A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial

Mark R. Hanudel; Marciana L. Laster; Anthony A. Portale; Aditi Dokras; Raymond P. Quigley; German A.Lozano Guzman; Joshua J. Zaritsky; Nicole A. Hayde; Frederick J. Kaskel; Mark M. Mitsnefes; Jorge A. Ramirez; Peace D. Imani; Poyyapakkam R. Srivaths; Amy J. Kogon; Michelle R. Denburg; Tom D. Blydt-Hansen; Loretta Z. Reyes; Larry A. Greenbaum; Darcy K. Weidemann; Bradley A. Warady; David A. Elashoff; Susan R. Mendley; Tamara Isakova; Isidro B. Salusky

doi:10.1007/s00467-022-05492-7

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial

Mark R. Hanudel, Marciana L. Laster, Anthony A. Portale, Aditi Dokras, Raymond P. Quigley, German A.Lozano Guzman, Joshua J. Zaritsky, Nicole A. Hayde, Frederick J. Kaskel, Mark M. Mitsnefes, Jorge A. Ramirez, Peace D. Imani, Poyyapakkam R. Srivaths, Amy J. Kogon, Michelle R. Denburg, Tom D. Blydt-Hansen, Loretta Z. Reyes, Larry A. Greenbaum, Darcy K. Weidemann, Bradley A. WaradyDavid A. Elashoff, Susan R. Mendley, Tamara Isakova, Isidro B. Salusky^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Review article › peer-review

5 Scopus citations

Abstract

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production—dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3–4 (ClinicalTrials.gov Identifier NCT04741646).

Original language	English (US)
Pages (from-to)	2547-2557
Number of pages	11
Journal	Pediatric Nephrology
Volume	37
Issue number	11
DOIs	https://doi.org/10.1007/s00467-022-05492-7
State	Published - Nov 2022

Funding

The work in this manuscript has been performed with the support of the National Institute of Diabetes, Digestive, and Kidney Disease of the National Institute of Health research grants U01-DK122013 (IBS) and K23-DK123378 (MLL). MRH has received research funding from Akebia Therapeutics, Inc. BAW and IBS are consultants for Akebia Therapeutics, Inc. The FIT4KiD study is a phase 2, randomized, double-blind, placebo-controlled trial, designed to evaluate the effects of ferric citrate on iFGF23 in children with CKD stages 3–4. Depending on eGFR, the prevalence of elevated FGF23 concentrations (as measured by the total FGF23 assay) in children with CKD stages 3–4 is ~ 60–100% []. FIT4KiD was approved and is funded by NIH/NIDDK through a cooperative agreement (U01-DK122013) among 12 clinical sites (Table ). The study protocol was approved by a central Institutional Review Board (Washington University in St. Louis, IRB #202012083, approved 2/26/21) and by the Data and Safety Monitoring Board appointed by NIDDK (approved on 6/2/20).

Keywords

Chronic kidney disease
Ferric citrate
Fibroblast growth factor 23
Pediatrics

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Nephrology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00467-022-05492-7

Cite this

Hanudel, M. R., Laster, M. L., Portale, A. A., Dokras, A., Quigley, R. P., Guzman, G. A. L., Zaritsky, J. J., Hayde, N. A., Kaskel, F. J., Mitsnefes, M. M., Ramirez, J. A., Imani, P. D., Srivaths, P. R., Kogon, A. J., Denburg, M. R., Blydt-Hansen, T. D., Reyes, L. Z., Greenbaum, L. A., Weidemann, D. K., ... Salusky, I. B. (2022). A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial. Pediatric Nephrology, 37(11), 2547-2557. https://doi.org/10.1007/s00467-022-05492-7

@article{0b9c3ad20ba742e688ca0288476a9bb1,

title = "A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial",

abstract = "Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production—dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3–4 (ClinicalTrials.gov Identifier NCT04741646).",

keywords = "Chronic kidney disease, Ferric citrate, Fibroblast growth factor 23, Pediatrics",

author = "Hanudel, \{Mark R.\} and Laster, \{Marciana L.\} and Portale, \{Anthony A.\} and Aditi Dokras and Quigley, \{Raymond P.\} and Guzman, \{German A.Lozano\} and Zaritsky, \{Joshua J.\} and Hayde, \{Nicole A.\} and Kaskel, \{Frederick J.\} and Mitsnefes, \{Mark M.\} and Ramirez, \{Jorge A.\} and Imani, \{Peace D.\} and Srivaths, \{Poyyapakkam R.\} and Kogon, \{Amy J.\} and Denburg, \{Michelle R.\} and Blydt-Hansen, \{Tom D.\} and Reyes, \{Loretta Z.\} and Greenbaum, \{Larry A.\} and Weidemann, \{Darcy K.\} and Warady, \{Bradley A.\} and Elashoff, \{David A.\} and Mendley, \{Susan R.\} and Tamara Isakova and Salusky, \{Isidro B.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

doi = "10.1007/s00467-022-05492-7",

language = "English (US)",

volume = "37",

pages = "2547--2557",

journal = "Pediatric Nephrology",

issn = "0931-041X",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "11",

}

Hanudel, MR, Laster, ML, Portale, AA, Dokras, A, Quigley, RP, Guzman, GAL, Zaritsky, JJ, Hayde, NA, Kaskel, FJ, Mitsnefes, MM, Ramirez, JA, Imani, PD, Srivaths, PR, Kogon, AJ, Denburg, MR, Blydt-Hansen, TD, Reyes, LZ, Greenbaum, LA, Weidemann, DK, Warady, BA, Elashoff, DA, Mendley, SR, Isakova, T & Salusky, IB 2022, 'A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial', Pediatric Nephrology, vol. 37, no. 11, pp. 2547-2557. https://doi.org/10.1007/s00467-022-05492-7

TY - JOUR

T1 - A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial

AU - Hanudel, Mark R.

AU - Laster, Marciana L.

AU - Portale, Anthony A.

AU - Dokras, Aditi

AU - Quigley, Raymond P.

AU - Guzman, German A.Lozano

AU - Zaritsky, Joshua J.

AU - Hayde, Nicole A.

AU - Kaskel, Frederick J.

AU - Mitsnefes, Mark M.

AU - Ramirez, Jorge A.

AU - Imani, Peace D.

AU - Srivaths, Poyyapakkam R.

AU - Kogon, Amy J.

AU - Denburg, Michelle R.

AU - Blydt-Hansen, Tom D.

AU - Reyes, Loretta Z.

AU - Greenbaum, Larry A.

AU - Weidemann, Darcy K.

AU - Warady, Bradley A.

AU - Elashoff, David A.

AU - Mendley, Susan R.

AU - Isakova, Tamara

AU - Salusky, Isidro B.

PY - 2022/11

Y1 - 2022/11

N2 - Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production—dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3–4 (ClinicalTrials.gov Identifier NCT04741646).

AB - Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production—dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3–4 (ClinicalTrials.gov Identifier NCT04741646).

KW - Chronic kidney disease

KW - Ferric citrate

KW - Fibroblast growth factor 23

KW - Pediatrics

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U2 - 10.1007/s00467-022-05492-7

DO - 10.1007/s00467-022-05492-7

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AN - SCOPUS:85125546004

SN - 0931-041X

VL - 37

SP - 2547

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JO - Pediatric Nephrology

JF - Pediatric Nephrology

IS - 11

ER -

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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