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Abstract: TH-PO511

Treating CKD-Related Anemia with Erythropoietin and HIF- Prolyl Hydroxylase Inhibitors Improves FGF-23-Dependent and -Independent Outcomes

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
  • Clinkenbeard, Erica, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Ni, Pu, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Tippen, Samantha P., IU School of Medicine, Indianapolis, Indiana, United States
  • Agoro, Rafiou, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Thompson, William R., Indiana University, 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

In chronic kidney disease (CKD), high blood concentrations of the phosphaturic hormone FGF23 are associated with increased odds for patient mortality (>6-fold). Our lab has identified anemia as a potent driver of FGF23 expression. Patients with CKD ultimately develop anemia as the kidneys lose the ability to produce erythropoietin (EPO), in parallel with mineral metabolism alterations. We hypothesized that mitigating anemia through treatment with either recombinant EPO or HIF-PHi (hypoxia inducible factor-prolyl hydroxylase inhibitors), currently in clinical trials that elevate endogenous EPO, would reduce circulating bioactive, ‘intact’ FGF23 (‘iFGF23’), thereby improving the pathogenic manifestations of CKD.

Methods

Using a novel murine inducible stem cell line (MPC2), we showed that the HIF-PHDi FG-4592 (Roxadustat) directly induced Fgf23 mRNA when differentiated into osteoblast-like cells (8-16 fold, p<0.01). Additionally, FG-4592 injection dose-dependently increased iFGF23 2-9 fold (p<0.05) in wild type (WT) mice with normal renal function. To determine the effects in CKD, mice were placed on a casein control or adenine diet to induce CKD, which resulted in markedly elevated iFGF23, hyperphosphatemia, hyperparathyroidism, and anemia. Separate cohorts were treated with either recombinant EPO or FG-4592.

Results

iFGF23 was significantly elevated (70-fold, p<0.01) in saline-treated CKD mice compared to controls. In CKD mice, EPO treatment improved total serum iron, and FG-4592 treatment led to marked induction of serum EPO (p<0.01). Importantly, circulating iFGF23 was significantly attenuated (>70%; p<0.05) in the CKD mice with EPO or FG-4592 administration, demonstrating that anemia is a primary driver of FGF23 in CKD. As expected with elevated iFGF23 in CKD mice, Cyp24a1 mRNA increased (p<0.01), favoring low 1,25D. In contrast, both EPO and FG-4592 significantly enhanced Cyp27b1 (p<0.05) and suppressed Cyp24a1 (p<0.01) mRNAs in CKD mice, suggesting improved 1,25D synthesis. Indeed, EPO injection significantly increased serum 1,25D in control and CKD mice (p<0.05).

Conclusion

Collectively, these results support that treatment for anemia, via EPO or HIF-PHDi, leads to improved FGF23-dependent and -independent outcomes.

Funding

  • NIDDK Support