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Abstract: PO0312

HIF-PHI Improves Anemia and Controls Circulating FGF-23 in a CKD Model

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Noonan, Megan L., 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
  • Swallow, Elizabeth A., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • White, Kenneth E., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

The phosphaturic hormone FGF23 is a critical factor in chronic kidney disease-mineral and bone disorder (CKD-MBD), with elevated levels in blood associated with increased odds for patient mortality (>6-fold). Anemia is a potent driver of FGF23 expression, and patients with CKD ultimately develop anemia as the kidneys lose the ability to produce erythropoietin (EPO), in concert with FGF23-mediated alterations in mineral metabolism. Our goal was to investigate a HIF-PHI (hypoxia-inducible factor prolyl hydroxylase inhibitor) for effects on anemia-dependent FGF23 levels and key outcomes in a mouse model of CKD.

Methods

Female C57BL6 mice were fed a casein control or adenine-containing diet to induce CKD, which resulted in markedly elevated iFGF23 and BUN, hyperphosphatemia, and anemia. After 12 weeks of CKD induction, mice were treated with the HIF-PHI BAY 85-3934 (‘BAY’; Molidustat) at a human equivalent dose every other day for 3 weeks.

Results

Compared to saline controls, BAY elevated serum EPO and restored CBCs to normal levels in CKD mice. iFGF23 was significantly elevated in saline-treated CKD mice (120-fold, p<0.01). Importantly, circulating iFGF23 was significantly attenuated (>60%; p<0.05) in BAY-treated mice with CKD, coinciding with downregulated renal Egr-1 expression (p<0.01). Renal 1,25D anabolic Cyp27b1 and catabolic Cyp24a1 mRNAs were up and downregulated, respectively, in BAY-treated CKD mice. This extended treatment resulted in decreased BUN (p<0.01) and reduced expression of renal fibrosis markers (p<0.01). The bone marrow Erfe, Transferrin receptor, and EpoR mRNAs were all upregulated (p<0.05-p<0.01), and liver hepcidin expression was downregulated in both control and CKD groups treated with BAY (p<0.05-p<0.01). HIF activation in osteoblasts/osteocytes is associated with increased bone mass, therefore we investigated femur trabecular parameters and cortical porosity, however saw no effect with BAY over this time course. Serum alkaline phosphatase was significantly elevated in CKD-BAY mice compared to CKD controls (p<0.01), suggesting increased osteoblast activity.

Conclusion

Collectively, these results support that resolving anemia using a HIF-PHI may improve kidney function and lower FGF23 during CKD, potentially providing modifiable outcomes beyond improving iron utilization for this patient population.

Funding

  • NIDDK Support