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      Resistance of dialyzed patients to erythropoietin

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          Abstract

          Resistance to recombinant human erythropoietin is a common condition in dialyzed patients with chronic kidney disease and is associated with more hospitalizations, increased mortality and frequent blood transfusions. The main cause of hyporesponsiveness to recombinant human erythropoietin in these patients is iron deficiency. However, a high proportion of patients does not respond to treatment, even to the use of intravenous iron, which indicates the presence of other important causes of resistance. In addition to the iron deficiency, the most common causes of resistance include inflammation, infection, malnutrition, inadequate dialysis, and hyperparathyroidism, although other factors may be associated. In the presence of adequate iron stores, other causes should be investigated and treated appropriately.

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          IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.

          Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
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            Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences.

            Protein-energy malnutrition (PEM) and inflammation are common and usually concurrent in maintenance dialysis patients. Many factors that appear to lead to these 2 conditions overlap, as do assessment tools and such criteria for detecting them as hypoalbuminemia. Both these conditions are related to poor dialysis outcome. Low appetite and a hypercatabolic state are among common features. PEM in dialysis patients has been suggested to be secondary to inflammation; however, the evidence is not conclusive, and an equicausal status or even opposite causal direction is possible. Hence, malnutrition-inflammation complex syndrome (MICS) is an appropriate term. Possible causes of MICS include comorbid illnesses, oxidative and carbonyl stress, nutrient loss through dialysis, anorexia and low nutrient intake, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hyporesponsiveness, high rate of cardiovascular atherosclerotic disease, decreased quality of life, and increased mortality and hospitalization in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, hypocreatininemia, and hypohomocysteinemia, a "reverse epidemiology" of cardiovascular risks can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed. Successful management of MICS may ameliorate the cardiovascular epidemic and poor outcome in dialysis patients. Clinical trials focusing on MICS and its possible causes and consequences are urgently required to improve poor clinical outcome in dialysis patients.
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              Assessing iron status: beyond serum ferritin and transferrin saturation.

              The increasing prevalence of multiple comorbidities among anemic patients with chronic kidney disease has made the use of serum ferritin and transferrin saturation more challenging in diagnosing iron deficiency. Because serum ferritin is an acute-phase reactant and because the inflammatory state may inhibit the mobilization of iron from reticuloendothelial stores, the scenario of patients with serum ferritin >800 ng/ml, suggesting iron overload, and transferrin saturation <20%, suggesting iron deficiency, has become more common. This article revisits the basis for the Kidney Disease Outcomes Quality Initiative recommendations regarding the use of serum ferritin and transferrin saturation in guiding iron therapy, then explores some of the newer alternative markers for iron status that may be useful when serum ferritin and transferrin saturation are insufficient. These newer tests include reticulocyte hemoglobin content, percentage of hypochromic red cells, and soluble transferrin receptor, all of which have shown some promise in limited studies. Finally, the role of hepcidin, a hepatic polypeptide, in the pathophysiology of iron mobilization is reviewed briefly.
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                Author and article information

                Contributors
                Journal
                Rev Bras Hematol Hemoter
                Rev Bras Hematol Hemoter
                Revista Brasileira de Hematologia e Hemoterapia
                Sociedade Brasileira de Hematologia e Hemoterapia
                1516-8484
                1806-0870
                17 February 2015
                May-Jun 2015
                17 February 2015
                : 37
                : 3
                : 190-197
                Affiliations
                [a ]Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
                [b ]Hospital Felício Rocho, Belo Horizonte, MG, Brazil
                Author notes
                [* ] Corresponding author at: Av. Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil. karinabgb@ 123456gmail.com
                Article
                S1516-8484(15)00025-0
                10.1016/j.bjhh.2015.02.001
                4459468
                26041422
                3dfdd38b-ac4d-4c83-a348-6c935f4b4e5e
                © 2015 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 23 July 2014
                : 24 November 2014
                Categories
                Update Article

                Hematology
                dialysis,erythropoietin,iron
                Hematology
                dialysis, erythropoietin, iron

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