Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats
Milan Theurl,
Manfred Nairz,
Andrea Schroll,
Thomas Sonnweber,
Malte Asshoff,
David Haschka,
Markus Seifert,
Wolfgang Willenbacher,
Doris Wilflingseder,
Wilfried Posch,
Anthony T. Murphy,
Derrick R. Witcher,
Igor Theurl,
Günter Weiss
Affiliations
Milan Theurl
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria;Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria
Manfred Nairz
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
Andrea Schroll
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
Thomas Sonnweber
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
Malte Asshoff
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
David Haschka
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
Markus Seifert
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
Wolfgang Willenbacher
Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria
Doris Wilflingseder
Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria
Wilfried Posch
Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria
Anthony T. Murphy
Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA
Derrick R. Witcher
Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA
Igor Theurl
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
Günter Weiss
Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria
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.
