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Abstract: TH-OR16

Distinct Effects of FGF23, Iron and Phosphate on Mineral Metabolism and Kidney Function in Mice with CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Courbon, Guillaume, Nortwestern University, Chicago, Illinois, United States
  • Martinez-Calle, Marta, Nortwestern University, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Nortwestern University, Chicago, Illinois, United States
  • Martin, Aline, Nortwestern University, Chicago, Illinois, United States
  • David, Valentin, Nortwestern University, Chicago, Illinois, United States
Background

Elevated levels of fibroblast growth factor 23 (FGF23), hyperphosphatemia and iron deficiency are common complications of chronic kidney disease (CKD) and strong predictors of disease progression and death. We have previously found that administration of ferric citrate (FC), an iron-based, oral phosphate binder, to mice with CKD reduced dietary phosphate absorption and FGF23, increased iron stores, slowed CKD progression and prolonged survival. This suggests that FGF23, phosphate and/or iron play a major role in CKD progression.

Methods

To distinguish between the individual and combined effects of FGF23, phosphate and iron in CKD, we fed WT and Col4a3KO mice (CKD model) from 4-10wks either control (Ctr), low iron (LI), low phosphate (LP), 1% carbonyl iron (CI) or ferric citrate (FC) diets . To further study the role of iron in CKD, we compared the effects of these diets to mice receiving iv ferric derisomaltose (FD) using biochemical, histological and RNAseq analyzes.

Results

CKD mice showed higher serum FGF23, PTH, phosphate and low calcitriol levels and administration of LI diet further accentuated these differences. Surprisingly, phosphate restriction in LP-CKD mice minimally reduced hyperphosphatemia and PTH levels and had no effect on FGF23. In sharp contrast, all iron containing diets reduced PTH and FGF23 levels. Surprisingly, similar effects were observed in mice receiving iv iron, suggesting that iron deficiency is a stronger predictor of FGF23 excess in CKD than hyperphosphatemia. Compared to Ctr-CKD mice, FC enriched diets showed the strongest potential to reduce FGF23 (-68%), and serum phosphate (-37%) and the only treatment to increase calcitriol (+220%). Biochemical, histological and RNAseq analyses also showed that only the combined reductions of phosphate and FGF23, and iron repletion, achieved by FC treatment, improved kidney function and slowed CKD progression. These benefits were fully reversed when FC-treated mice received a daily dose of 30ng/g of rFGF23 during 28 days. FGF23 administration increased renal inflammatory signaling and further accentuated CKD progression.

Conclusion

Our results suggest that combined corrections of FGF23, phosphate and iron slows CKD progression and suggest that FGF23 plays a major role in CKD progression independently of other disease modifiers.

Funding

  • NIDDK Support