Abstract: PO0330
Dissecting Ferric Citrate- and FGF-23-Associated Mineral Metabolism During the Anemia of CKD
Session Information
- Bone and Mineral Metabolism: Basic
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Liesen, Michael P., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Noonan, Megan L., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Clinkenbeard, Erica, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Ni, Pu, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Agoro, Rafiou, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Hum, Julia M., Marian University, Indianapolis, Indiana, United States
- White, Kenneth E., Indiana University School of Medicine, Indianapolis, Indiana, United States
Group or Team Name
- White Laboratory
Background
Ferric citrate (FC) is a dual therapy used in patients with chronic kidney disease (CKD). This drug is given as a phosphate (Pi) binder for dialysis-dependent CKD, and for iron deficiency anemia in non-dialysis CKD due to delivery of elemental iron. Elevated Pi and anemia both lead to increased FGF23 during CKD, however, the roles of iron and FGF23 on CKD pathologies are unclear.
Methods
Iron and Pi utilization was tested in a mouse model of CKD receiving FC, with and without osteocyte deletion of FGF23 (flox-Fgf23/Dmp1-Cre). Male mice (n=4-7) with the genotype flox-Fgf23/Dmp1-Cre+ and -Cre- were placed on a customized 0.2% adenine (AD)-containing diet for 6 weeks to induce CKD in the presence or absence of 0.5% FC.
Results
After the diet regimen, iFGF23 increased significantly in all CKD mice (p<0.05-0.01). iFGF23 was lower in Cre+ mice fed FC (p<0.01), with Cre+ AD-only mice following a similar trend, demonstrating that the Dmp1-Cre was effective in reducing circulating FGF23. Cre+ mice fed AD-only had higher serum Pi than Cre- controls (p<0.05), and regardless of treatment, the Cre+ mice had higher BUN (P<0.01), showing that FGF23 was required to maintain serum Pi and lessen renal disease. Total serum iron was higher in all mice receiving FC, demonstrating effectiveness of the drug. Consistent with increased serum iron in the FC fed mice, liver Tfrc, BMP6, and hepcidin mRNAs were increased regardless of genotype (p<0.05-0.01); liver IL6 showed decreased mRNA expression in FC fed mice (p<0.01). Key enzymes that control 1,25D production in kidney were also examined. In Cre+/- mice fed FC the 1,25D anabolic enzyme Cyp27b1 was higher (p<0.05-0.01), and catabolic Cyp24a1 was lower (p<0.01), suggesting that FC may aid in restoring vitamin D metabolism in CKD.
Conclusion
In sum, delivery of FC during genetic reductions in FGF23 allowed the identification of FGF23-dependent and -independent actions in CKD. Loss of FGF23 was associated with higher serum Pi and worse renal function, demonstrating that FGF23 was protective of mineral metabolism, an effect independent of FC. In contrast, FC had FGF23-independent actions during CKD of increasing serum iron, correcting inflammation markers, and restoring the balance of Cyp24a1 and Cyp27b1 mRNAs, potentially providing beneficial effects on renal 1,25D metabolism.
Funding
- Commercial Support –