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Segregating the effects of ferric citrate-mediated iron utilization and FGF23 in a mouse model of CKD
Michael P Liesen1,2, Megan L Noonan1, Pu Ni1
1Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Insights
Ferric citrate (FC) therapy in chronic kidney disease (CKD) impacts iron and phosphate (Pi) metabolism. FGF23 loss worsens Pi and BUN, suggesting FGF23 protects mineral balance in CKD.
Area of Science:
- Nephrology
- Mineral and Bone Metabolism
- Biochemistry
Background:
- Ferric citrate (FC) treats phosphate (Pi) binders and iron deficiency anemia (IDA) in chronic kidney disease (CKD).
- Elevated Pi and IDA increase FGF23, but the roles of iron and FGF23 in CKD are unclear.
- Understanding these roles is crucial for managing CKD complications.
Purpose of the Study:
- To investigate the interplay between iron, Pi, and FGF23 metabolism in a mouse model of CKD.
- To determine the effects of FC and FGF23 deficiency on mineral metabolism and inflammation in CKD.
Main Methods:
- A mouse model of CKD was established using adenine, treated with or without ferric citrate (FC).
- Osteocyte-specific deletion of Fgf23 was induced using Dmp1-Cre.
- Serum biochemistry, liver gene expression, and bone parameters were analyzed.
Main Results:
- FC increased serum iron and altered renal vitamin D metabolism markers.
- FGF23 deficiency in CKD mice led to higher serum Pi and BUN, indicating a protective role for FGF23.
- FC treatment reduced inflammatory markers (IL-6 mRNA) and increased iron-related genes (Tfrc, Bmp6, hepcidin).
Conclusions:
- FGF23 plays a protective role in CKD mineral metabolism, independent of FC.
- FC offers ancillary benefits in CKD by maintaining iron levels and modulating inflammation.
- FC and FGF23 exert both dependent and independent effects on CKD pathophysiology.
Abstract:
Ferric citrate (FC) is an approved therapy for chronic kidney disease (CKD) patients as a phosphate (Pi) binder for dialysis-dependent CKD, and for iron deficiency anemia (IDA) in non-dialysis CKD. Elevated Pi and IDA both lead to increased FGF23, however, the roles of iron and FGF23 during CKD remain unclear. To this end, iron and Pi metabolism were tested in a mouse model of CKD (0.2% adenine) ± 0.5% FC for 6 weeks, with and without osteocyte deletion of Fgf23 (flox-Fgf23/Dmp1-Cre). Intact FGF23 (iFGF23) increased in all CKD mice but was lower in Cre+ mice with or without FC, thus the Dmp1-Cre effectively reduced FGF23. Cre+ mice fed AD-only had higher serum Pi than Cre- pre- and post-diet, and the Cre+ mice had higher BUN regardless of FC treatment. Total serum iron was higher in all mice receiving FC, and liver Tfrc, Bmp6, and hepcidin mRNAs were increased regardless of genotype; liver IL-6 showed decreased mRNA in FC-fed mice. The renal 1,25-dihydroxyvitamin D (1,25D) anabolic enzyme Cyp27b1 had higher mRNA and the catabolic Cyp24a1 showed lower mRNA in FC-fed mice. Finally, mice with loss of FGF23 had higher bone cortical porosity, whereas Raman spectroscopy showed no changes in matrix mineral parameters. Thus, FC- and FGF23-dependent and -independent actions were identified in CKD; loss of FGF23 was associated with higher serum Pi and BUN, demonstrating that FGF23 was protective of mineral metabolism. In contrast, FC maintained serum iron and corrected inflammation mediators, potentially providing ancillary benefit.
