Anemia of
chronic disease is a multifactorial disorder, resulting mainly from
inflammation-driven reticuloendothelial
iron retention, impaired erythropoiesis, and reduced
biological activity of
erythropoietin.
Erythropoiesis-stimulating agents have been used for the treatment of
anemia of
chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of
hepcidin, a key regulator of
iron homeostasis, are increased in patients with
anemia of
chronic disease and linked to the pathogenesis of this disease, because
hepcidin blocks cellular
iron egress, thus limiting availability of
iron for erythropoiesis. We tested whether serum
hepcidin levels can predict and affect the therapeutic efficacy of
erythropoiesis-stimulating agent treatment using a well-established rat model of
anemia of
chronic disease. We found that high pre-treatment
hepcidin levels correlated with an impaired hematologic response to an
erythropoiesis-stimulating agent in rats with
anemia of
chronic disease. Combined treatment with an
erythropoiesis-stimulating agent and an inhibitor of
hepcidin expression,
LDN-193189, significantly reduced serum
hepcidin levels, mobilized
iron from tissue stores, increased serum
iron levels and improved
hemoglobin levels more effectively than did the
erythropoiesis-stimulating agent or
LDN-193189 monotherapy. In parallel, both the
erythropoiesis-stimulating agent and
erythropoiesis-stimulating agent/
LDN-193189 combined reduced the expression of
cytokines known to inhibit erythropoiesis. We conclude that serum
hepcidin levels can predict the hematologic responsiveness to
erythropoiesis-stimulating agent therapy in
anemia of
chronic disease. Pharmacological inhibition of
hepcidin formation improves the
erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of
erythropoiesis-stimulating agent dosages, costs and side effects.