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

Abstract

Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.

• Authors: Connor Francis, Guillaume Courbon, Claire Gerber, Samantha Neuburg, Xueyan Wang, Corey Dussold, Maralee Capella, Lixin Qi, Tamara Isakova, Rupal Mehta, Aline Martin, Myles Wolf, Valentin David
• Journal: Kidney international (Kidney Int) Vol. 96 Issue 6 Pg. 1346-1358 (12 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 31668632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Autoantigens
• Collagen Type IV
• Ferric Compounds
• Fgf23 protein, mouse
• type IV collagen alpha3 chain
• Fibroblast Growth Factors
• ferric citrate
• Fibroblast Growth Factor-23

Topics

• Animals
• Autoantigens (genetics)
• Collagen Type IV (genetics)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Ferric Compounds (pharmacology, therapeutic use)
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (blood)
• Heart (drug effects)
• Kidney (drug effects)
• Mice
• Mice, Knockout
• Renal Insufficiency, Chronic (blood, drug therapy)