A Hepcidin Inhibitor Mobilizes Iron for Incorporation Into Red Blood Cells in an Adenine-Induced Chronic Kidney Disease Model in Rats.

Anemia is prevalent in patients with chronic kidney disease (CKD). A key feature of the anemia of CKD is limited iron availability for efficient erythropoiesis despite adequate body iron stores. It is now well established that excess levels of the iron regulatory hormone hepcidin in CKD are responsible for decreasing expression of the iron exporter ferroportin, thereby blocking iron absorption from the diet and iron release from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in patients.

We developed a modified adenine-induced kidney disease model of anemia in rats by giving a diet supplemented with 0.75% adenine for 3 weeks followed by a normal diet for 3 weeks. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which has previously been shown to lower hepcidin levels, was able to mobilize iron into the plasma and improve iron-restricted erythropoiesis in adenine-treated rats.

The modified adenine model had a higher survival rate than previously reported models, while maintaining irreversible renal failure and anemia. Adenine-treated rats had increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin, and inappropriately low EPO levels relative to the degree of anemia. LDN-193189 lowered hepatic hepcidin mRNA and mobilized stored iron into plasma in adenine-treated rats. Moreover, the iron was efficiently incorporated into hemoglobin in reticulocytes. However, LDN-193189 alone did not prevent anemia progression in our model.

Lowering hepcidin improved iron availability, but did not improve anemia in an adenine-induced kidney disease model in rats. Co-administration of hepcidin lowering agents with erythropoiesis stimulating agents (ESAs) may be useful as a combination therapy to correct iron balance and thereby reduce the ESA dose needed to achieve target hemoglobin levels.

Sun:FerruMax Pharmaceuticals Inc: Consultancy. Lin:Ferrumax Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties. Babitt:Ferrumax Pharmaceuticals, Inc: Equity Ownership.