losartan-potassium and Iron-Overload

Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron-regulatory hormone hepcidin, erythropoietic activity stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders.

Topics: Anemia; Bone Morphogenetic Proteins; Erythropoiesis; Erythropoietin; Hepatocytes; Hepcidins; Humans; Iron; Iron Overload; Macrophages; Peptide Hormones

Anemia is a common complication in patients with chronic kidney disease (CKD), mainly due to inadequate renal production of erythropoietin. In hemodialysis (HD) patients this condition may be aggravated by iron deficiency (absolute or functional). The correction of this anemia is usually achieved by treatment with erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies questioning the safety of ESAs (especially at higher doses) changed the pattern of anemia treatment in CKD patients. According to the new guidelines, when transferrin saturation is lower than 30% and ferritin lower than 500 ng/mL, a trial with iron should be started, to avoid therapy with ESAs or at least to reduce the doses needed to treat the anemia. Recent reports showed increasing ferritin levels, towards values above 800 ng/mL, in CKD patients treated according to the guidelines. In this review we focus on the risks of the increased iron use to treat CKD anemia, namely, iron overload and toxicity, increased risk of infections, as well as mortality.

Topics: Anemia, Iron-Deficiency; Drug Dosage Calculations; Epoetin Alfa; Erythropoietin; Ferritins; Hematinics; Humans; Iron; Iron Overload; Kidney; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Survival Analysis; Transferrin

The management of anemia in patients with chronic kidney disease (CKD) is difficult. The availability of erythropoiesis-stimulating agents (ESAs) has increased treatment options for previously transfusion-requiring patients, but the recent evidence of ESA side effects has prompted the search for complementary or alternative approaches. Next to ESA, parenteral iron supplementation is the second main form of anemia treatment. However, as of now, no systematic approach has been proposed to balance the concurrent administration of both agents according to individual patient's needs. Furthermore, the potential risks of excessive iron dosing remain a topic of controversy. How, when and whether to monitor CKD patients for potential iron overload remain to be elucidated. This review addresses the question of risk and benefit of iron administration in CKD, highlights the evidence supporting current practice, provides an overview of standard and potential new markers of iron status and outlines a new pharmacometric approach to physiologically compatible individualized dosing of ESA and iron in CKD patients.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Hematinics; Humans; Iron Compounds; Iron Overload; Renal Insufficiency, Chronic

Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of 'osteohematology' as an emerging research field in MDS and outline clinical implications.

Topics: Animals; Bone Marrow; Cytokines; Disease Progression; Epigenesis, Genetic; Erythropoietin; Hematopoietic Stem Cells; Humans; Iron; Iron Overload; Mesenchymal Stem Cells; Myelodysplastic Syndromes; Osteoblasts; Parathyroid Hormone; Signal Transduction

To determine the impact of adjuvant ascorbic acid therapy on erythropoietin-hyporesponsive, anemic patients undergoing hemodialysis.. The online databases of PubMed, Cochrane library, IPA, CINAHL, EMBASE, clinicaltrial.gov, WHO trial registry and PyschINFO were used.. Studies comparing ascorbic acid to a control, with participants receiving erythropoietin and hemodialysis, and reported outcomes for hemoglobin or transferring saturation.. Two independent researchers reviewed titles and abstracts to determine relevance and extracted study design, dose, duration, baseline values, and outcomes.. Five studies met all the criteria and were used for final analysis. The calculated weighted mean difference between hemoglobin in the ascorbic acid group versus the control group was 0.96 g/dL (95% CI, 0.78 to 1.14). The calculated weighted mean difference between transferrin saturation in the ascorbic acid treatment group versus the control was 8.26% (95% CI, 6.59 to 9.94).. Adjuvant ascorbic acid significantly raises hemoglobin levels in patients with erythropoietin hyporesponsiveness undergoing hemodialysis. The significant rise in transferrin saturation indicates that this positive effect on erythropoietin response may be due to increased iron utilization.

Topics: Adult; Anemia; Antioxidants; Ascorbic Acid; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Renal Dialysis

Anemia is inevitable as chronic kidney disease (CKD) advances. With the advent of erythropoietin-stimulating agents (ESAs), considerable improvement has been achieved in the management of anemia. However, some patients show a reduced response to ESAs.. Many factors affect the response to ESA treatment. CKD is now considered as an inflammatory disorder and this understanding led to the recognition of the central role of inflammation in ESA resistance. Inflammation is related to untoward outcomes, including atherosclerosis and anemia, in the CKD population. Furthermore, recognition of deleterious effects of proinflammatory markers at different levels of erythropoiesis led to a change in the name of 'anemia of chronic disease' to anemia of inflammation.. The discovery of hepcidin as the major controller of iron metabolism in anemia of inflammation answered many questions regarding the interaction of erythropoietin, iron and bone marrow. Hepcidin production in the liver is driven by three major factors: inflammation, iron overload and anemia/hypoxia. Hepcidin levels are increased in patients with CKD due to the interaction of many factors; a comprehensive understanding of these pathways is thus critical in the effort to alleviate anemia of inflammation and ESA resistance.. In this review, we discussed the epidemiology, determinants and consequences of anemia of inflammation in CKD patients with special emphasis on the central role of hepcidin along with molecular pathways driving its production.

Topics: Anemia; Antimicrobial Cationic Peptides; Bone Marrow; Chronic Disease; Erythropoietin; Hepcidins; Humans; Inflammation; Iron; Iron Overload; Kidney Diseases

β-Thalassemia is a genetic disorder caused by mutations in the β-globin gene and characterized by chronic anemia caused by ineffective erythropoiesis, and accompanied by a variety of serious secondary complications such as extramedullary hematopoiesis, splenomegaly, and iron overload. In the past few years, numerous studies have shown that such secondary disease conditions have a genetic basis caused by the abnormal expression of genes with a role in controlling erythropoiesis and iron metabolism. In this article, the most recent discoveries related to the mechanism(s) responsible for anemia/ineffective erythropoiesis and iron overload are discussed in detail. Particular attention is paid to the pathway(s) controlling the expression of hepcidin, which is the main regulator of iron metabolism, and the Epo/EpoR/Jak2/Stat5 signaling pathway, which regulates erythropoiesis. Better understanding of how these pathways function and are altered in β-thalassemia has revealed several possibilities for development of new therapeutic approaches to treat of the complications of this disease.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; beta-Thalassemia; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Iron; Iron Overload; Receptors, Erythropoietin

Divalent metal transporter 1 (DMT1) is the protein that allows elemental iron entry into the duodenal cell. It is expressed ubiquitously and it also allows the iron exit from the endosomes. This protein plays a central role in iron metabolism and it is strictly regulated. Several animal models elucidate its role in physiology. Recently three patients affected with DMT1 deficiency have been described. This recessively inherited condition appears at birth with severe microcytic anemia. Serum markers could be particularly useful to establish a correct diagnosis: high serum iron, normal total iron-binding capacity (TIBC), increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR). Increased free erythrocyte protoporphyrins (FEPs) could address the diagnosis to iron-deficient anemia. All patients appeared to respond to erythropoietin (Epo) administration. Because mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) did not change during Epo treatment, it was concluded that Epo did not improve iron utilization of the erythroblasts but likely reduced the degree or intensity of apoptosis, affecting erythropoiesis. Moreover liver iron overload was present and documented in all of the affected patients. In this review we analyze the role of DMT1 in iron metabolism and the major causes of reduction and their consequences in animal models as well in humans, and we attempt to define the correct treatment for human mutants.

Topics: Anemia; Animals; Biomarkers; Cation Transport Proteins; Disease Models, Animal; Erythropoiesis; Erythropoietin; Genotype; Hematinics; Humans; Iron; Iron Overload; Iron-Binding Proteins; Mutation; Phenotype; Treatment Outcome; Up-Regulation

The history of retinopathy of prematurity (ROP) gives a prime example of how dangerous the uncontrolled introduction of a new medical treatment--particularly in the field of neonatology--may be. The most important risk factors for the development of ROP are the immaturity of premature infants as well as uncontrolled and/or inadequate treatment with oxygen. In comparison to the fetus, the premature infant is exposed to a nonphysiologically high oxygen concentration. This hyperoxia leads to formation of aggressive oxygen radicals on the one hand and, on the other hand, to temporarily reduced production of growth factors such as vascular endothelial growth factor and erythropoietin, which both play an important role in the pathogenesis of ROP. The most important measure to prevent ROP is restrictive and carefully monitored oxygen treatment. Medical treatment to prevent ROP includes injection of D-penicillamine and retinol, but the available data are still limited, particularly with regard to the long-term effects of this treatment. A higher oxygenation in prethreshold ROP does not lead to recovery of ocular findings, but it increases the incidence of pulmonary complications. A reduction of light intensity in neonatal intensive care units proved not to be efficient for preventing ROP. To avoid blindness, standardized screening of the risk group is needed.

Topics: Erythrocyte Transfusion; Erythropoietin; Gestational Age; Humans; Hyperoxia; Infant, Newborn; Iron Overload; Mass Screening; Oxygen Inhalation Therapy; Recombinant Proteins; Referral and Consultation; Retinopathy of Prematurity; Risk Factors

For cancer treatment-related anemia, it is recommended to use erythropoietin or darbepoetin alpha by the National Comprehensive Cancer Network (NCCN). The guideline proposed the risk assessment for anemia, as well. The introduction of erythropoietin or darbepoetin alpha for anemia in treated cancer patients is based on the improvement of quality of life. For patients with myelodysplastic syndrome (MDS), those with 5q- anomaly is recommended to use lenalidomide and low-risk MDS patients without 5q- and serum erythropoietin of less than 500 mU/ml are recommended to treat with erythropoietin or darbepoetin alpha. These new agents are currently under clinical trials in Japan.

Topics: Anemia; Benzoates; Clinical Trials as Topic; Darbepoetin alfa; Deferasirox; Erythropoietin; Hematinics; Humans; Iron Chelating Agents; Iron Overload; Lenalidomide; Myelodysplastic Syndromes; Neoplasms; Thalidomide; Triazoles

A long-term observational study of Hb E-beta-thalassemia in Sri Lanka is beginning to define some of the genetic and environmental factors that are responsible for its remarkable phenotypic variability. In this population there is a very small difference between the steady-state hemoglobin levels between the mild and severe phenotypes, and it has been possible to stop transfusion in many of those who have been on long-term treatment of this kind. These preliminary observations, made over the last 7 years, provide directions for future research into this increasingly important disease.

Topics: Adolescent; Adult; beta-Thalassemia; Blood Transfusion; Case Management; Child; Child, Preschool; Combined Modality Therapy; Erythropoietin; Female; Genetic Heterogeneity; Hemoglobin E; Hemoglobins; Humans; Infant; International Cooperation; Iron Overload; Longitudinal Studies; Male; Middle Aged; Phenotype; Pregnancy; Pregnancy Complications, Hematologic; Severity of Illness Index; Splenectomy; Sri Lanka; Transfusion Reaction

Allogenic blood transfusion may be required for the treatment of anemia due to a hematologic disease, the consequences of chemotherapy or other circumstances, such as haemorrage and/or surgery. Transfusion becomes indispensable to prevent the side effects of anemia, such as hypoxia, palpitations, tachycardia, cardiac ischemia and fatigue. However, frequent transfusions can cause several acute problems such as hemolysis, anaphylactic shock and septic shock but also chronic problems such as iron overload (hemochromatosis), alloimmunisation and metabolic disturbances. Each of these complications can produce serious consequences and could even be sometimes fatal. Therefore we should recognise, prevent and if necessary treat all these hazards. Our article emphasises the potential chronic problems. For hemochromatosis, an iron chelator (deferoxamine) should be administered. In the presence of allo-immunisation the more compatible ABO blood group must be chosen and blood products be eliminated by filtration, when there has been blood reaction. When an allo-graft of hematopoitic tissues is considered an irradiation of blood products is necessary. Research is being carried out to develop substitute products for transfusion (haemoglobine solutions) or molecules acting on the syntheses of haemoglobine (butyrate arginine). The efficacy of erythropoitine, (EPO) is well recognised for stimulation of haemoglobine syntheses in renal failure and oncology.

Topics: Anaphylaxis; Chronic Disease; Erythropoietin; Hemolysis; Humans; Iron Overload; Shock, Septic; Transfusion Reaction

Iron sufficiency is critical for rapidly developing fetal and neonatal organ systems. The majority of iron in the third trimester fetus and the neonate is found in the red cell mass (as hemoglobin), with lesser amounts in the tissues as storage iron (e.g. ferritin) or functional iron (e.g. myoglobin, cytochromes). Iron is prioritized to hemoglobin synthesis in red cells when iron supply does not meet iron demand. Thus, non-heme tissues such as the skeletal muscle, heart and brain will become iron deficient before signs of iron-deficiency anemia. Gestational conditions that result in lower newborn iron stores include severe maternal iron deficiency, maternal hypertension with intrauterine growth retardation and maternal diabetes mellitus. Stable, very low birthweight premature infants are also at risk for early postnatal iron deficiency because they accrete less iron during gestation, grow more rapidly postnatally, are typically undertreated with enteral iron and receive fewer red cell transfusions. Conversely, iron overload remains a significant concern in multiply transfused sick preterm infants because they have low levels of iron-binding proteins and immature antioxidant systems.. The highly variable iron status of preterm infants combined with their risk for iron deficiency and toxicity warrants careful monitoring and support in the newborn and postdischarge periods.

Topics: Anemia, Iron-Deficiency; Combined Modality Therapy; Erythrocyte Transfusion; Erythropoietin; Female; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Iron Compounds; Iron Metabolism Disorders; Iron Overload; Maternal-Fetal Exchange; Perinatology; Pregnancy; Recombinant Proteins; Risk Assessment; Risk Factors; Severity of Illness Index

Topics: Aged; Erythropoietin; Fatal Outcome; Hematopoiesis, Extramedullary; Humans; Iron Overload; Leukemia, Erythroblastic, Acute; Male; Postoperative Complications; Primary Myelofibrosis; Spleen; Splenectomy; Splenomegaly; Transfusion Reaction

Stimulation of red blood cell precursors by Epoetin alfa results in a predictable, dose-dependent increase in red blood cell mass. Iron is an important substrate that supports red blood cell and hemoglobin development. Patients who receive Epoetin alfa therapy typically require intravenous iron supplementation to ensure proper red cell formation. Target and ceiling iron levels should be determined on the basis of safety considerations, the predicted clinical response, and individual patient replacement needs. Nurses can use clinical parameters such as body weight, baseline and target hemoglobin values, and iron losses from blood and other sources to estimate iron replacement doses, thereby providing a guide for appropriate iron replacement.

Topics: Anemia, Iron-Deficiency; Body Weight; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Epoetin Alfa; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Ferritins; Hematinics; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron Compounds; Iron Overload; Kidney Failure, Chronic; Nurse's Role; Nursing Assessment; Recombinant Proteins; Renal Dialysis; Safety Management; Transferrin

The treatment of porphyria cutanea tarda (PCT) in patients with chronic renal failure poses a therapeutic challenge. In the absence of renal failure, phlebotomy and oral antimalarials have been the standard of care for PCT. However, in the presence of renal failure, associated chronic anemia often precludes the use of phlebotomy, and oral antimalarials are usually ineffective. We describe a patient with severe symptomatic PCT and chronic renal failure whose disease was successfully managed with a combination of high-dose erythropoietin and small volume phlebotomy. We also review several previously reported approaches to management of PCT in the setting of renal failure, which include small repeated phlebotomy, erythropoietin, deferoxamine, chloroquine, plasma exchange, high-efficiency/high-flux hemodialysis, cholestyramine, charcoal hemoperfusion, and kidney transplantation. An algorithm for the management of these patients is proposed.

Topics: Adult; Algorithms; Erythropoietin; Female; Humans; Iron Overload; Kidney Failure, Chronic; Phlebotomy; Porphyria Cutanea Tarda; Renal Dialysis

Increasing use of maintenance parenteral iron in the erythropoietin (EPO) era has been accompanied by growing concern about iron overload. This article attempts to put the issue of iron overload in hemodialysis patients into perspective. The condition is less common in all dialysis patients today than it was in the pre-EPO era, since fewer patients are being transfused and EPO therapy shifts iron into erythroid cells. Patients with end stage renal disease (ESRD) are less likely than patients with hemochromatosis to develop iron-induced organ dysfunction. Diagnosis of iron overload is best accomplished through liver biopsy. Clinically significant iron overload, which rarely occurs if ESRD patients are properly managed, can be treated in most EPO-treated renal failure patients by simply withholding parenteral iron therapy.

Topics: Anemia, Iron-Deficiency; Biopsy; Drug Monitoring; Erythropoietin; Ferritins; Hematinics; Hematocrit; Humans; Iron Overload; Kidney Failure, Chronic; Nursing Assessment; Practice Guidelines as Topic; Renal Dialysis; Risk Factors; Tissue Distribution; Transfusion Reaction

Iron overload was a common complication in patients with chronic renal failure treated with dialysis prior to the availability of recombinant human erythropoietin (rHuEPO) therapy. Iron overload was the result of hypoproliferative erythroid marrow function coupled with the need for frequent red blood cell transfusions to manage symptomatic anemia. The repetitive use of intravenous iron with or without the use of red blood cell transfusions also contributed to iron loading and was associated with iron deposition in liver parenchymal and reticuloendothelial cells; however, there were no abnormal liver function tests or evidence of cirrhosis unless viral hepatitis resulted from the transfusions. With rHuEPO therapy, the excess iron stores were shifted back into circulating red blood cells as the anemia was partially corrected, and red blood cells were lost from circulation by the hemodialysis procedure. After several years of rHuEPO therapy, most hemodialysis patients required iron supplements to replace the continuing blood losses related to hemodialysis. The potential complications of iron overload (parenchymal iron deposition, permanent organ damage, increased risk of bacterial infections, and increased free radical generation) are reviewed in the context of this setting.

Topics: Anemia; Bacterial Infections; Erythropoietin; Free Radicals; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Recombinant Proteins

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin sa

Topics: Aluminum; Anemia; Erythropoietin; Hemoglobinopathies; Hemolysis; Humans; Infections; Inflammation; Iron; Iron Deficiencies; Iron Overload; Kidney Failure, Chronic; Recombinant Proteins; Thalassemia

Anemia in cancer patients has many etiologies. Iron therapy clearly is indicated in patients whose anemias are associated with iron deficiency. However, a frequent cause of anemia in cancer is the "anemia of chronic disorders," in which, although functional iron may be low, tissue iron remains normal or high. Administration of iron with erythropoietin to such patients requires careful and frequent evaluation of hematologic and iron values. Inadvertent iron loading can contribute to deterioration of a variety of organ systems, as well as to increased proliferation of neoplastic cells.

Topics: Anemia; Erythropoietin; Humans; Iron; Iron Overload; Neoplasms; Recombinant Proteins

Intensive iron therapy is now a generally accepted adjunct for the treatment of renal anemia with recombinant human erythropoietin. However, with the emerging role of iron in cardiovascular disease, carcinogenesis, infectious diseases, and other disorders, it is no longer appropriate to assume that any amount of stored iron is safe until proven otherwise. In this article, the history and current status of the "iron hypothesis" on ischemic heart disease are briefly reviewed, followed by comments on iron management practices for renal patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Female; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Recombinant Proteins

Absolute and functional iron deficiency is the most common cause of epoetin (recombinant human erythropoietin) hyporesponsiveness in renal failure patients. Diagnostic procedures for determining iron deficiency include measurement of serum iron levels, serum ferritin levels, saturation of transferrin and percentage of hypochromic red blood cells. Patients with iron deficiency should receive supplemental iron, either orally or intravenously. Adequate intravenous iron supplementation allows reduction of epoetin dosage by approximately 40%. Intravenous iron supplementation is recommended for all patients undergoing haemodialysis and for pre-dialysis and peritoneal dialysis patients with severe iron deficiency. During the maintenance phase (period of epoetin therapy after correction of iron deficiency), the use of low-dose intravenous iron supplementation (10 to 20 mg per haemodialysis treatment or 100 mg every second week) avoids iron overtreatment and minimises potential adverse effects. Depending on the degree of pre-existing iron deficiency, markedly higher iron doses are necessary during the correction phase (period of epoetin therapy after correction of iron deficiency) [e.g. intravenous iron 40 to 100 mg per haemodialysis session up to a total dose of 1000 mg]. The iron status should be monitored monthly during the correction phase and every 3 months during the maintenance phase to avoid overtreatment with intravenous iron.

Topics: Anemia, Iron-Deficiency; Citric Acid; Drug Combinations; Drug Monitoring; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Ferrous Compounds; Glucaric Acid; Humans; Infusions, Intravenous; Injections, Intravenous; Iron Compounds; Iron Overload; Iron-Dextran Complex; Kidney Failure, Chronic; Sorbitol

Erythropoietin (EPO) plays a central role in the regulation of red blood cell (RBC) production. Since iron is an essential element for erythropoiesis and hemoglobin (Hb) synthesis, its importance is heightened in patients treated with epoetin alfa. Stimulation of erythropoiesis following the administration of epoetin alfa is associated with several changes in iron metabolism; indeed, plasma ferritin levels fall as a result of increased utilization of iron by the expanding erythroid marrow. The administration of epoetin alfa can therefore lead to a state of relative iron deficiency. Thus, iron supplementation is essential to maximize the effect of epoetin alfa-induced erythropoiesis.

Topics: Adult; Anemia, Hypochromic; Bone Marrow; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Iron Deficiencies; Iron Overload; Male; Middle Aged; Recombinant Proteins

Excess of iron and oxidant injury shortly after birth may be associated with neonatal morbidities in preterm infants.. The aim was to determine whether administration of erythropoietin without iron supplementation decreases iron load and morbidity.. In a randomized trial, we administered erythropoietin (EPO 250IU/kg daily during the first 6days of life) or placebo to 39 preterm infants (BW 700-1500g, GA≤30.0weeks).. The iron status, postnatal morbidities and follow-up at the age of two years were investigated.. In all, 21 EPO- and 18 placebo-treated infants were recruited. A requirement of red blood cell transfusions during first 28days was similar between the study groups. EPO treatment decreased total serum iron concentration (p=0.035). EPO supplementation had no significant effect on serum transferrin receptors or reactive non-protein-bound iron. There were no differences in neonatal morbidity or in survival without major neurological abnormality at two years of age.. A 6-day course of EPO decreased the iron load in preterm infants. There was no change in reactive, non-protein bound iron plasma levels and no influence on the outcomes during early childhood. Whether the neurocognitive effects of early EPO treatment can be detectable later in childhood remained to be verified.

Topics: Erythropoietin; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Iron; Iron Overload; Male

Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 μg/L (range 825-11287 μg/L), were treated with deferiprone (L1) in a daily dose of 40-90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4-24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 μg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 μg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30-40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 μg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO).

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Deferiprone; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Granulocyte Colony-Stimulating Factor; Humans; Iron Chelating Agents; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Pyridones; Recombinant Proteins; Treatment Outcome

Patients with E/beta(0) thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long-term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18-20 mg/kg) for 24+/-9 months, hydroxyurea with sodium phenyl butyrate (n=8) and hydroxyurea with erythropoietin (n=9), each for approximately 6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1.3 g/dl steady-state increase in haemoglobin in 40% of patients, and a milder response (

Topics: Adolescent; beta-Thalassemia; Blood Transfusion; Child; Drug Therapy, Combination; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Female; Fetal Hemoglobin; Hemoglobins; Humans; Hydroxyurea; Iron Overload; Male; Phenylbutyrates; Prospective Studies; Recombinant Proteins; Treatment Outcome

Intravenous ascorbic acid administration (IVAA) could override recombinant human erythropoietin (rHuEPO) resistance in hemodialysis patients with iron overload. We investigated the hematopoietic response to IVAA in iron-overloaded hemodialysis patients. We included 36 patients whose ferritin levels were higher than 500 microg/L and who needed more than 100 U/kg/week of rHuEPO. The study included an initial phase (500 mg IVAA twice weekly was administered to all of the patients for 8 weeks) and a maintenance phase (patient groups were formed; Group 1 received IVAA 500 mg/week for 8 weeks and Group 2 received no therapy). We observed a significant increase in hematocrit and transferrin saturation and a decrease in the percentage of hypochromic red cells and ferritin levels at the end of the initial phase. The total weekly-required rHuEpo dose and rHuEpo/hemoglobin also fell significantly after the initial phase. The response remained stable in patient groups during the maintenance phase. In 6 nonresponders, the hypochromic red cells were <10%. In conclusion, IVAA effectively overrides rHuEPO resistance in iron-overloaded hemodialysis patients.

Topics: Adult; Anemia, Iron-Deficiency; Ascorbic Acid; Drug Resistance; Erythropoietin; Female; Hematopoiesis; Humans; Iron Overload; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Functional iron deficiency may develop and cause erythropoietin resistance in haemodialysis patients with iron overload. Controversy remains as to whether intravenous iron medication can improve this hyporesponsiveness due to decreased iron availability, or whether iron therapy will aggravate haemosiderosis. Intravenous administration of ascorbic acid has been shown to effectively circumvent resistant anaemia associated with iron overload in a small preliminary study. To elucidate further the possible mechanisms of this resistance, a parallel, comparative study was conducted to compare the effects of intravenous iron and ascorbate therapies in iron-overloaded haemodialysis patients.. Fifty haemodialysis patients with serum ferritin of > 500 microg/l were randomly divided into two protocols. They were further stratified into controls (Control I, n = 11) and intravenous iron group (IVFE, n = 15) in protocol I; and into controls (Control II, n = 12) and intravenous ascorbic acid group (IVAA, n = 12) in protocol II. Controls had a haematocrit of > 30% and did not receive any adjuvant therapy. IVFE and IVAA patients were hyporesponsive to erythropoietin and functionally iron deficient. Ferric saccharate (100 mg dose) was administered intravenously postdialysis on five consecutive dialysis sessions in the first 2 weeks; and ascorbic acid (300 mg dose) thrice a week for 8 weeks. Red cell and iron metabolism indices were examined before and following therapy.. Mean values of haematocrit and transferrin saturation were significantly lower, and erythropoietin dose was higher in IVFE and IVAA patients compared to controls. Intravenous iron therapy neither improved erythropoiesis nor reduced erythropoietin dose during 12 weeks. Iron metabolism indices significantly increased at 2 and 6 weeks, but decreased at 12 weeks returning to the baselines. In contrast, mean haematocrit significantly increased from 25.8+/-0.5 to 30.6+/-0.6% with a concomitant reduction of 20% in erythropoietin dose after 8 weeks of ascorbate therapy. Serum ferritin modestly fell but with no statistical significance. The enhanced erythropoiesis paralleled a rise in transferrin saturation from 27+/-3 to 48+/-6% and serum iron from 70+/-11 to 107+/-19 microg/dl (P<0.05).. Short term intravenous iron therapy cannot resolve the issue of functional iron deficiency in haemodialysis patients with iron overload. Intravenous administration of ascorbic acid not only facilitates iron release from storage sites, but also increases iron utilization in the erythron. Our study draws attention to a potential adjuvant therapy, intravenous ascorbic acid, to treat erythropoietin-hyporesponsive anaemia in iron-overloaded patients.

Topics: Anemia; Ascorbic Acid; Erythropoietin; Female; Follow-Up Studies; Humans; Injections, Intravenous; Iron; Iron Overload; Male; Middle Aged; Oxalic Acid; Recombinant Proteins; Renal Dialysis

Functional iron deficiency occurs when recombinant human erythropoietin (rHuEPO) accelerates erythropoiesis to an extent that the iron availability cannot meet the anticipated demand. Such a phenomenon will reduce the optimal response to rHuEPO. To estimate the iron needs of functional iron deficiency in hemodialysis patients on rHuEPO therapy, we utilized a mathematical method. Forty hemodialysis patients were examined in the study, and all had a baseline serum ferritin (SF) level > 100 microg/l. They were stratified into patients with a transferrin saturation (TfS) value > or = 25% (group I) and those below this value (group II). The treatment protocol consisted of rHuEPO therapy in the two groups for 6 months and iron supplement only in group II. The target hemoglobin level was 10.5 g/dl, and iron metabolism indices were analyzed prior to and following therapy. The results showed (1) in group I (n = 20) hemoglobin rose from 7.5 +/- 0.9 to 10.7 +/- 0.7 g/dl (p < 0.01) and the mean SF level declined from 1,583 +/- 997 to 968 +/- 664 mg (p < 0.01); (2) in group II (n = 20) hemoglobin also increased from 7.8 +/- 0.9 to 10.6 +/- 0.8 g/dl (p < 0.01) following iron supplement, while the SF rose from 183 +/- 70 to 326 +/- 125 mg (p < 0.01); (3) TfS was significantly elevated in group II following iron therapy (18.9 +/- 4.8 vs. 34.5 +/- 9.1%, p < 0.01), and (4) the nomogram showed a sensitivity of 80%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 83% in estimating the iron status before rHuEPO therapy. We conclude that SF levels reflect iron stores and that TfS < 25% is an index of functional iron deficiency. Iron supplementation is not necessary in patients with SF > 100 microg/l and TfS > or = 25%. It seems rational to provide intravenous iron in EPO-resistant patients with functional iron deficiency (SF > 100 microg/l, TfS < 25%). This paper illustrates the importance that accurate assessment of iron needs by a mathematical method would enhance treatment efficacy and avoid iron overload in hemodialysis patients on rHuEPO therapy.

Topics: Anemia; Anemia, Iron-Deficiency; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Mathematics; Middle Aged; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis; Sensitivity and Specificity

Fifty patients treated with chronic hemodialysis (HD) were observed for 1 year. 24 of them (48%) did not require treatment with recombinant human erythropoietin (rHuEpo) (group I) because the permanent hemoglobin (Hb) concentration was > 5.9 mmol/l (9.5 g/dl), hematocrit > 30%. The remaining 26 patients (group II) permanently or periodically required rHuEpo treatment. After 6 months of initial observation and after 6 months of clinical study we made a comparison of endogenous erythropoietin (Epo) and iron status in two groups of patients. Patients not requiring treatment with rHuEpo had statistically significant higher Epo concentration and lower iron reserves than patients on rHuEpo treatment. We did not find significant differences in Hb, albumin and creatinine between patients in both groups. Hb concentration did not correlate with the level of Epo, serum creatinine, transferrin saturation, ferritin, iron reserves and time of dialysis therapy in both groups. In both groups we found a significant negative correlation between the concentration of Epo and iron stores. Our results indicate that in patients on HD treatment, plasma Epo level appears to depend either directly or indirectly on iron status.

Topics: Adult; Aged; Anemia; Blood Cell Count; Creatinine; Erythropoietin; Female; Hemoglobins; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Serum Albumin

Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia. Compared with Tfrcfl/fl;Alb-Cre- controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre- controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre- mice, ablation of hepatocyte Tfrc in a mouse model of β-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia.

Topics: Animals; beta-Thalassemia; Erythropoietin; Hemochromatosis Protein; Hepatocytes; Hepcidins; Homeostasis; Iron; Iron Overload; Mice; Mice, Knockout; Receptors, Transferrin

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Ferroptosis; Iron Overload; Mice

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Topics: Erythropoiesis; Erythropoietin; Female; Heme; Hemoglobins; Humans; Iron; Iron Overload; Pregnancy; Proteome; Sulfur

Abnormally high serum ferritin levels have been reported during pediatric ECMO, attributed to frequent red blood cell transfusion and suggestive of iron overload. However, the utility of ferritin for diagnosing iron overload is complicated by its response as an acute-phase reactant. In this study, we aimed to assess the utility of ferritin for diagnosing ECMO-related iron overload, with secondary aims of understanding its relationship with inflammation and erythropoiesis. Ferritin was elevated in all pediatric ECMO runs (median 459 ng/ml, IQR = 327.3-694.4). While intermittent elevations in serum iron were observed, all normalized prior to decannulation. Unreported previously, erythropoietin (EPO) remained well above normative values prior to and throughout ECMO runs, despite frequent transfusion and exposure to hyperoxia. Ferritin correlated poorly with serum iron [r(80) = 0.05, p = 0.65], but correlated well with IL-6 [r(76) = 0.48, p < 0.001] and EPO [r(81) = 0.55, p < 0.001]. We suggest that serum ferritin is a poor biomarker of iron overload in ECMO patients, and that future investigation into its relationship with EPO is warranted.

Topics: Child, Preschool; Erythropoietin; Extracorporeal Membrane Oxygenation; Ferritins; Humans; Infant; Infant, Newborn; Iron; Iron Overload; Pilot Projects; Prospective Studies

Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (

Topics: Animals; Bone Morphogenetic Protein 6; Erythropoietin; Female; Gene Expression Regulation; GPI-Linked Proteins; Hemochromatosis Protein; Hepcidins; Inhibitor of Differentiation Protein 1; Iron Deficiencies; Iron Overload; Iron, Dietary; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Specificity; Promoter Regions, Genetic; Protein Domains; Recombinant Proteins; Serine Endopeptidases; Spleen

Topics: Adult; Aged; Aged, 80 and over; Chelation Therapy; Erythropoietin; Female; Hematinics; Humans; Iron Chelating Agents; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Signal Transduction; STAT5 Transcription Factor; Tumor Suppressor Proteins

Transferrin receptor 2 (TFR2) is a transmembrane protein expressed mainly in hepatocytes and in developing erythroid cells and is an important focal point in systemic iron regulation. Loss of TFR2 function results in a rare form of the iron-overload disease hereditary hemochromatosis. Although TFR2 in the liver has been shown to be important for regulating iron homeostasis in the body, TFR2's function in erythroid progenitors remains controversial. In this report, we analyzed TFR2-deficient mice in the presence or absence of iron overload to distinguish between the effects caused by a high iron load and those caused by loss of TFR2 function. Analysis of bone marrow from TFR2-deficient mice revealed a reduction in the early burst-forming unit-erythroid and an expansion of late-stage erythroblasts that was independent of iron overload. Spleens of TFR2-deficient mice displayed an increase in colony-forming unit-erythroid progenitors and in all erythroblast populations regardless of iron overload. This expansion of the erythroid compartment coincided with increased erythroferrone (ERFE) expression and serum erythropoietin (EPO) levels. Rescue of hepatic TFR2 expression normalized hepcidin expression and the total cell count of the bone marrow and spleen, but it had no effect on erythroid progenitor frequency. On the basis of these results, we propose a model of TFR2's function in murine erythropoiesis, indicating that deficiency in this receptor is associated with increased erythroid development and expression of EPO and ERFE in extrahepatic tissues independent of TFR's role in the liver.

Topics: Animals; Bone Marrow Cells; Cytokines; Erythropoiesis; Erythropoietin; Hepcidins; Iron Overload; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Receptors, Transferrin; Spleen; Stem Cells

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

Topics: Animals; Carbon Tetrachloride Poisoning; Cation Transport Proteins; Cyclohexylamines; Cytokines; Erythropoiesis; Erythropoietin; Female; Ferroptosis; Hepatocytes; Homeostasis; Iron; Iron Overload; Iron, Dietary; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Phenylenediamines; Transferrin

β-Thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly, and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (ie, using hepcidin activators like Tmprss6-antisense oligonucleotides [ASOs]) or increase erythropoiesis (by erythropoietin [EPO] administration or modulating the ability of transferrin receptor 2 [Tfr2] to control red blood cell [RBC] synthesis). Targeting Tmprss6 messenger RNA by Tmprss6-ASO was proven to be effective in improving IE and splenomegaly by inducing iron restriction. However, we postulated that combinatorial strategies might be superior to single therapies. Here, we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by β-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single-allele deletion alone, respectively, exacerbated or did not improve splenomegaly in β-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, the combination of Tmprss6-ASO + EPO or Tmprss6-ASO + Tfr2 single-allele deletion produced significantly higher hemoglobin levels and reduced splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating IE and anemia in β-thalassemia and could provide guidance to translate some of these approaches into viable therapies.

Topics: Animals; beta-Thalassemia; Cells, Cultured; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Genetic Therapy; Iron; Iron Overload; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oligonucleotides, Antisense; Receptors, Transferrin; Serine Endopeptidases

Expression of hepcidin, the hormone regulating iron homeostasis, is increased by iron overload and decreased by accelerated erythropoiesis or iron deficiency. The purpose of the study was to examine the effect of these stimuli, either alone or in combination, on the main signaling pathway controlling hepcidin biosynthesis in the liver, and on the expression of splenic modulators of hepcidin biosynthesis. Liver phosphorylated SMAD 1 and 5 proteins were determined by immunoblotting in male mice treated with iron dextran, kept on an iron deficient diet, or administered recombinant erythropoietin for four consecutive days. Administration of iron increased liver phosphorylated SMAD protein content and hepcidin mRNA content; subsequent administration of erythropoietin significantly decreased both the iron-induced phosphorylated SMAD proteins and hepcidin mRNA. These results are in agreement with the recent observation that erythroferrone binds and inactivates the BMP6 protein. Administration of erythropoietin substantially increased the amount of erythroferrone and transferrin receptor 2 proteins in the spleen; pretreatment with iron did not influence the erythropoietin-induced content of these proteins. Erythropoietin-treated iron-deficient mice displayed smaller spleen size in comparison with erythropoietin-treated mice kept on a control diet. While the erythropoietin-induced increase in splenic erythroferrone protein content was not significantly affected by iron deficiency, the content of transferrin receptor 2 protein was lower in the spleens of erythropoietin-treated mice kept on iron-deficient diet, suggesting posttranscriptional regulation of transferrin receptor 2. Interestingly, iron deficiency and erythropoietin administration had additive effect on hepcidin gene downregulation in the liver. In mice subjected both to iron deficiency and erythropoietin administration, the decrease of hepcidin expression was much more pronounced than the decrease in phosphorylated SMAD protein content or the decrease in the expression of the SMAD target genes Id1 and Smad7. These results suggest the existence of another, SMAD-independent pathway of hepcidin gene downregulation.

Topics: Animals; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Hepcidins; Iron; Iron Deficiencies; Iron Overload; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Smad Proteins

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Transfusion; Erythropoietin; Female; Humans; Iron; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Proportional Hazards Models

The role of hepcidin in iron homeostasis in preeclamptic pregnant women is unclear. To test the hypothesis that increased serum iron in women diagnosed with preeclampsia results from decreased production of hepcidin, we performed an observational case-control study in which serum hepcidin concentration, dietary iron intake, hematological indices, iron status, liver function, and inflammatory markers in 18 preeclamptic women and 18 healthy normotensive pregnant women of similar age range were evaluated. Iron intake was established via a food frequency questionnaire, whereas hematological indices, iron status, liver function, and inflammatory markers were assessed using standard protocols. Hematocrit was significantly higher (P = .031) in the preeclamptic group compared with the control, whereas erythropoietin level was significantly lower (P = .003). The pronounced inflammatory status of preeclamptic women was confirmed by significantly higher concentrations of interleukin-6 (P = .001), tumor necrosis factor-α (P < .001), and ferritin (P < .001). Nonetheless, the preeclamptic group exhibited significantly higher serum iron (P = .012) and transferrin saturation (P = .006), and these alterations were accompanied by lower hepcidin levels (P = .047). No significant correlations between hepcidin concentration and iron status parameters were observed in either group. However, a positive and significant correlation between hepcidin concentration and C-reactive protein was observed in the preeclamptic group (r = 0.474; P = .047). We conclude that high serum iron in preeclamptic women is likely caused by low production of hepcidin, thus supporting the hypothesis originally stated.

Topics: Adolescent; Adult; C-Reactive Protein; Case-Control Studies; Diet Surveys; Erythropoietin; Female; Ferritins; Hematocrit; Hepcidins; Homeostasis; Humans; Inflammation; Interleukin-6; Iron; Iron Overload; Iron, Dietary; Nutritional Status; Pre-Eclampsia; Pregnancy; Transferrin; Tumor Necrosis Factor-alpha; Young Adult

β-thalassemias are genetic disorders characterized by anemia, ineffective erythropoiesis, and iron overload. Current treatment of severe cases is based on blood transfusion and iron chelation or allogeneic bone marrow (BM) transplantation. Novel approaches are explored for nontransfusion-dependent patients (thalassemia intermedia) who develop anemia and iron overload. Here, we investigated the erythropoietin (EPO) receptor partner, transferrin receptor 2 (TFR2), as a novel potential therapeutic target. We generated a murine model of thalassemia intermedia specifically lacking BM

Topics: Anemia; Animals; beta-Thalassemia; Cells, Cultured; Disease Models, Animal; Erythroid Cells; Erythropoiesis; Erythropoietin; Female; Gene Deletion; Genetic Therapy; Iron Overload; Male; Mice, Inbred C57BL; Receptors, Transferrin

Iron is an essential mineral for oxygen delivery and for a variety of enzymatic activities, but excessive iron results in oxidative cytotoxicity. Because iron is primarily used in red blood cells, defective erythropoiesis caused by loss of the erythroid growth factor erythropoietin (Epo) elevates iron storage levels in serum and tissues. Here, we investigated the effects of iron in a mouse model of Epo-deficiency anemia, in which serum iron concentration was significantly elevated. We found that intraperitoneal injection of iron-dextran caused severe iron deposition in renal interstitial fibroblasts, the site of Epo production. Iron overload induced by either intraperitoneal injection or feeding decreased activity of endogenous Epo gene expression by reducing levels of hypoxia-inducible transcription factor 2α (HIF2α), the major transcriptional activator of the Epo gene. Administration of an iron-deficient diet to the anemic mice reduced serum iron to normal concentration and enhanced the ability of renal Epo production. These results demonstrate that iron overload due to Epo deficiency attenuates endogenous Epo gene expression in the kidneys. Thus, iron suppresses Epo production by reducing HIF2α concentration in renal interstitial fibroblasts.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Erythropoietin; Fibroblasts; Iron; Iron Overload; Kidney; Male; Mice; Mice, Inbred C57BL

Iron overload is frequently reported in haemodialysis (HD) patients particularly those with chronic hepatitis C virus (HCV) infection. Soluble haemojuvelin (sHJV) has recently emerged as one of the significant regulators of iron homeostasis and hepcidin expression. The aim of the present study was to evaluate the potential associations of sHJV and hepcidin with inflammation, iron parameters and erythropoietin requirement in prevalent HD patients with HCV.. Serum sHJV and hepcidin were measured in 60 prevalent HD patients with [group I (n = 30)] and without [group II (n = 30)] HCV, and controls (n = 30) by enzyme-linked immunosorbent assay. Parameters related to anaemia, iron metabolism, inflammation, sHJV and hepcidin were measured.. Serum hepcidin in HCV positive versus negative groups was 89.40 ± 46.08 ng/mL and 224.1 ± 72.36 ng/mL, P = 0.000, respectively, while sHJV was 245 ± 1.338 ng/mL and 254 ± 0.762 ng/mL, P = 0.147, respectively in positive versus negative patients. In group I, hepcidin correlated with serum ferritin (r = -0.512 P = 0.005) and transferrin saturation (TSAT%) (r = 0.572, P = 0.000) and sHJV correlated with ferritin (r = 0.40, P 0.000), TSAT% (r = 0.450, P = 0.002) and a significant correlation also existed between sHJV and hepcidin (r = -0.259, P = 0.045). In the regression analysis, ferritin and TSAT% were able to predict sHJV; (standardized β = 0.52, P 0.001) and (standardized β = 0.48, P 0.010). Ferritin and sHJV were also able to predict hepcidin (standardized β = 0.627, P = 0.006) and (standardized β = 0.300, P = 0.007) in group I.. Soluble haemojuvelin levels seem to be associated with iron overload parameters and hepcidin levels in HCV positive HD patients.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Erythropoietin; Female; Ferritins; GPI-Linked Proteins; Hematinics; Hemochromatosis Protein; Hepatitis C, Chronic; Hepcidins; Humans; Iron; Iron Overload; Male; Middle Aged; Prevalence; Recombinant Proteins; Renal Dialysis

The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants.. The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs).. This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml.. Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia.. Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

Topics: Birth Weight; Bronchopulmonary Dysplasia; C-Reactive Protein; Ductus Arteriosus, Patent; Erythropoietin; Female; Ferritins; Gestational Age; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Iron Metabolism Disorders; Iron Overload; Japan; Logistic Models; Male; Multivariate Analysis; Prospective Studies; Sepsis

Matriptase-2 (TMPRSS6) is an important negative regulator of hepcidin expression; however, the effects of iron overload or accelerated erythropoiesis on liver TMPRSS6 protein content in vivo are largely unknown. We determined TMPRSS6 protein content in plasma membrane-enriched fractions of liver homogenates by immunoblotting, using a commercial antibody raised against the catalytic domain of TMPRSS6. Plasma membrane-enriched fractions were obtained by centrifugation at 3000 g and washing. TMPRSS6 was detected in the 3000 g fraction as a 120 kDa full-length protein in both mice and rats. Feeding of iron-deficient diet as well as erythropoietin treatment increased TMPRSS6 protein content in rats and mice by a posttranscriptional mechanism; the increase in TMPRSS6 protein by erythropoietin was also observed in Bmp6-mutant mice. Administration of high doses of iron to mice (200, 350 and 700 mg/kg) decreased TMPRSS6 protein content. Hemojuvelin was detected in the plasma membrane-enriched fractions of control animals as a full length protein of approximately 52 kDa; in iron deficient animals, the full length protein was partially cleaved at the N-terminus, resulting in an additional weak band of approximately 47 kDa. In livers from hemojuvelin-mutant mice, TMPRSS6 protein content was strongly decreased, suggesting that intact hemojuvelin is necessary for stable TMPRSS6 expression in the membrane. Overall, the results demonstrate posttranscriptional regulation of liver TMPRSS6 protein by iron status and erythropoietin administration, and provide support for the interaction of TMPRSS6 and hemojuvelin proteins in vivo.

Topics: Anemia, Iron-Deficiency; Animals; Bone Morphogenetic Protein 6; Disease Models, Animal; Erythropoietin; Female; GPI-Linked Proteins; Hemochromatosis Protein; Iron; Iron Deficiencies; Iron Overload; Liver; Male; Membrane Proteins; Mice; Mice, Knockout; Mutation; Rats; Serine Endopeptidases; Sodium-Potassium-Exchanging ATPase

Increasing numbers of reports have described hematopoietic improvement after iron chelation therapy in iron-overloaded patients. These observations indicate that excess iron could affect hematopoiesis unfavorably. To investigate how excess iron affects hematopoiesis in vivo, we generated iron-overloaded mice and examined hematopoietic parameters in these mice.. We generated iron-overloaded mice by injecting 200 mg of iron dextran into C57BL/6J mice, and immature hematopoietic cells in the bone marrow were evaluated by flow cytometric analyses, colony-forming assays, and bone marrow transplantation analyses. We also examined changes in molecular profiles of the hematopoietic microenvironment.. Iron-overloaded (IO) mice did not show significant defects in the hematopoietic data of the peripheral blood. Myeloid progenitor cells in the bone marrow were increased in IO mice, but the number and function of the erythroid progenitors and hematopoietic stem cells were not significantly affected. However, bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution, which indicates that excess iron impacts the hematopoietic microenvironment negatively. Microarray and quantitative RT-PCR analyses on the bone marrow stromal cells demonstrated remarkably reduced expression of CXCL12, VCAM-1, Kit-ligand, and IGF-1 in the iron-overloaded mice. In addition, erythropoietin and thrombopoietin levels were significantly suppressed, and increased oxidative stress was observed in the IO bone marrow and liver. Consequently, our findings indicate that excess iron can damage bone marrow stromal cells and other vital organs, disrupting hematopoiesis presumably by increased oxidative stress.

Topics: Animals; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cellular Microenvironment; Chemokine CXCL12; Erythropoietin; Gene Expression; Insulin-Like Growth Factor I; Iron Overload; Iron-Dextran Complex; Liver; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Microarray Analysis; Oxidative Stress; Stem Cell Factor; Thrombopoietin; Vascular Cell Adhesion Molecule-1

Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in Hbb(th3/+) mice with thalassemia intermedia, where it contributes to the suppression of hepcidin and the systemic iron overload characteristic of this disease.

Topics: Anemia; Animals; beta-Thalassemia; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoiesis; Erythropoietin; Gene Expression Profiling; Hemoglobins; Hemorrhage; Hepcidins; Hormones; Iron; Iron Overload; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

This study was aimed to investigate the changes of erythropoietin (EPO), hemoglobin(Hb) and recombinant EPO (rEPO) levels in MDS patients receiving iron chelation therapy, and to explore the relationship between EPO and serum ferritin(SF). A total of 172 MDS patients and 30 healthy controls were studied. The levels of SF, EPO, serum iron (SI), total iron binding capacity (TIBC), C-reaction protein (CRP) and Hb were measured respectively, the level of SF was adjusted according to the changes of CRP. Among them, there were 34 cases of low-risk (SF>1 000 mg/L) receiving deferoxamine therapy, whose changes of SF, EPO, SI, TIBC, Hb levels were detected and compared before and after treatment. Besides, the difference in the incidence of EPO resistance in iron overload group and non-iron overload group was assessed before and after therapy, and 58 cases of low-risk and EPO<1 000 U/L MDS patients were given rEPO therapy. The results showed that the level of EPO in non-iron overload group was higher than that in the normal control group (997.44 ± 473.48 vs 467.27 ± 238.49, P < 0.05). Obviously, the level of EPO in iron overload group was higher than that in non-iron overload group and control group (3257.59 ± 697.19 vs 997.44 ± 473.48, P = 0.012, 3257.59 ± 697.19 vs 467.27 ± 238.49, P = 0.002). Otherwise, the incidence of EPO resistance in iron overload group was higher than that in non-iron overload group (18/35 vs 2/23, P = 0.001), and the level of EPO and SF was positively related to each other in iron overload group (r = 0.310,P = 0.036). After receiving iron chelation therapy, the levels of SF, SI, TIBC and EPO in iron overload group were significantly lower than that before therapy (3942.38 ± 641.82 vs 2266.35 ± 367.31, P = 0.028;48.61 ± 10.65 vs 28.52 ± 12.61, P = 0.034;59.84 ± 12.62 vs 33.76 ± 15.43, P = 0.045;3808.01 ± 750.22 vs 1954.78 ± 473.18, P = 0.042). Moreover, the level of Hb increased (35 ± 18 vs 57 ± 21, P = 0.046) and the EPO resistance in some patients was decreased. It is concluded that iron chelation therapy can improve the efficacy of EPO to alleviate EPO resistance in patients wtih anemic MDS, decrease the pathological level of EPO, enhance Hb levels and reduce the dependency on blood transfusion.

Topics: Adult; Aged; C-Reactive Protein; Case-Control Studies; Chelation Therapy; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

To analyze the interconnection between erythropoiesis and iron metabolism, one of the issues raised in this study was to know iron bioavailability under physiopathological conditions. Our aim was to understand the functional axis response composed of erythropoietin (Epo)-hepcidin-ferroportin (FPN), when 2 dysfunctional states coexist, using an animal model of iron overload followed by hypoxia. FPN and prohepcidin were assessed by immunohistochemistry using rabbit anti-mouse FPN polyclonal and prohepcidin monoclonal antibodies. Goat-labeled polymer - horseradish peroxidase anti-rabbit EnVision + System (DAB) was used as the secondary antibody. Epo levels were measured by ELISA. Tissue iron was studied by Prussian blue iron staining. Erythropoietic response was assessed using conventional hematological tests. Iron overload increased prohepcidin that remained high in hypoxia, coexisting with high levels of Epo in hypoxia, with or without iron overload. In hypoxia, FPN was clearly evident in reticuloendothelial macrophages, more than in hypoxia with iron overload. Interestingly, duodenal FPN was clearly identified on the basolateral membrane in hypoxia, with or without iron overload. Our data indicate that 2 signals could induce the cell-specific response as follows: (i) iron signal, induced prohepcidin, which reduced reticuloendothelial FPN and reduced iron availability; and (ii) hypoxia signal, stimulated Epo, which affected iron absorption by stabilizing duodenal FPN and allowed iron supply to erythropoiesis independently of store size.

Topics: Animals; Biological Availability; Cation Transport Proteins; Duodenum; Enterocytes; Erythropoiesis; Erythropoietin; Female; Hepcidins; Hypoxia; Iron; Iron Overload; Macrophages; Mice; Spleen

Salmonella, a ubiquitous Gram-negative intracellular bacterium, is a food borne pathogen that infects a broad range of hosts. Infection with Salmonella Typhimurium in mice is a broadly recognized experimental model resembling typhoid fever in humans. Using a N-ethyl-N-nitrosurea (ENU) mutagenesis recessive screen, we report the identification of Ity16 (Immunity to Typhimurium locus 16), a locus responsible for increased susceptibility to infection. The position of Ity16 was refined on chromosome 8 and a nonsense mutation was identified in the ankyrin 1 (Ank1) gene. ANK1 plays an important role in the formation and stabilization of the red cell cytoskeleton. The Ank1(Ity16/Ity16) mutation causes severe hemolytic anemia in uninfected mice resulting in splenomegaly, hyperbilirubinemia, jaundice, extramedullary erythropoiesis and iron overload in liver and kidneys. Ank1(Ity16/Ity16) mutant mice demonstrated low levels of hepcidin (Hamp) expression and significant increases in the expression of the growth differentiation factor 15 (Gdf15), erythropoietin (Epo) and heme oxygenase 1 (Hmox1) exacerbating extramedullary erythropoiesis, tissue iron deposition and splenomegaly. As the infection progresses in Ank1(Ity16/Ity16), the anemia worsens and bacterial load were high in liver and kidneys compared to wild type mice. Heterozygous Ank1(+/Ity16) mice were also more susceptible to Salmonella infection although to a lesser extent than Ank1(Ity16/Ity16) and they did not inherently present anemia and splenomegaly. During infection, iron accumulated in the kidneys of Ank1(+/Ity16) mice where bacterial loads were high compared to littermate controls. The critical role of HAMP in the host response to Salmonella infection was validated by showing increased susceptibility to infection in Hamp-deficient mice and significant survival benefits in Ank1(+/Ity16) heterozygous mice treated with HAMP peptide. This study illustrates that the regulation of Hamp and iron balance are crucial in the host response to Salmonella infection in Ank1 mutants.

Topics: Anemia, Hemolytic; Animals; Ankyrins; Antimicrobial Cationic Peptides; Codon, Nonsense; Erythrocytes; Erythropoietin; Ethylnitrosourea; Gene Expression; Genetic Predisposition to Disease; Growth Differentiation Factor 15; Heme Oxygenase-1; Hepcidins; Heterozygote; Homozygote; Iron; Iron Overload; Liver; Membrane Proteins; Mice; Salmonella Infections; Salmonella typhimurium; Survival Analysis

Erythropoiesis in long-term hemodialyzed (LTH) patients is supported by erythropoietin (rHuEpo) and intravenous (IV) iron. This treatment may end up in iron overload (IO) in major organs. We studied such patients for the parameters of IO in the serum and in major organs.. Patients were treated with rHuEpo (6-8 x 10(3) units × 1-3/wk) and IV 100 mg ferric saccharate.. Of 115 patients, 21 had serum ferritin (SF) > 1000 ng/mL. This group was further analyzed. Their SF and transferrin saturation (TSAT) were 2688 ± 1489 ng/mL and 54.2 ± 32.7%, respectively (vs. 125-360 ng/mL and 20-50% in normal controls). Serum hepcidin was 60.1 ± 29.5 nm (vs. 10.61 ± 6.44 nm in controls) (P < 0.001). Nineteen patients had increased malonyldialdehyde, a product of lipid peroxidation, indicating oxidative stress. T2* MRI disclosed in 19 of 21 patients moderate to severe IO in the liver and spleen, in three of eight patients in the pancreas, but in no patient in the heart. After stopping IV iron for a mean of 12 months, while continuing rHuEpo, the mean SF decreased in 11 patients to 1682 ng/mL and the mean TSAT decreased to 28%, whereas hemoglobin did not change indicating that tissue iron was utilized.. High SF correlates with IO in the liver and spleen, but not in the heart.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Ferritins; Humans; Iron; Iron Overload; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Pancreas; Renal Dialysis; Spleen

Hemojuvelin (Hjv) is a key component of the signaling cascade that regulates liver hepcidin (Hamp) expression. The purpose of this study was to determine Hjv protein levels in mice and rats subjected to iron overload and iron deficiency.. C57BL/6 mice were injected with iron (200 mg/kg); iron deficiency was induced by feeding of an iron-deficient diet, or by repeated phlebotomies. Erythropoietin (EPO)-treated mice were administered recombinant EPO at 50 U/mouse. Wistar rats were injected with iron (1200 mg/kg), or fed an iron-deficient diet. Hjv protein was determined by immunoblotting, liver samples from Hjv-/- mice were used as negative controls. Mouse plasma Hjv content was determined by a commercial ELISA kit.. Liver crude membrane fraction from both mice and rats displayed a major Hjv-specific band at 35 kDa, and a weaker band of 20 kDa. In mice, the intensity of these bands was not changed following iron injection, repeated bleeding, low iron diet or EPO administration. No change in liver crude membrane Hjv protein was observed in iron-treated or iron-deficient rats. ELISA assay for mouse plasma Hjv did not show significant difference between Hjv+/+ and Hjv-/- mice. Liver Hamp mRNA, Bmp6 mRNA and Id1 mRNA displayed the expected response to iron overload and iron deficiency. EPO treatment decreased Id1 mRNA, suggesting possible participation of the bone morphogenetic protein pathway in EPO-mediated downregulation of Hamp mRNA.. Since no differences between Hjv protein levels were found following various experimental manipulations of body iron status, the results indicate that, in vivo, substantial changes in Hamp mRNA can occur without noticeable changes of membrane hemojuvelin content. Therefore, modulation of hemojuvelin protein content apparently does not represent the limiting step in the control of Hamp gene expression.

Topics: Animals; Bone Morphogenetic Proteins; Erythropoietin; GPI-Linked Proteins; Hemochromatosis Protein; Iron; Iron Deficiencies; Iron Overload; Iron, Dietary; Liver; Membrane Proteins; Mice; Mice, Inbred C57BL; Rats; Rats, Wistar; Signal Transduction

Transcription of the hepcidin (Hamp) gene is controlled by iron stores and the rate of erythropoiesis. Functional hierarchy between these two stimuli has not yet been completely established. It is also not known whether the erythropoiesis-related downregulation of Hamp expression utilises the bone morphogenetic protein/hemojuvelin (Bmp/Hjv) pathway. Hemojuvelin-mutant (Hjv-/-) mice treated with erythropoietin (EPO) at 50IU/mouse/day for three days displayed marked decrease in Hamp mRNA, demonstrating that hemojuvelin is not an indispensable component in EPO-induced Hamp gene downregulation. Irradiation of Hjv-/- mice prevented the EPO-induced decrease of Hamp mRNA, highlighting the role of erythropoiesis in Hamp gene regulation by EPO. After a single injection of EPO, Hamp mRNA levels were not significantly changed at 6h, but decreased at 10 and 24h. Chronic bleeding decreased hepatic Bmp6 mRNA levels; however, repeated EPO treatment did not change Bmp6 mRNA, suggesting that the erythropoietic regulator(s) act independently of the Bmp/Hjv pathway. Pretreatment of C57BL/6 mice with iron (5mg/mouse) almost completely inhibited the EPO-induced decrease of Hamp mRNA. This result suggests that administration of EPO to patients with transfusional iron overload is probably not associated with the risk of additional absorption of substantial amounts of iron from the diet.

Topics: Animals; Antimicrobial Cationic Peptides; Bone Morphogenetic Protein 6; Down-Regulation; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Gene Expression Regulation; GPI-Linked Proteins; Hemochromatosis Protein; Hepcidins; Iron Overload; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Polysaccharides; Recombinant Proteins; RNA, Messenger; Transcription, Genetic

Topics: Administration, Oral; Anemia, Iron-Deficiency; Erythropoietin; Ferric Compounds; Humans; Injections, Intramuscular; Injections, Intravenous; Iron; Iron Overload; Maltose; Recombinant Proteins; Renal Dialysis

Accumulating data suggest potential clinical relevant relationships between hepcidin-25 levels, iron stores, erythropoiesis effectiveness, and epoetin dose. The immunometric methods and mass spectroscopy are currently used to measure hepcidin-25, but no standard exists, and values, although similar in trends, differ in absolute value.. To investigate hepcidin levels and their relationship with peripheral iron indices, inflammation, and anemia therapy in patients on hemodialysis (HD).. A cross-sectional study in 78 patients from a single HD center. Hepcidin-25 was measured with enzyme-linked immunosorbent assay (ELISA), using a commercial kit (Bachem, UK).. Hepcidin-25 levels were similar to those previously reported in studies using the same antibody (median 113 [95% CI; 107-122 ng/mL]) and significant but weak correlations of hepcidin with transferrin (R2=0.06; p<0.04) and ferritin (R2=0.09; p<0.01) were found. A model of multiple regression analysis explained 57% of variation along hepcidin quartiles. Lower hepcidin levels were associated with higher transferrin levels (odds ratio 1.05 [1.01-1.09]), bigger iron doses (odds ratio 1.09 [1.02-1.15]), and an increased darbepoetin resistance index (odds ratio 4.3E+15 [11.15-1.6E+30]). An elevated serum C reactive protein was associated with increased hepcidin levels (odds ratio 0.70 [0.49-0.99]), while a higher ultrafiltration volume (odds ratio 4.30 [1.28-14.51]) and the male sex (odds ratio 0.04 [0.00-0.80]) were related to lower hepcidin levels.. Cohort number and composition. Hepcidin-25 ELISA assay.. A low hepcidin level in hemodialysis patients with high epoetin resistance index could be a useful marker of iron-restricted erythropoiesis, but confirmation by a therapeutical trial is necessary.

Topics: Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; C-Reactive Protein; Cross-Sectional Studies; Darbepoetin alfa; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Erythropoiesis; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Iron; Iron Deficiencies; Iron Overload; Male; Middle Aged; Renal Dialysis; Transferrin

Hepcidin, a liver-derived peptide induced by iron overload and inflammation, is a major regulator of iron homeostasis. As hepcidin decreases gastrointestinal iron absorption and recirculation from monocytes, over-expression is associated with the development of anaemia.. We studied the associations between circulating hepcidin levels and various laboratory parameters related to anaemia and/or inflammation in 20 patients on chronic haemodialysis. Furthermore, we determined the impact of dialysis and iron and/or erythropoietin (rhEpo) supplementation therapy on hepcidin serum concentrations. The patients were withheld from iron and rhEpo for 2 weeks before study entry. Hepcidin was measured by liquid chromatography-mass spectrometry (LC-MS/MS); serum iron and haematological parameters, cytokines and pro-hepcidin by commercially available enzyme-linked immunosorbent assays (ELISA) or standard automated methods.. While hepcidin levels at baseline were not correlated to pro-hepcidin, interleukin-6 or transforming growth factor-beta concentrations, we found significant associations with reticulocyte count (r = -0.55; P = 0.015), serum iron (r = 0.7; P = 0.004) and ferritin levels (r = 0.63; P = 0.004) and transferrin saturation (r = 0.69, P = 0.001). Dialysis using either a high or a low flux biocompatible dialyser resulted in a significant decrease of hepcidin concentrations, which returned to pre-dialysis values before the next dialysis session. When studying the effects of anaemia treatment, we observed a significant reduction of hepcidin levels following administration of rhEpo but not iron.. Hepcidin levels in stable haemodialysis patients appear to reflect systemic iron load, but not inflammation. Due to the negative association between reticulocyte counts and hepcidin, the reduction of circulating hepcidin concentrations by dialysis and/or rhEpo treatment may positively affect erythropoiesis.

Topics: Aged; Anemia; Antimicrobial Cationic Peptides; Cross-Sectional Studies; Erythropoietin; Female; Hepcidins; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Deferasirox is a new iron chelator approved recently for chelation therapy in iron-overloaded patients. It is considered safe and efficacious in most patients, but has not been tested formally in patients with end-stage renal disease. We report a case of a patient with end-stage renal disease secondary to sickle cell nephropathy who developed recurrent symptomatic hypocalcemia while on therapy and later reexposure with this medication for iron overload from long-term blood transfusions. This is the first case report of this complication with deferasirox therapy in a patient with end-stage renal disease.

Topics: Adult; Anemia, Sickle Cell; Benzoates; Deferasirox; Erythropoietin; Female; Humans; Hypertension; Hypocalcemia; Iron Chelating Agents; Iron Overload; Kidney Failure, Chronic; Peritoneal Dialysis; Transfusion Reaction; Triazoles

Body iron stores should be assessed regularly and accurately during erythropoietin (r-HuEPO) replacement therapy. To evaluate the accuracy of the current tests, transferrin saturation (TSAT) and serum ferritin levels, in assessing and monitoring body iron stores, we studied 24 regular hemodialysis patients (19 males, mean age 47+/-18 years, and mean duration on hemodialysis 15+/-13 months) on regular erythropoietin therapy over a 12 month period. Patients were classified as having normal, deficient, indeterminate, or overload status depending on the values of TSAT and serum ferritin. Using TSAT and serum ferritin, iron status could be determined in 16 (67%) patients only; 12 (50%) had adequate (or normal) iron status, 3 (12.5%) had iron deficiency, and one (4.2%) had iron overload. In the remaining 8 patients, iron status was indeterminate; six patients had high serum ferritin with low TSAT (functional iron deficiency), and two patients had high TSAT values and low serum ferritin. Serum ferritin alone had very low specificity in diagnosing iron overload. In conclusion, when used together, TSAT and serum ferritin have a low sensitivity for diagnosing the iron status of CKD patients on HD. When TSAT and serum ferritin values diverge, they become unreliable in guiding iron therapy, and this set of findings generally indicates functional iron deficiency. There is a clear need to use the newer indices, like reticulocyte hemoglobin concentration and percentage of hypochromic red cells, which are more sensitive. This is likely to make the diagnosis of iron status more accurate and may reduce the requirements and frequency of iron and r-HuEPO administration.

Topics: Adult; Anemia, Hypochromic; Biomarkers; Erythropoietin; Female; Ferric Compounds; Ferritins; Hematinics; Hematocrit; Hemoglobins; Humans; Iron; Iron Deficiencies; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis; Saudi Arabia; Sensitivity and Specificity; Time Factors; Transferrin; Treatment Outcome

Topics: Anemia; Clinical Protocols; Drug Monitoring; Erythropoietin; Health Services Needs and Demand; Hemoglobins; Humans; Iron Overload; Kidney Failure, Chronic; Outcome Assessment, Health Care; Philadelphia; Practice Guidelines as Topic; Quality Assurance, Health Care; Recombinant Proteins; Renal Dialysis

Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal enterocytes and iron transfer from the transferrin receptor endosomal cycle into the cytosol in erythroid cells. Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth and defective intestinal iron use and erythroid iron use. We report the hematologic phenotype of a child, compound heterozygote for 2 DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload. The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C). A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by Western blot analysis. The proband required blood transfusions until erythropoietin treatment allowed transfusion independence when hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL) were achieved. Hematologic data of this patient at birth and in the first years of life strengthen the essential role of DMT1 in erythropoiesis. The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by the up-regulation of other pathways of iron use.

Topics: Anemia; Cation Transport Proteins; Child, Preschool; Erythropoiesis; Erythropoietin; Heterozygote; Humans; Iron Overload; Iron-Binding Proteins; Mutation; Point Mutation; Sequence Deletion

Iron overload presenting as exacerbation of hepatic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation has not been previously described. We report 6 patients with established hepatic GVHD in whom iron overload (median serum ferritin, 7231 mug/dL; median transferrin saturation, 77%) resulting from a lifetime median of 20 units of packed red blood cell transfusions was manifested by worsening of liver function. Liver biopsies performed in 4 patients confirmed severe iron overload and also hepatic GVHD. Analysis for the C282Y and H63D hemochromatosis gene mutation was negative for the homozygous state in all 6 patients. Erythropoietin-assisted phlebotomy resulted in normalization of liver function at a median of 7 months and of serum ferritin at a median of 11 months. Immunosuppressive therapy was successfully tapered in all 4 patients who completed the phlebotomy program, and this supported the impression that iron overload, rather than GVHD, was the principal cause of liver dysfunction. At a median follow-up of 50 months (range, 18-76 months) from the transplantation and 25 months (range, 5-36 months) from ferritin normalization, all 4 patients require maintenance phlebotomy. We conclude that iron overload can mimic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and that maintenance phlebotomy is necessary after successful iron-reduction therapy.

Topics: Adult; Biopsy; Bone Marrow Transplantation; Combined Modality Therapy; Darbepoetin alfa; Diagnosis, Differential; Disease Progression; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Ferritins; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Iron Overload; Liver Diseases; Male; Middle Aged; Pancreatic Diseases; Phlebotomy; Prospective Studies; Recombinant Proteins; Skin Diseases; Transferrin; Transplantation Conditioning; Transplantation, Homologous

We report the efficacy, tolerability and cost of erythocytoapheresis plus recombinant human erythropoietin (rHuEPO) in three patients with severe hereditary hemochromatosis (HH). Results indicate that this regimen could be a valid therapeutic alternative in complicated HH patients. Its cost, however, limits its use to patients whose clinical conditions prevent a proper phlebotomy regimen.

Topics: Adult; Combined Modality Therapy; Cytapheresis; Erythropoietin; Hemochromatosis; Hemochromatosis Protein; Histocompatibility Antigens Class I; Humans; Iron Overload; Liver Cirrhosis; Male; Membrane Proteins; Middle Aged; Recombinant Proteins; Treatment Outcome

The guideline committee of Japanese Society for Dialysis Therapy (JSDT), chaired by Professor F. Gejyo of Niigata University, now publishes an original Japanese guideline entitled 'Guidelines for Renal Anemia in Chronic Hemodialysis Patients'. It includes the re-evaluation of the usage of recombinant human erythropoietin (rHuEPO) with the medical and economical arguments regarding the prognosis and the quality of life of Japanese hemodialysis patients. This guideline consists of 7 sections. The first section comprises the general definition and the differential diagnosis of anemia. The hemoglobin (Hb) level of the Japanese population seemed to be low when compared with that of the European and American populations. The second section describes the target Hb level in hemodialysis patients. Multivariate analysis of the data that were collected from dialysis institutions throughout the country showed that an Hb level of 10-11 g/dL (Ht level 30-33%) at the first dialysis session in a week is the ideal range for chronic hemodialysis patients in terms of the 3-5 year survival rate. The supine position at blood sampling and the sampling timing at the first dialysis session in a week might affect the lower setting of target Hb hematocrit (Ht), compared to that of European and American guidelines. However, we particularly recommended that an Hb level of 11-12 g/dL (Ht level from 33 to 36%) at the first dialysis session in a week is desirable in relatively young patients. In the third section, the markers of iron deficiency are discussed. The Transferin saturation test (TSAT) and serum ferritin were emphasized as the standard markers. The routes of administration of rHuEPO and its dosages are written in the fourth section. The subcutaneous route was associated with the occurrence of secondary red cell aplasia due to anti-rHuEPO antibodies; however, secondary red cell aplasia was seldom observed in the venous injection. From this fact we recommend venous injection for chronic hemodialysis patients. We advocate an initial dosage of 1500 U three times per week. The fifth section deals with the factors refractory to treatment with rHuEPO. If the patient shows an inadequate response to the usage of 9000 U per week, this condition defines the inadequate response to rHuEPO in Japan. Blood transfusion must be avoided where possible. The reasons for this and the adverse effects are interpreted in section six. In the final section, the adverse effects of rHuEPO are listed. A

Topics: Anemia; Anemia, Iron-Deficiency; Blood Transfusion; Diagnosis, Differential; Erythropoietin; Hematocrit; Humans; Iron Overload; Japan; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Societies, Medical; Treatment Failure

Recent report demonstrates that inadequate iron mobilization and defective iron utilization may cause recombinant erythropoieitin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. The effect of intravenous ascorbic acid (IVAA) in HD patients selected on the basis of iron overload and EPO resistance also has been proven. However, it is uncertain whether IVAA still works in diabetic ESRD patients with hyperferritinemia. Therefore, the aim of this study focusing on diabetic ESRD patients was to analyze the potential effect of low dose IVAA on improvement of anemia and erythropoiesis-related parameters when compared with control period.. This study consisted of 22 chronic hemodialysis patients with type II diabetes in a single dialysis unit. In studies of this type, all eligible patients are followed up, but the primary comparison is still between different sequentially treatment including control period and post-IVAA period in same patients. IVAA patients received ascorbic acid, 100 mg each administered intravenously three times per week for eight weeks of treatment and four months of post-treatment follow-up.. The demographic characteristics of 22 diabetic uremic patients show that mean age is 63.6 +/- 10.2 years old. The ratio of sex (M/F) = 10/12. Mean duration of HD is 46.7 +/- 33.2 months. As for the urea kinetic study between these two periods including KT/V, nPCR, and URR, there is no significantly different. As for anemia-related parameters, Hb and Hct increased significantly in post-IVAA period after 3 months compared with control period, while MCV did not increase significantly. Serum ferritin significantly decreased at study completion. The same situation is for iron. As for TS, it significantly increased at one month and further markedly increased at subsequent three months.. This study has demonstrated that short-term low dose IVAA therapy can facilitate iron release from reticuloendothelial system but also increase iron utilization in diabetic hemodialysis patients with iron overload. Therefore, IVAA is a potential adjuvant therapy to treat erythropoeitin-hyporesponsive anemia in iron-overloaded patients.

Topics: Aged; Anemia; Ascorbic Acid; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Follow-Up Studies; Free Radical Scavengers; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Taiwan; Time Factors; Treatment Outcome

Thrombocytopenia is a frequent hematological complication in patients with liver cirrhosis, but its pathogenesis is not clearly understood. We evaluated the effect of iron depletion by phlebotomy on platelet count in 62 consecutive iron overloaded patients with liver cirrhosis and thrombocytopenia. After a median follow-up of 30.2 months we observed a significant increase of platelet count in all patients (from mean baseline levels of 110.1 up to 168.22109/l at the end of follow-up, P<0.001) with platelet count normalization in 42 of them (67.7%). In addition, we observed a significant improvement of serum ALT levels (from pretreatment mean values of 126.7 up to 59.7 U/l at the end of follow-up, P<0.001) along with the reduction of serum ferritin levels and transferrin saturation during phlebotomy. Different pathogenetic mechanisms involving both humoral (erythropoietin and thrombopoietin, TPO) and physical (portal hypertension and hypersplenism) factors are here discussed to explain the platelet count increase following phlebotomy. Our results show that phlebotomy is effective not only in lowering iron overload, but also in improving liver function and thrombocytopenia in patients with liver cirrhosis.

Topics: Aged; Erythropoietin; Female; Follow-Up Studies; Humans; Hypersplenism; Hypertension; Iron Overload; Liver Cirrhosis; Male; Middle Aged; Phlebotomy; Platelet Count; Retrospective Studies; Thrombocytopenia; Thrombopoietin; Treatment Outcome

A postnatal hyporegenerative anemia may complicate Rh hemolytic disease. Intramedullary hemolysis, bone marrow suppression, and erythropoietin deficiency have been implicated etiologically. Treatment with recombinant erythropoietin (r-EPO) has yielded encouraging preliminary results. The authors describe an infant with Rh isoimmunization who developed severe hyporegenerative anemia unresponsive to a 5-week course of r-EPO. Two additional doses at 12 weeks resulted in brisk reticulocytosis, coinciding with a 16-fold decline in the anti-Rh(D) antibody titer. Thus, treatment with r-EPO may be ineffective when anti-Rh(D) antibody titers are high. The authors also show that erythropoietin deficiency in hyporegenerative anemia is not as frequent and severe as originally thought.

Topics: Adult; Anemia; Blood Transfusion, Intrauterine; Cholestasis, Intrahepatic; Drug Resistance; Erythroblastosis, Fetal; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Ferritins; Hepatomegaly; Humans; Immunity, Maternally-Acquired; Infant, Newborn; Iron Overload; Isoantibodies; Jaundice, Neonatal; Phototherapy; Pregnancy; Recombinant Proteins; Reticulocyte Count; Rh Isoimmunization; Rho(D) Immune Globulin; Time Factors

Porphyria cutanea tarda is treated with phlebotomies in the absence of renal failure. However, in patients on maintenance hemodialysis, this will lead to the need for high doses of erythropoietin. We describe the case of a 63-year-old hemodialysis patient who had chronic hepatitis C virus and developed porphyria cutanea tarda after iron overload due to repeated transfusions. She was treated with erythropoietin and phlebotomies reaching clinical remission 4 months after beginning treatment.

Topics: Erythropoietin; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Iron Overload; Kidney Failure, Chronic; Middle Aged; Porphyria Cutanea Tarda; Renal Dialysis

Treatment of the anemia of chronic renal failure with intravenous iron and erythropoietin is highly effective, but frequently leads to ferritin levels which are much higher than those seen in the general population. High ferritin concentrations raise concern about the potential toxicity of increased body iron stores.. We retrospectively evaluated parameters of iron metabolism over a 4-year period among all our chronic hemodialysis patients who had been receiving intravenous iron and erythropoietin. Initially, patients received intermittent infusions of 300 mg intravenous iron x 3 doses for a low ferritin or low percent saturation of total iron binding capacity (TIBC), but this protocol was subsequently changed to weekly or biweekly infusions of 50-100 mg.. We observed an improvement in average hemoglobin values, modest increases in serum iron and saturation of iron binding capacity, and a 125% increase in ferritin levels over 4 years. TIBC decreased. Overall, ferritin values increased 79 microg/l for each 1% increase in TIBC saturation. Ten patients with ferritin concentration greater than 1,000 pg/l received a three month course of vitamin C with no decline in the ferritin concentration.. Current protocols for iron delivery may result in progressive increases in ferritin levels. Concern about the risks of iron overload should temper the quantity of iron used in dialysis programs.

Topics: Anemia; Erythropoietin; Ferritins; Humans; Infusions, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Renal Dialysis; Retrospective Studies; Time Factors

Little information is available on the evolution of erythropoiesis after interruption of recombinant human erythropoietin (rHuEpo) therapy. Iron-overloaded rats received 20 daily injections of rHuEpo. During treatment, reticulocytes, soluble transferrin receptor (sTfR), and hematocrit increased progressively. This was accompanied by a substantial expansion of spleen erythropoiesis but a decrease in the bone marrow. Five weeks after treatment, rats developed a significant degree of a regenerative anemia. Erythropoietic activity, as assessed by reticulocytes, sTfR, erythroid cellularity, iron incorporation into heme, and the number of erythroid colonies, was severely depressed 3 weeks after cessation of rHuEpo. This was followed by regeneration of erythroblasts and reticulocytes at weeks 6 to 7 post-Epo, but erythroid progenitors recovered only partially by that time. The anemia was definitely corrected 2 months after cessation of rHuEpo treatment. Serum Epo levels remained elevated for several weeks, but the sensitivity of marrow erythroid precursors to Epo was preserved. No rat antibodies to rHuEpo were detected, and serum from post-Epo animals did not exert any inhibitory activity on erythropoiesis. In conclusion, after cessation of intensive rHuEpo therapy, there was a strong inhibition of erythropoietic activity with secondary anemia followed by late recovery. This was not due to antibodies or other soluble inhibitory factors, a defect in endogenous Epo production, or a loss of sensitivity to Epo. This may rather represent intrinsic erythroid marrow exhaustion, mostly at the level of erythroid progenitors but also at later stages of erythropoiesis.

Topics: Anemia; Animals; Bone Marrow Cells; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Iron Overload; Iron, Dietary; Male; Rats; Rats, Wistar; Receptors, Transferrin; Recombinant Proteins; Reticulocyte Count; Spleen; Splenectomy; Substance Withdrawal Syndrome; Time Factors

Preterm infants are prone to iron deficiency. Their total body iron content at birth is low and gets further depleted by clinical practices such as uncompensated phlebotomy losses and exogenous erythropoietin administration during the neonatal period. Early iron deficiency appears to adversely affect cognitive development in human infants. To maintain iron sufficiency and meet the iron demands of catch-up postnatal growth, iron supplementation is prudent in preterm infants. A dose of 2-4 mg/kg/day is recommended for preterm infants who are fed exclusively human milk. A dose of 6 mg/kg/day or more is needed with the use of exogenous erythropoietin or to correct preexisting iron deficiency. However, due to the poor antioxidant capabilities of preterm infants and the potential role of iron in several oxidant-related perinatal disorders, indiscriminate iron supplementation should be avoided.

Topics: Anemia, Iron-Deficiency; Breast Feeding; Dietary Supplements; Erythropoietin; Ferritins; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Iron Overload; Iron, Dietary; Milk, Human; Nutrition Assessment; Nutritional Requirements; Recombinant Proteins

Topics: Anemia, Iron-Deficiency; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hemoglobins; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Iron overload may induce liver toxicity after hematopoietic stem cell transplantation (HSCT), but it is not known if iron depletion prior to HSCT can reduce the risk of severe toxicity in this setting. We used subcutaneous recombinant erythropoietin (EPO) (25 UI/kg) three times a week and phlebotomy once a week, to prevent liver toxicity in a patient with advanced acute leukemia and liver disease due to severe iron overload, previous drug toxicity and hepatitis C viral infection. Over the 9 months prior to allogeneic HSCT, 34 phlebotomies were carried out. Serum ferritin dropped from 2964 to 239 microg/l and the ALT dropped to near normal values. At allogeneic HSCT no liver toxicity was observed, suggesting that iron depletion in the pretransplant period may contribute to reducing transplant-related toxicity in selected cases.

Topics: Adult; Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Humans; Iron Overload; Leukemia, Promyelocytic, Acute; Liver; Phlebotomy; Recombinant Proteins; Transplantation, Homologous

Assessment of iron status is important, because iron deficiency and overload have pathologic consequences. Serum ferritin, the function of which is unknown, is frequently used to assess labile iron stores for the purpose of ensuring their adequacy for erythropoiesis. However, measurable ferritin levels can be increased when tissue ferritin is released during cellular injury, and erythropoietic blockade can increase the labile iron pool, elevating serum ferritin levels despite suppressed erythropoiesis. Erythropoietin-stimulated red blood cell (RBC) production can quickly decrease the labile cellular iron pool and reduce serum ferritin, unless supplemental iron is supplied. A serum ferritin level less than 12 microg/L indicates that there is no iron in the stores (absolute iron deficiency), and levels above 15 microg/L may still not be sufficient to meet erythropoietic demand. This is particularly true in patients receiving erythropoietin, in which the stimulated erythropoiesis requires extra iron supplies. Because of the limitations of serum ferritin measurements and questions regarding the effects of free iron, clinicians need not be too alarmed by high serum ferritin levels. At the very least, safety concerns must be balanced against the real need for iron supplementation to maintain adequate erythropoiesis.

Topics: Anemia, Iron-Deficiency; Erythropoiesis; Erythropoietin; Ferritins; Humans; Iron; Iron Deficiencies; Iron Overload; Renal Dialysis

Multiple blood transfusions were often required to treat anemia in uremia patients before the era of recombinant human erythropoietin (r-HuEPO). Iron overload thus frequently occurred in chronic hemodialysis patients. Desferrioxamine (DFO) is an effective chelating agent, which can remove excessive iron and can enhance erythropoiesis. Large dose DFO treatment is a therapy associated with the development of severe complications. In this study, a low dose DFO regime was used to treat iron overloaded hemodialysis patients. The efficacy and side effects of this regiment were evaluated.. Eight iron overloaded chronic hemodialysis patients were enrolled in this study. All patients received DFO 500 mg intravenously twice-a-week for eight months. Serum aluminum, transferrin saturation (TFS) and r-HuEPO requirement were recorded before and after DFO treatment. Serum ferritin and hematocrit (Hct) were measured before, during, and after the DFO withdrawal period. All patients were evaluated and followed closely during treatment.. Changes in aluminum, TFS and r-HuEPO dosage were unremarkable (p > 0.05). Hct increased significantly after eight months of DFO treatment (from 25.3% to 27.0%, p < 0.05). Ferritin level was reduced by 43.2% at the end of treatment and an evident decline of ferritin was achieved after four months of treatment (2102 ng/mL to 1166 ng/mL, p < 0.05). All patients tolerated the treatment well and no complications were found.. Low dose DFO can chelate iron effectively in chronic hemodialysis patients. This treatment can enhance erythropoiesis without adverse effects.

Topics: Anemia; Chelating Agents; Deferoxamine; Erythropoiesis; Erythropoietin; Female; Ferritins; Humans; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

A patient with diabetes mellitus caused by secondary hemochromatosis was treated using recombinant human erythropoietin and phlebotomy. A total of 12 g of iron had been infused in the patient because of iron deficiency anemia. Blood glucose level was 17.3 mmol/L, and hemoglobin A1c level was 9.0% at admission. He was treated using phlebotomy (400 mL per week), along with subcutaneous injection of 3,000 U of recombinant human erythropoietin three times a week. After approximately 100 days, a total of 5,500 mL of blood (2.75 g iron) could be removed. Serum ferritin level decreased from 10,000 micrograms/L to 4,807 micrograms/L. Fasting and maximum serum C-peptide immunoreactivity values during 100-g oral glucose tolerance tests were improved from 0.14 nmol/L to 0.42 nmol/L and from 1.84 nmol/L to 2.61 nmol/L, respectively. This case suggests that pancreatic beta-cell recovers in diabetes caused by hemochromatosis by reducing iron overload during a short period.

Topics: Aged; Blood Glucose; C-Peptide; Combined Modality Therapy; Diabetes Mellitus; Erythropoietin; Ferritins; Hemochromatosis; Humans; Iron; Iron Overload; Islets of Langerhans; Male; Phlebotomy; Recombinant Proteins