title: Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats.
abstract: 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.
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria Department of Ophthalmology and Optometry, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Milan
authors.initials: M
authors.lastname: Theurl
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sonnweber
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Malte
authors.initials: M
authors.lastname: Asshoff
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Haschka
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Department of Internal Medicine V, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Willenbacher
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Wilflingseder
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Posch
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Murphy
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria guenter.weiss@i-med.ac.at igor.theurl@i-med.ac.at.
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Innsbruck, Austria guenter.weiss@i-med.ac.at igor.theurl@i-med.ac.at.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D000740:Anemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D004338:Drug Combinations; D004357:Drug Synergism; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D006397:Hematinics / Q000494:pharmacology*; D064451:Hepcidins / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007501:Iron / Q000819:agonists / Q000097:blood*; D011135:Polysaccharides, Bacterial; D011379:Prognosis; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D004338:Drug Combinations; C578703:Hamp protein, rat; D006397:Hematinics; D064451:Hepcidins; C554430:LDN 193189; D011135:Polysaccharides, Bacterial; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D007371:Interferon-gamma; D007501:Iron