Mechanism of Action and Clinical Attributes of Auryxia® (Ferric Citrate)

Ganz

Bino

Salusky

2019

Drugs

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Chronic kidney disease (CKD) is a major cause of morbidity and premature mortality and represents a significant global public health issue. Underlying this burden are the many complications of CKD, including mineral and bone disorders, anemia, and accelerated cardiovascular disease. Hyperphosphatemia and elevated levels of fibroblast growth factor 23 (FGF23) have been identified as key independent risk factors for the adverse cardiovascular outcomes that frequently occur in patients with CKD. Auryxia ® (ferric citrate; Keryx Biopharmaceuticals, Inc., Boston, MA, USA) is an iron-based compound with distinctive chemical characteristics and a mechanism of action that render it dually effective as a therapy in patients with CKD; it has been approved as a phosphate binder for the control of serum phosphate levels in adult CKD patients treated with dialysis and as an iron replacement product for the treatment of iron deficiency anemia in adult CKD patients not treated with dialysis. This review focuses on Auryxia, its mechanism of action, and the clinical attributes that differentiate it from other, non-pharmaceutical-grade, commercially available forms of ferric citrate and from other commonly used phosphate binder and iron supplement therapies for patients with CKD. Consistent with the chemistry and mechanism of action of Auryxia, multiple clinical studies have demonstrated its efficacy in both lowering serum phosphate levels and improving iron parameters in patients with CKD. Levels of FGF23 decrease significantly with Auryxia treatment, but the effects associated with the cardiovascular system remain to be evaluated in longer-term studies.

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“…Moreover, experimental data in uremic rats indicated that vitamin D treatment reduced LVH, FGFR-4 expression, and calcineurin/nuclear factor of activated T cells (NFAT) signaling activation, and, therefore, showing calcitriol cardioprotective effects [108]. Encouraging experimental data also indicate that early administration of ferric citrate slows CKD progression, lowers FGF23 levels, and improves cardiac function and survival [109]. Hence, LVH can be treated in CKD and CV risk can be reduced, either by lowering FGF23 levels or by inhibiting its effect on the FGFR-4.…”

Section: Role Of Fgf23mentioning

confidence: 99%

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

Rroji

Figurek

Spasovski³

2020

Toxins

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Cardiovascular (CV) disease is highly prevalent in the population with chronic kidney disease (CKD), where the risk of CV death in early stages far exceeds the risk of progression to dialysis. The presence of chronic kidney disease-mineral and bone disorder (CKD-MBD) has shown a strong correlation with CV events and mortality. As a non-atheromatous process, it could be partially explained why standard CV disease-modifying drugs do not provide such an impact on CV mortality in CKD as observed in the general population. We summarize the potential association of CV comorbidities with the older (parathyroid hormone, phosphate) and newer (FGF23, Klotho, sclerostin) CKD-MBD biomarkers.

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Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease

Cited by 51 publications

References 58 publications

FGF23 and Phosphate–Cardiovascular Toxins in CKD

FGF23 and Phosphate–Cardiovascular Toxins in CKD

Mechanism of Action and Clinical Attributes of Auryxia® (Ferric Citrate)

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

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