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Abstract: FR-PO501

Effects of Low-Dose Ferric Citrate on Hematologic and FGF23 Parameters in High-Hepcidin Murine Models with and Without CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hanudel, Mark R., UCLA, Los Angeles, California, United States
  • Rappaport, Maxime, UCLA, Los Angeles, California, United States
  • Gabayan, Victoria Rivka, UCLA, Los Angeles, California, United States
  • Salusky, Isidro B., UCLA, Los Angeles, California, United States
  • Nemeth, Elizabeta, UCLA, Los Angeles, California, United States
  • Ganz, Tomas, UCLA, Los Angeles, California, United States
Background

Ferric citrate (FC) is an effective phosphate binder and iron supplement in CKD patients. FC-delivered iron is enterally absorbed, despite high hepcidin levels, but the specific absorption mechanism and its regulation remain unknown. We assessed the effects of FC in Tmprss6 knockout (TKO) mice, a model characterized by high hepcidin levels and resultant iron-refractory iron-deficiency anemia, without or with the addition of adenine-induced CKD, which exacerbates anemia and iron restriction.

Methods

Wild-type (WT) and TKO mice were fed diets with or without 0.2% adenine for 6 weeks (to induce CKD), with or without 0.1% FC for the last 3 of the 6 weeks (corresponding to an adult human FC dose of ~2 tablets thrice daily). Blood and tissues were then collected for analysis.

Results

In the absence of CKD, TKO mice compared to WT mice had significantly higher serum hepcidin, lower liver iron, lower serum iron, lower hemoglobin, higher serum erythropoietin (EPO), higher bone and marrow Fgf23 mRNA, and higher plasma C-terminal (total) FGF23, but no difference in circulating intact FGF23. In TKO mice, despite high serum hepcidin, FC administration significantly decreased serum phosphate, increased liver iron, increased serum iron, increased hemoglobin, decreased serum EPO, decreased bone and marrow Fgf23 mRNA, and decreased plasma total FGF23.

With adenine-induced CKD, TKO mice had the highest hepcidin levels. FC treatment caused no significant changes in serum phosphate, liver iron, or serum iron, but significantly increased hemoglobin, with a trend towards lower serum EPO. FC therapy significantly decreased bone Fgf23 mRNA, marrow Fgf23 mRNA, and plasma total FGF23, but not intact FGF23. Despite the very high hepcidin levels, FC increased duodenal ferroportin protein in the CKD TKO mice.

Conclusion

In the high-hepcidin TKO mice, low-dose FC was sufficient to increase enteral iron absorption and ferroportin expression, improve the anemia of both iron deficiency and CKD, and decrease FGF23 expression. FC may decrease FGF23 expression through decreased enteral phosphate absorption, improved iron status, and/or decreased EPO levels. Although murine FC dosing needs to be optimized, the models of FC absorption despite high hepcidin levels will facilitate examination of the mechanisms involved.

Funding

  • Commercial Support