losartan-potassium and Chronic-Disease

The important association of erythropoietin (EPO) serum levels and chronic obstructive pulmonary disease (COPD) with anemia has been inadequately studied and remains a controversial issue. We aimed to shed light on this matter by comparing EPO levels in anemic and non-anemic COPD patients, along with a review of published literature. This cross-sectional study was conducted on COPD patients referred to the pulmonary clinic of Shahid Faghihi Hospital and Motahari clinic, Shiraz, Iran, for one year. We measured complete blood count, red blood cell indices, serum iron, TIBC and ferritin levels, serum EPO levels, and body mass index. Among 35 patients in this study, 28 males and 7 females were enrolled with a mean age of 54.57 ± 8.07 years. The average Forced expiratory volume in first second (FEV1) was 37.26 ± 7.33% and FEV1/FVC was 0.46 ± 0.12. Mean EPO levels were 30.29 ± 2.066 mU/mL. No statistically significant association was observed among erythropoietin levels and Hb, COPD severity, and age. There was no significant difference in EPO levels between anemic and non-anemic patients. EPO level, against the traditional expectation, didn't increase in COPD patients. EPO production also didn't compensate for the anemia of chronic disease which considers as a common comorbid disorder in these patients.

Topics: Anemia; Chronic Disease; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

Anaemia of chronic disease (ACD) is generated by the activation of the immune system by autoantigens, microbial molecules or tumour antigens resulting in the release of cytokines that cause an elevation of serum hepcidin, hypoferraemia, suppression of erythropoiesis, decrease in erythropoietin (EPO) and shortening of the half-life of red blood cells. Anaemia is usually normocytic and normochromic, which is the most prevalent after iron deficiency anaemia, and it is the most frequent in the elderly and in hospitalized patients. If the anaemia is severe, the patient's quality of life deteriorates, and it can have a negative impact on survival. Treatment is aimed at controlling the underlying disease and correcting anaemia. Sometimes intravenous iron and EPO have been used, but the therapeutic future is directed against hepcidin, which is the final target of anaemia.

Topics: Aged; Anemia; Chronic Disease; Erythropoietin; Hepcidins; Humans; Iron; Quality of Life

Heart Failure (HF) is recognized as an important public health concern worldwide, especially in developed countries, due to its high rate of morbidity and mortality. Although new pharmacological and non-pharmacological agents have improved the clinical sequelae of HF in patients, its mortality remains high, especially among the elderly. Erythropoietin (EPO), a glycoprotein, besides its traditional role in promoting erythropoiesis and production of erythroid progenitors, its beneficial role in reducing infarct area and improving heart function through EPO-induced antiapoptotic and antioxidant effects have been increasingly recognized. This review gathers the evidence to date about the effectiveness of EPO in HF patients. In addition to the growing evidence of EPO in the treatment of HF in the animal studies for improving cardiac function and infarct size, more clinical studies are needed to assess the role of EPO treatment in the management of HF.

Topics: Animals; Antioxidants; Chronic Disease; Erythropoietin; Heart Failure; Humans

Topics: Adaptation, Physiological; Altitude Sickness; Calcium; Chronic Disease; Endothelium, Vascular; Erythropoietin; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth; Pulmonary Edema; Vascular Diseases; Vascular Remodeling; Vasoconstriction

Anemia in the setting of chronic inflammatory disorders is a very frequent clinical condition, which is, however, often neglected or not properly treated given the problems often caused by the diseases underlying the development of anemia. Mechanistically, anemia is mainly caused by inflammation-driven retention of iron in macrophages making the metal unavailable for heme synthesis in the course of erythropoiesis, and further by impaired biological activity of the red blood cell hormone erythropoietin and the reduced proliferative capacity of erythroid progenitor cells. Anemia can be aggravated by chronic blood loss, as found in subjects with gastrointestinal cancers, inflammatory or infectious bowel disease, or iatrogenic blood loss in the setting of dialysis, all resulting in true iron deficiency. The identification of such patients is a clinical necessity because these individuals need contrasting therapies in comparison to subjects suffering from only classical anemia of chronic disorders. The diagnosis is challenging because no state of the art laboratory test is currently available that can clearly separate patients with inflammatory anemia from those with additional true iron deficiency. However, based on our expanding knowledge on the pathophysiology of inflammatory anemia, new diagnostic markers, including the iron-regulatory hormone hepcidin, and hematologic parameters emerge. Apart from traditional anemia treatments such as blood transfusions, recombinant erythropoietin, and iron, including new high-molecular-weight formulations, new therapeutics are currently under preclinical and clinical evaluation. These novel compounds aim at correcting anemia by multiple pathways, including antagonizing the inflammation- and hepcidin-driven retention of iron in the monocyte-macrophage system and thereby promoting the supply of iron for erythropoiesis or by stimulating the endogenous formation of erythopoietin via stabilization of hypoxia-regulated factors.

Topics: Anemia; Animals; Chronic Disease; Erythropoietin; Hepcidins; Humans; Iron

Erythropoiesis, the bone marrow production of erythrocytes by the proliferation and differentiation of hematopoietic cells, replaces the daily loss of 1% of circulating erythrocytes that are senescent. This daily output increases dramatically with hemolysis or hemorrhage. When erythrocyte production rate of erythrocytes is less than the rate of loss, chronic anemia develops. Normal erythropoiesis and specific abnormalities of erythropoiesis that cause chronic anemia are considered during three periods of differentiation: a) multilineage and pre-erythropoietin-dependent hematopoietic progenitors, b) erythropoietin-dependent progenitor cells, and c) terminally differentiating erythroblasts. These erythropoietic abnormalities are discussed in terms of their pathophysiological effects on the bone marrow cells and the resultant changes that can be detected in the peripheral blood using a clinical laboratory test, the complete blood count.

Topics: Anemia; Animals; Blood Cell Count; Blood Platelets; Cell Differentiation; Chronic Disease; Erythrocytes; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Leukocytes

Anemia is a frequent comorbidity of heart failure and is associated with poor outcomes. Anemia in heart failure is considered to develop due to a complex interaction of iron deficiency, kidney disease, and cytokine production, although micronutrient insufficiency and blood loss may contribute. Currently, treatment of anemia of heart failure lacks clear targets and specific therapy is not defined. Intravenous iron use has been shown to benefit anemic as well as nonanemic patients with heart failure. Treatment with erythropoietin-stimulating agents has been considered alone or in combination with iron, but robust evidence to dictate clear guidelines is not currently available. Available and emerging new agents in the treatment of anemia of heart failure will need to be tested in randomized, controlled studies.

Topics: Age Factors; Aged; Anemia; Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Incidence; Inflammation Mediators; Iron; Male; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sex Factors

Since erythropoietin (EPO) and EPO receptor (EPOR) are expressed in the central nervous system (CNS) beyond hematopoietic system, EPO illustrates a robust biological function in maintaining neuronal survival and regulating neurogenesis and may play a crucial role in neurodegenerative diseases.. EPO is capable of modulating multiple cellular signal transduction pathways to promote neuronal survival and enhance the proliferation and differentiation of neuronal progenitor cells. Initially, EPO binds to EPOR to activate the Janus-tyrosine kinase 2 (Jak2) protein followed by modulation of protein kinase B (Akt), mammalian target of rapamycin, signal transducer and activators of transcription 5, mitogen-activated protein kinases, protein tyrosine phosphatases, Wnt1 and nuclear factor κB. As a result, EPO may actively prevent the progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis and motor neuron diseases.. Novel knowledge of the cell signaling pathways regulated by EPO in the CNS will allow us to establish the foundation for the development of therapeutic strategies against neurodegenerative diseases. Further investigation of the role of EPO in neurodegenerative diseases can not only formulate EPO as a therapeutic candidate, but also further identify novel therapeutic targets for these disorders.

Topics: Animals; Chronic Disease; Drug Design; Erythropoietin; Humans; Molecular Targeted Therapy; Neurodegenerative Diseases; Neurogenesis; Neurons; Receptors, Erythropoietin; Signal Transduction

EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the "primary injury response" or apoptosis, and mid- and long-term effects for example the stimulation of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP)-conform clinical trials. Thus, the initiation of more scientifically sound trials is indicated.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Graft Survival; Humans; Nerve Regeneration; Plastic Surgery Procedures; Regenerative Medicine; Skin; Surgical Flaps; Wound Healing; Wounds and Injuries

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases, with an increasing rate in morbidity and mortality. In recent years, there has been a greater awareness about the clinical importance of systemic effects and other chronic conditions associated with COPD, as these significantly impact on the course of disease. The most studied extrapulmonary manifestations in COPD include the presence of concomitant cardiovascular disease, skeletal muscle wasting, osteoporosis and lung cancer. Anaemia is a recognised independent marker of mortality in several chronic diseases. Recent studies have shown that anaemia in patients with COPD may be more frequent than expected, with a prevalence ranging from 5% to 33%. Some evidence suggests that systemic inflammation may play an important pathogenic role, but anaemia in COPD is probably multifactorial and may be caused by others factors, such as concealed chronic renal failure, decreased androgenic levels, iron depletion, angiotensin-converting enzyme inhibitor treatment and exacerbations. Low levels of haemoglobin and haematocrit in COPD patients have been associated with poor clinical and functional outcomes as well as with mortality and increased healthcare costs. Despite the potential clinical benefit of successfully treating anaemia in these patients, evidence supporting the importance of its correction on the prognosis of COPD is uncertain.

Topics: Acute Disease; Androgens; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Exercise Tolerance; Glomerular Filtration Rate; Health Resources; Hemoglobins; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Renal Insufficiency, Chronic; Renin-Angiotensin System

Even though anemia is a significant comorbidity regularly observed in patients with chronic heart failure (HF), only in recent years systematic therapeutic research has been started. This article aims to review the aspects of anemia in chronic HF that are relevant for making treatment decisions, beginning with the definition of anemia and its incidence and prevalence of anemia in patients with chronic HF. Considering the etiology and prognostic impact of anemia in chronic HF, several treatment options will be considered. The latter are the application of erythropoiesis-stimulating agents (erythropoietin or darbepoetin alfa) or in the application of intravenous iron (e.g., iron carboxymaltose). According to the results seen in the FAIR-HF trial, iron supplementation should be particularly considered to improve symptoms and quality of life. Intravenous iron application may result in higher compliance and much faster treatment response than oral iron. The RED-HF study will show whether use of darbepoetin alfa in anemic patients with chronic HF will reduce the combined endpoint of death for any reason or hospitalization for heart failure.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Prognosis

The relationships between erythropoietin (EPO), iron, and erythropoiesis and the presence of iron-restricted erythropoiesis have important implications in anemia management. Iron-restricted erythropoiesis occurs in the presence of one or more iron deficiency syndromes: absolute iron deficiency, functional iron deficiency, and/or iron sequestration. Absolute iron deficiency is a common nutritional deficiency in women's health, pediatrics, and the elderly and is therefore an important public health problem. Functional iron deficiency occurs in patients with significant EPO-mediated erythropoiesis or therapy with erythropoiesis-stimulating agents, even when storage iron is present. Iron sequestration mediated by hepcidin is an underappreciated but common cause of iron-restricted erythropoiesis in patients with chronic inflammatory disease. The challenge for treating and laboratory-based physicians is to understand the contributory role(s) of each of these syndromes, so that the potential value of emerging and innovative pharmacologic strategies can be considered as options in patient blood management.

Topics: Aged; Antimicrobial Cationic Peptides; Child; Child, Preschool; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Hepcidins; Humans; Infant; Inflammation; Iron; Iron Deficiencies; Iron Metabolism Disorders; Male; Middle Aged; Syndrome

Chronic heart failure is a common disorder associated with unacceptably high mortality rates. Chronic renal disease and anemia are two important comorbidities that significantly influence morbidity and mortality in patients with chronic heart failure (CHF). Progress in CHF again may cause worsening of kidney function and anemia. To describe this vicious cycle, the term cardio-renal anemia syndrome has been suggested. Iron deficiency is part of the pathophysiology of anemia in both CHF and chronic kidney disease, which makes it an interesting target for treatment of anemia in cardio-renal anemia syndrome. Recently, studies have highlighted the potential clinical benefits of treating iron deficiency in patients with CHF, even if these patients are nonanemic. This article summarizes studies investigating the influence of iron deficiency with or without anemia in chronic kidney disease and CHF and gives an overview of preparations of intravenous iron currently available.

Topics: Anemia, Iron-Deficiency; Cardio-Renal Syndrome; Chronic Disease; Erythropoietin; Ferric Compounds; Hematinics; Humans; Iron

Anemia is a significant cause of morbidity and lowers the quality of life of patients suffering from chronic kidney disease (CKD). Iron deficiency is the most important cause of erythropoietin (EPO) hyporesponsiveness in CKD. EPO administration significantly increases the costs of CKD management. It follows that paramount importance must be given to enhancing responsiveness to EPO thereby ensuring that the patient derives maximum benefit. Intravenous iron (IVI) administration has been used for decades to replenish body iron stores. Multiple preparations of Iron are available in the market. However, IVI administration is fraught with dangers like adverse drug reactions, susceptibility to infection, and, as recently postulated, direct cellular toxicity. Traditional approaches to IVI administration have focused on multiple administrations of lower doses for fear of adverse reactions. However, recent studies have demonstrated that higher doses can be safely administered in a single infusion, thereby reducing hospitalization costs and patient inconvenience. Newer preparations of IVI are relatively safer, easier to administer and efficacious. Preparations like Iron sucrose, ferumoxytol, ferric carboxymaltose and iron isomaltoside do not require test doses and allow higher doses to be administered at a time with cost and effect benefits.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Injections, Intravenous; Iron; Iron Deficiencies; Kidney Diseases

Anaemia of chronic disease is the second most common form of anaemia worldwide, and is seen in a variety of inflammatory, infective and malignant diseases. Functional iron deficiency is fundamental to the pathogenesis of the anaemia, and the polypeptide, hepcidin, plays a key role. Diagnosis may be difficult, but new automated red cell indices, algorithms for detection of functional iron deficiency, and assays for hepcidin levels are being developed. Management of the causative disease process will usually improve haemoglobin levels, but where this is not possible, erythropoietic stimulating agents are often used, although there are still concerns about potential adverse effects, especially thromboembolism. There is increasing evidence that supplemental iron given parenterally can safely overcome the functional iron deficiency. Inhibitors of hepcidin, and various inflammatory modulators show promise for the future.

Topics: Algorithms; Anemia; Antimicrobial Cationic Peptides; Chronic Disease; Diagnosis, Differential; Erythropoietin; Hepcidins; Humans; Iron

Topics: Anemia; Chronic Disease; Dietary Supplements; Erythropoietin; Iron; Iron, Dietary; Recombinant Proteins

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

Biomarkers have been used to diagnose and prognosticate the progress and outcome of many chronic diseases such as neoplastic and non communicable diseases. However, only recently did the field of malaria research move in the direction of actively identifying biomarkers that can accurately discriminate the severe forms of malaria. Malaria continues to be a deadly disease, killing close to a million people (mostly children) every year. One life-threatening complication of malaria is cerebral malaria (CM). Studies carried out in Africa have demonstrated that even with the best treatment, as high as 15-30% of CM patients die and about 10-24% of CM survivors suffer short-or long-term neurological impairment. The transition from mild malaria to CM can be sudden and requires immediate intervention. Currently, there is no biological test available to confirm the diagnosis of CM and its complications. It is hoped that development of biomarkers to identify CM patients and potential risk for adverse outcomes would greatly enhance better intervention and clinical management to improve the outcomes. We review here what is currently known regarding biomarkers for CM outcomes. A Pub Med literature search was performed using the following search terms: "malaria," "cerebral malaria," "biomarkers," "mortality" and "neurological sequelae." This search revealed a paucity of usable biomarkers for CM management. We propose three main areas in which researchers can attempt to identify CM biomarkers: 1) early biomarkers, 2) diagnostic biomarkers and 3) prognostic biomarkers.

Topics: Angiopoietin-1; Angiopoietin-2; Antimalarials; Biomarkers; Chemokine CXCL10; Chronic Disease; Disease Management; Early Diagnosis; Erythropoietin; Humans; Malaria, Cerebral; Prognosis; Severity of Illness Index; Survival Rate

Topics: Acidosis; Anemia; Bone Diseases, Metabolic; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Diet, Protein-Restricted; Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Kidney Diseases; Male; Nephrology; Renin-Angiotensin System

After iron deficiency anemia the anemia of chronic disorder is the second most frequent anemia, and in hospitalized patients and/or patients suffering from chronic disease, especially infection, cancer and autoimmune disorders it is even the most frequent anemia. Morphologically it belongs to the normochromic, normocytic, hyporegeneratoric anemias. Pathogenetically it is induced by the upregulation of hepcidin, a recently detected acute phase protein with most important regulatory function in the iron-household. As a consequence of elevated hepcidin at the same time iron absorption in the bowel as well as iron release from macrophages are reduced, resulting in sequestration of iron in the RES and therefore functional iron deficiency. The other reason is a blunted release of erythropoetin (EPO) with at the same time reduced effectiveness due to down-regulation of EPO-receptors on erythroid cells. Treatment consists first of all in the therapy of the underlying disease and possibly in the combined application of EPO and iron.

Topics: Anemia; Chronic Disease; Dietary Supplements; Erythropoietin; Humans; Iron

Blood transfusion is a not causal therapeutic option in symptomatic anemia. For long time, since the discovery of the blood circulation and the first experiments in transfusion over 300 years ago, blood transfusions were the only possibility to improve the tissue oxygenation. Pretransfusion testing of the blood components as well as of the donor and the recipient has made transfusion of allogeneic blood increasingly safe. Despite transfusion reactions still do occur, they have considerably diminished, inter alia by the introduction of hemovigilance systems and decreasing the hemoglobin value used as transfusion trigger, hence performing less unnecessary transfusions. In chronic anemia, usually accepted transfusion triggers today are 70 g/l hemoglobin in patients without comorbidities. The use of erythropoetin stimulating agents is widely used and should - after a careful examination of the anemia - be considered early in the treatment plan in patients with chronic anemic.

Topics: Anemia; Blood Transfusion; Chronic Disease; Erythropoietin; Humans; Transfusion Reaction

TREAT was a recently concluded, and well-powered and designed, study of anemia treatment in chronic kidney disease (CKD). Unlike most previous studies of ESA treatment in nondialysis CKD, TREAT was a placebo-controlled trial. The placebo group in TREAT provides a unique long-term view of a conservative approach to anemia management in nondialysis CKD. The course of mean Hgb levels in the placebo group ran counter to expectations, increasing over time. We discuss possible reasons for this, including a new hypothesis that there may be an erythropoietin 'honeymoon phase' similar to that observed in diabetes mellitus. We propose investigation of this phenomenon as it could lead to less expensive and safer approaches to treatment of CKD anemia.

Topics: Anemia; Animals; Chronic Disease; Controlled Clinical Trials as Topic; Erythropoietin; Humans; Kidney Diseases

This article examines the potential mechanisms underlying adverse risk observed in four randomized controlled trials of anemia correction in chronic kidney disease (CKD) patients.. The Normal Hematocrit Study, Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency, and Trial to Reduce Cardiovascular Events with Aranesp Therapy demonstrate increased risk of mortality and/or cardiovascular complications with targeting of a higher hemoglobin (Hb) in CKD patients. Although a higher Hb level was targeted in these trials, erythropoiesis-stimulating agent (ESA) exposure itself might account for the observed increased risk. This is because, in these trials, achieving a normal or near normal Hb was associated with improved survival and reduced cardiovascular risk. Indeed, it was the 'targeting' of a higher Hb with ESA that seemed to be the problem. Observational data, although conflicting, on the whole provide support for high dosage of ESA being harmful but cannot, by their very nature, prove causality.. After 20 years of ESA use, is it plausible that ESAs could be toxic? How does one reconcile conflicting observational data with a hypothesis that postulates ESA toxicity? Does the biology of erythropoietin provide a mechanistic explanation? The answers to these questions, among others, will be important in charting a future role for ESAs in treating CKD anemia.

Topics: Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Randomized Controlled Trials as Topic

After the patents of biopharmaceuticals have expired, based on specific regulatory approval pathways copied products ("biosimilars" or "follow-on biologics") have been launched in the EU. This article summarizes experiences with hematopoietic medicines, namely the epoetins (two biosimilars traded under five different brand names) and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists should be familiar with the legal and pharmacological specialities of biosimilars: The production process can differ from that of the original, clinical indications can be extrapolated, glycoproteins contain varying isoforms, the formulation may differ from the original, and biopharmaceuticals are potentially immunogenic. Only on proof of quality, efficacy and safety, biosimilars are a viable option because of their lower costs.

Topics: Anemia; Antineoplastic Agents; Biological Products; Chronic Disease; Drug Utilization; Erythropoietin; European Union; Filgrastim; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Humans; Isoantibodies; Kidney Diseases; Legislation, Drug; Marketing; Neoplasms; Patents as Topic; Polyethylene Glycols; Quality Control; Recombinant Proteins; Red-Cell Aplasia, Pure; Therapeutic Equivalency; World Health Organization

In chronic kidney disease, anemia and oxidative stress are common features and both are involved in increasing morbidity and mortality. However, their relationship is still a matter of debate. This article is a review of published data and our experience and is intended to debate the pro and contra arguments concerning renal anemia and its 2 main therapeutic approaches, that are, erythropoietin and intravenous iron supplementation, as additional causes of oxidative stress in end-stage renal disease patients. To date, it seems more likely that renal anemia itself is the main contributor, and intravenous iron further enhances oxidative stress associated with chronic kidney disease. Future randomized prospective trials, with "hard" clinical end-points, are needed to establish the real effect of biochemical pro-oxidative changes on patient's outcome.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Iron; Kidney Diseases; Lipid Peroxidation; Lipoproteins, LDL; Oxidants; Oxidative Stress; Renal Dialysis

Red blood cells (RBCs) often have a short circulating half-life in hemodialysis patients, which increases the difficulty of achieving a stable hemoglobin level. Fluctuations in erythropoietin (EPO) levels contribute to this increased RBC turnover because a decline in the level of EPO triggers the preferential destruction of newly-formed RBC, a process termed neocytolysis. The RBCs that are released during the treatment of renal anemia are often hypochromic, with a low content of iron; these RBCs are vulnerable to rapid turnover because iron-deficiency affects RBCs in several ways, such as, increased exposure of the phagocytic signaling molecule phosphatidylserine, loss of deformability, and increased oxidative stress. Both EPO fluctuation and the release of iron-deficient RBCs are characteristic events occurring during the management of renal anemia, and the shorter RBC lifetime is a component of the large fluctuations in hemoglobin level seen in patients on hemodialysis.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythrocyte Aging; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Phagocytosis; Phosphatidylserines; Renal Dialysis

Anaemia is a relatively frequent co-morbidity of chronic heart as well as chronic renal failure. In both conditions, it represents a strong and independent predictor of increased morbidity and mortality. Aetiology of this anaemia is multi-factorial. A number of various factors play a role in its development, e.g. inadequate erythropoietin production in the kidneys, bone marrow inhibition, iron deficiency as well as haemodilution associated with fluid retention. Treatment strategies aim at two directions. One is the stimulation of erythropoiesis with recombinant human erythropoietin or its analogues such as darbepoetin alpha. The other involves iron substitution, administered preferably intravenously for improved efficacy and tolerability. Clinical studies evaluating treatment of anaemia in chronic heart failure with erythropoiesis-stimulating agents conducted so far were ofa small scale, were not controlled with placebo and usually assessed proxy parameters. Their results suggested that effective treatment of anaemia in patients with chronic heart failure improves exertion tolerance, clinical status (NYHA class) as well as the quality of life and reduces the need for blood transfusions. Recently completed TREAT study was the first large morbidity and mortality study evaluating treatment of anaemia with an erythropoietin analogue compared to placebo. On a sample of more than 4000 patients with diabetes mellitus, chronic renal failure and significant anaemia, this study has shown that effective treatment of anaemia with darbepoetin alpha did not affect at all the incidence of cardiovascular and renal events; on the other hand, it had lead to a nearly two-fold increase in the incidence of cerebrovascular events. Some doubts about the safety of treatment with erythropoiesis-stimulating agents have occurred in the past based on the studies of anaemia treatment in patients with cancer and renal diseases. An answer to the question whether the treatment of anaemia associated with chronic heart failure affects positively the patient prognosis will be provided following the completion of the currently running morbidity and mortality RED-HF study.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron

Anaemia is common in patients with chronic heart failure (HF), and erythropoiesis stimulating proteins (ESPs) are frequently used for its treatment. However, recent studies in patients with malignancies and renal failure have raised concerns about the safety of these agents.. To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality.. A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed.. Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included.. Seven randomised controlled trials were identified that enrolled 650 patients, of whom 363 were treated with ESPs and 287 with placebo. ESP treatment had a significantly lower risk of HF hospitalisation (risk ratio (RR) = 0.59; 95% CI 0.41 to 0.86; p = 0.006).There was no significant difference in the mortality risk between the two groups (RR = 0.69; 95% CI 0.39 to 1.23; p = 0.21). No significant differences were observed in the occurrence of hypertension or venous thrombosis.. In chronic HF, treatment with ESPs is not associated with a higher mortality rate or more adverse events, whereas a beneficial effect on HF hospitalisation is seen. These outcomes are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anaemia correction in patients with chronic HF.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

This review summarizes the evidence for a hypertensinogenic effect of Erythropoietin (Epo) in normal human subjects and predialysis, hemodialysis, and continuous ambulatory peritoneal dialysis (CAPD) patients. The possible mechanisms of Epo-induced hypertension are examined with in vivo animal and in vitro data, as well as pathophysiological human studies in both normal subjects and CKD patients. The evidence for a hypertensinogenic effect of erythropoiesis-stimulating agents (ESAs) in normal subjects, predialysis CKD, hemodialysis, and CAPD patients is compelling. Epo increases BP directly and notably independently of its erythropoietic effect and its effect on blood rheology. The potential for the development of future agents that might act as specific stimulators of erythropoiesis, devoid of direct hemodynamic side effects is underscored.

Topics: Anemia; Animals; Arteries; Blood Pressure; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Hematinics; Humans; Hypertension; Kidney Diseases; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Risk Assessment

The purpose was to evaluate changes in the left ventricular mass index (LVMi) among anemic chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients treated with recombinant human erythropoietin (EPO).. A systematic review of the literature, reporting LVMi for patients before and after EPO therapy, was performed. The change in LVMi from baseline to the end of treatment was calculated and stratified by severity of anemia at baseline, target hemoglobin (Hb), and stage of kidney disease.. Fifteen eligible studies involving 1731 patients were identified. Cohorts with severe anemia at baseline (<10 g/dl), when given EPO using a lower target level (Hb 12 g/dl or Hct > 36%). The effect size was similar in direction for both CKD and ESRD cohorts.. Aggregated results from multiple studies suggest that in severe anemia conventional Hb targets for EPO therapy are associated with a reduction in LVMi, but that in moderate anemia target Hb above 12 g/dl does not have a significant beneficial impact on LVMi compared with conventional targets.

Topics: Anemia; Biomarkers; Chronic Disease; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Kidney Failure, Chronic; Recombinant Proteins; Severity of Illness Index; Time Factors; Treatment Outcome

Besides stimulating erythropoiesis, erythropoietin (EPO) exerts powerful proangiogenic and antiapoptotic effects. These erythropoiesis-independent effects are potentially useful as a supplement for the treatment of chronic heart failure (CHF). EPO may improve microvascular capacity of ischemic myocardial tissue and could thereby (partially) restore myocardial function. In addition, EPO could protect cardiomyocytes from hypoxic damage and prevent them from apoptosis. However, the clinical value of these erythropoiesis-independent effects for the treatment of CHF remains to be elucidated. Small-sized trials evaluating the effects of EPO treatment on surrogate endpoints in patients with CHF showed positive effects in general; however, their mutual results are not always unambiguous. Moreover, increasing hematocrit levels with EPO has been associated with increased blood viscosity and an inherent risk of thromboembolic events. A currently running multicenter phase III trial is designed to provide clarity concerning the effects of EPO on outcome and safety in patients with CHF. Focusing primarily on outcome, however, does not provide insight into the mode of action and isolated benefits of the erythropoiesis-independent effects of EPO. Further exploration of these effects is a key issue to gain knowledge of the full potential of EPO for the treatment of CHF.

Topics: Anemia; Animals; Apoptosis; Chronic Disease; Erythropoietin; Heart Failure; Humans; Myocardial Reperfusion

Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines 'a diseasome of physical inactivity'. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.

Topics: Abdominal Fat; Adipose Tissue; Adiposity; Animals; Brain-Derived Neurotrophic Factor; Chronic Disease; Cytokines; Erythropoietin; Exercise; Humans; Inflammation; Interleukin-15; Interleukin-6; Motor Activity; Muscle, Skeletal; Receptor Cross-Talk

Topics: Anemia; Chronic Disease; Disease Progression; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Diseases; Prognosis; Quality of Life; Recombinant Proteins; Treatment Outcome

Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.

Topics: Anemia; Animals; Blood Platelets; Blood Pressure; Causality; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Drug Overdose; Endothelin-1; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Morbidity; Nitric Oxide; Oxidative Stress

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Mortality; Oxygen Consumption; Prevalence; Prognosis; Randomized Controlled Trials as Topic; Severity of Illness Index

Topics: Anemia; Biomarkers; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Folic Acid; Hematinics; Hemoglobins; Humans; Iron; Kidney Diseases; Recombinant Proteins; Treatment Outcome; Vitamin B 12

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Charcoal; Chronic Disease; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Life Style; Mineralocorticoid Receptor Antagonists

Chronic kidney disease (CKD) is now recognized as a risk factor of both end-stage renal disease (ESRD) and independently cardiovascular disease (CVD). Therefore, a specific renoprotective intervention is strongly recommended, including blood pressure control as well as anemia improvement with erythropoietin stimulating agents (ESAs). Treatment of renal anemia with ESAs has been proved to improve quality of life (QOL) and finally reduce patient mortality. Recently, Silverberg, et al. created a novel clinical entity of Cardio-Renal Anemia (CRA) syndrome, in which anemia plays a key role for worsening both CKD and cardiac performance in a vicious circle. An appropriate and vigorous treatment of anemia has now been accepted to terminate or weaken the circle. Recently, two large-scaled randomized controlled trials were reported, being the CREATE (cardiovascular risk reduction by early anemia treatment with epoetin beta) study and the CHOIR (correction of hemoglobin and outcomes in renal insufficiency) study. They demonstrated that early initiation of ESA treatment and targeting at higher hemoglobin level (near normal level) failed to show the lowering effects for cardiovascular events as compared to a group in which Hb targeting was lower (sub-normal level) in pre-dialysis CKD patients. While there has been many argues in these reports especially about baseline patients characteristics, being a quite high incidence of severe cardiovascular co-morbidity. Thus, further evidences should be accumulated to resolve a proper target level of Hb in ESA treatment.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Disease Progression; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Syndrome

Patients with chronic kidney disease (CKD) are exposed to extremely higher risks of atherothrombotic complications of the cardio- and cerebrovascular systems. In pertinent meta-analyses, overviews, editorials and comments, it has been considered unproven, on the basis of current data from randomized controlled trials, that a higher hemoglobin (Hb) value provides overall-survival benefits for CKD. At present, there is a "gray zone" between the intervention threshold of Hb < 9 g/dl and an Hb level > 13 g/dl, at which CKD is associated with a higher risk of cardiovascular events. This paper discusses in depth the hemostaseological hypothesis of increased mortality as a result of higher Hb levels during treatment of renal anemia with erythropoiesis-stimulating agents (ESA). It seems to be clearly evident that ESA activate platelets directly and indirectly, and that pathologically extended bleeding time is normalized when an Hb level of 10 g/dl is reached; from the hemostaseological perspective, a threshold level for treatment of renal anemia with ESA is thus defined. According to the present state of knowledge, an Hb target range of 10-11 g/dl seems reasonable for renal anemia; this is also compatible with current recommendations by ESA producers and the Food and Drug Administration (FDA). This target range avoids the upper and lower risk levels for Hb, and probably ensures a positive ESA effect on quality of life; it is much more cost-efficient than the target range of 11-12 g/dl recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2007.

Topics: Age Factors; Aged; Anemia; Bleeding Time; Blood Transfusion; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Follow-Up Studies; Hematinics; Hemoglobinometry; Hemoglobins; Hemolysis; Humans; Kidney Diseases; Meta-Analysis as Topic; Platelet Activation; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Survival Analysis; Time Factors

Anemia is a very common clinical problem in patients with chronic kidney disease (CKD) and is associated with increased morbidity and mortality in these patients. Erythropoietin is a hormone synthesized that is deficient in the majority of patients with advanced kidney disease, thereby predisposing these patients to anemia. The other cause of anemia is deficiency of iron. Iron deficiency anemia is common in people with CKD and its importance in supporting erythropoiesis is unquestioned, especially in those patients treated with erythropoietin. Intravenous iron is frequently used to treat anemia in CKD patients and is very efficacious in increasing hemoglobin but at the same time there are some safety issues associated with it. The objective of this review is to assess the frequency of adverse drug events associated with four different iron formulations: two iron dextran products known as high and low molecular weight iron dextran, iron sucrose, and sodium ferric gluconate complex. Several electronic databases were searched. In general, with the exception of high molecular weight iron dextran, serious or life-threatening adverse events appeared rare. Iron sucrose has the least reported adverse events and high molecular weight iron dextran has the highest number of reported adverse events. Low molecular weight iron dextran and ferric gluconate fall in between these two for number of adverse drug events.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Databases, Factual; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Kidney Diseases; Safety

Diabetic nephropathy is traditionally considered to be a primarily glomerular disease, although this contention has recently been challenged. Early tubular injury has been reported in patients with diabetes mellitus whose glomerular function is intact. Chronic hypoxia of the tubulointerstitium has been recognized as a mechanism of progression that is common to many renal diseases. The hypoxic milieu in early-stage diabetic nephropathy is aggravated by manifestations of chronic hyperglycemia-abnormalities of red blood cells, oxidative stress, sympathetic denervation of the kidney due to autonomic neuropathy, and diabetes-mellitus-induced tubular apoptosis; as such, tubulointerstitial hypoxia in diabetes mellitus might be an important early event. Chronic hypoxia could have a dominant pathogenic role in diabetic nephropathy, not only in promoting progression but also during initiation of the condition. Early loss of tubular and peritubular cells reduces production of 1,25-dihydroxyvitamin D3 and erythropoietin, which, together with dysfunction of their receptors caused by the diabetic state, diminishes the local trophic effects of the hormones. This diminution could further compromise the functional and structural integrity of the parenchyma and contribute to the gradual decline of renal function.

Topics: Animals; Calcitriol; Capillaries; Chronic Disease; Diabetic Nephropathies; Disease Progression; Erythropoietin; Filtration; Humans; Hyperglycemia; Hypoxia; Kidney; Kidney Glomerulus; Kidney Tubules; Oxidative Stress; Proteinuria; Receptors, Calcitriol

Anemia is common in patients with chronic heart failure, and is related to increased morbidity and mortality. The etiology of anemia in heart failure is complex and still not fully resolved. The review will describe current advances in the understanding of the pathophysiology of anemia and the potential therapeutic effects of recombinant human erythropoietin.. Recent attempts to resolve the preponderant etiology of anemia in chronic heart failure have further defined its multifactorial nature. Impaired renal perfusion and function resulting in blunted erythropoietin production as well as impaired erythropoiesis in the bone marrow account for a vulnerable erythropoietic system. Moreover, fluid retention causes hemodilutional anemia. Correction of anemia with recombinant human erythropoietin seems feasible and is currently being evaluated in a phase 3 clinical trial. In addition, recombinant human erythropoietin improves cardiac function in chronic heart failure through the recruitment of endothelial progenitor cells and exerts cytoprotective effects during acute myocardial infarction. Although recombinant human erythropoietin shows great promise, we should not neglect other treatable causes of anemia.. Although the etiology of anemia in chronic heart failure is clearly multifactorial, correction of anemia with recombinant human erythropoietin seems promising. In addition to correction of anemia, recombinant human erythropoietin might exert important protective and regenerative effects on the myocardium.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Recombinant Proteins

Anemia of chronic disease (ACD) is a mild to moderate anemia seen with many infections and inflammatory disorders. These patients have low serum iron, but high serum ferritin levels. As for the pathogenesis of ACD, previous studies have reported several abnormalities, such as insufficient EPO production, impaired growth response of erythroid progenitors to EPO, and shortened survival of erythrocytes, due to the inflammatory cytokines. However, recent analyses have clearly shown that hepcidin, of which expression is induced by inflammatory cytokines such as IL-1beta and IL-6, suppresses the expression of the iron transporter, ferroportin-1, thereby inhibiting the absorption of iron from the duodenum, the release of iron from the reticulo-endothelial system. So, the abnormal expression of hepcidin alone may be able to explain the unique iron metabolism in ACD.

Topics: Anemia; Antimicrobial Cationic Peptides; Cation Transport Proteins; Chronic Disease; Cytokines; Duodenum; Erythroid Precursor Cells; Erythropoietin; Ferritins; Hepcidins; Humans; Infections; Inflammation; Inflammation Mediators; Intestinal Absorption; Iron; Iron Deficiencies

The biology of iron in relation to anemia is best understood by a review of the iron cycle, since the majority of iron for erythropoiesis is provided by iron recovered from senescent erythrocytes. In iron-deficiency anemia, storage iron declines until iron delivery to the bone marrow is insufficient for erythropoiesis. This can be monitored with clinical indicators, beginning with low plasma ferritin, followed by decreased plasma iron and transferrin saturation, and culminating in red blood cells with low-Hb content. When adequate dietary iron is provided, these markers show return to normal, indicating a response to the dietary supplement. Anemia of inflammation (also known as anemia of chronic disease, or ACD) follows a different course, because in this form of anemia storage iron is often abundant but not available for erythropoiesis. The diagnosis of ACD is more difficult than the diagnosis of iron-deficiency anemia, and often the first identified symptom is the failure to show a response to a dietary iron supplement. Confirmation of ACD is best obtained from elevated markers of inflammation. The treatment of ACD, which typically employs erythropoietin (EPO) supplements and intravenous iron (i.v.-iron), is empirical and often falls shorts of therapeutic goals. Dialysis patients show a complex pattern of anemia, which results from inadequate EPO production by the kidney, inflammation, changes in nutrition, and blood losses during treatment. EPO and i.v.-iron are the mainstays of treatment. Patients with heart failure can be anemic, with incidence as high as 50%. The causes are multifactorial; inflammation now appears to be the primary cause of this form of anemia, with contributions from increased plasma volume, effects of drug therapy, and other complications of heart disease. Discerning the mechanisms of anemia for the heart failure patient may aid rational therapy in each case.

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Diseases; Hematinics; Humans; Inflammation; Iron; Kidney Diseases; Male; Recombinant Proteins

An association between anaemia, poor functional status and, compared to non-anaemic patients, worse clinical status and a higher risk of hospitalisation and death has been consistently reported in chronic heart failure (CHF), although cause an effect has not been proven. While it is attractive to think that correction of a co-morbidity that exacerbates already diminished delivery of oxygen to the tissues in heart failure is likely to beneficial, the possible haemodynamic effects of increasing haemoglobin, for example vasoconstriction, might not be. Consequently, the balance of benefit and risk of anaemia correction in CHF is uncertain, may vary according to the severity of anaemia (and other factors) and needs to be properly evaluated. To date, most studies of anaemia correction in CHF have used erythropoiesis stimulating agents (ESAs). The trials with erythropoietin have been of small size, uncontrolled or unblended/single blind, raising concerns again about interpretation of subjective outcomes. In addition, the analyses of these trials have been suboptimal. Two double-blind, placebo-controlled, darbepoetin studies have been published in full. Neither showed an improvement in functional capacity or consistent effect on patient reported symptoms/quality of life. Darbepoetin is, however, currently being tested in a large-scale, phase III morbidity and mortality trial, the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF) which should contribute important information of the safety and efficacy of ESAs in this syndrome. Other approaches, notably parenteral iron supplementation, are also being evaluated and other agents for anaemia correction are under development.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies

Erythropoietin is a haematopoietic hormone with extensive non-haematopoietic effects. The discovery of an erythropoietin receptor outside the haematopoietic system has fuelled the research into the beneficial effects of erythropoietin for various conditions, predominantly in cardiovascular disease. Experimental evidence has revealed the cytoprotective and angiogenic properties of erythropoietin and it seems that the erythropoietin-erythropoietin receptor system provides a powerful backbone against acute and chronic myocardial ischemia, each gaining from the different properties of erythropoietin. Clinical trials in which erythropoietin was titrated to achieve certain haematocrit levels have generated equivocal results. It has been suggested that a (too) high haematocrit is undesirable in cardiovascular disease. We have shown that intermittent (low-dose) erythropoietin administration, that does not increase haematocrit substantially, suffices to activate the beneficial downstream pathways of erythropoietin. We postulate that intermittent administration or a lower than conventional dose of erythropoietin, not only aimed at increasing haemoglobin at high levels, will provide powerful cellular protection and will improve cardiac outcome, without the side effects of erythropoietin associated with increased haematocrit.

Topics: Animals; Cardiovascular Physiological Phenomena; Chronic Disease; Erythropoietin; Heart Diseases; Heart Failure; Humans; Receptors, Erythropoietin; Recombinant Proteins

After almost 20 years, anemia in chronic kidney disease (CKD) and its treatment remain the focus of multiple questions for clinicians and investigators. The optimal hemoglobin (Hb) for patients with CKD is controversial and different targets are probably required for different populations. The current literature does not support an upper Hb target >12 g/dl and there is a clear demonstration of increased risk with Hb targets >13 g/dl. With this narrow target of 11-12 g/dl, fluctuations in Hb concentration are commonly observed in patients being treated with erythropoiesis-stimulating agents (ESAs). Studies to date provide a suggestion of an association between Hb cycling and mortality, but they have been primarily exploratory in nature and clinical trials comparing treatment strategies leading to different degrees of Hb variability are needed. The great majority of incidences of pure red cell aplasia (PRCA) was associated with ESA therapy and was first recognized several years ago after a change in the formulation in which human serum albumin was eliminated and replaced by polysorbate-80 in patients on epoetin alfa (Eprex). Years later, a registry (PRIMS) was established by the health authorities as part of a reapproval of the subcutaneous route to confirm that the cause of PRCA has been eliminated. The ongoing PRIMS study is a 3-year observation period prospective multicenter and international (Europe and Australia) registry that could serve as a model for assessment of the immunogenicity profiles of currently marketed and future ESAs. The association with a change in formulation makes PRCA of interest to the biotechnology industry as well as the medical community because it raises the broader question of the potential immunogenicity of biopharmaceuticals in general.

Topics: Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Methoxy polyethylene glycol-epoetin beta (Mircera) is a continuous erythropoietin receptor activator, with a long half-life (approximately 130 hours). In patients with anaemia associated with chronic kidney disease (CKD), both on and not on dialysis, who had not previously received an erythropoiesis-stimulating agent (ESA), methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 weeks resulted in a smooth and steady rise in haemoglobin levels. The response rates were high (up to 97.5%) in these patients at the end of the correction period; response rates with the comparator ESAs (epoetin alfa or beta, or darbepoetin alfa) were up to 96.3%. Moreover, patients with CKD on dialysis who had previously been treated with an ESA maintained stable haemoglobin levels (within +/-1 g/dL of baseline and within a range of 10-13.5 g/dL) when directly converted to methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 or 4 weeks. Methoxy polyethylene glycol-epoetin beta is generally well tolerated, with most adverse events being of mild to moderate severity, consistent with the co-morbidities known to occur in this patient group and those reported with other ESAs. In conclusion, in patients with anaemia associated with CKD, subcutaneous or intravenous methoxy polyethylene glycol-epoetin beta achieved a high haemoglobin response rate (ESA-naive patients) when administered once every 2 weeks and maintained stable haemoglobin levels (patients previously treated with ESAs) when administered once monthly.

Topics: Anemia; Chronic Disease; Clinical Trials, Phase III as Topic; Drug Costs; Economics, Pharmaceutical; Erythropoietin; Hematinics; Humans; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks.

Topics: Anemia; Antineoplastic Agents; Bone Marrow Transplantation; Chronic Disease; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Iron; Neoplasms; Practice Guidelines as Topic; Radiotherapy; Thromboembolism

Endocrine abnormalities are common in patients with chronic kidney disease (CKD) and lead to sexual dysfunction, anemia, hyperparathyroidism, and altered mineral metabolism. Common clinical problems include disturbances in menstruation in women, erectile dysfunction in men, and decreased libido and infertility in both sexes. Organic factors tend to be prominent and are related to uremia and other comorbid illnesses. Psychological factors and depression may exacerbate the primary problem. Alterations in the hypothalamic-pituitary axis are seen early in CKD and tend to worsen after patients start dialysis. Hypogonadism plays a dominant role in male sexual function, whereas changes in hypothalamic-pituitary function predominate in female sexual dysfunction. In patients on dialysis, treatment strategies include optimizing dose of dialysis, correction of anemia with erythropoietin, and correction of hyperparathyroidism. Successful kidney transplantation may restore normal sexual function, especially in younger patients.

Topics: Androgens; Chronic Disease; Erythropoietin; Female; Hormone Replacement Therapy; Humans; Hypogonadism; Kidney Diseases; Kidney Transplantation; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Recombinant Proteins; Sexual Dysfunction, Physiological; Sildenafil Citrate; Sulfones; Testosterone

Anemia is a well recognized complication of chronic kidney disease and is associated with significant morbidity. It is important for clinical care to identify appropriate treatments and targets for hemoglobin. This review describes current understandings of the treatment of anemia using the most recent published articles.. Numerous studies, including observational and randomized control trials, of varying sizes and using both surrogate and hard outcomes have been published. On balance, there is little to support normalization of hemoglobin in the chronic kidney disease population. While some studies have described harm, there are some issues related to overinterpretation based on study trial reporting. The treatment of anemia can be successfully achieved with the use of oral or intravenous iron and erythropoiten-stimulating agents. Caution should be exercised when treating those with significant cardiovascular morbidity, and those who require very high doses of erythropoiten-stimulating agents to achieve normal hemoglobin.. Large observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and randomized control trials fail to show a benefit of normalized hemoglobin. Anemia therapy does improve quality of life. In the current era of aggressive chronic kidney disease management, it does not appear that anemia therapy attenuates left ventricular growth or changes cardiovascular outcomes.

Topics: Anemia; Chronic Disease; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Treatment Outcome

The recombinant human erythropoietins epoetins alfa and beta have relatively short half-lives ( approximately 24 h by subcutaneous route) and have traditionally been administered 2 or 3 times a week for the treatment of anaemia in patients with chronic kidney disease. However, multiple weekly injections are inconvenient for both the patient and the healthcare provider. With the introduction of the longer-acting erythropoiesis-stimulating agent darbepoetin alfa, there has been growing interest in longer dosing intervals for erythropoiesis-stimulating agents. Data from several randomized studies have shown that darbepoetin alfa is effective in maintaining haemoglobin levels when administered (subcutaneously, intravenously or both) every 2 weeks in dialysis patients, and every 2 weeks or monthly in patients with chronic kidney disease not yet receiving dialysis. Moreover, intravenous administration with darbepoetin alfa does not require a higher dosage compared with the subcutaneous route. Epoetins alfa and beta have also been studied in similar schedules, although few data from well-designed studies are available. Current data suggest that once-weekly administration of these forms of epoetin is feasible in dialysis patients, but dose increases are often required when switching patients from traditional twice- or thrice-weekly schedules. Also, administration of epoetins every other week is feasible in selected patients with chronic renal insufficiency. Further study is required to clarify the optimum schedule for epoetins in these settings.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Economics, Pharmaceutical; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Chronic Disease; Comorbidity; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Diseases; Nephrology

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Female; Gene Expression; Glomerular Filtration Rate; Hemoglobins; Humans; Iron; Kidney Diseases; Kidney Failure, Chronic; Male; Prognosis; Quality of Life; Recombinant Proteins; Renal Dialysis; Risk Factors

Topics: Benzamides; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Imatinib Mesylate; Interferon-alpha; Piperazines; Primary Myelofibrosis; Protein-Tyrosine Kinases; Pyrimidines; Quinazolines; Recombinant Proteins; Splenectomy; Thalidomide

Anaemia is common after solid organ transplantation. Although many impressive experimental data about the organoprotective properties of erythropoietin (EPO) have been reported, there are only scant clinical and experimental data about EPO use after solid organ transplantation. Since the treatment targets of anaemia in chronic kidney disease cannot be transferred to organ recipients for several reasons (rejection, immunosuppression, infection), the recommendations for optimal targets in the treatment of anaemia remain uncertain. Moreover, further studies will be necessary to clarify whether EPO administration might have haemoglobin-independent beneficial effects.

Topics: Anemia; Chronic Disease; Endothelial Cells; Erythropoietin; Heart Transplantation; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Liver Transplantation; Organ Transplantation; Pilot Projects; Recombinant Proteins; Risk; Stem Cells; Treatment Outcome

C.E.R.A., a continuous erythropoietin receptor activator, has been developed for the treatment of anaemia in patients with chronic kidney disease. Compared with other erythropoiesis-stimulating agents, C.E.R.A. has a unique pharmacological profile, including a longer elimination half-life and slower clearance rate. This allows C.E.R.A. to be administered at extended intervals up to once every month. Phase III clinical trials have shown that C.E.R.A. once every 2 weeks corrects anaemia in erythropoiesis-stimulating agent-naive patients who are on or are not on dialysis, whereas once-monthly C.E.R.A. maintains stable haemoglobin levels when patients are directly converted from more frequent epoetin or darbepoetin alpha administration. C.E.R.A. is well tolerated. This review summarises clinical data on C.E.R.A. and discusses the potential effect of this novel agent on clinical practice.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Hematinics; Humans; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins; Treatment Outcome

Renal anemia is a well-recognized complication of chronic kidney disease (CKD), and the deficiency of erythropoietin (EPO) is the primary cause. Observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and renal failure, cardiac failure, and anemia all may interact to cause or worsen each other, the so-called cardio-renal anemia syndrome. Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). From a mechanistic point of view, however, the therapeutic benefits of ESA could be far beyond the correction of anemia. ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. A pleiotropic effect of EPO has been shown in the central nervous system, the cardiovascular system, and the kidney. While recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients, the results of these studies do not negate renoprotective effects of EPO. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA.

Topics: Anemia; Cardiotonic Agents; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Diseases; Neuroprotective Agents

In patients with primary as well as secondary chronic kidney disease (CKD), anemia has been identified as an independent risk factor for progression. In these patients anemia is thought to be a surrogate parameter for tissue hypoxia that perpetuates preexisting renal tissue injury, and treatment of anemia with recombinant human erythropoietin (rHuEPO) was therefore expected to retard progression. However, results of recently published large trials in patients with CKD did not fulfill these expectations. The reason for the discrepant findings may be distinct molecular pathways and/or EPO tissue receptor affinities that mediate the effect of EPO on erythropoiesis and tissue protection by EPO. A pivotal intracellular pathway is the activation of Akt (i.e., serine/threonine protein kinase B), but further potential pathways have been identified that may play an important role in tissue protection. In this study, we review data on the non-hematological effects of rHuEPO in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogue substances that are not related to anemia correction.

Topics: Animals; Chronic Disease; Disease Progression; Erythropoietin; Humans; Kidney; Kidney Diseases; Receptors, Erythropoietin; Recombinant Proteins; Regeneration

Anemia is a frequently encountered problem of chronic kidney disease (CKD) and deteriorates as renal function declines. Anemia increases the risk of death in CKD patients with diabetes and hypertension, which are the 2 leading causes of CKD. Recent studies suggest that correction of anemia improves patient quality of life and may delay the progression to end-stage renal disease. Anemia is often only treated in the late stages of CKD or after the initiation of renal replacement therapy. Thus, anemia of CKD is often unnoticed and lacks appropriate treatment. To practically manage high-risk patients with CKD and its associated cardiovascular diseases, it is mandatory to diagnose and appropriately treat anemia of CKD earlier. The optimal level of hemoglobin for greatest clinical benefit is unclear, but at present, it is recommended to remain > or = 11 g/dL. This paper provides recommendations for the diagnosis and management of anemia associated with CKD based on international practice guidelines.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases

Stage 3 chronic kidney disease (CKD), which is characterized by a glomerular filtration rate of 30 to 60 mL/min/1.73 m2 (reference range, 90-200 mL/min/1.73m2 for a 20-year-old, with a decrease of 4 mL/min per decade), affects approximately 8 million people in the United States. Anemia is common in patients with stage 3 CKD and, if not corrected, contributes to a poor quality of life. Erythropoiesis-stimulating agents (ESAs), introduced almost 2 decades ago, have replaced transfusions as first-line therapy for anemia. This review summarizes the current understanding of the role of ESAs in the primary care of patients with anemia of CKD and discusses pharmacological and pharmacoeconomic issues raised by recent data. Relevant studies in the English language were identified by searching the MEDLINE database (1987-2006). Two ESAs are currently available in the United States, epoetin alfa and darbepoetin alfa. More frequent dosing with epoetin alfa is recommended by the labeled administration guidelines because it has a shorter half-life than darbepoetin alfa. Clinical experience also supports extended dosing intervals for both these ESAs. Use of ESAs in the management of anemia of CKD is associated with improved quality of life, increased survival, and decreased progression of renal failure. Some evidence suggests that ESAs have a cardioprotective effect. However, correction of anemia to hemoglobin levels greater than 12 g/dL (to convert to g/L, multiply by 10) appears to increase the risk of adverse cardiac outcomes and progression of kidney disease in some patients. The prescription of ESAs in the primary care setting requires an understanding of the accepted use of these agents, the associated pharmacoeconomic challenges, and the potential risks. This review considers the need to balance effective ESA dosing intervals against the potential risks of treatment.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Disease Progression; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Ferric Compounds; Ferritins; Heart Failure; Hematinics; Humans; Kidney Diseases; Physician's Role; Primary Health Care; Quality of Life; Recombinant Proteins

Critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units (ICUs) receive at least one allogeneic red blood cell (RBC) unit and average close to 5 U of RBCs during their ICU admission. RBC transfusion is not risk-free, and there is little evidence that "routine" transfusion of stored allogeneic RBCs is beneficial to critically ill patients. It is clear that most critically ill patients can tolerate hemoglobin levels as low as 7 g/dL, and therefore, a more conservative approach to RBC transfusion is warranted. Anemia of critical illness is a distinct clinical entity characterized by blunted erythropoietin (EPO) production and abnormalities in iron metabolism identical to what is commonly referred to as anemia of chronic disease. As such, the bone marrow in many of these patients responds to the administration of exogenous EPO, in spite of their underlying critical illness. The efficacy of perioperative recombinant human erythropoietin (rHuEPO) has been demonstrated in a variety of elective surgical settings. Similarly, in critically ill patients, rHuEPO therapy will also stimulate erythropoiesis. In randomized placebo-controlled trials, therapy with rHuEPO resulted in a significant reduction in allogeneic RBC transfusions. Strategies to increase the production of RBCs are complementary to other approaches to reduce blood loss in the ICU and decrease the transfusion threshold in the management of all critically ill patients.

Topics: Anemia; Blood Loss, Surgical; Chronic Disease; Critical Illness; Elective Surgical Procedures; Erythrocyte Transfusion; Erythropoietin; Humans; Iron; Recombinant Proteins

Most patients with chronic kidney disease eventually become anemic. We should view the management of anemia in these patients as part of the overall management of the many clinically relevant manifestations of chronic kidney disease. Erythropoiesis-stimulating agents (ESAs) are safe and should be used, as treating anemia may forestall some of the target-organ damage of chronic kidney disease.

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron; Kidney Diseases; Practice Guidelines as Topic; Recombinant Proteins; Renal Dialysis

The partial correction of ESRD anemia by recombinant human erythropoietin (EPO) has resulted both in generalized improvement in quality of life and physical activity and in reduced mortality and hospitalization rate. The question remains as to whether normalizing hemoglobin (Hgb) is desirable in patients with chronic kidney disease (CKD). This review provides an analysis and commentary on the available reports and, for the most part, randomized, controlled trials on the topic. In dialysis patients, normalization of Hgb is associated with improved quality of life and exercise capacity but not with reduced mortality and hospitalization rate. Moreover, no significant changes in the degree of left ventricular hypertrophy have been demonstrated. By contrast, an increased mortality rate has been reported for hemodialysis patients with overt cardiovascular disease (CVD) when randomly assigned to normal hematocrit by EPO. Data regarding patients who have CKD but are not yet on renal replacement therapy are scarce, and the effects of EPO on renal disease progression require further elucidation through controlled trials. The conclusion that can be drawn from the available studies is that Hgb >11 g/dl is the minimum required to achieve improved quality of life in patients with CKD, whereas values >12 g/dl are not recommended for patients with overt CVD. Finally, Hgb normalization might reasonably be restricted to a selected population of younger, employed, and active individuals, provided that they do not have CVD.

Topics: Chronic Disease; Clinical Trials as Topic; Disease Progression; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

In patients with liver disease, thrombocytopenia is a clinical feature that may represent an obstacle to invasive diagnostic or therapeutic procedures, chemotherapy, and anti-viral treatment. Stimulation of the bone marrow is the most promising therapeutic intervention for thrombocytopenia in patients with chronic liver disease. The description of thrombopoietin and its (de)regulation in patients with chronic liver disease have disclosed new treatment opportunities. Indeed, pharmacologic treatment options for thrombocytopenia can be divided into treatments targeted at the thrombopoietin receptor (synthetic thrombopoietins and thrombopoietin-mimetic agents), and use of cytokines with general thrombopoietic potential. Unfortunately, use of synthetic thrombopoietin was hampered by the development of neutralizing antibodies, and thrombopoietin mimetic agents have not yet entered clinical studies. Interleukin-11 proved to be useful in increasing platelet count in patients with chronic liver disease, although its use is limited by side-effects. Erythropoietin has shown promising results in improving thrombocytopenia in cirrhotic patients. In patients with chronic liver disease, safe and well-tolerated treatments aimed at improving thrombocytopenia are still lacking. Larger studies are needed to evaluate and better characterize the thrombopoietic potential of erythropoietin. Human studies with thrombopoietin-mimetic agents are eagerly awaited in order to assess both effectiveness and safety of these drugs.

Topics: Chronic Disease; Controlled Clinical Trials as Topic; Erythropoietin; Humans; Liver Diseases; Platelet Count; Receptors, Erythropoietin; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

The aims of the present review are to summarize and to discuss the role of hypoxia-inducible factor-1 (HIF-1) and the expression and functions of vasoactive substances in chronic hypoxemia with specific focus in the liver and the carotid body. Vascular remodelling and vasoactive substances play important functional roles in the adaptive response to chronic hypoxemia for the maintenance of oxygen homeostasis in all systems in man. HIF-1 regulates the gene expression of vasoactive substances such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and enzymes for producing nitric oxide (NO). Recent studies have shown the effect of chronic hypoxia on the expression of HIF-1alpha and HIF-1-target genes in multiple organ systems including the liver and the carotid body. Results are consistent with increases in the hematocrit levels, pulmonary arterial pressure and right heart mass developed during chronic hypoxia. In addition, the carotid body is also hyperplastic and increases in organ mass with increased levels of HIF-1alpha and the vasoactive substances. These molecules increase the mitotic activity and modulate the excitability of the chemoreceptor. Intriguingly, the liver morphology, serum alanine aminotransferase and 8-isoprostane levels are within normal range in chronic hypoxia, suggesting the absence of significant oxidative stress. Yet, the HIF-1alpha is upregulated and the mRNA and protein levels of VEGF, ET-1, inducible and constitutive NO synthases are elevated in the liver during chronic hypoxia. In conclusion, the adaptive response to long-term hypoxemia involves compensatory mechanisms mediated by expressing significant levels of HIF-1alpha and vasoactive substances regulated by HIF-1.

Topics: Animals; Carotid Arteries; Chronic Disease; Endothelin-1; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Liver; Nitric Oxide; Oxygen; Transcription Factors; Vascular Endothelial Growth Factor A

Many patients with congestive heart failure (CHF) fail to respond to maximal CHF therapy and progress to end stage CHF with many hospitalizations, poor quality of life (QoL), progressive chronic kidney disease (CKD) which can lead to end stage kidney disease (ESKD), or die of cardiovascular complications within a short time. One factor that has generally been ignored in many of these people is the fact that they are often anemic. The anemia in CHF is due mainly to the frequently-associated CKD but also to the inhibitory effects of cytokines on erythropoietin production and on bone marrow activity, as well as to their interference with iron absorption from the gut and their inhibiting effect on the release of iron from iron stores. Anemia itself may further worsen cardiac and renal function and make the patients resistant to standard CHF therapy. Indeed anemia in CHF has been associated with increased severity of CHF, increased hospitalization, worse cardiac function and functional class, the need for higher doses of diuretics, progressive worsening of renal function and reduced QoL. In both controlled and uncontrolled studies of CHF, the correction of the anemia with erythropoietin (EPO) and oral or intravenous (IV) iron has been associated with improvement in many cardiac and renal parameters and an increased QoL. EPO itself may also play a direct role in improving the heart unrelated to the improvement of the anemia--by reducing apoptosis of cardiac and endothelial cells, increasing the number of endothelial progenitor cells, and improving endothelial cell function and neovascularization of the heart. Anemia may also play a role in the worsening of acute myocardial infarction and chronic coronary heart disease (CHD) and in the cardiovascular complications of renal transplantation. Anemia, CHF and CKD interact as a vicious circle so as to cause or worsen each other- the so-called cardio renal anemia syndrome. Only adequate treatment of all three conditions can prevent the CHF and CKD from progressing.

Topics: Anemia; Cardiology; Chronic Disease; Erythropoietin; Heart Failure; Humans; Interdisciplinary Communication; Iron; Kidney Diseases; Nephrology; Syndrome

The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in chronic kidney disease (CKD) and to identify determinants of the variation in epoetin alfa:darbepoetin alfa dose ratios across studies.. A systematic review of the literature for comparative switch and non-switch studies of epoetin alfa and darbepoetin alfa treatments in CKD for the period 2000-2005 was performed. Two reviewers independently assessed the quality of the information. Data on the study design and outcomes were collected for each selected study. The dose ratio from epoetin alfa to darbepoetin alfa was calculated for each study, and the results were reported stratified by study characteristics. To control for differences in study design and characteristics that could explain the variability in the relative dosages of the two agents across studies, multivariate regression analysis was conducted. Based on these results, a dose conversion ratio for Canada was estimated.. A total of 21 studies involving 16 378 patients exposed to epoetin alfa or darbepoetin alfa in CKD were identified. Univariate analysis of the dose ratios indicated a mean dose ratio of 217:1 (IU of epoetin alfa:mug of darbepoetin alfa). Results from the multivariate analysis demonstrated that the study design (i.e., switch study versus straight comparison studies) and geographical coverage (i.e., United States) affected the results. Based on the multivariate analysis, the dose conversion ratio between epoetin alfa and darbepoetin alfa for Canada was 169:1.. Despite limitations associated with switching studies and the limited total number of studies available, this systematic review based on aggregated results provides further evidence to the clinical community that the dose conversion ratio for epoetin alfa:darbepoetin alfa in CKD patients in Canada is approximately 169:1. At that ratio, treatment with epoetin alfa is 11-18% cheaper than treatment with darbepoetin alfa in Canada.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Multivariate Analysis; Recombinant Proteins

Topics: Age Factors; Altitude; Altitude Sickness; China; Chronic Disease; Erythropoietin; Female; Free Radicals; Humans; Male; Prevalence; Respiration; Sex Factors; Tibet

Recently there has been considerable interest in the associations between blood hemoglobin (Hb) level, renal function, and cardiovascular disease. Anemia is a common feature of end-stage renal disease, but it also accompanies lesser degrees of chronic kidney disease (CKD). The degree of anemia roughly approximates the severity of CKD. Anemia seen in diabetes has been linked to diabetic nephropathy; however, diabetes itself affects the hematologic system in several ways. Anemia is associated with left ventricular hypertrophy, cardiovascular morbidity, progressive loss of kidney function, and poor quality of life. Anemia seems to act as a mortality multiplier; that is, at every decrease in Hb below 12 g/dL, mortality increases in patients with CKD, cardiovascular disease, and those with both. Unlike blood transfusion, treatment of anemia with exogenous erythropoietin in patients with cardiorenal disease has shown promise in reducing morbidity and in improving survival and quality of life. Increasing the Hb level from less than 10 g/dL to 12 g/dL has resulted in favorable changes in left ventricular remodeling, improved ejection fraction, improved functional classification, and higher levels of peak oxygen consumption with exercise testing. Clinical trials are underway to test the role of erythropoietin in patients with CKD and in patients with heart failure.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Comorbidity; Diabetes Complications; Erythropoietin; Humans; Prevalence; Prognosis; Renal Insufficiency; Risk Factors

Topics: Anemia; Animals; Blood Transfusion; Chronic Disease; Erythroid Precursor Cells; Erythropoietin; Homeostasis; Humans; Iron

Classic iron deficiency (ID) does not represent a challenge for the laboratory and physicians. The anemia that accompanies infection, inflammation, and cancer, commonly termed anemia of chronic disease (ACD), features apparently normal or increased iron stores. However, 20% of these patients have iron-restricted erythropoiesis (functional ID), an imbalance between the iron requirements of the erythroid marrow and the actual iron supply. Functional ID leads to a reduction in red cell hemoglobiniza-tion, causing hypochromic microcytic anemia. The diagnosis of functional ID in real time is based on measuring the hemoglobin content of reticulocytes. An examination of the biochemical markers of iron metabolism demonstrates weaknesses in the diagnosis of functional ID. We developed a diagnostic plot for the assessment of iron status in ACD and the detection of advancing ID in patients with ID, ACD, and the combined state of functional ID and ACD. The plot indicates the correlation between a marker of the iron supply for erythropoiesis (ie, the ratio of the soluble transferrin receptor value to the logarithm of the ferritin value) and the reticulocyte hemoglobin content and functions as a marker of iron demand. The diagnostic plot shows good selectivity for assessing the iron status of disease-specific anemias such as classic ID, end-stage renal failure, cancer-related anemia, and the anemia of infection and inflammation. The therapeutic implications of the diagnostic plot are to differentiate patients who should be administered oral iron supplements, recombinant human erythropoietin (r-HuEPO), or a combination of r-HuEPO and iron. The response of erythropoiesis to r-HuEPO depends on the iron supply and the proliferation of erythropoiesis. The lack of an increase or a decrease in reticulocyte hemoglobin levels indicates a nonresponder to r-HuEPO or functional ID.

Topics: Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Homeostasis; Humans; Iron

Anemia is a common problem in the management of elderly patients. Anemia in the elderly is linked to an increase in morbidity and mortality, and serves as an independent variable associated with poor outcomes. In the elderly population, anemia is a risk factor for cardiovascular health and early death, contributes to fatigue, and negatively impacts on cognitive function, physical function, and the quality of life and serves as a marker of increased vulnerability. A greater understanding of pathophysiology of anemia in the setting of chronic disease has provided insights into the rationale for the potential clinical application of erythropoietic agents in the treatment of anemia. The impact of erythropoietic therapy, as it relates to specific afflictions affecting the older age patient, including diminished exercise tolerance, frailty, loss of functional capacity, immobility, depression, increased care needs and cardiovascular fitness, remains to be determined and is worthy of further investigation.

Topics: Age Factors; Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans

Health care decision-making is affected by the values of patients and providers, available resources, and information substantiating effectiveness (or efficacy) of a particular therapy. A number of factors contribute to our growing need for evidence-based decision-making. Our aging population generally requires greater medical attention in a system with limited resources devoted to health care. Technologic advances have produced an ever-expanding range of expensive treatment options. Patients, and their providers, expect early access to these emerging therapies. Patients also expect care of universally high quality, even as respected authorities suggest there exists a substantial gap between these expectations and the care actually delivered. Evidence based decision-making offers the opportunity to use medical evidence to reduce uncertainty regarding research information and improve the value of health care delivered. Evidence based medicine (EBM) is the 'conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.' It combines clinical judgment and experience, best available scientific evidence, and patient preferences to improve medical decision-making. Though often incorrectly maligned as cookbook medicine that dismisses any research findings that do not derive from randomized clinical trials, it provides clinicians, health care systems, payers and policymakers with tools to appropriately evaluate the research evidence that substantiates various therapies and integrate that evidence with clinical expertise and patient's values in medical decision-making. The erythropoietic stimulants epoetin and darbepoetin have shown efficacy in improving anemia of chronic renal failure and following chemotherapy for many patients. In some studies these agents have also improved health-related quality of life. Unfortunately, only 60-80% of patients treated with erythropoietic stimulants respond, and like many emerging therapies, they are quite expensive. Likewise, there is substantial variation in their usage, suggesting both inappropriate use and non-usage. Reimbursement coverage decisions for erythropoietic stimulants have been hampered by the lack of high-quality evidence in certain applications. Physicians are increasingly turning to evidence-based medicine resources (guidelines, systematic reviews) to inform their decisions regarding application of new therapies. Evidence-based medicine offers healt

Topics: Anemia; Antineoplastic Agents; Chronic Disease; Erythropoiesis; Erythropoietin; Evidence-Based Medicine; Humans; Neoplasms; Quality of Life

Recombinant human erythropoietin (epoetin) was first used for the treatment of anemia resulting from renal disease in 1986. During the first 10 years of its use, there were only three cases of epoetin-induced antibodies reported, which resulted in pure red cell aplasia (PRCA). Between 1998 and 2002, 191 chronic kidney disease patients developed PRCA during the course of epoetin treatment. Clinical characteristics of patients with PRCA include an absolute resistance to epoetin therapy, with a rapid development of severe anemia and very low reticulocyte count. In addition, patients developed high titre, high affinity neutralizing antibodies, which are detectable by immunoassays. The diagnosis of PRCA requires the onset of severe anemia, erythropoietin neutralizing antibodies in circulation, the lack of red cell precursors in the bone marrow aspirate, and normal to elevated transferrin saturation. Patients require blood transfusions to maintain an acceptable level of hemoglobin. Cessation of epoetin treatment alone does not improve PRCA. Patients have required immunosuppressive treatment. However, the most efficacious treatment has been kidney transplantation accompanied by immunosuppressive agents that prevent organ rejection. Evaluating patients receiving recombinant epeoetin therapy who experience a sudden loss of epoetin efficacy for the possibility of antibody-mediated PRCA is crucial. Timely identification and treatment of this rare syndrome can prevent the development of severe red blood cell transfusion requirements and the potential complications of iron overload, which results from these transfusions.

Topics: Anemia; Antibodies; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

The vascular events that happen during ischemic stroke worsen outcomes in patients by causing edema, hemorrhagic transformation, and general neurologic tissue compromise. In the past 2 decades, clinical trials in patients after ischemic stroke focused on neuroprotection, but these strategies have failed in providing actual benefit. Vascular protection represents a new field to be explored in acute ischemic stroke in order to develop new approaches to therapeutic intervention.. We identified tactics likely to provide vascular protection in patients with ischemic stroke. These tactics are based on knowledge of the molecular processes involved.. The pathologic processes due to vascular injury after an occlusion of a cerebral artery can be separated into acute (those occurring within hrs), subacute (hrs to days), and chronic (days to mo). Targets for intervention can be identified for all three stages. In the acute phase, superoxide is the predominant mediator, followed by inflammatory mediators and proteases in the subacute phase. In the chronic phase, proapoptotic gene products have been implicated. Many already-marketed therapeutic agents (statins, angiotensin modulators, erythropoietin, minocycline, and thiazolidinediones), with proven safety in patients, have been shown to have activity against some of the key targets of vascular protection.. Currently available pharmacologic agents are poised for clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiotensin-Converting Enzyme Inhibitors; Brain; Brain Edema; Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Minocycline; Stroke; Thiazolidinediones; Thrombolytic Therapy

Heart failure represents a major public health problem in the industrialized countries and despite of optimal medical treatment its mortality remains high. The history of its management reflects growth and changes in our understanding of its pathophysiology. In the past, pharmacological treatment of heart failure was aimed only at relieving edema and improving hemodynamics. Today, however, a major aim of treatment is to antagonize the sympathetic nervous system and renin-angiotensin-aldosterone system, to avert harmful effects of neurohormonal activation on the myocardium and peripheral vessels. Currently, the major pharmacological treatments for heart failure are diuretics, ACE inhibitors, beta-blockers and (in NYHA classes III-IV) aldosterone antagonists. Some patients may also require specific treatment with additional drugs (e.g. anti-arrhythmia agents, anticoagulants, or vasodilators) or procedures such as coronary revascularization, or implantable devices such as pacemakers and implantable cardioverter defibrillators, or resynchronization devices. Patients with end-stage heart failure may require cardiac transplantation or ventricular assist devices. This review is summarized the recent practical drug therapy of heart failure and the results of the newer clinical trial.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Defibrillators, Implantable; Digitalis Glycosides; Diuretics; Endothelin Receptor Antagonists; Erythropoietin; Heart Failure; Heart-Assist Devices; Humans; Hungary; Immunologic Factors; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Peptide Hydrolases; Primary Prevention; Risk Factors; Severity of Illness Index; Vasopressins

Erythropoiesis-stimulating agents have dramatically changed the management of renal anaemia since their introduction almost 20 years ago. However, optimal dosing route and frequency are still a matter of debate. Intravenous application of recombinant human erythropoietin should be limited to haemodialysis patients and must be given three times weekly, as any reduction to this dosing frequency leads to a major increase in dose requirements. Administering recombinant human erythropoietin-beta once weekly via the subcutaneous route is effective. If conversion from the subcutaneous to the intravenous route is required, dose requirements for recombinant human erythropoietin therapy remain a subject of discussion.

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Despite clinical practice guidelines for the management of anaemia of chronic kidney disease and a growing literature concerning the treatment of renal anaemia in diverse patient groups, there remain uncertainties over definitions and descriptions for optimal management of renal anaemia. The patients most likely to derive the greatest long-term benefit from correction of anaemia are those with chronic kidney disease who are pre-dialysis. Early intervention to correct anaemia has the potential to impact on the progression of chronic kidney disease and affect patient morbidity, hospitalization rates, quality of life and mortality. This review considers current guidance on anaemia management, the evidence behind the guidance and the data shortfalls in an attempt to provide a topical overview of current understanding and future directions for optimal management of renal anaemia, particularly in high-risk groups.

Topics: Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Diseases; Referral and Consultation; Renal Dialysis

Resistance to erythropoiesis-stimulating agents (ESA) in patients with chronic kidney disease (CKD) can be associated with evidence of enhanced systemic inflammatory responses. This review considers the inflammatory mechanisms thought to be involved in the development and aetiology of anaemia of CKD that may help our understanding and management of patients with ESA resistance. The potential role of nutritional support and of anti-inflammatory therapies in managing resistance to ESA therapy is discussed and explored.

Topics: Anemia; Anti-Inflammatory Agents; Antioxidants; Chronic Disease; Drug Resistance; Erythropoiesis; Erythropoietin; Ferritins; Humans; Inflammation; Iron; Kidney Diseases; Nitric Oxide; Nutritional Support; Reactive Oxygen Species; Recombinant Proteins

The pathogenetic mechanisms underlying the clonal myeloproliferation and reactive marrow fibrosis that characterize myelofibrosis with myeloid metaplasia (MMM) are poorly understood. Recent advances into the pathophysiology of the disease have not yet translated into effective therapeutic options for patients. There is no standard treatment, and no therapies identified yet, besides allogeneic stem cell transplantation, that will significantly change the natural history of MMM. Treatment is therefore palliative and is geared towards alleviating symptoms of the disease and improving blood counts. Conventional therapies for anemia include androgens and corticosteroids. Cytoreductive agents such as hydroxyurea are indicated for symptomatic organomegaly and the control of leucocytosis or thrombocytosis. Several novel agents have been investigated in the recent past, and include antiangiogenic agents and signal transduction inhibitors that target the angiogenic and fibrogenic cytokines that have been implicated in the pathogenesis of the detrimental bone marrow stromal reaction. Ultimately, an improved understanding of the biological factors that cause the clonal myeloproliferation in MMM will lead to the development of effective therapeutic interventions.

Topics: Androgens; Angiogenesis Inhibitors; Antineoplastic Agents; Azacitidine; Benzamides; Chronic Disease; Decitabine; Erythropoietin; Humans; Imatinib Mesylate; Piperazines; Primary Myelofibrosis; Pyrimidines; Quinolones; Recombinant Proteins

The anaemia associated with chronic renal failure is multi-factorial. Although a relative erythropoietin deficiency is a major factor, it has also been recognized in recent times that uraemia is a chronic inflammatory state, and thus patients with renal failure also develop anaemia due to mechanisms associated with chronic inflammation. Thus, patients with chronic renal failure have activation of various immune cells, both monocytes and T-cells. These mononuclear cells have also been shown to release pro-inflammatory cytokines such as IL-1, IL-6, TNF-alfa and interferon gamma. These cytokines, particularly TNF-alfa and interferon gamma, are known to cause significant suppression of erythropoiesis. The exact molecular mechanism for this effect is not yet clear, but interferon gamma is an important stimulator of apoptosis in various cell types, including erythroid progenitor cells. This effect may be potentiated by other cytokines such as TNF-alfa, and this might then antagonise the anti-apoptotic action of erythropoietin on erythroid progenitors cells, thus reducing responsiveness to exogenous erythropoietic therapy. Chronic renal failure is also associated with increased hepcidin production which may also exacerbate the anaemia by inducing a functional iron deficiency in such patients.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Inflammation; Renal Insufficiency

The importance of anemia in chronic kidney disease (CKD) has become increasingly well recognized over recent years, as have the benefits of treating anemic CKD patients with recombinant human erythropoietin (rHuEPO, epoetin). As well as reducing the need for blood transfusions and the complications associated with renal failure in CKD patients, rHuEPO treatment decreases patient morbidity and mortality, particularly as a result of cardiovascular disease. The strong correlation between anemia, renal failure and cardiac failure is one that has received much attention recently, with each factor recognized to cause the other to worsen in a 'vicious cycle'. Recent studies have concentrated on the possible benefits of anemia treatment in patients with CHF. Currently available data suggest improvements in CHF symptoms, left ventricular ejection fraction (LVEF) and a reduction of hospitalizations associated with anemia correction through epoetin treatment. Available data from CKD patients suggest that anemia management should begin as early as possible, although the optimal target level for individual patients is as yet unclear. In addition to the currently available evidence, additional large, randomized, controlled studies are required to further define the morbidity/mortality benefits of epoetin treatment in CHF patients with anemia.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Prognosis

Recombinant human erythropoietin (rHuEPO) is a hormone essential for normal erythropoiesis. The rHuEPO receptor is distributed in the cardiovascular system predominantly in endothelial cells and cardiomyocytes. RHuEPO has potentially beneficial effects on cardiovascular system, including anti-apoptic, mitogenic and angiogenic activity. On the other hand rHuEPO improves anemia observed in some patients with heart failure. Direct cardiac activity of rHuEPO and indirect influence on anemia suggest that rHuEPO therapy is safe and useful in chronic heart failure patients and other cardiovascular settings.

Topics: Cardiology; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Heart Failure; Humans; Recombinant Proteins; Signal Transduction

Several studies showed that anaemia is commonly observed in patients with Chronic Heart Failure (CHF) and is associated with worsened symptoms and survival. When anaemia in these patients is treated with erythropoietin (EPO), a significant improvement in cardiac function and symptoms was observed. Although it was originally believed that EPO specifically acted on haematopoietical cells, recent evidence demonstrated several non-haematopoietical effects. Ischaemia/reperfusion experiments in rat heart and brain showed large infarct reduction when treated with EPO. Other effects of EPO are related to its pro-angiogenic effects on endothelial cells, which could be of potential value in patients with ischaemic heart disease. These preclinical findings suggest that EPO may have potential effects in cardiovascular disease beyond correction of haemoglobin levels.

Topics: Anemia; Apoptosis; Cardiac Output, Low; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Neovascularization, Pathologic; Recombinant Proteins; Stroke

Anemia can be the cause of heart failure, but also its consequence. The pathogenesis of anemia in chronic heart failure (CHF) has yet to be fully elucidated, but is likely to be complex. Epidemiologic studies suggest that kidney dysfunction (by reducing the erythropoietic response to anemia), inflammation (by inducing erythropoietin resistance), decreased body mass index, old age, female gender, and poor clinical status may be important factors in the development of anemia in CHF. Intestinal malabsorption, chronic aspirin use, and proteinuria predisposes to iron deficiency. Proinflammatory cytokines are likely to play a significant role in anemia in CHF by generating the "anemia of chronic illness" that is a hallmark of inflammatory conditions. Few studies have investigated the mechanisms of anemia in CHF. There is a need for such studies.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Risk Factors

Anemia occurs frequently in chronic heart failure (CHF) patients and is associated with increased morbidity and mortality risk. Clinical trials with recombinant human erythropoietin in patients with chronic kidney disease and concomitant structural heart disease have demonstrated beneficial effects on ventricular remodeling but variable effects on clinical outcome. Preliminary clinical trials in patients with CHF demonstrate that erythropoietin therapy is well-tolerated and associated with short-term clinical benefits. The optimum target hemoglobin, erythropoietin dosing regimen, and role of iron supplementation in patients with CHF are not known. Darbepoetin alfa is a glycosylated derivative of erythropoietin with a prolonged half-life that may allow less frequent dosing in CHF populations. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in CHF patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Humans; Morbidity; Randomized Controlled Trials as Topic; Renal Insufficiency; Treatment Outcome

Derangements of iron metabolism may be present in critically ill patients who develop anemia during a stay in the intensive care unit. Iron supplementation may be appropriate, especially if an underlying nutritional disorder is present. It may be even more critical to replace iron when erythropoietin therapy is used because of the consumption of iron stores that occurs during heme synthesis. Iron therapy is not without risks, and controversy persists regarding the potential for iron overload and infections. Clinical trials that define the optimal dose, route, and timing of iron administration in critically ill patients are lacking. However, studies of iron supplementation in chronic kidney disease, pregnancy, and anemia of prematurity may provide some guidance about approaches to treatment. Clinical evidence and limitations that can assist clinicians in managing iron therapy in the intensive care unit are presented.

Topics: Administration, Oral; Adult; Anaphylaxis; Anemia; Chronic Disease; Critical Care; Dietary Supplements; Erythroblasts; Erythropoietin; Female; Humans; Infant; Infant Care; Infant, Newborn; Infant, Premature; Iron; Iron-Dextran Complex; Kidney Diseases; Pregnancy

Iron deficiency anaemia is one of the most common disorders in the world. Also, one third of inflammatory bowel disease (IBD) patients suffer from recurrent anaemia. Anaemia has significant impact on the quality of life of affected patients. Chronic fatigue, a frequent IBD symptom itself, is commonly caused by anaemia and may debilitate patients as much as abdominal pain or diarrhoea. Common therapeutic targets are the mechanisms behind anaemia of chronic disease and iron deficiency. It is our experience that virtually all patients with IBD associated anaemia can be successfully treated with a combination of iron sucrose and erythropoietin, which then may positively affect the misled immune response in IBD.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Fatigue; Folic Acid; Humans; Inflammatory Bowel Diseases; Iron; Quality of Life; Recombinant Proteins; Vitamin B 12 Deficiency

Topics: Aluminum; Anemia; Angiotensin-Converting Enzyme Inhibitors; Carnitine; Chronic Disease; Drug Resistance; Erythropoietin; Humans; Hyperparathyroidism, Secondary; Inflammation; Iron Deficiencies; Kidney Failure, Chronic; Malnutrition; Recombinant Proteins; Renal Dialysis

Despite the high prevalence and significant morbidity and mortality rates of chronic kidney disease (CKD) related to cardiovascular disease, it remains vastly understudied. Most of the current practice recommendations come from small under-powered prospective studies, retrospective reviews, and assuming patients with CKD will similarly benefit from medications and treatments as patients with normal renal function. In addition, because of the previous lack of a consistent definition of CKD and how to measure renal function, definitions of the degree of renal dysfunction have varied widely and compounded the confusion of these data. Remarkably, despite patients with CKD representing the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus, there has been a systematic exclusion of patients with CKD from therapeutic trials. This review outlines our current understanding of CKD as a cardiovascular risk factor, treatment options, and the future directions that are needed to treat cardiovascular disease in patients with CKD.

Topics: Cardiovascular Diseases; Chronic Disease; Erythropoietin; Glomerular Filtration Rate; Humans; Hyperhomocysteinemia; Kidney Diseases; Myocardial Revascularization; Oxidative Stress; Recombinant Proteins; Risk Factors; United States

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see ). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration

Topics: Anemia; Bone Marrow Transplantation; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Neoplasms; Quality of Life; Survival Analysis; Thromboembolism

The anemia of chronic disease (ACD) is a hypoproliferative anemia defined by a low serum or plasma iron concentration in the presence of adequate reticuloendothelial iron stores. It is been established that ACD results from the effects of cytokines that mediate the immune or inflammatory response. During the past 3 years, the clinical scope of this syndrome has been expanded beyond the traditional chronic infectious, inflammatory, or neoplastic diseases to include other, often acute, syndromes in which the same pathogenetic mechanisms are operating. An improved understanding of the use of the soluble transferrin receptor concentration in clinical medicine has enhanced the ability to diagnose ACD, and further experience with the use of recombinant human erythropoietin in the management of severely affected patients with ACD has provided a basis for rational and effective management. Ongoing studies of the mechanisms contributing to the development of ACD continue to elucidate the pathogenesis of this common and clinically significant syndrome.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Receptors, Transferrin; Syndrome

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Prospective Studies

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

Topics: Acute-Phase Reaction; Anemia; Chronic Disease; Erythropoietin; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Protein-Energy Malnutrition; Quality of Life; Recombinant Proteins; Renal Dialysis; Syndrome; Wasting Syndrome

Polycythemia is one of the key factors involved in the chronic mountain sickness syndrome, a condition frequent in Andean natives but whose causes still remain unclear. In theory, polycythemia may be secondary to abnormalities in ventilation, occurring during day or night (e.g. due to sleep abnormalities) stimulating excessive erythropoietin (Epo) production, or else it may result from either autogenous production, or from co-factors like cobalt. To assess the importance of these points, we studied subjects with or without polycythemia, born and living in Cerro de Pasco (Peru, 4330m asl, CP) and evaluated the relationship between Epo and respiratory variables both in CP and sea level. We also assessed the relationship between sleep abnormalities and the circadian rhythm of Epo. Polycythemic subjects showed higher Epo in all conditions, lower SaO2 and hypoxic ventilatory response, higher physiological dead space and higher CO2, suggesting ventilatory inefficiency. Epo levels could be highly modified by the level of oxygenation, and were related to similar directional changes in SaO2. Cobalt levels were normal in all subjects and correlated poorly with hematologic variables. The diurnal variations in Epo were grossly abnormal in polycythemic subjects, with complete loss of the circadian rhythm. These abnormalities correlated with the levels of hypoxemia during the night, but not with sleep abnormalities, which were only minor even in polycythemic subjects. The increased Epo production is mainly related to a greater ventilatory inefficiency, and not to altered sensitivity to hypoxia, cobalt or sleep abnormalities. Improving oxygenation can represent a possible therapeutic option for this syndrome.

Topics: Altitude Sickness; Autonomic Nervous System; Chronic Disease; Circadian Rhythm; Erythropoietin; Humans; Hypoxia; Indians, South American; Peru; Polycythemia; Respiratory Physiological Phenomena; Sleep

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

The anemia of chronic disease traditionally is defined as a hypoproliferative anemia of no apparent cause that occurs in association with an inflammatory, infectious, or neoplastic disorder, and resolves when the underlying disorder is corrected. Disordered iron metabolism as manifested by a low serum iron, decreased serum transferrin, decreased transferrin saturation, increased serum ferritin, increased reticuloendothelial iron stores, increased erythrocyte-free protoporphyrin, and reduced iron absorption, is a characteristic feature of the anemia of chronic disease and has been thought to be a major factor contributing to the syndrome. A mild shortening of red cell life span also occurs. However, we now know that impaired erythropoietin production and impaired responsiveness of erythroid progenitor cells to this hormone are also important abnormalities contributing to the anemia of chronic disease, and appear to be due to the effects of inflammatory cytokines. Increased intracellular iron may also have a role in the inhibition of erythropoietin production, since the oxygen sensor is a hemoprotein. While the role of inflammatory cytokines in the pathogenesis of anemia of chronic disease appears unequivocal, it has become apparent that disordered iron metabolism, while characteristic of this form of anemia, may not be central to its pathogenesis. It is undisputed that iron absorption is reduced, and that iron administered intravenously is rapidly sequestered in the reticuloendothelial system; however, iron delivery to the bone marrow is not impaired, and erythroid iron utilization is not markedly depressed in anemia of chronic disease. Importantly, recombinant erythropoietin therapy can correct the anemia of chronic disease, but it cannot correct the anemia due to iron deficiency. This refutes the concept that the lack of available iron is central to the pathogenesis of the syndrome. Indeed, it is highly likely that abnormalities such as reduced iron absorption and decreased erythroblast transferrin-receptor expression largely result from decreased erythropoietin production and inhibition of its activity by inflammatory cytokines.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Iron

Anemia management programs typically strive to maintain hemoglobin (Hb) levels in the target range of 11 to 12 g/dL recommended by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). Although nephrology clinicians are constantly alert for conditions that cause hyporesponse to Epoetin alfa therapy, management protocols generally focus on assessing and managing acute disorders that affect the production of red blood cells. A more difficult clinical challenge is how to systematically manage patients with conditions that chronically affect the erythropoietic response and are intractable to routine therapies. This article addresses the etiology and management of chronic conditions that require a specialized anemia management approach to ensure that patients can achieve targeted Hb levels and associated clinical and quality of life benefits. Examples include chronic inflammatory disorders, severe secondary hyperparathyroidism, malignancies, human immunodeficiency virus (HIV), and kidney transplant failure.

Topics: Aged; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Female; HIV Infections; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Neoplasms

Chronic anemia of variable severity occurs in more than two-thirds of patients with multiple myeloma (MM) as a consequence of the B cell malignancy. Its pathogenesis is multifactorial. Besides the altered inflammatory cytokine network, other events are held responsible, namely persistent defect of erythropoietin due to the kidney failure, shortening of red cell survival, accumulation of the serum monoclonal component and platelet dysfunction. Our recent studies have demonstrated that excessive erythroblast apoptosis promoted by myeloma cells drives the appearance of anemia, in particular in patients with severely progressive disease. A number of clinical trials have provided evidence for the effectiveness of recombinant human erythropoietin (rHuEPO-alpha: epoetin alpha) in improving the deregulated erythropoiesis in MM, since it acts as a major erythroid growth factor by exerting a specific anti-apoptotic effect. In the majority of these studies, the long-term treatment of MM-associated anemia with rHuEPO-alpha induced a significant improvement of erythropoiesis, as shown by a stable increase of hemoglobin values (> or = 2g/dL) and reduction of transfusion requirements. In a recent trial which included both a double-blind and an open-label phase, we have documented that rHuEPO-alpha induces a stable improvement of anemia in more than 75% of patients and a significant decrease of fatigue, with an overall recovery of the quality of life. Patients receiving a placebo also achieved similar results in the open-label phase, when they were switched to rHuEPO-alpha.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blood Transfusion; Cell Differentiation; Chronic Disease; Clinical Trials as Topic; Cytokines; Epoetin Alfa; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Multiple Myeloma; Quality of Life; Recombinant Proteins; Treatment Outcome

Erythropoetin therapy has been approved for treatment of medical anemia since 1989. The adoption of this strategy has been rapid in some settings (e.g., renal failure patients) and progressive in others (e.g., cancer patients). Although the risks of blood transfusion have declined substantially, risks associated with (untreated) anemia have undergone new scrutiny. Options such as novel erythropoiesis-stimulating protein bring new alternatives to blood transfusion. Erythropoietin therapy is undergoing renewed scrutiny in the management of anemia, not only because of traditional concerns regarding blood risks but because emerging evidence suggests that improved patient outcomes result from management of anemia.

Topics: Anemia; Chronic Disease; Erythrocytes; Erythropoietin; Growth Substances; Humans

This paper describes three recent, related surveys of anaemia management practice in patients with chronic kidney disease, with particular emphasis on initiation of epoetin therapy. It also compares current practice with the European Best Practice Guidelines (EBPG) for anaemia management. The European Survey of Anaemia Management (ESAM) was a 6 month, longitudinal prospective survey of anaemia management in dialysis patients. Although most survey data concerned patients already on dialysis, some retrospective data concerned initiation of dialysis and epoetin therapy. These findings led to the Predialysis Survey of Anaemia Management (PRESAM), a cross-sectional, retrospective survey of patients beginning dialysis, focusing on referral to renal centres and anaemia management in the year preceding dialysis. The Early Renal Insufficiency Referral Survey (ERIRS) is a further cross-sectional survey currently in progress, investigating referral practices during pre-dialysis care. Collectively, these three surveys provide a wealth of data about pre-dialysis anaemia management. ESAM included data from 14527 patients, PRESAM from 4333 patients, and data from 724 patients enrolled in ERIRS have been analysed. The evidence indicates that, at the time of referral to a renal centre, most patients have haemoglobin concentrations well below the levels recommended by the EBPG. Haemoglobin concentrations are lowest in patients referred within the month prior to the initiation of dialysis. Most patients do not start epoetin treatment until dialysis is initiated, despite having haemoglobin concentrations below the level recommended by the EBPG for the initiation of epoetin. Patients who are referred earlier (i.e. those under the care of the renal centre nephrologist for more than a month before the initiation of dialysis) tend to have higher haemoglobin concentrations and are more likely to be receiving epoetin therapy. Such patients are in the minority, however, indicating that pre-dialysis anaemia management practices continue to fall short of the recommendations of the EBPG.

Topics: Anemia; Chronic Disease; Comorbidity; Erythropoietin; Humans; Kidney Diseases; Nephrology; Referral and Consultation; Renal Dialysis

In patients with chronic kidney disease (CKD), sensitivity to recombinant human erythropoietin (r-HuEPO, epoetin) is of clinical and economic importance. Insight into factors that influence sensitivity and response to epoetin is essential for the adequate management of anaemia. Some factors influencing response to epoetin, such as gender, age, length of time on dialysis, type of dialysis and co-morbidities such as haemoglobinopathy, are not susceptible to clinical intervention. However, many other factors can be controlled. Iron deficiency is the most common factor that limits the response to epoetin. Adequate monitoring of iron status and iron supplementation in patients with CKD will result in a more efficient epoetin response. Increased dialysis dose is associated with improvements in haemoglobin outcome and reduced requirements for epoetin. Dialysis water quality (both chemical and biological) is also important in determining the response to epoetin; 'ultrapure' water reduces epoetin requirements. Some patients, despite adequate epoetin and iron therapy, still have epoetin resistance (low haemoglobin and/or high epoetin requirements). Raised C-reactive protein and/or low albumin may reflect long-standing inflammatory pathology and indicate a need for investigation.

Topics: Aging; Chronic Disease; Drug Resistance; Erythropoietin; Humans; Injections, Subcutaneous; Iron Deficiencies; Kidney Diseases; Recombinant Proteins; Renal Dialysis; Sex Characteristics

Anaemia is an important component of diabetic nephropathy but only recently has it attracted the attention of diabetologists and nephrologists. In diabetic patients, anaemia is the result of diminished erythropoietin production and, to a lesser degree, of increased excretion of erythropoietin in the urine, whereas erythropoietin responsiveness remains unchanged. Although erythropoietin concentrations are predictive of the rate of progression of renal disease, epidemiological studies have failed to show lower haemoglobin concentrations in patients with diabetic compared with non-diabetic renal disease with impaired renal function. However, inappropriately low erythropoietin concentrations and anaemia have been reported in subcohorts of diabetic patients. Further studies are required to determine whether reversal of anaemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, retinopathy and peripheral arterial disease.

Topics: Anemia; Chronic Disease; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Prevalence

In order to be transmitted by their mosquito vector, malaria parasites undergo sexual reproduction, which occurs between specialized male and female parasites (gametes) within the blood meal in the mosquito. Nothing was known about how Plasmodium determines the sex of its gametocytes (gamete precursors), which are produced in the vertebrate host. Recently, erythropoietin, the vertebrate hormone controlling erythropoiesis in response to anaemia, was implicated in Plasmodium sex determination in animal models of malaria. This review examines the available information and addresses the relevance of such a sex determining mechanism for Plasmodium falciparum transmission to mosquitoes, with special reference to low gametocytaemias.

Topics: Anemia; Animals; Chronic Disease; Culicidae; Environment; Erythropoietin; Female; Germ Cells; Humans; Malaria; Male; Plasmodium; Plasmodium falciparum; Sex Determination Processes; Sex Ratio

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Iron; Male; Recombinant Proteins

Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.

Topics: Anemia; Cardiac Output, Low; Chronic Disease; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins

The beneficial effects of treating the anaemia of dialysis-dependent patients with erythropoietin on the improvement of cardiac status, exercise capacity, cognitive function and quality of life are well established. Equally, if not more important is the reduction in morbidity and mortality that accompanies the treatment of anaemia with epoietin. These documented improvements in outcomes of care notwithstanding, mortality and morbidity due to cardiovascular disease (CVD) remain high in dialysis patients. Recent epidemiological evidence indicates that: (i) the prevalence of CVD is very high in patients at the start of dialysis; (ii) pre-existing CVD is the major risk factor for mortality and morbidity on dialysis; (iii) CVD begins early in the course of kidney disease, shows an inverse relationship to kidney function and increases in prevalence and severity with progression of kidney disease; and (iv) corrective measures, which take 3-5 years to show a favourable effect, must be instituted well before the initiation of dialysis. Hypertension and anaemia, which develop in the course of progressive reduction in kidney function, are the principal risk factors for the prevalence of left ventricular hypertrophy (LVH) in those with chronic kidney disease, and their treatment has been shown to arrest or reverse LVH in these individuals. Whereas the treatment of hypertension early in the course of kidney disease has been incorporated into clinical practice, there has been reluctance in the treatment of anaemia because of the possibility of worsening kidney function with epoietin, as shown in rats. There is now convincing evidence that epoietin has no potential adverse effect on kidney function in humans. While the most compelling reason for the early treatment of the anaemia of kidney disease is its beneficial effect on cardiovascular function, other documented potential benefits are improvements in exercise capacity, cognitive function and quality of life.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Prevalence; Renal Replacement Therapy; Risk Factors; Time Factors

The use of hematopoietic growth factors has increased rapidly during the last decade. Among the growth factors available, erythropoietin (EPO) was the first growth factor to be used clinically. To date, EPO has shown activity in the treatment of the tumor-associated anemia and for correction of tumor hypoxia, however, when compared with transfusion of erythrocytes EPO treatment did not significantly prolong survival in cancer patients in any published study so far. Recently, novel extramedullary EPO receptors have been identified leading to a better understanding of the molecular mechanisms of action of EPO. Results from these experiments and from several clinical studies suggest that EPO treatment may be beneficial for patients with (chronic) infections (HIV, inflammatory bowel disease, septic episodes) and for treatment of the fatigue syndrome following cancer chemotherapy. In addition, EPO may also improve stem cell engraftment following high-dose chemotherapy and can increase survival rates of patients with aplastic anemia and myelodysplastic syndrome. Currently, new EPO derivatives, synthetic fusion proteins and gene therapeutic studies are under clinical investigation suggesting that the EPO-induced effects may be increased significantly by these agents in the future.

Topics: Anemia, Aplastic; Chronic Disease; Erythropoietin; Fatigue; Genetic Therapy; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; HIV Infections; Humans; Infections; Myelodysplastic Syndromes; Receptors, Erythropoietin; Recombinant Proteins

Since its introduction, recombinant human erythropoietin (rHuEPO) has become the standard of care for renal anemia. Because of its relatively short half-life, however, it generally is administered two to three times per week. Darbepoetin alfa (novel erythropoiesis stimulating protein [NESP]) is a longer acting erythropoietic agent that allows less frequent dosing to treat anemia. Decreased dosing frequency should result in enhanced patient compliance and convenience and minimize the burden of frequent administration on staff. NESP is biochemically distinct from rHuEPO, having five N-linked carbohydrate chains (two more than rHuEPO). In animal studies, NESP had a half-life approximately three times longer than rHuEPO and raised hemoglobin effectively when administered less frequently than rHuEPO. NESP has been evaluated in clinical trials of dialysis and chronic kidney disease patients. Pharmacokinetic data confirmed that patients with anemia required less frequent dosing with NESP than rHuEPO. After intravenous administration, the mean elimination half-life of NESP was 25.3 hours versus 8.5 hours for rHuEPO. In patients who are rHuEPO-naive and in patients previously managed with rHuEPO, NESP is as effective as rHuEPO for maintaining hemoglobin concentration when administered intravenously or subcutaneously at a reduced frequency of once weekly or once every other week. NESP is well tolerated and has a safety profile comparable to that of rHuEPO. There have been no reports of antibody formation associated with NESP. NESP is an important new tool for physicians to use in the treatment of anemia of chronic kidney disease.

Topics: Anemia; Animals; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Half-Life; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins

* The high rate of proliferation required of the bone marrow renders it highly susceptible to the influence of external factors. * Anaemia is the most common haematological abnormality seen in systemic disorders. * In the anaemia of chronic disease, erythropoietin production is reduced and proliferation of erythroid progenitor cells is also impaired; this anaemia can generally be alleviated by correction of the underlying disease process. * The status of the endocrine system must always be considered in evaluation of a normocytic, normochromic anaemia. * Anaemia in infection can be due to host or parasite factors or to the treatment administered. * Anaemia due to malignant disease responds to erythropoietin therapy in many cases; failure to respond is a poor prognostic sign.

Topics: Anemia; Chronic Disease; Diagnosis, Differential; Erythropoietin; Hemoglobinometry; Humans

Anemia of chronic disease (ACD) is the most frequent anemia found in hospitalized patients, often occurring in subjects suffering from chronic inflammatory disorders. The underlying diversion of iron traffic leads to a withdrawal of the metal from the sites of erythropoiesis and the circulation to the storage compartment in the reticuloendothelial system, thus resulting, at the same time, in hypoferremia and hyperferritinemia. Proinflammatory and antiinflammatory cytokines, acute-phase proteins, and radicals are prominently involved in causing these disturbances of iron homeostasis. The role of these factors, as well as the pathophysiological reasons for the development of ACD, is discussed in this review.

Topics: Acute-Phase Proteins; Anemia; Chronic Disease; Erythropoietin; Free Radicals; Hormones; Humans; Iron; Receptors, Transferrin; Recombinant Proteins; Th1 Cells; Th2 Cells

The anemia found in patients with chronic infectious, inflammatory, and neoplastic disorders, known as the anemia of chronic disease (ACD), is one of the most common syndromes in medicine. A characteristic finding of the disorders associated with ACD is increased production of the cytokines that mediate the immune or inflammatory response, such as tumor necrosis factor, interleukin-1, and the interferons. All the processes involved in the development of ACD can be attributed to these cytokines, including shortened red cell survival, blunted erythropoietin response to anemia, impaired erythroid colony formation in response to erythropoietin, and abnormal mobilization of reticuloendothelial iron stores. In this review, advances in the understanding of the diagnostic, pathophysiologic, and therapeutic aspects of this syndrome are summarized.

Topics: Anemia; Cell Survival; Chronic Disease; Cytokines; Diagnosis, Differential; Erythrocytes; Erythropoietin; Humans; Inflammation; Syndrome

Topics: Anemia; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Cytokines; Erythropoietin; Ferritins; Humans

We experienced a patient on continuous ambulatory peritoneal dialysis (CAPD) who showed hypererythropoietinemia (Epo concentration: 86.7 mU/ml, normal range: 8-36 mU/ml), erythrocytosis, high renin concentration (26.5 pg/ml) and chronic hypotension. In this patient the erythrocytosis progressed along with exacerbation of the chronic severe hypotensive state. This patient had systemic circulatory insufficiency as suggested by the fact that he had a fibrous myocardium and an increased anion gap. We hypothesized that circulatory insufficiency due to chronic severe hypotension may lead to the stimulation of the Epo production, due to a decreased oxygen supply to peripheral tissues and/or to the stimulation of the renin angiotensin system even in patients with end-stage renal failure.

Topics: Aged; Chronic Disease; Erythropoietin; Fatal Outcome; Humans; Hypotension, Orthostatic; Kidney; Kidney Failure, Chronic; Male; Myocardium; Peritoneal Dialysis, Continuous Ambulatory; Renin

Topics: Anemia; Chronic Disease; Erythrocyte Count; Erythropoiesis; Erythropoietin; Humans; Infections; Kidney Failure, Chronic; Neoplasms; Rheumatic Diseases

In many patients with malignant haematological and oncological diseases during the disease the haemoglobin concentration declines. Anaemia can be due to blood losses, less frequently to nutritional deficiency. One of frequent causes is the humoral effect of malignant disease on haematopoiesis and the development of anemia of chronic disease. Anemia of chronic disease has a complex etiology. Decreased production of erythropoietin is one of the participating factors and the pharmacological doses of erythropoietin can restore the number of erythrocytes to normal value. The authors present basic information on chronic anaemia of malignant diseases and principles of erythropoietin treatment of these patients.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

Polycythemia vera shares basic features of pathogenesis with other subtypes of the group of chronic myeloproliferative disorders. All myelopoietic cells are derived from one transformed hemopoietic stem cell. Genetic instability of mitotic clonal cells explains the risk of leukemic transformation, which may be enhanced by cytoreductive treatment. Recent data show that erythroid hyperplasia is not due to erythropoietin hypersensitivity, but rather to abnormal stimulation by other cytokine growth factors. Treatment as established by clinical trials has almost normalized life expectancy in older patients, but the optimal strategy for subgroups of patients is still unknown. For younger patients, new and potentially curative approaches should be investigated.

Topics: Animals; Chronic Disease; Clinical Trials as Topic; Cytokines; Disease Progression; Erythropoietin; Growth Substances; Humans; Life Expectancy; Polycythemia Vera; Practice Guidelines as Topic; Primary Myelofibrosis; Rabbits

Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients. Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemodynamics adversely or to precipitate the onset of end-stage renal failure. Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery. Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects. Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Postoperative Complications; Recombinant Proteins

A patient with advanced multiple myeloma (MM) and renal failure presented a severe chronic anemia requiring frequent blood transfusions. Treatment with recombinant human erythropoietin (rHuEPO) led to a rapid improvement of anemia, and further blood transfusions were not required. Pathophysiological studies about the erythropoiesis in patients with MM and trials with rHuEPO in myeloma-associated anemia are commented.

Topics: Aged; Anemia; Chronic Disease; Combined Modality Therapy; Erythropoietin; Fatal Outcome; Female; Humans; Immunoglobulin kappa-Chains; Kidney Failure, Chronic; Multiple Myeloma; Recombinant Proteins

The anemia found in patients with chronic infectious, inflammatory and neoplastic disorders, known as the anemia of chronic disease (ACD), is one of the most common syndromes in medicine. A characteristic finding of the disorders associated with ACD is increased production of the cytokines which mediate the immune or inflammatory response, such as tumor necrosis factor, interleukin 1 and the interferons. All the processes involved in the development of ACD can be attributed to these cytokines, including shortened red cell survival, blunted erythropoietin response to anemia, impaired erythroid colony formation in response to erythropoietin and abnormal mobilization of reticuloendothelial iron stores. Improved understanding of the role played by cytokines in the pathogenesis of ACD may lead to the development of more specific therapy for this syndrome.

Topics: Anemia; Animals; Chronic Disease; Cytokines; Erythroid Precursor Cells; Erythropoietin; Hematopoiesis; Humans; Iron

Topics: Anemia; Biological Transport; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Inflammation Mediators; Iron

The anemia associated with chronic infectious, inflammatory, and malignant diseases is characterized by a blunted erythropoietin response; for any given decrease in hemoglobin or hematocrit, the increase in serum or plasma erythropoietin is less than would be found in an equally anemic patient with iron deficiency. This observation provides a rationale for the use of recombinant human erythropoietin in the treatment of the anemia in these diseases. During the past year, new information has been reported on the pathophysiology of erythropoiesis in chronic infectious, inflammatory, and neoplastic diseases, and on the use of recombinant human erythropoietin for this anemia. This article reviews these developments.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Humans; Infections; Inflammation; Neoplasms; Recombinant Proteins

We report the case of a 22-year-old woman with onset of erythrocytosis at the age of 9 years. Endocrinological and radiological examinations revealed an elevated catecholamine level and the presence of multiple abdominal tumors. After the removal of the tumors, the catecholamine level normalized, whereas erythropoietin remained at the same level and erythrocytosis persisted. The tumor lysate contained considerable amounts of catecholamine but not erythropoietin. Moreover, no erythropoietin mRNA was detected in the tumor by in situ hybridization. These data suggest that this paraganglioma did not produce erythropoietin. A review of the literature showed the existence of patients with early-onset erythrocytosis complicated with paraganglioma, whose erythrocytosis was not relieved even after the resection of paraganglioma.

Topics: Abdominal Neoplasms; Adult; Chronic Disease; Cyclic AMP; Epinephrine; Erythropoietin; Female; Humans; Norepinephrine; Paraganglioma; Polycythemia

The anemia of chronic disease may be viewed simply as the anemia that accompanies chronic inflammatory, infectious, or neoplastic disorders. Because these conditions are very common, the anemia of chronic disease is one of the most frequent anemias encountered, and is only second in incidence to iron-deficiency anemia. The anemia of chronic disease is primarily an anemia due to underproduction of red cells, with low reticulocyte production, and is most often a normochromic, normocytic anemia. However, in 30% to 50% of patients, the red cells are hypochromic and microcytic and, most often, the serum iron, total iron-binding capacity, and transferrin saturation are reduced in the presence of adequate iron stores. Although the differential diagnosis includes other underproduction anemias, such as those caused by vitamin and mineral deficiencies, renal failure, endocrinopathies, and myelodysplasia, it generally is easily distinguished from these conditions. Nevertheless, an understanding of the pathogenesis of this condition, as well as a means of alleviating the anemia when the chronic disorder persists, has remained elusive. Recently, major advances have occurred toward understanding the pathogenesis of the anemia of chronic disease and its treatment, and these advances are reviewed.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Anemia, Hypochromic; Animals; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Cytokines; Erythropoietin; Humans; Incidence; Neoplasms; Recombinant Proteins

We review data concerning site and regulation of erythropoietin (EPO) production, its effects on target tissue, routes of administration and clinical applications. In the anaemia of chronic renal failure (ACRF) treatment with recombinant human erythropoietin (r-Hu-EPO) has been shown to be effective in both improvement of the anaemia and increase in quality of life. In the anaemia of chronic disease (ACD), associated with various malignant, infectious and inflammatory disorders, many investigators have demonstrated an inappropriately low EPO response to anaemia. Therapeutic trials in patients with ACD mostly lacked sufficient numbers of patients for evaluation of the effects. The results obtained from some studies in AIDS and rheumatoid arthritis and the effect on the number of units of autologous blood obtained from patients planned for elective surgery are encouraging, however. Adverse reactions of r-Hu-EPO treatment are mainly confined to the ACRF population and include hypertension, shunt thrombosis and pain at the injection site. The exact mechanism of action of EPO is not yet fully understood. Large scale clinical trials are required to establish its effects on both the anaemia and quality of life in anaemias other than ACRF.

Topics: Anemia; Chronic Disease; Clinical Protocols; Clinical Trials as Topic; Drug Administration Schedule; Erythropoietin; Humans; Infections; Inflammation; Kidney Failure, Chronic; Neoplasms

Recombinant human erythropoietin (r-HuEPO) has been shown to be remarkably effective in raising the hemoglobin concentrations and improving the quality of life of patients with chronic renal disease. It is currently under investigation for treatment of patients with nonrenal anemias associated with cancer chemotherapy, acquired immunodeficiency syndrome, rheumatoid arthritis, and other chronic illnesses. To date, investigators have shown that patients with mild anemia and low endogenous erythropoietin (EPO) production may be good candidates for such treatment. Conversely, studies have shown that patients with severe anemia and serum EPO concentrations of above 500 mU/mL apparently do not respond to doses used for patients with mild anemia or chronic renal disease. Large doses of r-HuEPO may be of use in such patients, and clinical trials are in progress to determine if it is at least possible to make these patients transfusion-independent.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

There exists a potential for change in the approach to the management of the patient with chronic disease, specifically, the anemia of chronic disease (ACD). One of the components in the pathophysiology of ACD is inadequate erythropoietin response. Normally, as anemia develops, the erythropoietin level does not begin to increase until the hematocrit level decreases below 35%. However, the increase in the erythropoietin level is blunted in ACD. Increasing the hematocrit level by transfusion or recombinant human erythropoietin (r-HuEPO) treatment can subjectively and objectively improve the ACD patient's symptoms and performance. Although objective data in support of blood transfusions do exist, this treatment can carry risks of acute and chronic reactions, infection, and possibly immunosuppression. Treatment with r-HuEPO is a safer, nontransfusion means of increasing the hematocrit level of the patient with ACD symptoms.

Topics: Anemia; Animals; Blood Transfusion; Chronic Disease; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

We reviewed studies on the role of erythropoietin (Epo) in the anaemia of chronic disease (ACD) in rheumatoid arthritis (RA). A relatively impaired Epo response to the anaemia was found in a number of studies although in others serum Epo level was the same as in other types of anaemia. Some arguments are found in favor of a reduced bone marrow-Epo sensitivity although these reflect results mainly from in vitro experiments. It is not yet established whether bone marrow macrophage Epo production is impaired in ACD. In two cases Epo administration to RA patients resulted in increased erythropoiesis. It was concluded that impaired Epo production or reduced bone marrow Epo sensitivity might be associated with ACD but it is not certain whether these factors are causally linked with ACD or side phenomena of RA disease activity. Future Epo treatment in RA and ACD will possibly solve this question.

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Humans

Topics: Blood Transfusion; Chronic Disease; Erythrocyte Transfusion; Erythropoietin; Humans; Purpura; Uremia

The anemia of chronic disease (ACD) is defined as a mild anemia associated with a chronic inflammatory, infectious or neoplastic illness and with a characteristic disturbance of iron metabolism. Many of the findings in ACD can be accounted for by release of a monokine called leukocyte endogenous mediator (LEM), endogenous pyrogen, or interleukin-1. This substance is released from "activated" monocytes. Bacterial endotoxins, certain lymphokines and phagocytic challenges are among the factors stimulating its biosynthesis. LEM induces fever, leukocytosis, biosynthesis. LEM induces fever, leukocytosis, and a variety of biochemical changes, including hypoferremia and alterations in plasma protein synthesis, collectively known as the "acute phase response." It is proposed that ACD results from the long-term elaboration of LEM and that release of this material is the common pathogenetic factor found in the illnesses that are associated with ACD. Some suggestions are made for testing the hypothesis. The hypoferremia associated with ACD is probably caused by defective release of iron from cells--particularly from macrophages, but also from hepatocytes and intestinal epithelium. Two possible mechanisms for this abnormality have been proposed: liberation of lactoferrin from neutrophilic leukocytes and induction of apoferritin synthesis. Neither mechanism has been established. Erythrokinetic studies in ACD have detected a modest reduction of erythrocyte survival without an adequate compensatory increase in the rate of red cell production. The reduced erythrocyte survival is probably related to an increase in phagocytic activity by activated macrophages. Impaired bone marrow response is partly related to the restricted iron supply, but there is substantial evidence for an additional defect in erythropoietin secretion. In some malignant diseases, there is evidence of an additional abnormality: impaired marrow response to a normal amount of erythropoietin. The nature of the erythropoietic defects and the relation of LEM to them remain to be established.

Topics: Anemia; Animals; Apoferritins; Bone Marrow; Chronic Disease; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Ferritins; Hematopoietic Stem Cells; Humans; Interleukin-1; Iron; Lactoferrin; Macrophages; Mice; Neutrophils; Rabbits; Rats

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Diagnosis, Differential; Erythropoiesis; Erythropoietin; Humans; Iron; Neoplasms

Topics: Altitude; Biological Transport; Chronic Disease; Erythropoietin; Heart Diseases; Hemoglobins, Abnormal; Humans; Hypoxia; Lung Diseases; Lung Diseases, Obstructive; Oxygen; Oxygen Consumption; Polycythemia

Topics: Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Animals; Body Temperature Regulation; Cell Membrane; Cell Survival; Chromium Radioisotopes; Chronic Disease; Endotoxins; Erythrocytes; Erythropoiesis; Erythropoietin; Fever; Hematocrit; Hemolysis; Hot Temperature; Iron; Lipid Metabolism; Mononuclear Phagocyte System; Phagocytosis; Rabbits; Spleen

Topics: Acute Disease; Animals; Arteries; Chronic Disease; Erythropoietin; Hematopoietic System; Hemoglobins; Humans; Hypoxia; Methods; Mice; Oxygen; Partial Pressure; Time Factors

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Copper; Disease Models, Animal; Endotoxins; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Freund's Adjuvant; Hematocrit; Humans; Infections; Iron; Mononuclear Phagocyte System; Neoplasms; Porphyrins; Protein Binding; Rats; Transferrin

Topics: Anemia; Anemia, Aplastic; Animals; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Immune Sera; Kidney; Kidney Diseases; Lipids; Mercaptopurine; Polycythemia Vera

Topics: Adult; Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Platelets; Blood Urea Nitrogen; Bone Marrow Cells; Chronic Disease; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Feedback; Female; Hemolysis; Hemostasis; Humans; Hypertension, Malignant; Iron; Kidney; Kidney Concentrating Ability; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Oxygen Consumption; Plasma Volume; Uremia

Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa.. This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia.. Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant.. These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia.. ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017).. gov Identifier: NCT03350347 (November 22, 2017).

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Patient Satisfaction; Renal Insufficiency, Chronic

To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.. Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.. Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities.. Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.. ClinicalTrials.gov: NCT02811263.

Topics: Acute Disease; Chronic Disease; Cohort Studies; Double-Blind Method; Erythropoietin; Female; Gestational Age; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Placenta Diseases; Pregnancy; Risk Factors

Anemia aggravates the disease course and the survival rate of chronic heart failure (CHF) patients. The purpose of the study was to investigate the level of erythropoietin (EPO) in CHF patients with anemic syndrome, with the aim to more accurately assess the severity of the disease and its treatment, depending on the anemia degree.. Patients with ischemic CHF of I-IV functional class (FC) with and without anemia were examined (total number of patients=208, patients with anemia=174). The EPO was determined using the enzyme-linked immunosorbent assay. Before treatment, the patients underwent the following medical therapy: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, long-acting nitrates, diuretics, digoxin, and beta-blockers at individual doses. Depending on the plasma EPO level, the CHF patients with anemia were divided into four randomized groups in terms of treatment.. Normal erythropoietinemia was found in 36.2% of the CHF patients with anemic syndrome (I-III FC), hypoerythropoietinemia in 44.8% (III-IV FC), and hypererythropoietinemia in 18.96% (III-V FC). The EPO level in the blood plasma of the patients with I-II FC CHF with hypoerythropoietinemia, who were treated with methoxy polyethylene glycol-epoetin β (MEB), increased by 2.2 times. Combination therapy with disease-modifying drugs and MEB led to a significant increase in the plasma EPO level in the CHF patients with hypoerythropoietinemia.. It was shown that the EPO level in patients with CHF and anemia did not always drop. Hypererythropoietinemia in patients with CHF and anemia leads to an unfavorable treatment prediction. This necessitates the investigation of the EPO level in all patients with CHF before and after treatment, with the aim of correcting the anemic syndrome. The research showed that the combined therapy of patients with CHF and anemia using MEB medication and iron with regard to the EPO level in the blood plasma improved their overall physical condition, reduced heart failure symptoms and hospitalization frequency, and demonstrated a clear tendency to reduce the general mortality rate.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Digoxin; Diuretics; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Nitrates; Severity of Illness Index

Im Rahmen der vorliegenden Studie sollte der Einfluss des Weichteilschadens auf das klinische Ergebnis nach offener Ellenbogenluxation untersucht werden.. Von Oktober 2008 bis August 2015 wurden insgesamt 230 Patienten mit Ellenbogenluxation behandelt. Diese retrospektive Studie umfasst 21 Fälle von offenen Ellenbogenluxationen. Das Durchschnittsalter der Patienten betrug 49 Jahre alt (20–83 Jahre), 6 Patienten waren weiblich (29%), 15 männlich (71%). Das Bewegungsausmaß des verletzten und unverletzten Ellenbogens wurde erhoben und das funktionelle Ergebnis u. a. mittels Mayo Elbow Performance Score (MEPS), Mayo Wrist Score (MWS) und dem Disability of Arm, Shoulder and Hand (DASH) Score erfasst. Zusätzlich wurden Komplikationen und Revisionsoperationen aufgezeichnet. Der Einfluss des Weichteilschadens (I°/II° offen vs. III° offen) und des Luxationstyps (einfach vs. komplex) auf das klinische Ergebnis wurde analysiert.. Offene Ellenbogenluxationen können mit einem zufriedenstellenden klinischen Ergebnis einhergehen. Insbesondere komplexe offene Ellenbogenluxationen sind jedoch sehr komplikationsbehaftet, wobei neurovaskuläre Komplikationen am häufigsten auftreten.. The current high rate of multidrug-resistant gram-negative bacteria infections among hospitalised patients with cUTIs in the studied area is alarming. Our predictive model could be useful to avoid inappropriate antibiotic treatment and implement antibiotic stewardship policies that enhance the use of carbapenem-sparing regimens in patients at low risk of multidrug-resistance.. The results indicated differential patterns of Inhibition of Return between the High and Low shape/weight based self-worth groups. The High group displayed increased inhibition of return for the shape/weight stimuli relative to control stimuli, while the Low group displayed reduced inhibition of return for the shape/weight stimuli compared to control stimuli. The ED group displayed a similar pattern of results to the High group, but this did not reach significance.. The current findings indicate that young women without an eating disorder who base their self-worth on shape/weight display a pattern of avoidance of shape/weight stimuli that is in direct contrast to those at low risk of developing eating disorders. The possible implications of these specific patterns of inhibition of return across those at varying levels of risk for an eating disorder are discussed along with their implications for intervention approaches.. These results indicated that Sr. An unusually high HbA

Topics: Activities of Daily Living; Acute Disease; Adalimumab; Adaptation, Physiological; Adenosine Triphosphate; Adipose Tissue; Administration, Intravaginal; Adolescent; Adsorption; Adult; Adverse Childhood Experiences; Age Distribution; Age Factors; Aged; Aged, 80 and over; Air Pollution, Indoor; Aldehyde Oxidase; Alginates; Alloys; alpha-Globins; Aluminum Hydroxide; Alveolar Bone Loss; Anaerobiosis; Anesthesia, General; Anesthetics; Animals; Anovulation; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Bacillus cereus; Bacterial Typing Techniques; Bacteroidetes; Base Composition; Biocompatible Materials; Biofilms; Biological Availability; Biological Transport; Biosensing Techniques; Bipolar Disorder; Blood Glucose; Body Mass Index; Bone Regeneration; Boranes; Brachial Artery; Butyric Acid; Candida albicans; Carbon; Carcinoembryonic Antigen; Cell Differentiation; Cell Line, Tumor; Cell Respiration; Cell Survival; Cells, Cultured; Cerebrovascular Circulation; Charcoal; Child; Child Health; China; Chloride Channels; Chlorides; CHO Cells; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromium; Chronic Disease; Chronic Periodontitis; Circular Dichroism; Cities; Cohort Studies; Comamonadaceae; Comorbidity; Coronary Artery Disease; Corrosion; Cricetinae; Cricetulus; Cross Infection; Cross-Sectional Studies; Crowding; Culture Media; Cytokines; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diarylheptanoids; Diclofenac; Disability Evaluation; Diterpene Alkaloids; DNA; DNA Mutational Analysis; DNA, Bacterial; Drug Liberation; Drug Resistance, Multiple, Bacterial; Electrochemical Techniques; Electrodes; Electrolytes; Endothelium, Vascular; Enterococcus faecalis; Epithelial Cell Adhesion Molecule; Epithelial Cells; Erbium; Erythropoietin; Ethanol; Ethylenediamines; Fast Foods; Fatty Acids; Female; Fermentation; Ferric Compounds; Fibroblasts; Flavobacteriaceae; Fluorides; Fluorodeoxyglucose F18; Food Microbiology; Formaldehyde; Furaldehyde; Gamma Cameras; Gene Expression; Geologic Sediments; Glucose Tolerance Test; Glycated Hemoglobin; Glycolipids; Glycosylation; Gracilaria; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Guanine; Health Surveys; HeLa Cells; Hemoglobins, Abnormal; Hexosamines; High Fructose Corn Syrup; High-Intensity Interval Training; Hip Fractures; Hippocampus; HLA-B27 Antigen; Hospitalization; Housing; Humans; Hydrogen-Ion Concentration; Hydrolysis; Hydroxides; Hypercapnia; Hypertension; Hypocreales; Hypromellose Derivatives; Image Processing, Computer-Assisted; Incidence; Indole Alkaloids; Indonesia; Inflammation Mediators; Infrared Rays; Insulin Resistance; Intercalating Agents; Ion Transport; Ionophores; Japan; Kinetics; Kluyveromyces; Letrozole; Linear Models; Lipopolysaccharides; Liposomes; Liver; Lung Diseases; Magnesium Hydroxide; Magnetic Resonance Spectroscopy; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Electron, Transmission; Middle Aged; Mitochondria; Mitochondria, Muscle; Molecular Docking Simulation; Molecular Structure; Muscle, Skeletal; Mutant Proteins; Mutation; Mutation, Missense; Nanocomposites; Nanoparticles; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Nucleic Acid Hybridization; Obesity; Occupational Exposure; Oceans and Seas; Odds Ratio; Organometallic Compounds; Osteogenesis; Ovulation Induction; Oxidation-Reduction; Particle Size; Periodontal Ligament; Permeability; Phaseolus; Phenotype; Philippines; Phosphatidylethanolamines; Phospholipids; Photochemical Processes; Phylogeny; Pichia; Pigmentation; Plant Extracts; Polycystic Ovary Syndrome; Polysaccharides; Postprandial Period; Pregnancy; Pregnancy Rate; Prevalence; Product Surveillance, Postmarketing; Progesterone; Progestins; Protein Engineering; Pseudomonas aeruginosa; Psoriasis; Public Facilities; Rats; Rats, Wistar; Receptors, Thyrotropin; Recombinant Proteins; Reproducibility of Results; Republic of Korea; Retrospective Studies; Rhodobacteraceae; Risk; Risk Assessment; Risk Factors; RNA, Ribosomal, 16S; ROC Curve; Saccharomyces cerevisiae; Salinity; Saliva; Seawater; Seaweed; Sensitivity and Specificity; Sequence Analysis, DNA; Sex Factors; Silver Compounds; Smokers; Social Class; Socioeconomic Factors; Soil Microbiology; Solubility; Soy Foods; Spectrometry, Mass, Electrospray Ionization; Spondylitis, Ankylosing; Staphylococcus aureus; Static Electricity; Steroids; Strontium; Sucrose; Surface Properties; Survival Rate; Sweden; Swine; Synapses; Synchrotrons; Tandem Mass Spectrometry; Tannins; Tea; Temperature; Terpenes; Thalidomide; Thermodynamics; Thiadiazoles; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy; Time Factors; Tissue Distribution; Titanium; Toilet Facilities; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ubiquinone; Urinary Tract Infections; Vaginal Creams, Foams, and Jellies; Venezuela; Vitamin K 2; Waist Circumference; Waste Disposal, Fluid; Wastewater; Water Microbiology; Water Pollutants, Chemical; Whole Body Imaging; X-Ray Diffraction; Young Adult; Ytterbium; Yttrium; Yttrium Radioisotopes; Zinc Compounds

We assess and compare the efficacy of anemia treatment in pregnant women with anemia of chronic disease with true iron deficiency and in women with iron deficiency anemia.. Because of frequent true iron deficiency in pregnant women with anemia of chronic disease, anemia of chronic disease in pregnancy is often falsely diagnosed as iron deficiency anemia.

Topics: Adult; Anemia, Iron-Deficiency; Chronic Disease; Drug Therapy, Combination; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Iron; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; Treatment Outcome

To study correlation between concentration of pathological cytokines and erythropoietin inpatients with chronic heart failure anemic syndrome and also to prove importance of this communication for need of appointment erythropoietin excitants.. 94 patients with chronic heart failure of New York Heart Association (NYHA) class III-IV a left ventricular ejection fraction of 40% or less withanemia w ere idied in inveslain (58 males, 36 females). Anemia was detected when hemoglobin (b) was less than 120 g/l in males and less than in females. 46 patients received traditional treatment of CHF (I group) and 48 patients were treated additionally with erythropoietin (EPO) (II group). Percutaneous EPO 50 IU monthly to patients without iron deficiency for a period of 6 months. Echocardiography parameters, plasma NT and pro-BNP, cytokines, EPO, feritin and 6-minute walking test were assessed at baseline and after treatment.. in patients with CHF and anemia in II group erythropoietin treatment increased Hb levels by 22.4% (p < 0.05) and erythropoietin serum levels by 29.3 +/- 14.3 IU/ml (p < 0.001). Increased erythropoietin level was associated with decrease of cytokines levels: IL 1 by 36.6% (p < 0.001), IL 6 by 54.3% (p < 0.05), TNF alpha by 48.3% (p < 0.05) compared with patients in I group. In erythropoietin-treated patients there is a significant increase of LVEF by 19.04% (p < 0.05) compared with patients from I group. A greater 6-minute distance walked on exercise testing increased by 76.6% (p < 0.05) after treatment with erythropoieitin.. Correction of anemia in patients with chronic heart failure with percutaneous erythropoietin injections 50 IU monthly for 6 month period to improve erythropoietin deficit and cytokines aggression and associated anemia, symptoms and quaity of life.

Topics: Anemia; Chronic Disease; Cytokines; Epoetin Alfa; Erythropoietin; Exercise Test; Female; Heart Failure; Hemoglobins; Humans; Interleukin-1; Male; Middle Aged; Recombinant Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Topics: Aged; Anemia; Biomarkers; Chi-Square Distribution; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Spain; Time Factors; Treatment Outcome

Hemodialysis treatment induces markers of inflammation and oxidative stress, which could affect hemoglobin levels and the response to erythropoietin use. This study sought to determine whether high-flux dialysis would help improve markers of renal anemia, inflammation, and oxidative stress compared with low-flux dialysis.. In a prospective, controlled study, 221 patients undergoing maintenance hemodialysis and receiving darbepoetin-alfa treatment (mean age, 66 years; 55% male) from 19 centers were screened in a 20-week run-in period of low-flux hemodialysis with a synthetic dialysis membrane. Thereafter, 166 patients were enrolled and randomly assigned to receive a synthetic high-flux membrane or to continue on low-flux dialysis for 52 weeks. Data on myeloperoxidase, oxidized LDL, high-sensitivity C-reactive protein, and the Malnutrition Inflammation Score were collected at baseline and after 52 weeks; routine laboratory data, such as hemoglobin, ferritin, and albumin, and the use of darbepoetin-alfa, were also measured in the run-in period. Results After 52 weeks, the low-flux and the high-flux groups did not differ with respect to hemoglobin (mean ± SD, 11.7±0.9 g/dl versus 11.7±1.1 g/dl; P=0.62) or use of darbepoetin-alfa (mean dosage ± SD, 29.8±24.8 μg/wk versus 26.0±31.1 μg/wk; P=0.85). Markers of inflammation, oxidative stress, or nutritional status also did not differ between groups.. Over 1 year, high-flux dialysis had no superior effects on hemoglobin levels or markers of inflammation, oxidative stress, and nutritional status. These data do not support the hypothesis that enhanced convective toxin removal would improve patient outcome.

Topics: Aged; C-Reactive Protein; Chronic Disease; Darbepoetin alfa; Endpoint Determination; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Nutritional Status; Oxidative Stress; Prospective Studies; Renal Dialysis; Serum Albumin

The continuous erythropoietin receptor activator (C.E.R.A.) has a long half-life, a relatively low binding affinity for the erythropoiesis receptor and low systemic clearance. These characteristics permit once-monthly dosing, which could reduce staffing requirements and be advantageous for patients. However, outcomes observed during controlled trials of C.E.R.A. have not been assessed under everyday clinical conditions in which physicians make all therapeutic decisions based on their own experience, rather than according to a pre-defined protocol.. This study aimed to assess whether the efficacy and safety of C.E.R.A. reported during controlled trials are reproducible under routine clinical conditions.. This was a non-interventional, single-cohort, multicentre study carried out in 92 specialist nephrology clinics and private practices in Germany. The study included patients with non-dialysis chronic kidney disease and anaemia, with or without current erythropoiesis stimulating agent (ESA) therapy. C.E.R.A. initiation and dosing was at the discretion of the physician. The primary efficacy variable was the proportion of patients for whom all measured haemoglobin (Hb) values during months 7-9 were within the range 11-12 g/dL ('responders').. 335 patients received ≥1 dose of C.E.R.A.; 150 had previously received ESA therapy. The mean number of doses was 7.6 per patient over a mean follow-up of 7.9 months. Mean ± SD Hb was 10.7 ± 1.1 g/dL at baseline and 11.3 ± 1.1 g/dL at the final visit (efficacy population, n = 205). The primary endpoint, all measured Hb values during months 7-9 within the range 11-12 g/dL, was achieved by 19.0% (39/205) of patients, increasing to 41.5% for Hb 11-13 g/dL, 42.0% for 10-12 g/dL and 76.6% for Hb ≥10 g/dL. Hb fluctuation during months 7-9 was ≤1 g/dL in 185/205 patients (90.2%). C.E.R.A. was well tolerated without novel safety concerns.. Hb levels remained stable during routine use of C.E.R.A. in an unselected population of non-dialysis chronic kidney disease patients with anaemia. C.E.R.A. was administered approximately monthly compared with 3-7 doses per month on previous ESA therapy.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Female; Germany; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Reproducibility of Results

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-β or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Biosimilar Pharmaceuticals; Chronic Disease; Epoetin Alfa; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Neoplasms; Prospective Studies; Recombinant Proteins; Thrombosis; Time Factors; Treatment Outcome; Young Adult

Neutrophil-gelatinase associated lipocalin (NGAL), a tubular injury marker, is associated with iron metabolism in hemodialysis patients. We investigated whether serum NGAL levels reflect iron metabolism in combined chronic heart failure and chronic kidney disease (CHF/CKD) and whether treatment with low-dose erythropoietin stimulating agent (ESA) modulates NGAL levels.. In the EPOCARES trial (ClinTrialsNCT00356733) serum NGAL, hepcidin-25, transferrin saturation (TSAT), reticulocyte hemoglobin content (Ret-He) and endogenous erythropoietin (EPO) levels were measured.. Baseline serum NGAL levels correlated with cystatin C (r=0.767, p<0.001) and baseline EPO levels (r=-0.395, p=0.003). There was no correlation with baseline TSAT, Ret-He, and hepcidin-25 levels. After two weeks, NGAL levels decreased in the ESA-group (p=0.02), while there was no change in the no-ESA group (p=0.62). The magnitude in NGAL decrease in the ESA-group correlated with baseline EPO levels (r=0.431, p=0.01).. In contrast to in HD patients, in combined CKD/ CHF, serum NGAL levels did not correlate with iron metabolism, hence NGAL might reflect tubular damage in these patients. NGAL levels inversely correlated with baseline EPO levels and decreased in response to short-term ESA treatment, which might reflect an effect of ESA on tubular damage. These findings need to be confirmed and alternative explanations should be evaluated.

Topics: Acute-Phase Proteins; Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Erythropoietin; Female; Heart Failure; Hepcidins; Humans; Iron; Lipocalin-2; Lipocalins; Male; Prospective Studies; Proto-Oncogene Proteins; Regression Analysis; Renal Insufficiency, Chronic; Transferrin

If controllable, stem cell activation following injury has the therapeutic potential for supporting regeneration in acute or chronic wounds. Human dermally-derived stem cells (FmSCs) were exposed to the cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in the presence of erythropoietin (EPO). Cells were cultured under ischemic conditions and phenotypically characterized using flow cytometry. Topical EPO application was performed in three independent clinical wound healing attempts. The FmSCs expressed the receptor for EPO. EPO had a strong inhibitory effect on FmSC growth in the absence of IL-6 and TNF-α. With IL-6, the EPO effects were reversed to that of growth stimulation. TNF-α had the strongest stimulatory effect. In contrast, IL-1β had an inhibitory effect. Topically applied EPO considerably enhanced wound healing and improved wound conditions of acute and chronic wounds. Site specificity of stem cell activation is mediated by IL-6 and TNF-α. In trauma, EPO ceases its inhibitory role and reverts to a clinically relevant boosting function. EPO may be an important therapeutic tool for the topical treatment of acute and chronic wounds.

Topics: Acute Disease; Adult; Aged; Biomarkers; Cell Proliferation; Cells, Cultured; Child, Preschool; Chronic Disease; Cytokines; Dermis; Drug Synergism; Erythropoietin; Female; Flow Cytometry; Humans; Male; Middle Aged; Phenotype; Receptors, Erythropoietin; Sequence Analysis, Protein; Stem Cells; Wounds and Injuries

Darbepoetin alfa (KRN321) is a recombinant protein that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. The efficacy and safety of KRN321 administered subcutaneously to patients on peritoneal dialysis (PD) were tested.. In a multicenter, open-label, single-arm study, KRN321 was administered subcutaneously to patients on PD for 26-28 weeks. Ninety-six patients initially were given a 60 μg subcutaneous dose once every 2 weeks until a target of Hb (11.0-13.0 g/dL) was achieved. Thereafter, their dose was every 2 or 4 weeks.. After the target of Hb was reached in most subjects (96.9%), it was maintained with KRN321 administered every 2 or 4 weeks. On completion of (or withdrawal from) study, 65 subjects (67.7%) maintained the target Hb. Although a number of adverse event related to hypertension occurred, their incidence did not appear to be related to Hb or its rate of increase. These events could be controlled adequately by interrupting or reducing the dose, and/or treatment with antihypertensives.. The efficacy and safety of KRN321 when administered subcutaneously for 28 weeks to PD patients were confirmed. It was suggested that the quality of life of patients can be improved by treatment with KRN321 due to the reduced frequency of administration.

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Japan; Kaplan-Meier Estimate; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Quality of Life; Time Factors; Treatment Outcome

This study aims to examine predictors of cardiovascular mortality and morbidity in patients with chronic kidney disease (CKD). Individuals with the triad of diabetes, CKD, and anemia represent a significant proportion of patients with cardiovascular disease and are at particularly high risk for adverse outcomes.. Using Cox proportional hazards models, we identified independent predictors of the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for myocardial ischemia, or heart failure (HF) in 3,847 patients in the TREAT, 961 (25%) of whom experienced this outcome. The predictors (ranked by χ(2) value) were prior HF (hazard ratio [HR] 1.74, 95% CI 1.51-2.01), age (HR 1.03, 95% CI 1.02-1.04 per year), log urine protein/creatinine ratio (HR 1.19, 95% CI 1.13-1.26 per log unit ), C-reactive protein ≥6.6 mg/L (HR 1.44, 95% CI 1.23-1.69, compared with C-reactive protein ≤3.0 mg/L), and abnormal electrocardiogram (HR 1.42, 95% CI 1.21-1.66 ), all P < .0001. Addition of cardiac-derived biomarkers (subset of first 1,000 patients enrolled) significantly enhanced risk estimation, with N-terminal pro B-type natriuretic peptide becoming the highest ranked predictor of outcome (HR 1.30, 95% CI 1.15-1.46 per log unit, P < .001) and troponin T providing additional predictive information. These biomarkers improved risk classification in 17.8% (9.4%-26.2%) of patients.. In patients with diabetes, CKD, and anemia, cardiovascular risk is most strongly predicted by age, history of HF, C-reactive protein, urinary protein/creatinine ratio, abnormal electrocardiogram, and 2 specific cardiac biomarkers, serum N-terminal pro B-type natriuretic peptide and troponin T, which are elevated in many. These findings suggest ways to improve cardiovascular risk stratification of patients with predialysis CKD, support the concept of cardiorenal syndrome, and may help target therapy.

Topics: Aged; Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Prognosis

Mitomycin C (MC) is used as therapy against solid tumors, also combined with other chemotherapeutic agents or radiotherapy. It may cause acute, subacute, or chronic anemia capable of modifying the results of chemo- and radiotherapy. Erythropoietin may be lowered by cancer itself or because of chemoradiotherapy. There are few studies investigating the relationship between erythropoietin and chronic anemia.We prospectively analyzed the chronic anemia and erythropoietin in 38 patients with solid cancer. Patients were 40 to 82 years of age. MC was randomly given every 3 weeks as a single drug at 10 or 20 mg/m². When myelotoxicity occurred the next therapy cycle was delayed until recovery. RBC indices, hemolysis, erythropoietin, liver and kidney function were studied. MC cycles were 136 (3.6 ± 1.4 per pt), 32 being delayed because of myelotoxicity.Hematocrit, hemoglobin and RBC were inversely related to the cumulative dose (r = 0.70 to 0.86; p 0.03 to 0.01) of MC. Other tests remained stable. Anemia occurred almost twofold earlier in the 20 mg/m² group (p=0.049). basal erythropoietin, already lower than in age and sex watched 81 non cancerous subjects (p<0.001), decreased during MC therapy (p<0.01). For each given MC mg/m² a 0.0372 Hb mg/dl reduction occurred. Chronic anemia due to MC is accompanied by erythropoietin reduction. These results can help in designing chemoradiotherapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Chemoradiotherapy; Chronic Disease; Disease Progression; Dose-Response Relationship, Drug; Erythrocytes; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Mitomycin; Neoplasms; Prospective Studies

The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Comorbidity; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Kidney Diseases; Male; Renal Dialysis

Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly.. Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11-13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50-53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953.. Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups.. Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

Topics: Aged; Anemia, Iron-Deficiency; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Carriers; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anaemia is a common complication of chronic kidney disease. A number of studies have identified an adverse association between haemoglobin (Hgb) variability and mortality. To date, no study has evaluated the impact of Hgb variability on mortality in the setting of a uniform Hgb target and erythropoiesis-stimulating agents (ESA) dosing strategy.. One hundred and fifty-four haemodialysis (HD) patients from a previous randomized anaemia management study were followed up for up to 6 years. The impact of Hgb variability and ESA dosing parameters on subsequent mortality risk were evaluated.. More rapid rises in Hgb (Hgb deflect(pos)) and ESA dose increases were independently associated with mortality in multivariate analysis, whereas more rapid Hgb declines (Hgb deflect(neg)) and ESA dose decreases were not. Each gram per litre per week increase in Hgb deflect(pos) was associated with an adjusted hazard ratio (HR) of 1.23 (1.03-1.48), while for every 1000-unit increase in ESA dose, the adjusted HR was 1.12 (1.01-1.24). Factors associated with positive Hgb deflections included frequency and magnitude of ESA dose changes, baseline Hgb, patient weight and presence of an HD catheter.. Rapid Hgb rises and greater average Eprex dose increases were independently associated with a higher mortality risk in HD patients after adjustment for baseline Hgb and Eprex dose. A randomized controlled trial evaluating different ESA dosing strategies in response to individual patient ESA responsiveness is needed.

Topics: Aged; Anemia, Iron-Deficiency; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Renal Dialysis; Retrospective Studies; Survival Rate; Treatment Outcome

Anaemia is common in patients with chronic kidney disease (CKD) and can be managed by therapy with erythropoiesis-stimulating agents (ESAs). Epoetin delta (DYNEPO, Shire plc) is the only epoetin produced in a human cell line. The aim of this study was to demonstrate the safety and efficacy of subcutaneously administered epoetin delta for the management of anaemia in CKD patients (predialysis, peritoneal dialysis or haemodialysis). This was a 1-year, multicentre, open-label study. Patients had previously received epoetin subcutaneously and were switched to epoetin delta at an identical dose to their previous therapy. Dose was titrated to maintain haemoglobin at 10.0-12.0 g/dL. The primary endpoint was mean haemoglobin over Weeks 12-24. Secondary analyses included long-term haemoglobin, haematocrit and dosing levels. Safety was assessed by monitoring adverse events, laboratory parameters and physical examinations.. In total 478 patients received epoetin delta, forming the safety-evaluable population. Efficacy analyses were performed on data from 411 of these patients. Mean +/- SD haemoglobin over Weeks 12-24 was 11.3 +/- 1.1 g/dL. Mean +/- SD weekly dose over Weeks 12-24 was 84.4 +/- 72.7 IU/kg. Haemoglobin levels were maintained for the duration of the study. Epoetin delta was well tolerated, with adverse events occurring at rates expected for a CKD patient population; no patient developed anti-erythropoietin antibodies.. Subcutaneously administered epoetin delta is an effective and well-tolerated agent for the management of anaemia in CKD patients, irrespective of dialysis status.. http://www.controlled-trials.com ISRCTN68321818.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Patient Dropouts; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Young Adult

Increased oxidative and nitrosative stress are important mediators of left ventricular (LV) and vascular dysfunction in patients with chronic heart failure (CHF). This study investigated the effects of darbepoetin alfa on plasma markers of oxidative and nitrosative stress in patients with CHF with anemia. Thirty patients with CHF (LV ejection fraction [LVEF] <40%, hemoglobin <12.5 g/dl, and serum creatinine <2.5 mg/dl) were randomly assigned (1:1) to receive either a 3-month darbepoetin alfa regimen at 1.5 microg/kg every 20 days plus oral iron or placebo plus oral iron. Plasma B-type natriuretic peptide (BNP), markers of oxidative (oxidative, malondialdehyde, carbonyl proteins; antioxidative, glutathione) and nitrosative (nitrotyrosine) stress, LVEF, and 6-minute walked distance were assessed at baseline and after treatment. A significant improvement in LVEF and 6-minute walked distance was observed in only darbepoetin-treated patients. Plasma BNP (F = 14.8, p = 001), malondialdehyde (F = 9.4, p = 0.006), protein carbonyl (F = 9.2, p = 0.006), and nitrotyrosine (F = 4.4, p = 0.045) were significantly decreased, along with an increase in antioxidative glutathione (F = 4.2, p = 0.049) after darbepoetin alfa treatment. These factors were unaffected in placebo-treated patients. Darbepoetin-induced percentages of change in carbonyl protein significantly correlated with respective changes in plasma BNP (r = 0.55, p <0.05) and LVEF (r = -0.46, p <0.05). Finally, a drug-induced percentage of decrease in nitrotyrosine significantly correlated with the respective improvement in 6-minute walked distance (r = -0.63, p <0.05). In conclusion, darbepoetin alfa attenuated deleterious effects of oxidative and nitrosative stress into the cardiovascular system of anemic patients with CHF, improving also cardiac function and exercise capacity.

Topics: Aged; Anemia; Cardiomyopathies; Chronic Disease; Darbepoetin alfa; Erythropoietin; Exercise Tolerance; Female; Heart Failure; Hematinics; Humans; Male; Middle Aged; Nitrosation; Oxidative Stress

The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet).. Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events).. This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation.. Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.

Topics: Administration, Oral; Adult; Anemia; Australia; Chronic Disease; Darbepoetin alfa; Delayed-Action Preparations; Erythropoietin; Ferritins; Ferrous Compounds; Hematinics; Hemeproteins; Hemoglobins; Humans; Iron; Kidney Diseases; Peritoneal Dialysis; Treatment Outcome

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Topics: Aged; Anemia; Biomarkers; Case-Control Studies; Chronic Disease; Cytokines; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Inflammation; Interleukin-6; Interleukin-8; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Tumor Necrosis Factor-alpha; Up-Regulation

Extending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life ( approximately 130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis.. STRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia) was a multicentre, open-label randomized phase III study to evaluate the efficacy and safety of intravenous C.E.R.A. administered once every 2 weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA). Adult patients on dialysis receiving stable intravenous DA once weekly (QW) or Q2W were randomized (1:1) to continue their current DA regimen (n = 156) or receive intravenous C.E.R.A. Q2W (n = 157) for 52 weeks. Doses were adjusted to maintain Hb levels within +/- 1.0 g/dl of baseline and between 10.0 and 13.5 g/dl. The primary endpoint was the mean Hb change between baseline and the evaluation period (weeks 29-36).. Most patients (>80%) received DA QW before randomization. The mean (95% CI) difference between C.E.R.A. and DA in the primary endpoint was 0.18 g/dl (-0.05, 0.41), within a pre-defined non-inferiority limit. C.E.R.A. was clinically non-inferior to DA (P < 0.0001) in maintaining Hb levels. Both treatments were well tolerated.. Stable Hb levels were successfully maintained in patients on haemodialysis directly converted to Q2W intravenous C.E.R.A. from DA.

Topics: Aged; Anemia; Australia; Canada; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Endpoint Determination; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Topics: Aged; Anemia; Chronic Disease; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Risk; Treatment Outcome

Optimal hemoglobin targets for chronic kidney disease patients receiving erythropoiesis-stimulating agents remain controversial. The effects of different hemoglobin targets on blood transfusion requirements have not been well characterized, despite their relevance to clinical decision-making.. Five hundred ninety-six incident hemodialysis patients without symptomatic cardiac disease were randomly assigned to hemoglobin targets of 9.5 to 11.5 g/dl or 13.5 to 14.5 g/dl for 96 wk using epoetin alfa as primary therapy and changes in left ventricular structure as the primary outcome (previously reported). Patients were masked to treatment assignment. Blood transfusion data were prospectively collected at 4-wk intervals.. The mean age and prior duration of dialysis therapy of the study population were 50.8 and 0.8 yr, respectively. Previously reported mortality was similar in low and high-target subjects, at 4.7 (95% confidence interval 3.0, 7.3) and 3.1 (1.8, 5.4) per hundred patient years, respectively. Transfusion rates were 0.66 (0.59, 0.74) units of blood per year in low and 0.26 (0.22, 0.32) in high-target subjects (P < 0.0001). Hemoglobin level at transfusion (7.7 [7.5, 7.9]) versus 8.1 [7.6, 8.5] g/dl) were similar with both groups. High hemoglobin target was a significant predictor of time to first transfusion independent of baseline associations (hazard ratio = 0.42; 95% confidence interval = 0.26-0.67).. In hemodialysis patients with comparatively low mortality risks, normal hemoglobin targets may reduce the need for transfusions.

Topics: Anemia; Blood Transfusion; Canada; Chronic Disease; Epoetin Alfa; Erythropoiesis; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

Darbepoetin alfa is used to treat renal anemia; however, little information is available concerning its use during the posttransplant period, especially in HCV-positive patients treated with ribavirin for active hepatitis C.. This study investigated the efficacy and safety of using darbepoetin alfa in this population during a 6-month treatment period. All anemic patients were HCV/RNA-positive, treated with ribavirin, and had impaired renal function. Patients (n=7) who had not been treated previously with recombinant human erythropoietin (rHuEPO) were placed in "group no rHuEPO." Patients previously with recombinant human erythropoietin (n=16; "group rHuEPO") were switched to darbepoetin alfa according to the European summary of product characteristics.. Seventy-three percent of the patients were men. The mean creatinine clearance at baseline was 58.7 -/+ 21.5 mL/min. All patients received an immunosuppressive treatment. Although mean hemoglobin levels remained stable in group no rHuEPO and increased in group rHuEPO, the difference was not statistically significant. Also, the median darbepoetin-alfa-weighted dose in group no rHuEPO increased while it remained stable in group rHuEPO, as did the median daily dosage of ribavirin; however, these differences were not statistically significant. Creatinine levels and creatinine clearance levels remained stable throughout the study. No significant medical events related to the treatment were reported during the study.. Darbepoetin alfa was found to be efficient and well tolerated in correcting renal anemia in transplant recipients treated with ribavirin for active hepatitis C.

Topics: Anemia; Antiviral Agents; Chronic Disease; Creatinine; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Liver Transplantation; Male; Pilot Projects; Postoperative Care; Prospective Studies; Retrospective Studies; Ribavirin; RNA, Viral; Treatment Outcome

Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-*, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin-* treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.

Topics: Aged; Anemia; Biomarkers; C-Reactive Protein; Chronic Disease; Cytokines; Darbepoetin alfa; Erythropoietin; Fas Ligand Protein; fas Receptor; Female; Heart Failure; Hematinics; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Male; Middle Aged; Solubility; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

This study examined the efficacy of C.E.R.A., a continuous erythropoietin receptor activator, for correcting anemia in patients who had chronic kidney disease (CKD) and were not on dialysis.. In this open-label, randomized, parallel-group, Phase III study, 324 adult patients with CKD not on dialysis nor receiving treatment with erythropoiesis-stimulating agents (ESAs) were randomly assigned (1:1) to receive subcutaneous C.E.R.A. once every 2 wk or darbepoetin alfa once weekly during an 18-wk correction period and a 10-wk evaluation period. Thereafter, patients receiving C.E.R.A. were randomly assigned to C.E.R.A. once every 2 wk or once monthly, and patients receiving darbepoetin alfa could receive darbepoetin alfa once weekly or once every 2 wk for a 24-wk extension period. Dosage was adjusted to achieve a hemoglobin (Hb) response and to maintain Hb +/-1 g/dl of the response level and 11 to 13 g/dl. Primary end points were Hb response rate during correction and evaluation and change in Hb concentration between baseline and evaluation.. Hb response rates were 97.5% for C.E.R.A. and 96.3% for darbepoetin alfa. Adjusted mean changes in Hb from baseline to evaluation were 2.15 g/dl (C.E.R.A.) and 2.00 g/dl (darbepoetin alfa). Analysis showed that C.E.R.A. once every 2 wk was as effective as darbepoetin alfa once weekly for correcting anemia. Hb levels remained stable in all groups during the extension period. C.E.R.A. and darbepoetin alfa were well tolerated.. Subcutaneous C.E.R.A. once every 2 wk corrects anemia in ESA-naïve patients who are not on dialysis.

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Although epoetin alfa is commonly initiated weekly (QW) in anemic chronic kidney disease (CKD) patients, recent evidence indicates that it can be initiated every 2 wk (Q2W) and used in maintenance therapy every 4 wk (Q4W). This study examined the feasibility of initiating epoetin alfa Q4W in anemic CKD patients not receiving dialysis.. This open-label study randomized subjects (1:2:2:2) to treatment with epoetin alfa 10,000 IU QW, 20,000 IU Q2W, 20,000 IU Q4W, or 40,000 IU Q4W for 16 wk. Subjects were > or =18 yr, had hemoglobin <11 g/dl, a glomerular filtration rate of 15 to 90 ml/min per 1.73 m(2), and had not received erythropoietic therapy within 8 wk. The primary analysis was a noninferiority comparison of the 40,000 IU Q4W to the 20,000 IU Q2W group in the per-protocol population with respect to hemoglobin change from baseline to the end of study.. Of 262 subjects randomized, 229 comprised the per-protocol population. Mean hemoglobin change from baseline for the 40,000 IU Q4W group (1.24 g/dl) was not inferior to the 20,000 IU Q2W group (1.11 g/dl) with the lower limit of 95% CI, -0.21 g/dl. In the QW, 20,000 IU Q2W, 20,000 IU Q4W, and 40,000 IU Q4W groups, 90%, 87%, 75%, and 86% of subjects, respectively, achieved a hemoglobin increase > or =1 g/dl. Serious adverse events were similar across all groups.. Epoetin alfa can be initiated Q4W in anemic CKD subjects.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Feasibility Studies; Female; Ferritins; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Iron Compounds; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Transferrin; Treatment Outcome; United States

Emerging evidence suggests that epoetin alfa can be administered at extended intervals of up to 4 wk. This open-label, randomized study was performed to characterize the pharmacokinetic and pharmacodynamic profiles of four dosing regimens of epoetin alfa administered subcutaneously in anemic patients who had chronic kidney disease and were not on dialysis.. Thirty-eight patients, enrolled from nine centers in the United States, were > or =18 yr of age and had hemoglobin <11.0 g/dl and GFR 12 to 60 ml/min per 1.73 m(2). Patients received one of four epoetin alfa dosing regimens: 50 IU/kg three times per week, 10,000 IU once weekly, or 20,000 IU every 2 wk for 36 d or 40,000 IU every 4 wk for 64 d. Each regimen provided a similar dosage of epoetin alfa over 4 wk. Dosage adjustments were not permitted.. Drug exposure to epoetin alfa over 4 wk, based on area under the curve, was somewhat higher with the extended interval regimens compared with the three-times-weekly regimen. Mean change in hemoglobin during the study period was similar for all regimens. No patients were transfused. Three patients experienced five serious adverse events, none of which was considered treatment related.. Extended dosing interval regimens of epoetin alfa yielded modest pharmacokinetic differences but a similar pharmacodynamic response, suggesting that less frequent, higher dosages of epoetin alfa may be as effective as the current three-times-weekly regimen in anemic patients who have chronic kidney disease and are not on dialysis.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Dialysis; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Reticulocyte Count; Treatment Outcome; United States

This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0.268 L/h), central volume of distribution (1.03 L), absorption rate constant (0.0554 h(-1)), and bioavailability (0.708) for a 35-kg male < or = 10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.

Topics: Adolescent; Child; Child, Preschool; Chronic Disease; Erythropoietin; Female; Humans; Infant; Kidney Diseases; Male; Models, Biological; Recombinant Proteins

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

Topics: Adult; Chronic Disease; Cognition; Cognition Disorders; Erythropoietin; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Growth Factors; Neuronal Plasticity; Placebo Effect; Recombinant Proteins; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia; Treatment Outcome

Patients with chronic idiopathic myelofibrosis (CIMF) usually present with anaemia. Treatment is often palliative and the majority of patients receive regular red blood cell (RBC) transfusions. Although recombinant human erythropoietin (rhu-EPO) has been proved effective for the treatment of anaemia in several chronic diseases, including haematological malignancies, its role in the treatment of the anaemia in CIMF is not well established. We report the beneficial effect of rhu-EPO administration in 20 patients with CIMF and discuss the parameters predicting favourable response.. Twenty patients with CIMF (9 women and 11 men) regularly treated with supportive RBC transfusions were included in the study. The median age was 70 years (range 45-81 years). Rhu-EPO, 10,000 U, was given subcutaneously 3 times a week. The median duration of therapy was 83 months, ranging from 13 to 87 months.. Treatment was considered effective if haemoglobin levels increased over 2 g/dl within 12 weeks after enrolment or the RBC transfusion requirements were reduced by 50% within the same interval. Twelve patients (60%) responded to therapy. Responders were mainly female, had smaller spleen size (p = 0.024), low RBC transfusion requirements (< or = 1-2 units per month), and significantly lower endogenous serum erythropoietin (EPO) and beta2-microglobulin (beta2-M) levels when compared with non-responders (p < 0.0001 and 0.00001, respectively). Treatment was well tolerated and none of the patients was withdrawn from the treatment protocol because of side effects.. Rhu-EPO administration is an effective, safe and well-tolerated treatment for patients with CIMF and anaemia leading to a significant reduction in RBC transfusion requirements. Factors predicting favourable response are low endogenous EPO and beta2-M serum levels and slight to moderate splenomegaly.

Topics: Aged; Aged, 80 and over; Anemia; beta 2-Microglobulin; Chronic Disease; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Primary Myelofibrosis; Recombinant Proteins; Spleen; Treatment Outcome

To demonstrate safety and efficacy of epoetin delta for the management of anaemia in predialysis patients with chronic kidney disease (CKD).. This was a multicentre, open-label, uncontrolled study with predialysis CKD patients who had previously received subcutaneous epoetin therapy. Patients were switched to epoetin delta from their previous therapy, at an identical dose. Dose was subsequently titrated to maintain haemoglobin at 10.0-12.0 g/dL. Study duration was 52 weeks.. The primary endpoint was average haemoglobin levels over Weeks 12, 16, 20 and 24. Secondary analyses were performed on the proportion of patients with haemoglobin and haematocrit levels over preset target levels, haemoglobin and haematocrit levels through to study end and dosing levels.. Haemoglobin levels were maintained at 11.3 +/- 1.2 g/dL over Weeks 12-24. Over 80% of the haemoglobin measurements and 95% of the haematocrit measurements were above the predefined target level (haemoglobin > or = 10 g/dL; haematocrit > or = 30%). Weekly dose levels did not change significantly over the course of the trial. Epoetin delta was well tolerated, with adverse events occurring at frequencies expected for this patient population; no patient developed neutralizing anti-erythropoietin antibodies.. Epoetin delta was an effective and well-tolerated agent for the management of anaemia in a subgroup of predialysis CKD patients.

Topics: Adult; Aged; Anemia; Cell Line; Chronic Disease; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Transferrin; Treatment Outcome

Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W).. This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrollment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb >or= 100 g/L during the evaluation period (weeks 21-33).. Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb >or= 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 microg. Darbepoetin alfa was considered to be well-tolerated.. Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.

Topics: Aged; Asian People; Australia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Treatment Outcome; White People

This Phase II study aimed to determine the optimal dose and administration schedule of continuous erythropoietin receptor activator (C.E.R.A.) given subcutaneously (s.c.) in patients receiving dialysis converting directly from s.c. epoetin therapy 1-3 times/week. An extension phase examined long-term safety and efficacy.. Patients were assigned to one of three C.E.R.A. dose groups determined by multiplying the previous weekly dose of epoetin by one of three ratios (0.4/150, 0.8/150, 1.2/150 for groups A, B and C, respectively). Within each group, patients were randomized to once weekly (QW), once every 3 weeks (Q3W) and once monthly (Q4W) schedules. Dose adjustments were not permitted for the first 6 weeks. The core study period was 19 weeks (21 weeks in the Q4W cohorts). Patients could enter a 12-month extension period at the same schedule, aiming to maintain haemoglobin (Hb) at 11-12 g/dL.. 137 patients entered the core period, and 62 continued into the extension period. A dose-dependent relationship was seen in the primary efficacy variable, change in Hb standardized to a 6 week period (p < 0.0001), but effect was independent of schedule. Hb levels were maintained throughout the study, with few dose changes. C.E.R.A. was generally well tolerated and the most frequent adverse event was hypotension.. The results suggest that s.c. C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients converting directly from epoetin 1-3 times/week. Achieving tight Hb control with few dose adjustments at extended administration intervals may offer health benefits and improvements in resource management.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Anemia; Chronic Disease; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anaemia is common in chronic heart failure (CHF) and associated with worse outcome. This randomized, double-blind, placebo-controlled study evaluated the effect of two darbepoetin alfa dosing regimens on haemoglobin (Hb) rate of rise and clinical effects in patients with CHF and anaemia.. Patients with CHF (>or=3 months), left ventricular ejection fraction (LVEF)

Topics: Administration, Cutaneous; Aged; Anemia; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Patient Satisfaction; Stroke Volume; Surveys and Questionnaires; Treatment Outcome

C.E.R.A., a continuous erythropoietin receptor activator, is in development to provide anemia correction and stable maintenance of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy and safety when administered up to once monthly in patients who have CKD and are on dialysis and randomly convert directly from epoetin alpha or beta one to three times weekly.. In this three-arm, comparator-controlled, open-label, randomized, parallel-group, Phase III study, 572 dialysis patients (> or =18 yr) who were receiving stable subcutaneous epoetin one to three times weekly were randomly assigned (1:1:1) to continue epoetin or to receive subcutaneous C.E.R.A. once monthly or twice monthly for 52 wk. Dosage was adjusted to maintain Hb +/-1.0 g/dl of baseline level. Primary end point was mean change in Hb level between baseline and the evaluation period (weeks 29 to 36).. Mean Hb levels during the evaluation period were similar between groups (once-monthly C.E.R.A. 11.5 g/dl; twice-monthly C.E.R.A. 11.7 g/dl; epoetin 11.5 g/dl). The difference between C.E.R.A. and epoetin in mean change (97.5% confidence interval) in Hb concentration between baseline and evaluation was -0.022 g/dl (-0.262 to 0.217) for once monthly and 0.141 g/dl (-0.098 to 0.380) for twice monthly. Analysis demonstrated that C.E.R.A. was as effective as epoetin in maintaining Hb and was well tolerated.. Subcutaneous C.E.R.A. once or twice monthly successfully maintained tight and stable Hb levels in patients who were on dialysis and randomly converted directly from epoetin one to three times weekly.

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis

To evaluate the efficacy and safety of the first human cell line-derived erythropoietin, epoetin-delta, in the management of anemia in patients with chronic kidney disease.. This was a multicenter, randomized, double-blind, parallel-group, active-control, Phase III study. Patients aged > or = 18 years with chronic renal disease requiring hemodialysis, with hemoglobin (Hb) levels in the range 9.6-12.4 g/dl, and who had been treated with recombinant erythropoietin for > or = 90 days before study entry were eligible. In the initial double-blind comparative study phase, patients were randomized in a 3:1 ratio to 24-week treatment with either intravenous (i.v.) epoetin-delta (ED) or epoetin-alpha (EA). Patients then entered a 28-week open-label phase, receiving i.v. ED at a dose equal to that of i.v. ED or EA which they received at the end of the blinded phase.. In total, 752 patients were randomized, of whom 555 patients subsequently received ED and 191 patients EA, with 583 patients (77.5%) completing the double-blind phase and entering the open-label phase. There was no significant difference between groups for the primary endpoint: the average Hb level from Weeks 12-24 of the study. The adjusted mean average Hb level for the modified intent-to-treat (mITT) population was 11.57 g/dl in the ED group (n = 491, mean dose 63.5 IU/kg) and 11.56 g/dl in the EA group (n = 175, mean dose 62.8 IU/kg). Efficacy was maintained on long-term use. Data for Weeks 12-52 show that ED maintained patients' Hb levels in the target range (10-12 g/dl) with a mean Hb level of 11.31 g/dl at a mean ED dose of 63.7 IU/kg. ED therapy was well tolerated, with a similar overall incidence of adverse events (AEs) (94.4%) to the EA group (92.1%) in the double-blind phase (most common events: hypotension, upper respiratory tract infection, muscle cramps, headache). AEs occurring during the open-label phase were generally similar in type and frequency to those reported during the double-blind phase.. The human cell line-derived erythropoietin, epoetin-delta, provides an effective, well tolerated new option for the management of anemia in patients with chronic kidney disease.

Topics: Anemia; Cell Line; Chronic Disease; Double-Blind Method; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins

Patients with chronic allograft nephropathy (CAN) very frequently suffer anemia. Correction of anemia by means of recombinant erythropoietin (rEpo) is possible and useful, but safety and efficacy must be assessed.. This multicenter, prospective, open study included patients with a cadaver renal transplant, CAN, and non-ferropenic anemia. The aim of the study was to determine the safety and efficacy of treatment with rEpo to target hematocrit (HCT) values around 35% and/or hemoglobin (Hb) levels of 11 g/dL.. Twenty-four patients were included: 71% males and 29% females aged 49.5 +/- 14 years. At last follow-up, 48% did not show anemia-related symptoms, and 19% experienced adverse events possibly or probably related to rEpo. In 86% of cases, anemia was corrected and in 71%, graft survival was conserved. Patients whose anemia was not corrected had poor initial renal function (sCr 5 +/- 1 mg/dL vs sCr 3.2 +/- 1 mg/dL, P = .028). Patients with graft survival showed correction of anemia (P = .001) on a relatively low dose of rEpo and without a significant increase in blood pressure.. All patients who had graft survival and only half of those who lost their graft showed a correction of anemia. The rEpo treatment neither accelerated nor decelerated renal failure. The difference between patients in whom anemia was corrected, or not, did not depend upon the previous level of HCT/Hb, but upon worse renal function. Thus, rEpo in patients with CAN is safe and effective, so administration should be initiated early to avoid adverse events deriving from anemia.

Topics: Adult; Anemia; Blood Pressure; Cadaver; Chronic Disease; Creatinine; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Kidney Transplantation; Male; Middle Aged; Safety; Tissue Donors; Transplantation, Homologous

C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, differs from traditional erythropoiesis-stimulating agents in its pharmacokinetic and receptor binding properties. This phase I, randomized, open-label, single-center, single-dose, 3-way crossover study in 42 healthy volunteers compared the pharmacokinetic and pharmacodynamic profile of C.E.R.A. 3.0 microg/kg after subcutaneous injection into the abdomen, arm, or thigh. The pharmacokinetic profile was similar at all 3 injection sites, with a prolonged apparent elimination half-life from 160 to 164 hours, area under the concentration-time curve from 4088 to 4323 ng.h/mL, and clearance/bioavailability from 0.64 to 0.68 mL/h/kg. C.E.R.A. produced a sustained erythropoietic response, and the pharmacodynamic profile (area under the reticulocyte count-time curve and maximum increase in reticulocyte count) was similar for all sites. C.E.R.A. was generally well tolerated, regardless of the administration site. This study suggests that C.E.R.A. has the potential to offer a choice of injection sites in clinical practice. The long half-life may permit effective anemia management with extended dosing intervals. Phase III clinical studies support the role of C.E.R.A. in managing anemia in patients with chronic kidney disease.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Cross-Over Studies; Drug Carriers; Erythropoietin; Female; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Experimental studies have demonstrated interleukin-6 and iron load induce expression of hepcidin (an iron regulatory peptide), whereas anemia and erythropoietin (EPO) suppress its expression. We are the first to explore the relationships of plasma prohepcidin (the pro-hormone of hepcidin) in patients undergoing chronic hemodialysis (HD).. We enrolled 71 chronic HD patients. During the preceding 3 months before enrollment, they all had steady weekly levels of haematocrit (Hct) and fixed subcutaneous doses of recombinant human EPO. Plasma levels of prohepcidin, proinflammatory cytokines, and EPO were determined by ELISA kits.. Of the patients, prohepcidin levels correlated positively with Hct, and negatively with interleukin-6 and EPO. Examined by a multivariate lineal regression method, we found Hct was the only significant predictor of plasma prohepcidin level. However, prohepcidin had no significant correlation with iron profiles.. Our findings suggest prohepcidin expression in chronic HD patients might be positively regulated by Hct.

Topics: Adult; Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; Chronic Disease; Cytokines; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematocrit; Hepcidins; Humans; Inflammation; Injections, Subcutaneous; Interleukin-6; Iron; Male; Middle Aged; Predictive Value of Tests; Protein Precursors; Recombinant Proteins; Renal Dialysis

This study is designed to assess the effect of early and complete correction of anemia by using recombinant human erythropoietin (epoetin) alfa on the progression of chronic kidney disease (CKD).. Patients were randomly assigned to achieve high (13 to 15 g/dL [130 to 150 g/L]) or low (11 to 12 g/dL [110 to 120 g/L]) hemoglobin-level targets during 4 months of stabilization, followed by 36 months of maintenance. Glomerular filtration rate (GFR) decrease was measured by using iohexol clearance. Quality of life, nutrition, and safety also were monitored.. Because of labeling changes for subcutaneous administration of epoetin alfa (Eprex; Johnson and Johnson, Schaffhausen, Switzerland), the study was terminated prematurely. There were 195 patients enrolled in each group; 108 high-hemoglobin and 133 low-hemoglobin patients entered the maintenance phase. Mean maintenance duration was 7.4 months for the high-hemoglobin group and 8.3 months for the low-hemoglobin group. GFR decrease was numerically, but not statistically significantly, lower with the high-hemoglobin group (0.058 versus 0.081 mL/min/1.73 m2/mo [< 0.01 mL/s/1.73 m2/mo]). Physical quality-of-life measures showed trends (Role-Physical, P = 0.055; Physical Function, P = 0.083) or statistically significant improvement (Vitality, P = 0.042) with high hemoglobin levels at the end of the stabilization phase. Adverse events were similar between groups. Cardiovascular adverse events occurred in 25% of the high-hemoglobin and 18% of the low-hemoglobin patients (P = 0.137). Neither epoetin dosage nor hemoglobin level was associated with cardiovascular adverse events or death.. These data suggest that normalization of hemoglobin levels in patients with CKD is safe. Longer duration studies are needed to clarify efficacy benefits with high hemoglobin levels.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Quality of Life; Recombinant Proteins

Darbepoetin alfa, an erythropoiesis-stimulating glycoprotein, has proved efficacious in the treatment of anemia of chronic kidney disease (CKD) in adult subjects. However, little information is available from pediatric populations. We conducted an open-label, non-inferiority, 28-week study comparing the efficacy of darbepoetin alfa with that of recombinant human erythropoietin (rHuEpo) in pediatric subjects with CKD. Subjects, aged 1-18, who were receiving stable rHuEpo treatment (n=124) were randomized (1:2) to either continue receiving rHuEpo or convert to darbepoetin alfa, with doses titrated to achieve and maintain hemoglobin (Hb) levels between 10.0 and 12.5 g/dl. Darbepoetin alfa was considered to be non-inferior to rHuEpo if the lower limit of the two-sided 95% confidence interval (CI) for the difference in the mean change in Hb between the two treatment groups was above -1.0 g/dl. The adjusted mean change in Hb between the baseline and the evaluation period for the rHuEpo and darbepoetin alfa groups was -0.16 g/dl and 0.15 g/dl, respectively, with a difference of 0.31 g/dl (95% CI: -0.45, 1.07) between the means. These results, and the comparable safety profiles, demonstrate that darbepoetin alfa is non-inferior to rHuEpo in the treatment of anemia in pediatric patients with CKD.

Topics: Anemia; Child; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male

Among lipid abnormalities observed in patients with chronic kidney disease (CKD) is a significant decrease in serum high-density lipoprotein cholesterol (HDL-C) levels. In a previously published randomized control trial, we showed that early erythropoietin (EPO) administration in a predialysis population slowed the progression of CKD. In the present nested substudy, we examine whether EPO has an influence on serum HDL-C levels in comparison to other lipid parameters in this population.. Eighty-eight patients with CKD stages 3 and 4 were enrolled in the study. Forty-five patients (group 1) were treated with EPO (50 U/kg/wk), targeting to increase hemoglobin levels to 13 g/dL or greater (>or=130 g/L). The other patients (group 2) remained without treatment until hemoglobin levels decreased to less than 9 g/dL (<90 g/L). The duration of the study was 12 months.. At the end of the study, we observed a statistically significant decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides in both groups. However, serum HDL-C levels significantly increased in only group 1 (from 42.5 +/- 10.4 to 55.9 +/- 8.1 mg/dL [1.10 +/- 0.27 to 1.45 +/- 0.21 mmol/L]; P < 0.001), whereas they were unchanged in group 2. In addition, a significant decrease in atherogenic LDL-C/HDL-C ratio was observed in only group 1. Importantly, the increase in serum HDL-C levels correlated positively with the increase in hemoglobin values in EPO-treated patients.. Our results show that EPO treatment of predialysis patients with CKD significantly increases serum HDL-C levels, which may represent an important antiatherogenic effect of this hormone.

Topics: Adult; Aged; Aged, 80 and over; Cholesterol, HDL; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis

Anemia has received increasing attention as an independent cardiovascular risk factor in patients with chronic kidney disease (CKD); a number of studies have highlighted its clear relationship with CKD mortality, because its impact on cardiac function leads to the development of left ventricular hypertrophy. However, despite the association between higher hemoglobin levels and better outcomes, a number of clinical studies have failed to demonstrate that fully correcting anemia has a positive effect on morbidity and mortality in patients with CKD. The Cardiovascular Reduction Early Anemia Treatment Epoetin beta (CREATE) study was designed from the hypothesis that, as anemia develops early in the course of CKD and nearly at the same time as cardiovascular disease, its earlier correction may provide better protection against the development of cardiovascular abnormalities. This randomized, multicenter, open-label, parallel-group trial involved 603 patients who had moderate anemia (hemoglobin 11 to 12.5 g/dl) and stage 3 to 4 CKD (estimated GFR 15 to 35 ml/min) and were randomly assigned to attain complete or partial anemia correction. The final results are due to be published within a few months, but the preliminary analyses do not show that complete anemia correction leads to any cardiovascular advantage, although the cardiovascular event rate was half that expected, possibly as a result of patient selection, trial effect, and improved medical care. The baseline findings also indicated that the burden of cardiovascular disease already is very high even in relatively early stages of CKD.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Risk Factors; Treatment Outcome

Anemia of chronic disease (ACD) is a frequent complication of chronic inflammation in rheumatoid arthritis (RA). Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting ACD, although with a variable rate of nonresponders. The first aim of this trial was to improve the response to rHuEpo by parenteral iron supplementation in cases of iron-deficient erythropoiesis (IDE). An additional goal was the evaluation of the zinc protoporphyrin content of erythrocytes (ZnPP), the soluble transferrin receptor (sTrfR) serum concentration, and the hemoglobin (Hb) content of reticulocytes (CHr) in stimulated erythropoiesis as diagnostic and prognostic parameters. Thirty RA patients with ACD were treated with subcutaneous 150 IU rHuEpo/kg body weight twice weekly. Intravenous iron supplementation (200 mg iron sucrose once weekly) was added in cases of IDE (n=23), which was defined by the presence of two of three criteria: saturation of transferrin (TrfS) < or =15%, hypochromic erythrocytes (HypoE) > or =10%, and a serum ferritin (Fn) concentration < or =50 microg/l. All 28 completers met the treatment goal, with an increase of the median Hb concentration from 10.3 g/dl to 13.3 g/dl. Epo treatment and iron supplementation was safe and well tolerated in all patients. Monitoring of Fn, TrfS, and HypoE every other week allowed a successful correction of anemia. Retrospective analysis of the evaluable parameters (CHr, sTrfR, and ZnPP) revealed no additional benefit for predicting or monitoring IDE in this setting, although the one or other may be advantageous in other therapeutic situations.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Biomarkers; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Deficiencies; Male; Middle Aged; Protoporphyrins; Receptors, Transferrin; Recombinant Proteins; Reticulocytes

In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions 1 month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin

Topics: Aged; Anemia; Biological Availability; Cardiac Output, Low; Chronic Disease; Cross-Over Studies; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged

Intravenous iron supplementation is an integral part of the management of anemia in patients with chronic kidney disease. Traditionally, this has been administered as an infusion over 1 or more hours, which requires the use of intravenous fluids and administration tubing, along with extra demands on patient and nursing time.. We prospectively investigated the safety and practicality of administering iron sucrose, 200 mg, as a bolus injection over 2 minutes in patients with chronic kidney disease. A total of 2,297 injections were administered to 657 patients. Any adverse events were recorded, including acute anaphylactoid reactions to the iron injection, along with the presence or absence of metallic taste and phlebitis, and these were classified as "serious" and "nonserious.". The most common adverse event was a mild and transient metallic taste that occurred during 412 injections (17.9%); in no case was this of significant distress to the patient. Excluding this, 2,240 injections (97.5%) proceeded uneventfully, and no case of phlebitis was recorded. Adverse events other than metallic taste were recorded in association with 57 injections (2.5%). Seven of these were caused by an acute anaphylactoid reaction to the intravenous iron. All 7 acute reactions resolved completely within 30 minutes with no sequelae, and none required hospitalization. The remaining 50 adverse events consisted of pain during the injection (n = 31), pain after the injection with or without some bruising (n = 9), nausea/gastrointestinal symptoms (n = 3), lethargy (n = 4), and lightheadedness (n = 3).. Administration of 200 mg of iron sucrose as an intravenous bolus injection over 2 minutes is a practical dosing regimen in patients with chronic kidney disease, resulting in considerable savings in time and cost.

Topics: Adult; Aged; Anaphylaxis; Anemia, Hypochromic; Chronic Disease; Cohort Studies; Dysgeusia; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Graft Rejection; Humans; Hypotension; Injections, Intravenous; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Prospective Studies

Chronic mountain sickness or Monge's disease is characterized by an excessive polycythemia in high-altitude dwellers, with a prevalence of 5 to 18% above 3,200 m. To date, no pharmacologic treatment is available.. We evaluated the efficacy of acetazolamide in the treatment of chronic mountain sickness and the importance of nocturnal hypoxemia in its pathophysiology.. A double-blind placebo-controlled study was performed in three groups of patients from Cerro de Pasco, Peru (4,300 m), treated orally for 3 weeks with placebo (n = 10), 250 mg of acetazolamide (n = 10), or 500 mg of acetazolamide (n = 10), daily.. Acetazolamide decreased hematocrit by 7.1% (p < 0.001) and 6.7% (p < 0.001), serum erythropoietin by 67% (p < 0.01) and 50% (p < 0.001), and serum soluble transferrin receptors by 11.1% (p < 0.05) and 3.4% (p < 0.001), and increased serum ferritin by 540% (p < 0.001) and 134% (p < 0.001), for groups treated with 250 and 500 mg of acetazolamide, respectively. Acetazolamide (250 mg) increased nocturnal arterial O(2) saturation by 5% (p < 0.01) and decreased mean nocturnal heart rate by 11% (p < 0.05) and the number of apnea-hypopnea episodes during sleep by 74% (p < 0.05). The decrease in erythropoietin was attributed mainly to the acetazolamide-induced increase in ventilation and arterial O(2) saturation.. Acetazolamide, the first efficient pharmacologic treatment of chronic mountain sickness without adverse effects, reduces hypoventilation, which may be accentuated during sleep, and blunts erythropoiesis. Its low cost may allow wide development with a considerable positive impact on public health in high-altitude regions.

Topics: Acetazolamide; Administration, Oral; Adult; Altitude Sickness; Blood Pressure; Carbonic Anhydrase Inhibitors; Chronic Disease; Circadian Rhythm; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Erythropoietin; Follow-Up Studies; Heart Rate; Hematocrit; Humans; Male; Oximetry; Oxygen Consumption; Treatment Outcome

This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.. One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.. One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).. This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Topics: Adult; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium; Canada; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Heart Ventricles; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Lipids; Male; Middle Aged; Organ Size; Parathyroid Hormone; Phosphates; Recombinant Proteins; Renal Dialysis; Single-Blind Method; Treatment Failure; Ultrasonography

To study the effect of treatment of renal anemia by combination of Bushen Jianpi Recipe (BJR, a Chinese experience recipe for supplementing Shen and supporting Pi) and low dosage erythropoietin (EPO), and the influence of treatment on change of serum tumor necrosis factor alpha (TNF-alpha) so as to explore the possible mechanism of integrative Chinese and western medicine (ICWM) in treating renal anemia.. Patients with renal anemia were randomly divided into two groups, the ICWM group and the control group, symptomatic and supporting treatment such as dialysis, supplementing of ferrous, foliac acid and vitamin B12, was given to both groups. Additionally, to the ICWM group, 50 IU/kg of EPO subcutaneous injection for twice every week, and oral intake of BJR, one dose per day taken in two parts, were given, and to the control group, EPO alone, 50 IU/kg by subcutaneous injecting, 3 times per week, was given. The therapeutic course for two groups was 3 months. Blood levels of hemoglobin (Hb), hematocrit (Hct), TNF-alpha were measured before treatment and the therapeutic effect was observed.. After treatment, the levels of Hb and Hct increased significantly in both groups (P < 0.01), comparison between the two groups in Hb and Hct after being treated for 3 months showed significant difference (P < 0.05). The serum level of TNF-alpha was markedly higher than normal range in both groups before treatment, it significantly lowered after treatment in the ICWM group (P < 0.05), but unchanged in the control group.. Combination of BJR and EPO could significantly inhibit the production of TNF-alpha, this may be an important factor for ICWM in effectively improving sensitivity to EPO.

Topics: Adult; Anemia; Chronic Disease; Drug Therapy, Combination; Drugs, Chinese Herbal; Erythropoiesis; Erythropoietin; Female; Glomerulonephritis; Humans; Male; Middle Aged; Phytotherapy; Recombinant Proteins; Tumor Necrosis Factor-alpha

Anemia occurs in approximately 47% of patients with chronic kidney disease (CKD) not on dialysis. Recombinant human erythropoietin (r-HuEPO, epoetin alfa) has been proven safe and effective for anemia treatment in patients with CKD using a three times-weekly regimen. The current study was conducted to evaluate the clinical safety and efficacy of a less frequent dosing regimen (once weekly) in this population.. This prospective, multicenter, open-label, non-randomized study enrolled 1,557 adult anemic (hemoglobin (Hb) < or = 10 g/dl) CKD patients not on dialysis. Epoetin alfa 10,000 U was administered subcutaneously once weekly for 16 weeks. Titration to 20,000 U once weekly at week 5 was permitted if patients had an increase in Hb < 1 g/dl. Safety and efficacy were assessed by changes in health-related quality of life (Linear Analog Scale Assessment (LASA) and Kidney Disease Questionnaire (KDQ)), changes in hematologic parameters and transfusion utilization, and incidence and severity of adverse events.. 1,338 patients were evaluable for efficacy. Mean Hb level increased from 9.1 g/dl at baseline to 11.6 g/dl at study completion (last observed value after baseline) (p < 0.0001). Overall, 89.8% of patients responded to once-weekly dosing, exhibiting an increase in Hb level of > or = 1 g/dl from baseline. The percentage of patients that required transfusion decreased from 11.1% (baseline) to 3.7% (during the study) (p < 0.0001). All quality-of-life parameters improved significantly from baseline (p < 0.0001). Mean LASA scores for energy, activity and overall quality of life increased from baseline to study completion by 27.9 mm (70.5%), 24.5 mm (57.0%) and 22.6 mm (47.4%), respectively. All 5 KDQ domains showed statistically significant improvements (p < 0.0001). Hb change was a strong predictor for all 5 KDQ domains and the overall score (p < 0.0001). Treatment with once-weekly epoetin alfa was well tolerated, similar to that reported with three times-weekly dosing.. Once-weekly epoetin alfa therapy is safe and effective for treating anemia in patients with CKD not on dialysis, and is associated with significant improvements in functional status and quality of life.

Topics: Aged; Analysis of Variance; Anemia; Blood Transfusion; Chronic Disease; Comorbidity; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Regression Analysis; Treatment Outcome

Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF.. Twenty-six anemic patients aged 57+/-11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [VO2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of VO2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P<0.05). There were significant increases in hemoglobin (11.0+/-0.5 to 14.3+/-1.0 g/dL, P<0.05), peak VO2 (11.0+/-1.8 to 12.7+/-2.8 mL. min(-1) x kg(-1), P<0.05) and exercise duration (590+/-107 to 657+/-119 s, P<0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups.. EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in VO2 is increased oxygen delivery from increased hemoglobin concentration.

Topics: Anemia; Chronic Disease; Erythrocyte Volume; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Forearm; Heart Failure; Hemodynamics; Hemoglobins; Humans; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Plasma Volume; Prospective Studies; Quality of Life; Single-Blind Method; Treatment Outcome; Vasodilation

A multicentre study evaluated the efficacy and safety of darbepoetin alpha administered weekly (QW), every 3 weeks (Q3W), and every 4 weeks (Q4W) to anaemic patients with cancer not concurrently receiving chemotherapy or radiotherapy. The QW portion (n=102) was an open-label, sequential, dose-escalation design; cohorts received darbepoetin alpha QW by subcutaneous (s.c.) injection at 0.5, 1.0, 2.25, or 4.5 micro g kg(-1) week(-1) for 12 weeks. The 12-week placebo-controlled, double-blind Q3W (6.75 micro g kg(-1)) and Q4W (6.75 or 10.0 micro g kg(-1)) schedules (n=86), which enrolled different patients, took place after the QW schedule and were followed by a 12-week, open-label phase. Patients were evaluated for change in haemoglobin end points and red blood cell transfusions, serum darbepoetin alpha concentration, and safety. Selected domains of health-related quality of life (HRQOL) were measured. With QW dosing, at least 70% of each cohort had a haemoglobin increase from baseline of > or =2 g dl(-1) or a concentration > or =12 g dl(-1) (haematopoietic response). In the 4.5 micro g kg(-1) QW cohort, all patients achieved a haematopoietic response (100%; 95% confidence interval (CI)=100, 100). In the Q3W and Q4W schedules, all cohorts had at least 60% of patients who achieved a haematopoietic response. Darbepoetin alpha effectively increases haemoglobin concentration when given QW, Q3W, or Q4W. Less-frequent administration may benefit patients with chronic anaemia of cancer and their caregivers alike.

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome

Topics: Anemia; Chronic Disease; Critical Care; Erythrocyte Transfusion; Erythropoietin; Hematocrit; Hemoglobinometry; Humans; Lung Volume Measurements; Oxygen; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Reference Values; Ventilator Weaning; Work of Breathing

High-flux haemodialysis (HD) has recently been vigorously promoted as a novel standard, and it can indeed efficiently reduce the occurrence of most uraemic symptoms due to middle molecular toxins and/or underdialysis. However, some symptoms remain problematical, particularly peripheral polyneuropathy (PPN). One of the possible reasons for this is that the patients may have low concentrations of some nutrients, e.g. vitamin B(6), necessary for normal peripheral neuron function.. Predialysis serum pyridoxal-5'-phosphate (P5P) level was determined in 36 chronic HD patients who were undergoing high-flux HD and receiving human recombinant erythropoietin. Among them, 26 patients suffered from PPN. Prior to supplementation, these 26 patients were examined and their neurological symptoms were ranked according to our PPN symptom score. Vitamin B(6) (60 mg/day) was randomly prescribed to 14 of them, and vitamin B(12) (500 microg/day) was prescribed to the others. After 4 weeks, all the patients were re-examined.. We found that predialysis serum P5P levels of HD patients with PPN were not significantly lower than those of matched HD patients without PPN. Nonetheless, it was demonstrated that supplementation with vitamin B(6) for 4 weeks significantly increased the predialysis level of P5P and dramatically attenuated PPN symptoms compared with initial symptoms. No improvement was observed in response to vitamin B(12) supplementation.. This result suggests that although vitamin B(6) deficiency could not be demonstrated in patients with chronic renal failure on high-flux HD, vitamin B(6) supplementation was effective in improving PPN symptoms of various aetiologies, possibly because of vitamin B(6) resistance to PPN in these patients.

Topics: Chronic Disease; Diabetic Neuropathies; Erythropoietin; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polyneuropathies; Pyridoxal Phosphate; Pyridoxine; Recombinant Proteins; Renal Dialysis; Vitamin B 12

Treatment with recombinant human erythropoietin (r-hu-Epo) in patients with rheumatoid arthritis (RA) and anaemia of chronic disease (ACD) resulted in improvement of both anaemia and disease activity. Utilities represent a generic and comprehensive quality of life measure, capable of integrating domain-specific information into one overall value which a patient assigns to his state of health. Therefore, the effect of r-hu-Epo on quality of life was studied by measuring utilities, derived from the rating scale and standard gamble, in a 52-week placebo-controlled randomised double-blind study with r-hu-Epo in 70 patients with active RA and ACD. Furthermore, the relation between anaemia as assessed by haemoglobin levels (Hb), disease activity as assessed with the Disease Activity Score (DAS), and utilities was investigated. Compared to the placebo group, significant improvement of Hb (P < 0.001), DAS (P = 0.01) and rating scale utilities (P = 0.002), but not of standard gamble utilities, was observed in the Epo group. Rating scale utilities correlated strongly with DAS (r = -0.47, P < 0.01), Hb (r = 0.37, P < 0.01) and changes in both DAS (r = -0.74, P < 0.01) and Hb (r = 0.44, P < 0.01). Both DAS and Hb contributed significantly to the variance in rating scale utilities (21% and 3% respectively) and to changes in rating scale utilities (43% and 3% respectively). Standard gamble utilities correlated less well with clinical disease variables than rating scale utilities did. These results indicate, that r-hu-Epo improves utility-derived health-related quality of life, most probably by improving both disease activity and anaemia. Utilities, particularly rating scale utilities, correlated well with conventional disease activity variables and proved sensitive to change. Utilities may be a useful tool for investigating quality of life in RA-patients.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Confidence Intervals; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Regression Analysis; Severity of Illness Index; Treatment Outcome

We evaluated the efficacy and safety of and compliance with rH-EPO (150 U/kg three times a week subcutaneously for up to 12 weeks) for treatment of anemia in childhood Crohn's disease (n = 4). The mean hemoglobin level before rH-EPO therapy was 109 gm/L (10.9 gm/dl) (range, 103 to 115 gm/L). The mean hemoglobin level in the three compliant children increased to 138 gm/L (13.8 gm/dl) after treatment. Response time for the correction of anemia ranged from 6 to 12 weeks (mean, 9.5 weeks). Resolution of symptoms of lethargy, poor appetite, and irritability occurred with correction of the anemia. The only adverse effect observed was transient local pain at the injection site.

Topics: Adolescent; Anemia; Child; Child, Preschool; Chronic Disease; Crohn Disease; Erythropoietin; Hemoglobins; Humans; Infant; Recombinant Proteins; Treatment Outcome

We investigated the efficacy and safety of subcutaneous recombinant human erythropoietin (rHuEpo) in 25 children with chronic renal allograft dysfunction (13 girls, 12 boys, mean age 15.8 +/- 4.2 years) for a treatment period of 9-162 (median 43) weeks. rHuEpo was started once weekly at a dose of 105 +/- 25 U/kg per week in 16 children, twice weekly at a dose of 175 +/- 70 U/kg per week in 6 children, and three times weekly at a dose of 270 +/- 28 U/kg per week in 3 children. The hematocrit increased in 21 children from 23.2% +/- 3.1% to 33% +/- 3.1% within 7.2 +/- 4.9 weeks at a mean rate of 1.98%/week. The hematocrit increase and rHuEpo starting dose were linearly related (delta hematocrit/week = 0.8+0.08 U/kg per week, r = 0.44, P < 0.05). The maintenance dose was 74 +/- 23 (43-114) U/kg per week. Four children failed to reach the target hematocrit, most likely due to noncompliance. Seventeen recurrences of anemia ("anemic episodes") during rHuEpo therapy were identified in 12 children, mostly associated with acute or insidious deteriorations in graft function. There was no acceleration of progression of graft dysfunction with rHuEpo treatment. We conclude that subcutaneous rHuEpo at a single weekly dose of 100 IU/kg per week is highly effective in children with chronic graft dysfunction. Children who appear to be rHuEpo resistant or experience rHuEpo-resistant episodes should be assessed for noncompliance, changes in graft function since the last dosage adjustment, and blood loss, such as seen in dysfunctional uterine bleeding in adolescent girls.

Topics: Adolescent; Adult; Anemia; Blood Pressure; Child; Chronic Disease; Erythropoietin; Female; Graft Rejection; Hematocrit; Humans; Injections, Subcutaneous; Kidney Function Tests; Kidney Transplantation; Male; Pain; Recombinant Proteins

Severe forms of epidermolysis bullosa result in a transfusion-dependent chronic anemia and are fatal. The cause of the anemia is unknown. We evaluated five children whose anemia failed to respond to oral iron but who became transfusion independent after treatment with intravenous iron and human recombinant erythropoietin.

Topics: Adolescent; Anemia, Refractory; Blood Transfusion; Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Epidermolysis Bullosa; Erythropoietin; Humans; Infant; Infusions, Intravenous; Iron; Iron Deficiencies; Recombinant Proteins

To evaluate the role of recombinant human erythropoietin (R-HuEpo) in reducing iron infusion, which may exacerbate free radical damage, leading to chronic lung disease.. A multicentre, randomised, placebo controlled, double blind study was carried out in four neonatal intensive care units in Yorkshire. Infants were randomly allocated and received either R-HuEpo (480 U/kg/wk) or placebo by twice weekly subcutaneous injection. The primary outcome measure was the number of days on respiratory support and a secondary outcome the number of blood transfusions required.. Forty two very low birthweight (VLBW) infants were randomly allocated. There was little difference in the need for respiratory support one month after randomisation, but subsequently there was a trend towards a reduction in the proportion requiring respiratory support in the R-HuEpo group (difference at three months -0.50, 95% confidence interval -1.00, 0.17). During stay in hospital, the median number of blood transfusions was lower for infants in the R-HuEpo group (difference in medians -2, 95% CI -4, 0). The study was stopped early because of failure to recruit babies at the expected rate.. R-HuEpo seems to reduce the number of days in oxygen for ill VLBW infants. These data could be used to construct a larger multicentre study to evaluate this effect further.

Topics: Blood Transfusion; Chronic Disease; Double-Blind Method; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Lung Diseases; Oxygen Inhalation Therapy; Recombinant Proteins; Respiration, Artificial

Forty-six patients with rheumatoid arthritis (RA) and documented anemia of chronic disease (Hb < 100/110 g/l) were randomized to receive either human recombinant erythropoietin (r-HuEPO, n = 36, 300 U/kg body weight) or placebo (n = 10) for 12 weeks in a multicenter study. An adequate response was defined as elevation of Hb > or = 120 g/l. Relevant clinical and laboratory assessments were made to evaluate efficacy and secure safety. A significant elevation in Hb from week 10 onwards was noted in twenty-six patients (five drop-outs) out of nine patients receiving placebo (one drop-out) (12 +/- 1.2 g/l vs 4 +/- 0.5 g/l; Hb elevation from 95 g/l to 107 g/l vs 93 g/l to 97 g/l, P < 0.05). Only 14.6%, however, were considered responders according to preset criteria. In the responders a lower initial CRP, a significant reduction in ESR but not in CRP was seen compared to the remaining r-HuEPO group. A significant elevation of energy level was noted in the r-HuEPO group; otherwise, no differences in clinical variables were seen. No serious adverse effects were noted. When analyzing patients receiving oral iron in combination with r-HuEPO and adding five additional, openly selected patients receiving both adequate iron supplementation and r-HuEPO, there was a significant weekly elevation of Hb from week 8 onwards in favor of combination therapy over the ones only receiving r-HuEPO (18 +/- 1.1 g/l vs 7 +/- 1.1 g/l, P < 0.05). The initial six responders had now reached ten of whom seven belonged to the combination therapy group. Response to r-HuEPO in RA patients appears to be dependent on availability of iron and on the degree of inflammation. If r-HuEPO treatment is considered, iron deficiency should always be corrected and strenuous efforts should have been made to control the disease itself.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Iron; Male; Middle Aged; Recombinant Proteins

Anaemia of chronic disease (ACD) is a common feature of active rheumatoid arthritis (RA). Inflammatory cytokines, particularly tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6), are thought to contribute to the pathogenesis of ACD, possibly by inhibiting erythropoietin (EPO) production. In this study, we examined the in vivo effects of TNF-alpha blockade with a chimeric monoclonal antibody, cA2, on erythropoiesis in RA patients with ACD. Administration of cA2 led to a dose-dependent increase in haemoglobin levels compared to placebo and these changes were accompanied by a reduction in both EPO and IL-6 levels. The data support the notion that TNF-alpha is important in the causation of ACD, but suggest a mechanism independent of EPO suppression. Instead, TNF-alpha may act directly on bone marrow red cell precursors.

Topics: Anemia; Antibodies, Monoclonal; Arthritis, Rheumatoid; C-Reactive Protein; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Hemoglobins; Humans; Interleukin-6; Male; Recombinant Fusion Proteins; Tumor Necrosis Factor-alpha

To study whether recombinant human erythropoietin (r-hu-Epo) improves anaemia and reduces disease activity in patients with rheumatoid arthritis and anaemia of chronic disease (ACD).. A 52 week placebo controlled randomised double blind trial with r-hu-Epo was performed in 70 patients with active rheumatoid arthritis and ACD. Thirty four patients were treated with 240 U kg-1 r-hu-Epo subcutaneously, initially three doses weekly, while 36 patients received placebo.. A significant increase of haemoglobin from a median of 112 to 135 g litre-1 occurred in the Epo group within six weeks and could be sustained with reduced doses (median 240 U kg-1 once weekly). Sustained benefit compared to placebo was also apparent by six weeks for disease activity, as indicated by the Paulus 20% response rate. Of patients in the Epo group, 32% eventually showed a Paulus 20% response, compared to 8% of the placebo group (P = 0.016). Significant differences in favour of the Epo group were also observed in the secondary disease activity measures Ritchie index, number of swollen joints, pain score, ESR, and patients' global assessment of disease activity. C reactive protein concentrations did not change significantly.. Treatment of ACD in rheumatoid arthritis with r-hu-Epo is effective in restoring normal haemoglobin levels and also exerts a beneficial effect on disease activity.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins

Cord blood pH, lactate, hypoxanthine, and erythropoietin levels have all been used as markers of either acute or chronic asphyxia. We sought to determine whether these index values were significantly different in infants with or without meconium-stained amniotic fluid.. Fifty-six pregnant women in spontaneous labor at term were divided into two groups on the basis of the presence or absence of meconium-stained amniotic fluid. All meconium-stained fluid was centrifuged, and the volume percentage of particulate matter (i.e., meconium) was recorded. Umbilical artery blood and mixed arterial and venous cord blood were obtained at each delivery. Lactate, hypoxanthine, and erythropoietin levels were measured. Statistical analysis included Student t test and rank sum statistics where appropriate. Normal and Spearman correlation coefficients were also used.. There were no significant differences in mean umbilical artery pH (7.26 +/- 0.06 vs 7.25 +/- 0.10), lactate levels (32.8 +/- 10 mg/dl vs 30.4 +/- 14.2 mg/dl), and hypoxanthine levels (13.4 +/- 6.7 mumol/L vs 14.0 +/- 6.0 mumol/L) in newborns with meconium (n = 28) compared with controls (n = 28). Erythropoietin levels were significantly greater in newborns with meconium (median 39.5 mIU/ml vs 26.8 mIU/ml, p = 0.039). There was no correlation between the amount of particulate matter and any marker of asphyxia.. There was no correlation between markers of acute asphyxia (i.e., umbilical artery blood pH, lactate, or hypoxanthine) and meconium. However, erythropoietin levels were significantly elevated in newborns with meconium-stained amniotic fluid. This latter marker may better correlate with chronic asphyxia.

Topics: Acute Disease; Adolescent; Adult; Amniotic Fluid; Asphyxia Neonatorum; Biomarkers; Chronic Disease; Erythropoietin; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; Hypoxanthines; Infant, Newborn; Lactates; Meconium

Recombinant human erythropoietin (rHuEPO) was administered to males undergoing hemodialysis, and its effects on penile erection and hypothalamus-pituitary-gonadal hormone levels were studied. The subject consisted of 18 males undergoing hemodialysis ranging in age from 22 to 58 years (mean 45.3 years). Chronic glomerulonephritis was present in 16, and diabetic nephropathy in 2, as underlying disease. rHuEPO was administered intravenously at 1,500 U 3 times a week with a target to increase the Ht value to 25% or above. Penile erection was evaluated subjectively by a questionnaire based on a visual analogue scale and objectively by semi quantitative measurement of nocturnal penile tumescence (NPT) using an erectometer. Of the 18 patients, subjective improvements in penile erection were observed in 13 (72%), and objective improvements in NPT were observed in 10 (56%). The administration of rHuEPO may alleviate hyperprolactinemia but was found to have no effect on the FSH, LH, Zn, or HS-PTH level. rHuEPO was suggested to be fairly effective for the treatment of sexual disorders.

Topics: Adult; Chronic Disease; Diabetic Nephropathies; Erectile Dysfunction; Erythropoietin; Glomerulonephritis; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Penile Erection; Recombinant Proteins; Renal Dialysis; Testis

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Humans

Chronic anemia is a common complication in patients with cancer, especially in those with advanced disease or who are under intensive chemotherapy. Because homologous blood transfusions involve some hazards, the safety and efficacy of recombinant human erythropoietin (r-HuEPO) in the treatment of anemic patients with cancer with and without concomitant chemotherapy were studied.. One-hundred two cancer patients with hemoglobin less than 11 g/dl, ferritin greater than 30 micrograms/l, and creatinine < 220 mumol/l were enrolled in the study, 94 were eligible for efficacy evaluation. Sixty-eight patients received chemotherapy (CT group) and 26 had no cytotoxic cancer treatment (NT group). Recombinant human erythropoietin was administered subcutaneously at a dose of 150 U/kg three times per week for 6 weeks; in nonresponders the dose was doubled for the subsequent 6 weeks. Response was defined as the achievement of a hemoglobin increase of 2g/dl. Clinical and laboratory parameters, including serum erythropoietin (EPO) levels, performance status, and quality of life, were investigated at baseline and monitored at regular intervals thereafter.. Response was achieved by 52% and 62% of CT and NT patients, respectively. The highest response rates were observed in patients with lung cancer or with a histology of squamous cell carcinoma (both 80%). In responding patients, the symptoms of anemia subsided. They no longer needed blood transfusions after 4 weeks of therapy; and both their performance status and quality of life improved significantly. The NT patients achieved slightly more favorable results on lower weekly doses: 450 U/kg/week in NT versus 570 U/kg/week in CT patients. Serum EPO levels were higher in nonresponders at baseline and further increased during the course of treatment. Recombinant human erythropoietin was well tolerated by all patients.. This multicenter study in a large patient collective shows that r-HuEPO treatment represents a safe and effective means to increase the red cell mass and eliminate the need for blood transfusions in approximately 50% of the patients with chronic anemia of cancer. Responding patients not only have increased levels of hemoglobin, but their performance status also improves significantly, and they enjoy a significantly enhanced quality of life.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Blood Transfusion; Carcinoma, Squamous Cell; Chronic Disease; Creatinine; Erythrocyte Volume; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Neoplasms; Quality of Life; Recombinant Proteins; Remission Induction

To investigate the possibility of correcting thrombocytopenia of chronic liver disease, 19 patients (6 male and 13 female) with long-term chronic liver disease and platelet count < or = 85,000/microliters were studied. Either a short-term course (7-20 days) of recombinant human erythropoietin, 4000 U daily SQ (12 patients) or placebo (7 patients) was administered. Treatment was interrupted if the platelets rose to > or = 100,000/microliters or if no significant increase was noted after 14 days. After treatment, platelets increased in the recombinant human erythropoietin group (from a baseline value of 70,000 +/- 11,184 to 101,250 +/- 37,625/microliters), while no difference was noted in the placebo group (70,714 +/- 9928 vs 70,000 +/- 10,231/microliters). The increase in the platelet count in the recombinant human erythropoietin group was significant, both compared to baseline values (paired Student's t-test, t = -3.80, p < 0.005) and to the results of treatment in the placebo group (unpaired Student's t-test, t = 2.71, p < 0.02). Eight out of 12 recombinant human erythropoietin-treated patients (66%) reached > or = 100,000/microliters platelets while four (33%) did not. In comparison to responders, non-responders had a significantly lower baseline platelet count (58,500 +/- 7937 vs 75,750 +/- 7498/microliters, t = -3.69, p = 0.004) and failed more frequently than responders to improve their haematocrit in response to recombinant human erythropoietin (Pearson chi 2 = 4.687, p = 0.03). When treatment was discontinued, the platelet count reverted to baseline in a few weeks. In conclusion, recombinant human erythropoietin treatment transiently corrected mild thrombocytopenia in patients with chronic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Blood Platelets; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Liver Diseases; Male; Middle Aged; Recombinant Proteins; Thrombocytopenia

Mean (+/- SD) serum erythropoietin (EPO) levels were 18.6 +/- 5.6 mU/ml in 180 normal Japanese subjects. Serum EPO levels were elevated with a negative correlation on a log scale (r = -0.864, P < 0.005) to hematocrit (Ht) values in anemic patients not associated with rheumatoid arthritis (RA) or chronic renal failure (CRF). Serum EPO levels in patients with RA (31.6 +/- 16.4 mU/ml) were relatively lower than those in normal subjects and anemic patients without RA or CRF when matched for comparative Ht values. Seven anemic patients with RA were treated by daily subcutaneous (sc) injection of recombinant EPO (rEPO, 500-1,000 U/day) for 4 weeks. The patients had initial Ht values of 25.1% or less and maintained stable clinical status. The treatment with rEPO raised serum EPO levels (53.8 +/- 15.2 mU/ml, P < 0.05), which resulted in an increase in Ht values (more than 3%) in 6 out of 7 patients with RA. The mean (+/- SD) Ht values at the end of the treatment with rEPO (500-1,000 U/day) were greater than those before the treatment in the 7 patients with RA (28.5 +/- 4.6 vs. 22.7 +/- 2.5%, P < 0.05). These findings suggest that chronic anemia associated with RA may be corrected by daily sc injection of a small dose of rEPO.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Child; Child, Preschool; Chronic Disease; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Time Factors

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Hypoxia; Renal Insufficiency, Chronic

This cohort study was designed to explore whether roxadustat or erythropoietin could affect thyroid function in patients with renal anemia.. The study involved 110 patients with renal anemia. Thyroid profile and baseline investigations were carried out for each patient. The patients were divided into two groups: 60 patients taking erythropoietin served as the control group (rHuEPO group) and 50 patients using roxadustat served as the experimental group (roxadustat group).. The results indicated that there were no significant differences in serum total thyroxine (TT4), total triiodothyronine (TT3), free triiodothyronine (FT3), free thyroxine (FT4) or thyroid stimulating hormone (TSH) between the two groups at baseline. After treatment, TSH, FT3, and FT4 were significantly lower in the roxadustat group than in the rHuEPO group (. Roxadustat may lead to a higher risk of thyroid dysfunction, including low TSH, FT3 and FT4, than rHuEPO in patients with renal anemia.

Topics: Anemia; Chronic Disease; Cohort Studies; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Inflammatory Bowel Disease (IBD) is recognized as a group of chronic inflammatory disorders, localized in the gastrointestinal tract, which does not have a cure known. Indeed, the pharmacological approaches, commonly used, demonstrate significant toxicity, which highlights the need of investigating new possible treatments. Erythropoietin (EPO) is clinically used in anemic patients, with chronic renal insufficiency, due to its erythropoietic effect. However, it has also been described other non-erythropoietic effects, such as an anti-inflammatory role. There is already preclinical evidence about its anti-inflammatory effect in the IBD context, namely in an acute model of colitis in mice. Therefore, it is relevant to ascertain its anti-inflammatory effect in a chronic model, but mainly its hematopoietic side effect, during chronic treatment.. This experiment aims to evaluate the efficacy and safety of EPO treatment in a chronic 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents.. The induction of chronic colitis consistedofn five weekly intrarectal administrations of 1% TNBS, and then mice were treated daily with 500 IU/Kg or 1000 IU/Kg of EPO, through intraperitoneal injections, for 14 days.. EPO demonstrated a significant anti-inflammatory effect, translated by a significant reduction of the concentration oftumorr necrosis factor-α, fecal calprotectin, and fecal hemoglobin. Moreover, it has also been demonstrated to be safe, considering the cardiovascular system, in terms of extraintestinal manifestations, namely at renal and hepatic functions.. EPO demonstrated to be a promising pharmacological approach to be considered in the management of IBD, being an interesting target for drug repositioning.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colitis; Erythropoietin; Graft vs Host Disease; Inflammatory Bowel Diseases; Mice; Trinitrobenzenesulfonic Acid

Hypoxia-inducible factors (HIFs) play important roles in the pathogenesis of erythrocytosis in chronic mountain sickness (CMS). von Hippel-Lindau (VHL) is a key regulator of hypoxia that can direct the poly-ubiquitylation and degradation of HIFs. Epigenetic mechanisms are believed to contribute toward adaption to chronic hypoxia. Here, we investigated the contribution and mechanism of VHL methylation in rats with erythrocytosis in CMS.. The methylation status of VHL was measured via bisulfite sequencing PCR, while VHL, DNMT1, DNMT3α, and DNMT3β expression were assessed using real-time reverse transcription PCR and western blotting. HIF-2α and EPO expression levels in bone marrow were determined via immunohistochemical staining, and erythroid hyperplasia in bone marrow sections were observed with hematoxylin and eosin staining.. We found that chronic hypoxia triggered erythroid hyperplasia in the bone marrow and increased the quantity of peripheral red blood cells in CMS rats. Chronic hypoxia significantly induced methylation at the CpG site in the VHL promoter, decreased VHL expression, and increased HIF-2α and EPO expression. Chronic hypoxia increased DNMT3α and DNMT3β expression, consistent with the decrease in VHL expression. The DNA methyltransferase inhibitor 5-azacytidine reduced chronic hypoxia-induced erythroid proliferation in the bone marrow of rats with CMS by suppressing VHL methylation and DNMTs expression.. Our study suggests that VHL methylation contributes toward excessive erythrocytosis in CMS by upregulating the HIF-2α/EPO pathway in the bone marrow of rats. We demonstrated that the DNMT inhibitor 5-azacytidine can attenuate erythroid hyperplasia in the bone marrow by demethylating the VHL promoter.

Topics: Altitude Sickness; Animals; Basic Helix-Loop-Helix Transcription Factors; Chronic Disease; Disease Models, Animal; DNA Methylation; Erythropoietin; Gene Expression Regulation; Hypoxia; Male; Polycythemia; Rats; Rats, Sprague-Dawley; Von Hippel-Lindau Tumor Suppressor Protein

Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown.. We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure.. Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin.. Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

Topics: Aged; Anemia; Animals; Biomarkers; Blood Pressure; Chronic Disease; Disease Models, Animal; Erythropoietin; Female; Fibroblasts; Fibrosis; Gene Expression; Humans; Hypotension; Hypoxia; Kidney; Kidney Diseases; Male; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Renin; Signal Transduction

Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.

Topics: Altitude; Altitude Sickness; Chronic Disease; Erythroid Precursor Cells; Erythropoietin; Gene Expression Regulation; Genetic Predisposition to Disease; Homeostasis; Humans; Hypoxia; Iron; Leukocytes, Mononuclear; Oxygen; Transcriptome

An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM. Conversely, administration of IL-33 in healthy mice suppressed erythropoiesis, decreased hemoglobin expression, and caused anemia. Using purified erythroid progenitors in vitro, we show that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-κB activation and associated with altered signaling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-accelerated erythropoiesis in vivo. These results reveal a role for IL-33 in pathogenesis of anemia during inflammatory disease and define a new target for its treatment.

Topics: Anemia; Animals; Annexin A5; beta-Glucans; Bone Marrow; Cell Differentiation; Chronic Disease; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hematopoiesis; Inflammation; Injections; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Ki-67 Antigen; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Myelopoiesis; NF-kappa B; Phosphorylation; Receptors, Erythropoietin; Signal Transduction; Spondylarthritis

Anemia and iron deficiency are highly prevalent in chronic kidney disease (CKD) and in chronic heart failure. Both may epidemiologically predict future renal and/or cardiovascular events. However, anemia treatment with either erythropoietin or erythropoiesis-stimulating agents failed to induce a prognostic benefit in either CKD or chronic heart failure. Instead, in the subgroup of chronic dialysis patients, liberal intravenous iron supplementation was beneficial, and ongoing clinical trials are testing the prognostic implication of intravenous iron supplementation in chronic heart failure. Finally, HIF stabilizers are a new treatment option for anemia in chronic kidney disease, and safety studies are currently ongoing in CKD patients. Whether patients suffering from chronic heart failure might also benefit from this treatment is currently unknown.. THERAPIE MIT EISENPRäPARATEN:  Mit PIVOTAL erschien 2018 die erste kardiovaskuläre Endpunktstudie zur Eisensubstitution bei Dialysepatienten, die eine prognostische Überlegenheit einer Hochdosiseisentherapie gegenüber einer restriktiveren Eisenapplikation aufzeigte. Mit AFFIRM-AHF, IRONMAN, FAIR-HF2 und HEART-FID überprüfen aktuell gleich 4 Studien die Bedeutung einer intravenösen Eisenapplikation auf kardiovaskuläre Endpunkte bei Patienten mit Herzinsuffizienz. AUSBLICK:  HIF-Stabilisatoren erlauben eine orale Anämie-Behandlung bei chronischer Nierenerkrankung. Erste klinische Studien zeigten eine „Nichtunterlegenheit“ von HIF-Stabilisatoren gegenüber der Behandlung mittels rekombinanten Erythropoetins (EPO)/Erythropoese-stimulierenden Agenzien (ESA) in Bezug auf den Hämoglobinanstieg. Finale Ergebnisse großer Studien mit kardiovaskulären Endpunkten sind aktuell noch ausstehend. In diesen Studien muss das Sicherheitsprofil von HIF-Stabilisatoren überprüft werden, da HIF-Stabilisatoren die Transkription zahlreicher Gene auch jenseits der Hämatopoese verändern. In der klinischen Kardiologie spielen HIF-Stabilisatoren aktuell (noch) keine Rolle. Unter der Therapie mittels SGLT-II-Inhibitoren konnte ein Anstieg des Hämatokrits beobachtet werden, welcher sich nicht allein durch diuretische Effekte erklären lässt. Die genaue pharmakodynamische Wirkweise ist noch offen.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Renal Dialysis; Renal Insufficiency, Chronic

Vascular dementia is the second most common cause of dementia in older people and is characterized by the sudden onset of impairments in thinking skills and behavior, which generally occur following a stroke. Unfortunately, effective therapy for vascular dementia remains inadequate. Erythropoietin (EPO) is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. Recently, a prominent role for EPO has been defined in the nervous system, and there is growing interest in the potential therapeutic use of EPO for neuroprotection. However, whether it is protective from memory impairments and the underlying mechanisms of vascular dementia (VD) remains unknown. In the current study, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could restore impaired memory in 2-vessel occlusion (2VO) rats, a well-established vascular dementia animal model. EPO also rescued impairments in dendritic spines and cholinergic dysfunctions in the hippocampus. Moreover, EPO suppressed the overactivation of GSK-3β in the hippocampus by stimulating the JAK2/STAT5/PI3K/Akt signal pathway. Furthermore, we found that genetic knockdown of the EPO receptor (EPO-R) by shRNA blocks the neuroprotection conferred by EPO on memory in VD. We hypothesized that EPO treatment is able to rescue the memory impairments in VD by stimulating the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β pathway and suggest the potential usage of EPO in the therapy for VD.

Topics: Animals; Brain; Cerebrovascular Disorders; Cholinergic Neurons; Chronic Disease; Dendritic Spines; Disease Models, Animal; Erythropoietin; Fear; Gene Knockout Techniques; Glycogen Synthase Kinase 3 beta; Janus Kinase 2; Male; Memory Disorders; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar; Receptors, Erythropoietin; Signal Transduction; Spatial Memory; STAT5 Transcription Factor

Stress-induced allostatic load affects a variety of biological processes including synaptic plasticity, angiogenesis, oxidative stress, and inflammation in the brain, especially in the hippocampus. Erythropoietin (EPO) is a pleiotropic cytokine that has shown promising neuroprotective effects. Recombinant human EPO is currently highlighted as a new candidate treatment for cognitive impairment in neuropsychiatric disorders. Because EPO enhances synaptic plasticity, attenuates oxidative stress, and inhibits generation of proinflammatory cytokines, EPO may be able to modulate the effects of stress-induced allostatic load at the molecular level. The aim of this study was therefore to investigate how EPO and repeated restraint stress, separately and combined, influence (i) behavior in the novelty-suppressed feeding test of depression/anxiety-related behavior; (ii) mRNA levels of genes encoding proteins involved in synaptic plasticity, angiogenesis, oxidative stress, and inflammation; and (iii) remodeling of the dendritic structure of the CA3c area of the hippocampus in male rats. As expected, chronic restraint stress lowered the number of CA3c apical dendritic terminals, and EPO treatment reversed this effect. Interestingly, these effects seemed to be mechanistically distinct, as stress and EPO had differential effects on gene expression. While chronic restraint stress lowered the expression of spinophilin, tumor necrosis factor α, and heat shock protein 72, EPO increased expression of hypoxia-inducible factor-2α and lowered the expression of vascular endothelial growth factor in hippocampus. These findings indicate that the effects of treatment with EPO follow different molecular pathways and do not directly counteract the effects of stress in the hippocampus.

Topics: Animals; CA3 Region, Hippocampal; Chronic Disease; Dendrites; Erythropoietin; Gene Expression; Inflammation; Male; Neovascularization, Pathologic; Neuronal Plasticity; Oxidative Stress; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Psychological

Klotho, which is a life extension factor, and erythropoietin (EPO) have been introduced as effective neuroprotective factors in several neurological disorders. The present study is an attempt to examine the potential role of klotho and EPO in therapeutic effect of curcumin-loaded nanoparticles (NPs) in pentylenetetrazol (PTZ)-induced kindling model. In order to induce the kindling model, PTZ was administrated intraperitoneally (i.p.) at dose of 36.5 mg/kg every other day for 20 days. Male NMRI mice received pre-treatment of free curcumin or curcumin-loaded NPs (12.5 mg/kg, i.p.) 10 days before PTZ injection and this was continued until 1 h before each PTZ injection. Immunostaining against NeuN, as a marker of neuronal maturation, and EPO was performed on hippocampal brain sections. Quantitative real time polymerase chain reaction (qRT-PCR) was conducted to assess the expression levels of tumor necrosis factor-α (TNF-α), klotho and EPO in the hippocampus. Immunostaining data indicated that treatment with curcumin-loaded NPs significantly alleviates the neuronal cell death in PTZ receiving animals. Curcumin-loaded NPs effectively upregulated the levels of EPO and klotho in PTZ receiving animals. Furthermore, mRNA level of TNF-α was considerably reduced in animals undergone curcumin-loaded NPs treatment. Overall, the results of this study suggest that downregulation of TNF-α and consequent upregulation of klotho and EPO might contribute to the neuroprotective effect of curcumin-loaded NPs in experimental model of epilepsy.

Topics: Animals; Chronic Disease; Curcumin; Disease Models, Animal; DNA-Binding Proteins; Drug Carriers; Epilepsy; Erythropoietin; Glucuronidase; Hippocampus; Kindling, Neurologic; Klotho Proteins; Male; Mice; Nanoparticles; Nerve Tissue Proteins; Neurons; Neuroprotection; Neuroprotective Agents; Nuclear Proteins; Pentylenetetrazole; Random Allocation; Tumor Necrosis Factor-alpha; Up-Regulation

Topics: Adalimumab; Adolescent; Adult; Anemia; C-Reactive Protein; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Erythropoietin; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Inflammatory Bowel Diseases; Infliximab; Interleukin-6; Iron; Male; Middle Aged; Peptide Hormones; Tumor Necrosis Factor-alpha; Young Adult

We investigated the effects of glucocorticoids, erythropoietin (EPO) and spironolactone (SPL) n human fetal lung fibroblasts and human alveolar epithelial cells exposed to tracheal aspirate fluid (TAF) from extremely premature infants with chronic lung disease (CLD), characterized by fibrosis and changes in the alveolar epithelium.. Fibroblasts and epithelial cells (FHs 738Lu and A549, respectively) were treated with different concentrations of hydrocortisone (HDC), dexamethasone (DEX), betamethasone (BET), SPL, and EPO in the absence or presence of TAF from infants with CLD (gestational age, 25.3 ± 0.8 weeks; birthweight, 658 ± 77 g; postnatal age, 0-28 days) and assayed for proliferation.. Exposure to TAF resulted in a concentration-dependent proliferation of fibroblasts and epithelial cells. Proliferation of TAF-exposed fibroblasts was suppressed most significantly by 100 μmol/L DEX (21%, P = 0.046) and 300 mIU/mL EPO (18%, P = 0.02) and promoted most significantly by 0.4 μmol/L HDC (10%, P = 0.04). Epithelial proliferation was promoted by 4 μmol/L HDC (15%, P = 0.04), 10 μmol/L DEX (53%, P < 0.01), 0.2 μmol/L BET (56%, P < 0.01), and 300 mIU/mL EPO (35%, P < 0.01) in the presence of TAF. Treatment with glucocorticoids alone did not significantly affect fibroblast proliferation.. Glucocorticoids and EPO reduced fibroproliferation while promoting epithelial cell growth in vitro within certain dose ranges. Appropriate doses of glucocorticoids and EPO may be useful in the prevention and resolution of CLD in extremely premature infants.

Topics: Cell Proliferation; Cells, Cultured; Chronic Disease; Epithelial Cells; Erythropoietin; Female; Fibroblasts; Gestational Age; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lung Diseases; Male; Pulmonary Alveoli; Trachea

In many elderly patients with anemia, a specific cause cannot be identified. This study investigates whether erythropoietin levels are inappropriately low in these cases of "anemia of unknown etiology" and whether this trend persists after accounting for confounders.. This study includes all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient's anemia to one of ten etiologies: chronic kidney disease, iron deficiency, chronic disease, confirmed myelodysplastic syndrome (MDS), suspected MDS, vitamin B12 deficiency, folate deficiency, anemia of unknown etiology, other etiology, or multifactorial etiology. Iron deficiency anemia served as the comparison group in all analyses. We used linear regression to model the relationship between erythropoietin and the presence of each etiology, sequentially adding terms to the model to account for the hemoglobin concentration, estimated glomerular filtration rate (eGFR) and Charlson Comorbidity Index.. A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic disease and anemia of unknown etiology were lower by 48%, 46% and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin, eGFR and comorbidities.. We have shown that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This suggests that decreased erythropoietin production may play a key role in the pathogenesis of anemia of unknown etiology.

Topics: Aged; Aged, 80 and over; Anemia; Anemia, Iron-Deficiency; Biomarkers; Chronic Disease; Comorbidity; Erythropoietin; Female; Folic Acid Deficiency; Glomerular Filtration Rate; Hematologic Tests; Hemoglobins; Humans; Linear Models; Male; Middle Aged; Myelodysplastic Syndromes; Renal Insufficiency, Chronic; Retrospective Studies; Vitamin B 12 Deficiency

This study aimed to investigate the impacts of erythropoietin (EPO) on the electroretinogram b‑wave (ERG‑b), and on the mRNA and protein expression levels of hypoxia‑inducible factor‑1α (HIF‑1α), inducible nitric oxide synthase (iNOS), cyclooxygenase‑2 (COX‑2) and caspase‑9 in chronic ocular hypertension rats. Episcleral vein cauterization (EVC) was used to establish the chronic ocular hypertension rat model based on the intraocular pressure (IOP) value. ERG‑b and mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 in normal, EVC‑treated and EVC combined with EPO (EVC+EPO)‑treated rats were measured by electroretinography, RT‑PCR and western blotting, respectively. Moreover, the correlations of HIF‑1α with IOP, ERG‑b, iNOS, COX‑2 and caspase‑9 were evaluated. The mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 in EVC‑treated rats were increased significantly compared with normal rats. The peak expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 were respectively obtained 7, 7, 7 and 14 days postoperatively. Compared with EVC‑treated rats, EPO administration weakened the mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9. The mRNA expression level of HIF‑1α demonstrated a significant positive correlation with IOP and ERG‑b. HIF‑1α was positively correlated with iNOS, COX‑2 and caspase‑9 at the mRNA and protein levels. The protective effect of EPO on the retina of chronic ocular hypertension rats may be mediated by the HIF‑1 signaling pathway involving iNOS, COX‑2 and caspase‑9.

Topics: Animals; Caspase 9; Chronic Disease; Cyclooxygenase 2; Disease Models, Animal; Electroretinography; Epoetin Alfa; Erythropoietin; Hypoxia-Inducible Factor 1, alpha Subunit; Intraocular Pressure; Male; Neuroprotective Agents; Nitric Oxide Synthase Type II; Ocular Hypertension; Rats; Rats, Wistar; Recombinant Proteins; Retina; RNA, Messenger; Signal Transduction

Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency.. Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated.. Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency.. These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.

Topics: Anemia, Iron-Deficiency; Animals; Chronic Disease; Disease Models, Animal; Erythropoietin; Heart Failure; Iron Deficiencies; Male; Mice; Mice, Knockout; Myocardium; Receptors, Erythropoietin; Signal Transduction

Chronic hypoxia (CH), a disease state that accounts for significant morbidity and mortality in pediatrics, occurs in many children during critical periods of hippocampal development and cortical myelination. Hippocampal neurogenesis occurs throughout postnatal life and is important for normal development, thus impairment results in long-term cognitive deficits. Erythropoietin (EPO), a drug commonly known for its role in erythrogenesis, has recently been evaluated in neuroprotection in neonatal injury models and preterm brain injury. However, the effects of EPO therapy on hippocampal neurogenesis and myelination in pediatric CH are unknown. We show that CH decreases hippocampal neurogenesis in a pediatric mouse model. This decrease in early and late progenitors, and actively dividing cells is rescued with EPO treatment. Furthermore, we show that CH during this critical time decreases oligodendrocyte progenitor (OPC) populations in the cortex, leading to defective myelination. However, EPO therapy is only able to rescue the OPC but not the loss of mature myelin. Overall, our findings demonstrate that CH in developing mice has significant effects on hippocampal neurogenesis and OPCs, which can be rescued with EPO treatment. Future studies should confirm the role of this FDA-approved therapy in neuroprotection in at-risk pediatric populations.

Topics: Age Factors; Animals; Brain; Cell Count; Chronic Disease; Erythropoietin; Hippocampus; Hypoxia, Brain; Mice, Transgenic; Myelin Sheath; Neural Stem Cells; Neurogenesis; Neurons; Neuroprotective Agents; Oligodendroglia

Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

Topics: Acute Disease; Anemia; Anemia, Hemolytic; Animals; Butyrates; Cell Culture Techniques; Cells, Cultured; Chromatin; Chronic Disease; Disease Models, Animal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Fenofibrate; Glucocorticoids; Humans; Liver; Mice; Phenylhydrazines; Phenylurea Compounds; PPAR alpha; Receptors, Glucocorticoid; Signal Transduction

Anemia of chronic disease (ACD) is thought to impair the responsiveness of erythroid progenitor cells, but research has shown treatment with recombinant human erythropoietin (rhuEPO) can improve patient hemoglobin levels and, subsequently, overall patient health status and quality of life. A prospective pilot study was designed to estimate the prevalence of ACD in outpatients with spinal cord injury (SCI) and chronic pressure ulcers (PUs) and examine the impact of rhuEPO on PU healing in this population. The charts of 49 SCI patients with PUs were reviewed; of those, 17 had anemia (hemoglobin <110 g/L). The prevalence of anemia in SCI patients with PUs was found to be approximately 35%. From these 17 potential participants, 5 had improved hemoglobin levels during the screening period (rendering them ineligible), 1 withdrew due to illness, and 7 died, leaving 4 participants to complete the study. Four patients (2 men, 2 women, average age 57 ± 16.5 years) ultimately were enrolled. Wound area and depth and cytokines were measured before, during, and after 6 weeks of treatment with rhuEPO, with a 3-month follow-up. Laboratory tests measuring hemoglobin, C-reactive protein, and prealbumin were used to monitor nutritional status and treatment response. No statistically significant changes were observed with treatment. Wound surface area and depth had mean decreases of 1.35 cm(2) and 0.58 cm, respectively, immediately post-treatment. Participants' elevated C-reactive protein levels (91.1-14.2 mg/L) decreased with rhuEPO treatment, but returned to baseline levels post-treatment (83.2-14.3 mg/L). Prealbumin levels were consistently low (range of 0.1-0.21 g/L). This research indicates rhuEPO treatment may improve some outcomes for ACD-SCI PU patients, but larger randomized controlled trials are required. The results of this study suggest the prevalence of ACD in the SCI outpatient population with PUs is at least 35%, and increased vigilance of patient nutrition is recommended.

Topics: Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Pilot Projects; Pressure Ulcer; Prevalence; Prospective Studies; Quality of Life; Recombinant Proteins; Spinal Cord; Wound Healing

The rapid death of many spinal motor neurons after nerve root avulsion injury results in limited functional recovery following replantation surgery of avulsed nerves into the spinal cord. Therefore, we investigated the neuroprotective effect of erythropoietin (EPO) on motor neurons after nerve root avulsion injury using a rat model.. After C6 nerve root avulsion injury, EPO (2680 U/kg) was injected subcutaneously once a day for 3 consecutive days with various starting time points. At 28 and 56 days after injury, histological and immunohistological investigations were performed.. EPO-treated rats showed a significant increase in the number of surviving motor neurons at day 28 when the initial dose was started within 96 h after injury. In EPO-treated rats, superoxide formation in the motor neurons and proliferation of microglia were markedly suppressed in the acute phase. GAP-43-positive surviving motor neurons were significantly increased in EPO-treated rats at day 28. However, at 56 days after surgery, EPO-treated rats showed a much greater decrease of surviving motor neurons compared with those at day 28.. The neuroprotective effect of EPO is not long lasting, but may prolong the time before replantation surgery.

Topics: Acute Disease; Animals; Cell Survival; Cervical Vertebrae; Chronic Disease; Disease Models, Animal; Erythropoietin; Injections, Subcutaneous; Male; Microglia; Motor Neurons; Nerve Regeneration; Neuroprotective Agents; Radiculopathy; Random Allocation; Rats, Sprague-Dawley; Receptors, Erythropoietin; Spinal Cord; Superoxides; Treatment Outcome

Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis, and angiogenesis may be involved in the pathogenesis of this disease. The bone marrow niche is the primary site of erythropoiesis and angiogenesis. This study was aimed at investigating the associations of the levels of hypoxia-inducible factors (HIFs), erythropoietin (EPO), and erythropoietin receptor (EPOR), as well as microvessel density (MVD) in the bone marrow with CMS.. A total of 34 patients with CMS and 30 control subjects residing in areas at altitudes of 3000-4500 m were recruited for this study. The mRNA and protein expression of HIF-2α and EPO in the bone marrow cells was significantly higher in the CMS patients than in the controls. Moreover, changes in HIF-2α expression in CMS patients were significantly correlated with EPO and hemoglobin levels. In contrast, the expression of mRNA and protein expression of HIF-1α and EPOR did not differ significantly between the CMS and control patients. Increased MVD was observed in the bone marrow of the patients with CMS and it was significantly correlated with hemoglobin.. Bone marrow cells of CMS patients may show enhanced activity of the HIF-2α/EPO pathway, and EPO may regulate the erythropoiesis and vasculogenesis through autocrine or/and paracrine mechanisms in the bone marrow niche. The increased MVD in the bone marrow of CMS patients appears to be involved in the pathogenesis of this disease.

Topics: Adult; Altitude; Altitude Sickness; Basic Helix-Loop-Helix Transcription Factors; Bone Marrow; Case-Control Studies; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Male; Microvessels; Middle Aged; Neovascularization, Pathologic; Polycythemia; RNA, Messenger; Signal Transduction

Psychological stress affects different physiological processes including haematopoiesis. However, erythropoietic effects of chronic psychological stress remain largely unknown. The adult spleen contains a distinct microenvironment favourable for rapid expansion of erythroid progenitors in response to stressful stimuli, and emerging evidence suggests that inappropriate activation of stress erythropoiesis may predispose to leukaemic transformation. We used a mouse model to study the influence of chronic psychological stress on erythropoiesis in the spleen and to investigate potential mediators of observed effects. Adult mice were subjected to 2 hrs daily restraint stress for 7 or 14 consecutive days. Our results showed that chronic exposure to restraint stress decreased the concentration of haemoglobin in the blood, elevated circulating levels of erythropoietin and corticosterone, and resulted in markedly increased number of erythroid progenitors and precursors in the spleen. Western blot analysis revealed significantly decreased expression of both erythropoietin receptor and glucocorticoid receptor in the spleen of restrained mice. Furthermore, chronic stress enhanced the expression of stem cell factor receptor in the red pulp. Moreover, chronically stressed animals exhibited significantly increased expression of bone morphogenetic protein 4 (BMP4) in the red pulp as well as substantially enhanced mRNA expression levels of its receptors in the spleen. These findings demonstrate for the first time that chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis and leads to the prolonged activation of stress erythropoiesis pathways. Prolonged activation of these pathways along with an excessive production of immature erythroid cells may predispose chronically stressed subjects to a higher risk of leukaemic transformation.

Topics: Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors; Chronic Disease; Corticosterone; Down-Regulation; Erythropoiesis; Erythropoietin; Hemoglobins; Iron; Male; Mice; Mice, Inbred CBA; Organ Size; Receptors, Erythropoietin; Receptors, Glucocorticoid; Restraint, Physical; RNA, Messenger; Signal Transduction; Spleen; Stress, Psychological

Ghrelin, a 28 amino acid peptide, has diverse effects in body organs. Erythropoietin is a key mediator in increasing the red blood cells during hypoxia. Previously, we have shown that ghrelin has a polycythemic effect. In the present study, we evaluated the effect of ghrelin on erythropoietin gene expression with the aim to find out the mechanism of its effect.. Thirty two adult male Wistar rats were divided randomly into four groups. The hypoxic condition was induced by placing the rats into the hypoxic chamber with 11% oxygen for two weeks. Saline- and ghrelin-treated control rats remained in room with a regular air conditions. Erythropoietin gene expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). Plasma erythropoietin was measured by enzyme linked immunosorbent assay (ELISA).. After 2-weeks of hypoxia, erythropoietin transcripts and erythropoietin plasma levels were significantly increased in hypoxic animals compared with control animals. Ghrelin treatment decreased both plasma erythropoietin and erythropoietin gene expression only in the hypoxic rats.. Our data indicate that ghrelin might induce polycythemia through an erythropoietin-independent manner. However, to confirm this hypothesis and to find out the precise mechanism of this phenomenon further investigations are needed.

Topics: Animals; Chronic Disease; Erythropoietin; Gene Expression; Ghrelin; Hematocrit; Hypoxia; Kidney; Male; Random Allocation; Rats; Rats, Wistar

Rehabilitation is the only treatment option for chronic stroke deficits, but unfortunately, it often provides incomplete recovery. In this study, a novel combination of growth factor administration and rehabilitation therapy was used to facilitate functional recovery in a rat model of cortical stroke.. Ischemia was induced via injection of endothelin-1 into the sensorimotor cortex. This was followed by either a 2-week infusion of epidermal growth factor and erythropoietin or artificial cerebrospinal fluid into the ipsilateral lateral ventricle. Two weeks after ischemia, animals began an 8-week enriched rehabilitation program. Functional recovery was assessed after ischemia using the Montoya staircase-reaching task, beam-traversing, and cylinder test of forelimb asymmetry.. The combination of growth factor infusion and rehabilitation led to a significant acceleration in recovery in the staircase task. When compared with controls, animals receiving the combination treatment attained significant recovery of function at 4 weeks after stroke, whereas those receiving rehabilitation alone did not recover until 10 weeks. Significant recovery was also observed on the beam-traversing and cylinder tasks.. Combining behavioral rehabilitation with growth factor infusion accelerates motor recovery. These data suggest a promising new avenue of combination therapies that may have the potential to reduce the rehabilitation time necessary to recover from sensorimotor deficits arising from stroke.

Topics: Animals; Chronic Disease; Disease Models, Animal; Endothelin-1; Epidermal Growth Factor; Erythropoietin; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Stroke; Stroke Rehabilitation

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

Topics: Anemia; Animals; Biomarkers; Chronic Disease; Drug Combinations; Drug Synergism; Erythropoiesis; Erythropoietin; Female; Gene Expression; Hematinics; Hepcidins; Humans; Interferon-gamma; Iron; Polysaccharides, Bacterial; Prognosis; Pyrazoles; Pyrimidines; Rats; Rats, Inbred Lew; RNA, Messenger; Tumor Necrosis Factor-alpha

Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulating sEpoR could lead to higher Epo availability and ultimately to EE. We characterized the relationship between Epo and sEpoR, with hematocrit and hemoglobin concentration in healthy highlanders and CMS patients at 4,340 m in Cerro de Pasco, Peru. Our results show that EE patients show decreased plasma sEpoR levels and can be subdivided into two subgroups of normal and high plasma Epo concentration for the altitude of residence, with hemoglobin concentration rising exponentially with an increasing Epo-to-sEpoR ratio (Epo/sEpoR). Also, we showed that the latter varies as an inverse exponential function of arterial pulse O2 saturation. Our findings suggests that EE is strongly associated with higher Epo/sEpoR values, leading to elevated plasma Epo availability to bind mEpoR, and thereby a stronger stimulus for augmented erythropoiesis. Differences in the altitude normal and high Epo CMS patients with a progressively higher Epo/sEpoR supports the hypothesis of the existence of two genetically different subgroups suffering from EE and possibly different degrees of adaptation to chronic high-altitude hypoxia.

Topics: Adult; Altitude Sickness; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Peru; Polycythemia; Regression Analysis

To evaluate the efficiency of treatment for renal anemia in patients with chronic glomerulonephritis (CGN), by using erythropoietin and its combination with hypoxic altitude chamber training (HACT).. Sixty-three patients (41 men and 22 women) (mean age 37.1 ± 3.3 years) with CGN during the predialysis phase of chronic kidney disease (CKD) complicated by anemia. Hemoglobin (Hb), packed cell volume (PCV), and red blood cell indices (mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC)), platelet count, serum iron, fibrinogen, C-reactive protein (CRP) and creatinine levels were determined in all the patients at baseline and during a prospective follow-up. Glomerular filtration rate (GFR) was measured using with the Rehberg-Tareev test. Along with standard renal protective therapy, all the patients received either epoetin beta (n=31; Group 1) or its combination with HACT (n=32; Group 2). In Group 1 patients (n=31), erythropoietin (EPO) was given in an initial dose of 20-50 IU/kg thrice daily, followed by the dose being adjusted until the target Hb level was reached. Group 2 patients (n=32) received HACT cycles by the standard procedure in combination with EPO given in lower doses (20-50 IU/kg once weekly). A prospective .follow-up of the patients was carried out during one year.. Following one year, the number of patients who had achieved the target Hb level was 74.1% in Group 1 and 87.5% in Group 2. Over time, there were increases in the concentration of Hb (from 108.6 ± 19.4 to 124.5 ± 14.09 g/l; p<0.05), PCV, and red blood cell indices (MCV, MCHC) in the patients receiving EPO (Group 1). Besides an'anti-anemic effect, there was a significant decrease in the concentrations of fibrinogen from 6655 (4884-7634) to 3776 (3330-4884) mg/dL; (p<0.05), serum creatinine from 159 (89--261) to 138 (79-258) pmol/I (p<0,05), proteinuria from 2.955 (1.024-6.745) to 2.069 (0.539-4.279) (p<0.05), which was accompanied by an increase in GFR from 62.3 (37.0 - 107.4) to 76.9 (46.0-96.0) mi/min (p<0.05). In Group 2, the rise in the concentration of Hb (from 114.1 ± 11.7 to 132.0 ± 16.5 g/I (p<0.05), PCV, MCV, and MCHC proved to be more pronounced than that in Group 1 (p<0.05) and accompanied by an elevation in the counts of platelets (from 222.7 ± 19.8.10(9)/1 to 249.3 ± 21.9.10(9)/1 (p<0:05)) and red blood cells (from 4.0 ± 0.4-10(12)/1 to 4.34 ± 0.3 X 10(12)/I (p<0.05)). There was a more marked reduction in the degree of proteinuria from 3.092 (0.764-7.694) g at baseline to 1.600 (0.677-4.078) g one year later (p<0.05) than that in Group 1 (p<0.05). The increase in GFR from 60.1 (46.0-96.0) to 79.4 (44.0-120.0) ml/min (p<0.05) and the fall in the concentration of fibrinogen from 5555 (4884-7770) to 4107 (3776-5328) mg/dL (p<0.05) and serum creatinine from 166 (92-273) to 147 (92-152) μmol/L (p<0.05), which were observed in Group 2, were comparable to those in Group 1.. Epoetin beta used in patients with CGN has an anti-anemic effect and leads to improved renal nitrogen-excretory function. Erythropoietin in combination with HACT used in CGN provides a higher anti-anemic efficacy and a more pronounced antiproteinuric effect.

Topics: Adult; Anemia; Atmosphere Exposure Chambers; Chronic Disease; Combined Modality Therapy; Erythropoietin; Female; Glomerulonephritis; Humans; Hypoxia; Male; Middle Aged; Respiratory Therapy; Treatment Outcome

Approximately one-half of patients with inflammatory bowel disease (IBD) suffer from anemia, with the most prevalent cause being iron deficiency. Accompanying the anemia are increases in erythropoietin, a plasma protein that can initiate the feedback production of new red blood cells. Anemia also occurs in animal models that are used to investigate the mechanisms of IBD; however, the extent to which iron deficiency produces the anemia in these animal models is unknown. Also unknown in the different animal models of IBD is whether the anemia upregulates the production of erythropoietin or, alternatively, whether a decrease in erythropoietin contributes to the induction of anemia.. Two mouse models of colitis were used in this study: (1) acute 6-day ingestion of dextran sodium sulfate and (2) T-cell transfer into lymphopenic recipient mice. Measurements included indices of colitis severity, hematocrit, blood hemoglobin, plasma erythropoietin, serum iron concentration, plasma iron-binding capacities, transferrin saturation, and tissue iron concentrations.. Both models of colitis induced significant decreases in hematocrit, blood hemoglobin, and transferrin saturation, with the spleen and liver showing a decrease in iron content in the T-cell transfer model. Additionally, both models of colitis demonstrated significant increases in plasma erythropoietin and plasma iron-binding capacities.. The measurements of iron, whether in acute (dextran sodium sulfate) or chronic (T-cell transfer) models of colitis, were generally consistent with iron-deficient anemia, with large increases in erythropoietin indicative of tissue hypoxia. These changes in animal models of colitis are similar to those found in human IBD.

Topics: Acute Disease; Anemia; Animals; Chronic Disease; Colitis; Dextran Sulfate; Disease Models, Animal; Erythropoietin; Homeodomain Proteins; Humans; Interleukin-10; Iron; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes

Topics: Chronic Disease; Erythropoietin; Heart Failure; Humans; Neurotransmitter Agents; Renin-Angiotensin System; Sympathetic Nervous System

Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when the major erythropoietin-producing organ switches from the liver to the kidney, ISAM develop anaemia due to erythropoietin deficiency, which is curable by administration of recombinant erythropoietin. In ISAM severe chronic anaemia enhances transgenic green fluorescent protein and Cre expression driven by the complete erythropoietin-gene regulatory regions, which facilitates efficient labelling of renal erythropoietin-producing cells. We show that the majority of cortical and outer medullary fibroblasts have the innate potential to produce erythropoietin, and also reveal a new set of erythropoietin target genes. ISAM are a useful tool for the evaluation of erythropoiesis-stimulating agents and to trace the dynamics of erythropoietin-producing cells.

Topics: Age of Onset; Aging; Alleles; Anemia; Animals; Bone Marrow; Chronic Disease; Disease Models, Animal; Embryo Loss; Erythroblasts; Erythropoietin; Gene Expression Regulation; Green Fluorescent Proteins; Hematopoiesis; Humans; Integrases; Kidney; Liver; Mice; Mice, Knockout; RNA, Messenger; Staining and Labeling; Transgenes

Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction.. We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry.. Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r=-0.41, P=0.01) and soluble tumour necrosis factor receptor 2 (r=-0.38, P=0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P<0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P<0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients.. The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.

Topics: Aged; Anemia; Cells, Cultured; Chronic Disease; Down-Regulation; Drug Resistance; Erythroid Precursor Cells; Erythropoietin; Female; Flow Cytometry; Heart Failure; Humans; Janus Kinases; Male; Middle Aged; Receptors, Erythropoietin; Signal Transduction; STAT5 Transcription Factor

In order to maintain normal cellular function, mammalian tissue oxygen concentrations must be tightly regulated within a narrow physiological range. The hormone erythropoietin (EPO) is essential for maintenance of tissue oxygen supply by stimulating red blood cell production and promoting their survival. In this study we compared the effects of 290 Torr atmospheric pressure on the kidney EPO protein levels in young (4-month-old) and aged (24-month-old) C57BL/6 mice. The mice were sacrificed after being anesthetized, and kidney samples were collected and processed by Western blot analysis. Relatively low basal expression of EPO during normoxia in young mice showed significant upregulation in hypoxia and stayed upregulated throughout the hypoxic period (threefold compared to normoxic control), showing a slight decline toward the third week. Whereas, a relatively higher normoxic basal EPO protein level in aged mice did not show significant increase until seventh day of hypoxia, but showed significant upregulation in prolonged hypoxia. Hence, we confirmed that there is a progressively increased accumulation of EPO during chronic hypoxia in young and aged mouse kidney, and the EPO upregulation during hypoxia showed a similarity with the pattern of increase in hematocrit, which we have reported previously.

Topics: Aging; Animals; Blotting, Western; Chronic Disease; Erythropoietin; Hematocrit; Hypoxia; Kidney; Male; Mice; Mice, Inbred C57BL; Oxygen; Up-Regulation

In spite of improvement in obstetrical care, pregnancy in women with type 1 diabetes mellitus is associated with increased perinatal morbidity and mortality. Hyperglycemia during pregnancy causes excessive fetal growth and chronic fetal hypoxia as reflected in increased erythropoietin (EPO) levels in amniotic fluid (AF).. We hypothesized that the degree of fetal hypoxia would correlate with fetal oxidative and nitrosative stress as evidenced ty the concentration of specific biomarkers in AF.. 19 pregnant women with type 1 or insulin-treated gestational diabetes mellitus were studied. AF samples were collected and processed for EPO, meta-tyrosine, nitro-tyrosine and 8-hydroxy-2-deoxiguanosine by chemiluminescent immunoassay and high-performance liquid chromatography coupled to tandem mass spectrometry methods, respectively.. The mean (SD) of the last HbA1c concentration before delivery was 7.7% (1.1). Median gestational age was 258 days (range 231-268). Birth weight was 3,868 ± 695 g with a z-score >2 SD in 47% of the cases. A significant correlation was found between the concentrations of AF EPO and meta-tyrosine/phenylalanine ratio (p < 0.001), nitro-tyrosine (p < 0.01) and 8-oxo-dG/2dG ratio (p < 0.001).. We confirmed that fetuses of type 1 diabetes or insulin-treated gestational diabetes pregnancies experience chronic hypoxia as reflected by increased EPO concentrations in AF near term. Moreover, EPO levels significantly correlated with the concentration of oxidative and nitrosative stress biomarkers in AF. This pro-oxidant status may predispose newborn infants to poor postnatal adaptation and early neonatal complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amniocentesis; Amniotic Fluid; Biomarkers; Birth Weight; Chromatography, High Pressure Liquid; Chronic Disease; Deoxyguanosine; Diabetes Mellitus, Type 1; Diabetes, Gestational; Erythropoietin; Female; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoassay; Infant, Newborn; Insulin; Male; Nitrosation; Oxidative Stress; Pilot Projects; Pregnancy; Pregnancy in Diabetics; Tandem Mass Spectrometry; Tyrosine; Young Adult

The diagnosis of iron deficiency anemia (IDA) in the context of the anemia of chronic disease (ACD) in elderly patients is often difficult due to the existence of many disorders. Recent studies have shown that hepcidin measurement (combined with the existing diagnostic methods) may possibly help in the differential diagnosis of IDA and ACD.. The aim of the study was to evaluate the differential diagnostic value of serum prohepcidin in elderly patients with IDA and ACD.. The study included 65 individuals aged 65 years or more: 26 patients with ACD, 13 patients with IDA, and 26 age-matched controls. Prohepcidin, ferritin, soluble transferrin receptor, erythropoietin, and interleukin 6 (IL-6) were measured using the commercially available enzyme-linked immunosorbent assay kits. Complete blood count, total iron-binding capacity (TIBC), and iron, transferrin, and C-reactive protein (CRP) levels were assayed using the standard laboratory methods.. Prohepcidin concentrations were similar in patients with ACD (196.59 ng/ml) compared with those with IDA (230.16 ng/ml) (P = 0.35). Patients with ACD had significantly lower levels of TIBC compared with those with IDA (P <0.0001). Serum ferritin concentration in patients with ACD was almost 20-fold higher compared with those observed in patients with IDA (P <0.0001). CRP and IL-6 concentrations in patients with ACD were significantly higher compared with those with IDA.. The results of the study indicate that serum prohepcidin has limited value in the differential diagnosis of IDA and ACD in elderly patients.

Topics: Aged; Aged, 80 and over; Anemia; Anemia, Iron-Deficiency; Biomarkers; Chronic Disease; Diagnosis, Differential; Erythropoietin; Female; Ferritins; Hepcidins; Humans; Interleukin-6; Iron; Male; Predictive Value of Tests; Receptors, Transferrin

The involvement of erythropoietin in cardiac adaptation to acute and chronic (CHx) hypoxia was investigated in erythropoietin deficient transgenic (Epo-TAg(h)) and wild-type (WT) mice. Left (LV) and right ventricular functions were assessed by echocardiography and hemodynamics. HIF-1α, VEGF and Epo pathways were explored through RT-PCR, ELISA, Western blot and immunocytochemistry. Epo gene and protein were expressed in cardiomyocytes of WT mice in normoxia and hypoxia. Increase in blood hemoglobin, angiogenesis and functional cardiac adaptation occurred in CHx in WT mice, allowing a normal oxygen delivery (O2T). Epo deficiency induced LV hypertrophy, increased cardiac output (CO) and angiogenesis, but O2T remained lower than in WT mice. In CHx Epo-TAg(h) mice, LV hypertrophy, CO and O2T decreased. HIF-1α and Epo receptor pathways were depressed, suggesting that Epo-TAg(h) mice could not adapt to CHx despite activation of cardioprotective pathways (increased P-STAT-5/STAT-5). HIF/Epo pathway is activated in the heart of WT mice in hypoxia. Chronic hypoxia induced cardiac adaptive responses that were altered with Epo deficiency, failing to maintain oxygen delivery to tissues.

Topics: Adaptation, Physiological; Animals; Blotting, Western; Chronic Disease; Disease Models, Animal; Echocardiography; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Heart; Hemodynamics; Hypoxia; Male; Mice; Mice, Transgenic; Myocytes, Cardiac; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Topics: Anemia; Blood Transfusion; Chronic Disease; Disease Management; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Reference Standards; Renal Dialysis; Risk Adjustment

Anemia in patients with CKD is highly related to impaired erythropoietin (EPO) response, the timing and determinants of which remain unknown.. This study measured EPO levels and studied their relation to GFR measured by 51Cr-EDTA renal clearance (mGFR) in 336 all-stage CKD patients not receiving any erythropoiesis-stimulating agent.. In patients with anemia defined by World Health Organization criteria (hemoglobin [Hb] <13 g/dl in men and 12 g/dl in women), EPO response to Hb level varied by mGFR level. EPO and Hb levels were negatively correlated (r=-0.22, P=0.04) when mGFR was >30 ml/min per 1.73 m(2), whereas they were not correlated when mGFR was <30 (r=0.09, P=0.3; P for interaction=0.01). In patients with anemia, the ratio of observed EPO to the level predicted by the equation for their Hb level decreased from 0.72 (interquartile range, 0.57-0.95) for mGFR ≥60 ml/min per 1.73 m(2) to 0.36 (interquartile range, 0.16-0.69) for mGFR <15. Obesity, diabetes with nephropathy other than diabetic glomerulopathy, absolute iron deficiency, and high C-reactive protein concentrations were associated with increased EPO levels, independent of Hb and mGFR.. Anemia in CKD is marked by an early relative EPO deficiency, but several factors besides Hb may persistently stimulate EPO synthesis. Although EPO deficiency is likely the main determinant of anemia in patients with advanced CKD, the presence of anemia in those with mGFR >30 ml/min per 1.73 m(2) calls for other explanatory factors.

Topics: Adult; Aged; Chronic Disease; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Time Factors

Anemia can contribute to chronic allograft injury by limiting oxygen delivery to tissues, particularly in the tubulointerstitium. To determine mechanisms by which erythropoietin (EPO) prevents chronic allograft injury we utilized a rat model of full MHC-mismatched kidney transplantation (Wistar Furth donor and Lewis recipients) with removal of the native kidneys. EPO treatment entirely corrected post-transplant anemia. Control rats developed progressive proteinuria and graft dysfunction, tubulointerstitial damage, inflammatory cell infiltration, and glomerulosclerosis, all prevented by EPO. Normalization of post-transplant hemoglobin levels by blood transfusions, however, had no impact on chronic allograft injury, indicating that EPO-mediated graft protection went beyond the correction of anemia. Compared to syngeneic grafts, control allografts had loss of peritubular capillaries, higher tubular apoptosis, tubular and glomerular oxidative injury, and reduced expression of podocyte nephrin; all prevented by EPO treatment. The effects of EPO were associated with preservation of intragraft expression of angiogenic factors, upregulation of the anti-apoptotic factor p-Akt in tubuli, and increased expression of Bcl-2. Inhibition of p-Akt by Wortmannin partially antagonized the effect of EPO on allograft injury and tubular apoptosis, and prevented EPO-induced Bcl-2 upregulation. Thus non-erythropoietic derivatives of EPO may be useful to prevent chronic renal allograft injury.

Topics: Anemia; Animals; Apoptosis; Biomarkers; Blood Transfusion; Chronic Disease; Erythropoietin; Glomerulonephritis; Hematinics; Hemoglobins; Histocompatibility; Kidney; Kidney Diseases; Kidney Transplantation; Mice; Primary Graft Dysfunction; Proteinuria; Rats; Rats, Inbred Lew; Rats, Inbred WF; Time Factors

Topics: Chronic Disease; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Diseases; Patient Education as Topic; Physician-Patient Relations; Recombinant Proteins; Renal Dialysis; Risk Assessment; Risk Factors; Risk Management; Stroke; United States; United States Food and Drug Administration

Oxidative stress (OS) is involved in left ventricular hypertrophy (LVH). Short-term treatment with erythropoietin (EPO) in chronic kidney disease (CKD) complicated by anemia and LVH is associated with a reduction in left ventricular mass (LVM). We proposed to assess whether the pro-oxidant status of CKD influences these outcomes.. Predialysis patients (n = 76) with CKD and hemoglobin (Hb) levels < 11 g/dl received EPO for 6 months. The effects of this anemia correction on LVH regression were evaluated using echocardiography. Patients with LVM decrease > 10% were considered "responders" (n = 25) to treatment and those with LVM change < 10% were considered "non-responders" (n = 24). Measurement of OS included plasma and erythrocyte oxidized (GSSG) and reduced (GSH) glutathione, GSH redox ratio (GSSG/GSH), erythrocyte glutathione peroxidase (GPx) and oxidized LDL (Ox- LDL).. 49 patients completed the study. With EPO therapy, mean Hb levels increased from 9.9 ± 0.6 to 12.8 ± 1.5 g/ dl (p < 0.0001) and LVM index decreased from 69.2 ± 17.7 to 64.1 ± 19.6 g/m2.7 (p = 0.01). At 6 months, "non-responders" had higher systolic blood pressure, pulse pressure, GSSG and GSH redox ratio and lower GSH than "responders". In multivariate analysis, and following adjustment for confounding variables, systolic blood pressure and GSH redox ratio independently predicted LVH regression.. Blood pressure and plasma GSH redox ratio (a marker of OS) are important predictors of LVH regression in anemic predialysis patients treated with EPO.

Topics: Aged; Anemia; Biomarkers; Blood Pressure; Chi-Square Distribution; Chronic Disease; Erythropoietin; Female; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Lipoproteins, LDL; Logistic Models; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Recombinant Proteins; Time Factors; Treatment Outcome; Ultrasonography

Iron metabolism is an important factor of anemia in chronic kidney disease (CKD). Hepcidin is a regulator of iron homeostasis and has a major role in the anemia of chronic disease (ACD). Oxidative stress (OS) is also associated with iron metabolism. However, the clinical utility of hepcidin, especially its association with OS, in CKD patients not receiving dialysis is still unclear.. We recruited 117 patients (62 ± 15 years, 85 males, and median estimated glomerular filtration rate (eGFR) 22 ml/min/1.73 m2) with CKD not receiving dialysis. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, and serum hepcidin-25 were measured by ELISA and by liquid chromatography tandem mass spectrometry, respectively.. Hepcidin-25 was associated positively with ferritin, high-sensitive C-reactive protein (hsCRP) and 8-OHdG, and negatively with eGFR and hemoglobin. Sex, oral iron, hemoglobin, transferrin saturation (TSAT), ferritin, and hsCRP were independently associated with hepcidin-25 in a multiple regression model. In contrast, neither eGFR nor 8-OHdG independently affected hepcidin- 25.. The close association between hepcidin and serum ferritin, oral iron and hsCRP indicates that it plays a key role in the pathogenesis of anemia in patients with CKD not receiving dialysis. In contrast, effects of eGFR and OS were not apparent.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antimicrobial Cationic Peptides; C-Reactive Protein; Chronic Disease; Deoxyguanosine; Erythropoietin; Female; Hepcidins; Humans; Kidney Diseases; Male; Middle Aged; Oxidative Stress; Renal Dialysis

A cohort of rhesus macaques used in neuroscience research was found at routine examinations to have chronic anemia (spun Hct less than 30%). Four anemic (Hct, 24.8% ± 3.4%) and 10 control (39.6% ± 2.9%) macaques were assessed to characterize the anemia and determine probable cause(s); some animals in both groups had cephalic implants. Diagnostic tests included CBC, bone marrow evaluations, iron panels, and serum erythropoietin and hepcidin concentrations. Serum iron and ferritin were 15.8 ± 11.1 μg/dL and 103.8 ± 53.1 ng/mL, respectively, for the anemic group compared with 109.8 ± 23.8 μL/dL and 88.5 ± 41.9 ng/mL, respectively, for the control group. Erythropoietin levels were 16.2 to over 100 mU/mL for the anemic macaques compared with 0 to 1.3 mU/mL for the control group. Hepcidin results were similar in both groups. Because the findings of low iron, high erythropoietin, and normal hepcidin in the anemic macaques supported iron-deficiency anemia or anemia of chronic disease combined with iron-deficiency anemia, a regimen of 4 doses of iron dextran was provided. In treated macaques, Hct rose to 36.3% ± 6.8%, serum iron levels increased to 94.0 ± 41.9 μg/dL, and erythropoietin levels fell to 0.15 to 0.55 mU/mL. Maintenance of normal Hct was variable between macaques and reflected individual ongoing clinical events.

Topics: Age Factors; Anemia, Iron-Deficiency; Animals; Animals, Laboratory; Antimicrobial Cationic Peptides; Biomarkers; Blood Cell Count; Bone Marrow Examination; Chronic Disease; Dietary Supplements; Erythropoietin; Female; Ferritins; Hematinics; Hematocrit; Hepcidins; Iron; Iron Compounds; Macaca mulatta; Male; Monkey Diseases; Time Factors; Treatment Outcome

This study was conducted to investigate the effects of erythropoietin (Epo) on both acute and chronic limb ischemia (ALI and CLI) and to evaluate the differences in mechanisms according to the method of Epo administration. Hindlimb ischemia was made in BALB/c mice with femoral artery ligation. The mice were divided into four groups: Group 1 (control, no treatment), Group 2 (ALI, early multiple doses), Group 3 (ALI, early single high dose), Group 4 (CLI, late multiple doses). Blood flow ratio significantly increased in Group 2 in 4 weeks. Expression of pAkt and Erythropoietin receptor were significantly higher in Group 2 on postoperative day (POD) 7. The number of CD31- and vascular endothelial growth factor-positive cells were significantly higher in Group 2 on POD 7 and 56. Group 3 and 4 showed a tendency of higher cell counts than the control. The early sustained Epo was effective in improving blood flow through angiogenesis. In chronic phase, weekly multiple dosing of Epo induced angiogenesis, however, the blood flow ratio did not increase significantly. The results of this study suggest that Epo administration during the acute phase followed by maintenance for several days may be important for increasing blood flow and angiogenesis.

Topics: Acute Disease; Animals; Chronic Disease; Erythropoietin; Hindlimb; Ischemia; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Vascular Endothelial Growth Factor A

Topics: Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Renal Dialysis; United States

Topics: Algorithms; Anemia; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Risk Factors; Stroke; United States; United States Food and Drug Administration

Anemia of chronic disorders is a very important phenomenon and iron is a crucial factor of this complex process. To better understand this process and its influence on some other factors we have built a mathematical model of the human body iron homeostasis, which possibly most exactly would reflect the metabolism of iron in the case of anemia and inflammation. The model has been formulated in the language of Petri net theory, which allows for its simulation and precise analysis. The obtained results of the analysis of the model's behavior, concerning the influence of anemia and inflammation on the transferrin receptors, and hepcidin concentration changes are the valuable complements to the knowledge following from clinical research. This analysis is one of the first attempts to investigate properties and behavior of a not fully understood biological system on a basis of its Petri net based model.

Topics: Anemia; Antimicrobial Cationic Peptides; Chronic Disease; Cluster Analysis; Computer Simulation; Erythropoietin; Hepcidins; Homeostasis; Humans; Iron; Models, Biological; Receptors, Transferrin

Patients with renal graft dysfunction constitute an increasingly prevalent group of end-stage kidney disease (ESKD) patients that require dialysis therapy. These patients have special characteristics that set them apart from the ESKD general population. The aim of this study was to analyse the clinical condition and evolution of patients entering dialysis with a failed kidney graft at the time of restarting dialysis and over a year of therapy according to the K/DOQI guidelines, and to compare them with incidental patients with end-stage kidney disease. We also investigated whether the modality of kidney replacement therapy may determine the clinical improvement of transplant patients.. This is a retrospective observational study of 106 patients with ESKD followed up in the Ramon y Cajal Hospital. They were classified in two groups. Group one was made up of 50 failed native kidney patients who started dialysis between 2000 and 2009. Group two was comprised of 56 transplant patients with graft dysfunction who returned to dialysis between 1997 and 2009. We studied parameters of kidney function, anaemia, calcium-phosphorus metabolism, cardiovascular risk factors and nutritional status at the time both groups started on dialysis and one year later.. Both groups had a similar clinical status at the time they started on dialysis in most of the parameters analysed with the exception of anaemia. This was more severe in transplant patients, despite the fact that transplant patients received a higher dose of erythropoietin than non-transplant patients. One year later the main difference between both groups was the residual kidney function rate, higher in non-transplant patients. There were no significant differences in the parameters analysed in patients with a failed graft according to the modality of kidney replacement therapy.. Failed transplant patients start dialysis with more severe anaemia than patients entering dialysis for the first time. Twelve months later both groups present a similar clinical condition with the exception of residual kidney function, higher in failed native kidney patients. The method of dialysis treatment after kidney transplant failure did not have a bearing on the clinical improvement of our patients.

Topics: Adult; Aged; Anemia; Calcium; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Phosphorus; Postoperative Complications; Recurrence; Renal Dialysis; Retrospective Studies; Risk Factors; Treatment Outcome

In sickle cell disease (SCD), vigorous reticulocytosis is required to partially compensate for chronic hemolytic anaemia. Consequently, early renal damage, insufficient to cause azotemia but sufficient to cause erythropoietin deficiency and chronic relative reticulocytopenia (chRR), could have severe clinical consequences. chRR was defined as reticulocytes <250×10(9) /l despite haemoglobin <9 g/dl on ≥ two occasions ≥4 weeks apart. The influence of multiple variables including chRR on time from first clinic visit to death was evaluated in 306 SCD patients. In univariate analyses, fetal haemoglobin, indices of renal damage (serum creatinine, proteinuria), chRR and age, were associated with rate of death. In multivariate analysis, only age and chRR (Hazard ratio 3·6, 95% CI 2·049-6·327, P<0·0001) were significant, underlining that chRR could be an early and important clinical consequence of renal damage. Even in chRR patients with normal serum creatinine levels, low haemoglobin and low reticulocyte counts were associated with low erythropoietin levels. In the general population, evaluation of erythropoietin levels is prompted by the combination of anaemia and abnormal serum creatinine. In SCD patients, this standard approach can miss a substantial risk factor for early death. chRR could be a practical and important criterion for diagnosis of erythropoietin deficiency in SCD.

Topics: Adolescent; Adult; Age Factors; Anemia, Sickle Cell; Chronic Disease; Creatinine; Epidemiologic Methods; Erythropoietin; Female; Humans; Male; Middle Aged; Proteinuria; Reticulocyte Count; Young Adult

Chronic inflammation plays a pivotal role in the development of renal disease. Circadian sleep-wake rhythm is disturbed in renal disease. Awareness of other disturbed rhythms, such as inflammation processes, can affect the treatment of patients with renal disease. Knowledge of possibly related circadian misalignment of the cytokines erythropoietin (EPO), Insulin Growth Factor-1 (IGF-1) and interleukins (IL) however is limited. We therefore performed an observational study. The objective of this study was to characterize levels of EPO, IGF-1 and inflammation markers IL-6 and TNF-α, related to renal function.. The study population consisted of patients with various degrees of renal function, admitted to our hospital. During 24 hours, blood of 28 subjects with various degrees of renal function was collected every 2 hours. The patients were stable, not acutely ill and they were waiting for a procedure, such as elective surgery. Circadian parameters of EPO, IGF-1, IL-6 and TNF-α were measured in serum and were correlated with glomerular filtration rate (GFR) and Hb, using Pearson correlations.. Although diurnal variations in EPO level were found in 15 out of 28 patients, the curves did not show a consistent phase. The presence of an EPO rhythm was not related to GFR. No diurnal rhythm could be detected for IGF-1, IL-6 and TNF-α. Mean levels of IGF-1 were correlated inversely to mean levels of EPO (p=0.03). When divided based on GFR and Hb subjects with GFR 10-30 ml/min and lower Hb had the highest IGF-1 levels (p=0.02). A relationship between Il-6, TNF-α and EPO or GFR was not found.. The existence of a circadian (mis)alignment of EPO, IGF-1, IL-6 and TNF-α was not found. The association between high IGF-1 and low Hb suggests that EPO and IGF-1 have an alternating role, dependent on GFR, in stimulating erythropoiesis. These results could have consequences for the treatment of anemia.

Topics: Aged; Biomarkers; Chronic Disease; Circadian Rhythm; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Insulin-Like Growth Factor I; Interleukin-6; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Retrospective Studies; Tumor Necrosis Factor-alpha

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.

Topics: AC133 Antigen; Aged; Antigens, CD; Antigens, CD34; Biomarkers; Cell Proliferation; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelial Cells; Erythropoietin; Female; Glycoproteins; Hematinics; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Peptides; Philadelphia; Prospective Studies; Stem Cells; Time Factors; Treatment Outcome; Vasodilation

To accurately determine the causes of anemia and proportion of unexplained anemia in a racially diverse cohort of older adults after a comprehensive and standardized evaluation.. We evaluated results from a single-institutional university anemia clinic. Patients with anemia, defined as a hemoglobin less than 13.0 g/dL for men and less than 12.0 g/dL for women, underwent a prospective standardized history, physical examination, and laboratory measures, with additional studies including bone marrow examination as indicated. Empiric treatment trials were given for identified deficiencies.. One hundred and seventy-four primarily community-dwelling adults aged 65 years and older were evaluable. African Americans accounted for 69% of patients and whites were 27%. Anemia etiologies included iron deficiency anemia at 25.3%, anemia of chronic inflammation at 9.8%, and hematologic malignancy in 7.5%. Unexplained anemia in the elderly accounted for 43.7% and predominated in both African Americans and whites. The prevalence of iron deficiency anemia and hematologic malignancies did not differ by race. Unexplained anemia in the elderly showed a consistent phenotype composed of a hypoproliferative mild-to-moderate anemia with suppressed serum erythropoietin. Specifically, erythropoietin levels showed no correlation with hemoglobin concentration in unexplained anemia in the elderly (r = -.15, p = .19) as opposed to iron deficiency anemia (r = -.63, p < .0001).. In summary, an intensive hematologic evaluation reveals a wide number of anemia etiologies among older adults, including 7.5% with hematologic malignancies; nevertheless, unexplained anemia in the elderly prevails as the most common category in whites and African Americans.

Topics: Aged; Aging; Anemia; Anemia, Iron-Deficiency; Black or African American; Chronic Disease; Cohort Studies; Erythropoietin; Female; Hematologic Neoplasms; Hemoglobins; Humans; Inflammation; Male; Outpatient Clinics, Hospital; Prevalence; Prospective Studies; Referral and Consultation; White People

Anemia of chronic kidney disease (CKD) has been traditionally treated by erythropoiesis-stimulating agents (ESAs) and/or iron following manual determination of dose. We hypothesized that once-monthly (QM) algorithmically dosed darbepoetin α (DA) and iron administration would successfully treat anemia of CKD in ESA-naïve CKD subjects.. QM DA and iron doses were determined via a computerized program targeting a hemoglobin (Hb) of 10.5 - 12.5 g/dl in anemic, ESA-naïve, CKD Stages 3 - 5 subjects. Six consecutive QM doses were administered. Hb, ferritin, and transferrin saturation were recorded. Data are presented as means ± standard deviation.. Anemia was identified in 133 subjects, with a mean follow-up of 188 days. DA doses and Hb were significantly greater at Months 3 and 6 compared to baseline (p < 0.05); DA doses were 109 ± 68 μg and 118 ± 91, respectively, at Months 3 and 6. Hemoglobin levels were correspondingly 11.3 ± 1.1 g/dl and 11.3 ± 1.0. 78% of patients achieved the target Hb by 6 months of therapy. The elevation of Hb was greater in non-proteinuric than proteinuric subjects at 6 months of treatment (11.6 ± 0.8 g/dl vs. 11.0 ± 1.1; p < 0.05), despite lower DA dose (96 ± 76 μg vs. 139 ± 98; p < 0.05).. Successful treatment of the anemia of CKD by QM DA based upon a computerized dosing program was achieved by 6 months in 78% of ESA-naïve, CKD subjects.

Topics: Algorithms; Anemia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Drug Therapy, Computer-Assisted; Erythropoietin; Female; Ferritins; Ferrous Compounds; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Transferrin

Frequent dosing and requirements for dose adjustments of erythropoiesis-stimulating agents (ESAs) create significant burdens for healthcare providers and have been associated with hemoglobin (Hb) cycling, hampering maintenance of target Hb levels. We compared the frequency of dose changes in dialysis patients who received methoxy polyethylene glycolepoetin beta; (a continuous erythropoietin receptor activator (C.E.R.A.)) or a shorter-acting ESA.. Data were analyzed from three Phase III maintenance trials, using almost identical protocols, in dialysis patients treated with C.E.R.A. every 2 weeks (q2w) or every 4 weeks (q4w) or a comparator ESA (epoetin or darbepoetin alpha; at their previous dose/administration interval). Dosage was adjusted to maintain Hb ± 1 g/dl of baseline and 10 - 13.5 g/dl during titration (28 weeks) and evaluation (8 weeks), and 11 - 13 g/dl during follow-up (16 weeks).. Data were analyzed from 564 patients treated with C.E.R.A. q2w, 410 with C.E.R.A. q4w and 572 with comparator ESA at their usual dosing interval. Significantly fewer dose changes were needed in patients receiving C.E.R.A. q2w (p < 0.05) or C.E.R.A. q4w (p < 0.001) than in patients treated with comparator ESAs.. This retrospective analysis suggests that C.E.R.A. q4w maintains Hb levels in dialysis patients and requires fewer dose changes compared with other ESAs.

Topics: Anemia; Chronic Disease; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Anemia and inflammation are prevalent in diabetic patients with chronic kidney disease (CKD). The role of endogenous erythropoietin (EPO) in the pathophysiology of anemia in chronic diseases and its relationship to clinical outcomes remain uncertain. In this cohort study, we aimed to identify factors associated with endogenous EPO levels and investigate their relation to all-cause mortality.. Between 2004 and 2005, 215 patients with type 2 diabetes were enrolled. Exclusion criteria included stage renal disease ESRD and any form of anemia therapy. The association of EPO levels with clinical and laboratory variables was investigated by linear regression modeling. Predictors of all-cause mortality were evaluated by Cox proportional hazards analyses.. Patients (median age, 67 years; 52% men; median duration of diabetes, 10 years; median estimated GFR, 49 ml/min per 1.73 m²) were followed for up to 7.0 years. Forty-one patients died. Elevated EPO levels were independently associated with elevated C-reactive protein, low ferritin, and hypertension, in a multivariate model that also included age, cardiovascular disease, kidney function, albumin, cholesterol, and hemoglobin. Higher EPO levels were independently predictive for mortality, as were age, low levels of albumin, and cardiovascular disease.. In diabetic patients with CKD, elevated endogenous EPO levels were predictive for mortality and were related mainly to markers of inflammation, independent of kidney function, and despite low hemoglobin levels. Understanding the phenomenon of EPO resistance and iron dysregulation caused by inflammation is crucial for effective and safe treatment of anemia in patients with CKD.

Topics: Aged; Analysis of Variance; Anemia; Biomarkers; C-Reactive Protein; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Germany; Humans; Inflammation; Inflammation Mediators; Kaplan-Meier Estimate; Linear Models; Longitudinal Studies; Male; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

The study investigated the issues of iron metabolism under iron-deficiency anemia and chronic disorders anemia and dependencies of production of IL-1? and sICAM-1 immunoinflammatory markers from degree of severity and duration of anemia. The study data indicates that under iron-deficiency anemia lactoferrin and sICAM-1 are the negative regulators of hemopoiesis. The inhibition of transferrin expression by the proinflammatory cytokines is one of the causes of inefficient hemopoiesis under chronic disorders anemia.

Topics: Adult; Anemia, Iron-Deficiency; Biomarkers; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-1beta; Iron; Iron-Binding Proteins; Male; Middle Aged

The four currently available erythropoiesis-stimulating agents (ESAs), the main drugs for correcting anemia in patients with chronic kidney disease (CKD), are epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator. The last two have much longer half-lives, which means they can be administered less frequently. The expiry of the patents for epoetin alfa and epoetin beta some years ago opened up the way for the production of a number of biosimilars that are now marketed in the European Union. Because biosimilars cannot be identical to their originator, a complex and still-evolving regulatory policy has been generated, but there are still a number of issues concerning international naming, automatic substitution, and safety. All ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. Following the publication of a number of trials indicating no benefit (and even possible harm) when ESAs are used to aim at near-normal hemoglobin levels in CKD patients, the hemoglobin target has become a major subject of discussion. According to the position statement of the Anemia Group of the European Renal Best Practice, it should generally be about 11-12 g/dL; however, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; European Union; Hematinics; Hemoglobins; Humans; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

The relationship between the dressing and the wound is vital to clinical effectiveness. The more-or-less standard wound-surface coverings have been replaced with initial dressings, referred to as modern dressings, which contain an oily and sticky compound. They provide a moist medium by applying the basic mechanistic principles (liquid absorption and release). Other types of products and techniques modify the behaviour of wound cells by acting directly through irritation, biochemical stimulation or genetic modification of the cells, which accelerates the healing process.

Topics: Bandages; Becaplermin; Chronic Disease; Coated Materials, Biocompatible; Collagen; Debridement; Erythropoietin; Humans; Platelet-Derived Growth Factor; Protease Inhibitors; Proto-Oncogene Proteins c-sis; Skin Transplantation; Skin, Artificial; Wound Healing; Wounds and Injuries

The etiology of anemia is still unclear in patients with chronic heart failure (CHF). Hepcidin is an iron regulatory peptide that is synthesized in the liver to suppress iron absorption and utilization. Hepcidin synthesis is suppressed by anemia, hypoxia and erythropoiesis, and induced by inflammation. Inflammatory cytokines, such as interleukin-6 (IL-6), increase the synthesis of hepcidin, resulting in anemia of inflammation (AI). The serum hepcidin concentration in CHF patients with anemia was measured in order to better understand anemia in CHF.. Serum hepcidin-25, erythropoietin (EPO), ferritin and IL-6 concentrations were measured in 61 CHF patients. Among these patients, 36 patients had anemia. A group of 16 patients without cardiac disease or anemia were recruited as controls. Serum IL-6 and EPO were higher and hepcidin-25 was lower in CHF patients with anemia than in controls. Hepcidin-25 correlated with EPO and ferritin but not with IL-6. Results of multivariable regression analysis showed that independent predictors of serum hepcidin-25 included EPO and ferritin but not IL-6.. Serum hepcidin-25 concentrations were regulated by iron storage and erythropoiesis but not by IL-6 in CHF patients with anemia. These findings might indicate that AI is a minor cause of anemia in CHF.

Topics: Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Case-Control Studies; Chronic Disease; Down-Regulation; Erythropoietin; Female; Ferritins; Heart Failure; Hepcidins; Humans; Inflammation Mediators; Interleukin-6; Linear Models; Male; Middle Aged; Prospective Studies

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Randomized Controlled Trials as Topic; Recombinant Proteins

Anemia is common in chronic kidney disease (CKD). The CHOIR study found increased risk of a composite cardiovascular outcome when anemia was treated with epoetin-alfa to a target hemoglobin level of 13.5 as compared with 11.3 g/dl. Whether this increase applies to all patient subgroups equally is unclear. We discuss an analysis by Szczech and colleagues of the effects of the higher hemoglobin target in CKD patients with diabetes mellitus or congestive heart failure.

Topics: Anemia; Chronic Disease; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins

Topics: Anemia; Animals; Chronic Disease; Erythropoietin; Humans; Hypertension; Kidney Diseases; Oxidative Stress; Rats; Recombinant Proteins

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Kidney Transplantation

Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients.. This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated.. There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation.. Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction.

Topics: Administration, Oral; Aged; Biomarkers; Bone Density Conservation Agents; Bone Remodeling; C-Reactive Protein; Calcitriol; Calcium; Chelating Agents; Cholecalciferol; Chronic Disease; Darbepoetin alfa; Dietary Supplements; Ergocalciferols; Erythropoietin; Female; Hematinics; Humans; Hypertrophy, Left Ventricular; Inflammation Mediators; Kidney Diseases; Male; Middle Aged; Natriuretic Peptide, Brain; Parathyroid Hormone; Phosphorus; Polyamines; Prospective Studies; Renal Dialysis; Serum Albumin; Sevelamer; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

The aim of study was to analyze the results of anemia treatment with darbepoetin alfa and erythropoietin beta in patients with chronic kidney disease (3-5 stage of CKD) in predialysis period.. In the study the results of anemia treatment with darbepoetin alfa and erythropoietin beta were analyzed in respectively 35 and 20 patients during 11 months, and its influence on blood pressure and the rate of progression of chronic kidney disease. After 2 months of darbepoetin alfa treatment 10 mg/month and after 4 months of darbepoetin alfa treatment 20 mg/month the hemoglobin target serum levels in male and female patients were reached. In 3 patients the hemoglobin serum level was increased over 13 g/dl and was stable up to the end of treatment. During 11 months observation the value of blood pressure was not changed. Similarly, a creatinine serum level was stable in females but increased in males. Therapy with darbepoetin alfa was well tolerated, however some patients were complained for subcutaneous injection pain.. After erythropoietin beta treatment 2000 IU/week the hemoglobin target level in serum was achieved in 3 females after 9 months and 7 males after 6 months. In 3 patients, in one male after 6 months and two females after 8 months the hemoglobin serum levels were increased over 13 g/dl and was stable up to the end of treatment.. During 11 months of observation blood pressure was not changed but a creatinine serum level was increased in females and in males. Erythropoietin beta was well tolerated and injection pain was smaller compared to darbepoetin alfa.

Topics: Anemia; Blood Pressure; Chronic Disease; Creatinine; Darbepoetin alfa; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Pain; Treatment Outcome

Anemia is common in patients with chronic heart failure (HF) with an incidence ranging from 4% to 55% depending on the studied population. Several studies have highlighted that the prevalence of anemia increases with worsening heart failure as reflected by New York Heart Association classification. Additionally, several epidemiological studies have highlighted its role as a prognostic marker, linking it to worse outcomes including; malnutrition, increased hospitalizations, refractory heart failure and death. The pathophysiology of anemia is multifactorial and related to various factors including; hemodilution, iron losses from anti-platelet drugs, activation of the inflammatory cascade, urinary losses of erythropoietin and associated renal insufficiency. There are a host of epidemiological studies examining HF outcomes and anemia, but only a few randomized trials addressing this issue. The purpose of this article is to review the literature that examines the interrelationship of anemia and congestive HF, analyzing its etiology, impact on outcomes and also the role of associated kidney disease as well as cardiorenal syndrome both as a marker of morbidity and mortality.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis

To evaluate the effects of L-carnitine oral supplementation on anemia and cardiac function in patients on maintenance hemodialysis (HD), we studied 55 adult chronic HD patients at our center during the period from January 2006 to June 2006 and divided them into two groups; a group of 20 patients who received 1500 mg/day oral L-carnitine and a control group of 35 patients. Both groups were on erythropoietin therapy. Echogardiographic studies were performed before and at the end of the study. The mean hemoglobin levels were comparable in the L-carnitine group and the control group at the start and after 6 months of therapy (8.63 +/- 1.77 and 9.39 +/- 2.02 gm/dL, P = 0.18; 10.49 +/- 1.65 and 10.92 +/- 2.48 gm/dL, P = 0.76, respectively). The mean weekly maintenance dose of erythropoietin was not statistically significantly different in L-carnitine group (80.16 +/- 35.61 units/kg) and the control group (91.9 +/- 38.21 units/kg, P = 0.20). In addition no significant improvement could be observed in the echogardiographic findings in the L-carnitine group after therapy. We conclude that our study revealed no significant improvement in hemoglobin, erythropoietin dose and echocardiographic findings after six months of therapy. Long-term studies including larger number of patients are required to clarify the questionable role of L-carnitine in the HD patients.

Topics: Administration, Oral; Adult; Anemia; Carnitine; Chronic Disease; Dietary Supplements; Echocardiography; Egypt; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Time Factors; Treatment Outcome; Ventricular Function; Young Adult

Topics: Chronic Disease; Diuretics; Drinking Behavior; Drug Therapy, Combination; Erythropoietin; Hemodilution; Hemoglobins; Humans; Hydrochlorothiazide; Kidney Diseases; Losartan; Proteinuria; Renin-Angiotensin System; Urination

Topics: Anemia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Female; Humans; Hypersensitivity, Delayed; Injections, Subcutaneous; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

To determine the aqueous concentration of erythropoietin (EPO) in patients with and without glaucoma.. Prospective, comparative control study. Concentrations of EPO in the aqueous humor were measured using ELISA kits from 75 patients, of whom 55 had glaucoma (14 primary acute angle-closure glaucoma, PAACG; 26 primary chronic angle-closure glaucoma, PCACG; 11 primary open-angle glaucoma, POAG; 4 neovascular glaucoma, NVG), and 20 had cataract only as control.. EPO concentrations in eyes with glaucoma (71.0 +/- 12.0 mU/mL) were significantly higher than those in eyes with cataract (6.4 +/- 0.8 mU/mL, P < 0.001). There were no significant differences (P = 0.421) between PCACG (28.84 +/- 3.9 mU/mL) and POAG (20.2 +/- 2.0 mU/mL); however, EPO concentrations in eyes with PAACG (118.5 +/- 14 mU/mL) were significantly higher than these two chronic subtypes of glaucoma (P < 0.001, respectively). Unusually high EPO concentrations were detected in four eyes with NVG (319.5 +/- 47.7 mU/mL). No effect of age, gender, different eyes, body mass index of the aqueous humor EPO concentration could be detected (P > 0.05). No significant correlation was found between aqueous humor and plasma EPO concentrations in PAACG and control group (P = 0.285, 0.500, respectively).. Our prospective study suggests that the aqueous humor EPO concentrations are increased in eyes with glaucoma.

Topics: Acute Disease; Aged; Aqueous Humor; Case-Control Studies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Glaucoma, Angle-Closure; Glaucoma, Neovascular; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Prospective Studies

The objective was to determine the cost-effectiveness of treating anemic patients with chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) to a low (9-10.9 g/dL), intermediate (11-12 g/dL), or high (> 12 g/dL) hemoglobin level target compared with a strategy of managing anemia without ESAs.. Cost-utility analysis.. Publicly funded health care system. Anemic patients with CKD, overall and stratified into dialysis-/non-dialysis-dependent subgroups.. Decision analysis, health care payer, patient's lifetime.. Cost per quality-adjusted life-year (QALY) gained.. For dialysis patients, compared with anemia management without ESAs, using ESAs to target a low hemoglobin level is associated with a cost per QALY of $96,270. Given a lack of direct trials comparing low and intermediate targets, significant uncertainty exists between these strategies. Treatment to a high hemoglobin target was always associated with worse clinical outcomes and higher costs compared with a low hemoglobin target. Results were similar in non-dialysis-dependent patients with CKD, with a cost per QALY for a low target compared with no ESA of $147,980.. Given limitations in the available randomized controlled trials, we were able to model only 4 treatment strategies, balancing the need to consider relevant targets with the requirement for accurate estimates of clinical effect. We assumed that the efficacy of the different strategies would continue over a patient's lifetime.. Using ESAs to target a hemoglobin level > 12 g/dL is associated with worse clinical outcomes and significant additional cost compared with using ESAs to target lower hemoglobin levels (9-12 g/dL). Given a lack of studies comparing low (9-10.9 g/dL) and intermediate (11-12 g/dL) hemoglobin targets for clinical outcomes, including quality of life, the most cost-effective hemoglobin level target within the range of 9-12 g/dL is uncertain, although aiming for higher targets within this range will lead to higher costs.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Cohort Studies; Cost-Benefit Analysis; Decision Support Techniques; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Quality-Adjusted Life Years; Renal Dialysis

Topics: Aged; Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Health Care Rationing; Hematinics; Humans; Insurance Coverage; Medicare; Recombinant Proteins; United States

Topics: Aged; Anemia; Antimetabolites, Antineoplastic; Chronic Disease; Deoxycytidine; Erythropoietin; Gemcitabine; Hemolytic-Uremic Syndrome; Humans; Liver Neoplasms; Male; Pancreatic Neoplasms; Treatment Failure

In chronic heart failure (CHF), several plasma biomarkers identify subjects at risk of death over the midterm. However, their long-term predictive value in the context of other candidate predictors has never been assessed. This information may prove valuable in the management of a chronic disease with a long natural history, as CHF is today.. We aimed to assess the very-long-term prognostic power of a set of biomarkers to identify CHF patients at highest risk for all-cause mortality.. A group of 106 consecutive outpatients with CHF (85 male and 21 female, median age 56 y) was followed for 15 years. Echocardiographic tracings and blood samples were collected at study entry to evaluate cardiac function, plasma atrial natriuretic peptide (ANP), aldosterone, and erythropoietin, and plasma renin activity. The relationships between biomarkers, clinical and echocardiographic variables, and mortality were assessed.. After 15 years, 86 of the 106 patients (81%) had died. Multivariate analysis showed that ANP was the best independent predictor of survival over several clinical, echocardiographic, and humoral variables (hazard ratio: 5.62, 95% confidence interval: 3.37-9.39, P < 0.001 for plasma levels < median value of 71 pg/mL). Plasma renin activity and erythropoietin provided prognostic information in univariate analysis, but lost their predictive power when adjusted for covariates.. The present study represents the longest available follow-up of patients with CHF evaluating the prognostic power of multiple biomarkers. It shows that a simple assessment of plasma ANP levels is the strongest long-term predictor of death in all stages of heart failure.

Topics: Aldosterone; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Humans; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Proportional Hazards Models; Prospective Studies; Renin; Risk Assessment; Risk Factors; Survival Rate; Time Factors; Ultrasonography

Erythropoietin has transformed the treatment of the anemia of chronic kidney disease (CKD) by preventing the need for blood transfusions and improving the quality of life in all patients, including children. Anemia in children, in the age group 1-19 years, may be defined as hemoglobin (Hgb) levels < 12.1-13.5 g/dl for boys and < 11.4-11.5 g/dl for girls, based on the National Health and Nutrition Examination Survey (NHANES) norms. The prevalence of anemia in children ranges from 31.2% in stage 1 CKD to 93.3% in stages 4 and 5 CKD. The recent publication of trials evaluating the optimal hemoglobin level in adult CKD patients has generated considerable uncertainty about the target Hgb level in children with CKD. It is unclear whether generalizing of results from these trials in adults to children is appropriate. Adequately powered, randomized, controlled studies have not been conducted on children, and none to our knowledge are currently planned. The Food and Drug Administration (FDA) offers scant guidance on the Hgb target level for children, other than implying that it should be no different from that for adults. The purpose of this editorial is to critically scrutinize whether there is a benefit to the normalization of anemia in children with CKD and whether adoption of the results from adult studies is appropriate.

Topics: Adult; Anemia; Child; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Quality of Life; Recombinant Proteins

Anti-r-HuEpo associated PRCA developed in patients received subcutaneous injection of r-HuEpo for treatment of renal anemia in chronic kidney disease. This adverse immunological effect of r-HuEpo causes sudden loss of r-HuEpo efficacy, low circulating reticulocyte count and bone marrow biopsy shows an absence of erythroid precursor cells with normal cell population of non-erythroid lineage. There are postulation cause of anti-r-HuEpo associated PRCA including genetic factor, immunogenicity factor, storage and handlings factor and formulation of r-HuEpo product. Previous observation of our report showed an aggregation of HLA-DRB1*09 in four anti-r-HuEpo associated PRCA cases. This allele is rare in Caucasian (<1%) but more common in Thai population (8.4-12.5%). This study was aimed to investigate the possible association between HLA-DRB1*09 or other specific HLA and anti-r-HuEpo associated PRCA.. Twenty two cases of proven anti-r-HuEpo associated PRCA were recruited and studied retrospectively based on the incidence report of serious adverse drug reaction. The EDTA bloods were drawn for HLA typing using sequence specific primer polymerase chain reaction (SSP-PCR). The HLA data of 1,800 potential cadaveric kidney transplantation recipients in the waiting list as chronic kidney disease control and 1,500 potential bone marrow stem cell donors in national stem cell registry as healthy population control were retrieved from the database of Thai Red Cross for comparison.. The distribution of gene frequency of HLA-A, -B, -DR and -DQ alleles in anti-r-HuEpo associated PRCA cases showed high gene frequency of HLA-A*02, HLA-A*11 and HLA-A*24 for HLA-A loci, HLA-B*18, HLA-B*46, HLA-B*60 and HLA-B*62 for HLA-B loci, and HLA-DRB1*09, HLA-DRB1*12 and HLA-DRB1*15 for HLA-DR loci. There was a significant difference of HLA-DRB1*09 gene frequency (P < 0.001) which associated with HLA-DQB1*0309 between anti-r-HuEpo associated PRCA cases, and potential cadaveric kidney transplantation in the waiting list or potential national stem cell registry donor. The odd ratio of HLA-DRB1*09 allele for anti-r-HuEpo associated PRCA was 2.89 (95% CI: 1.88-4.46; p-value: <0.001).. Our data demonstrated the association of HLA-DRB1*09-DQB1*0309 and anti-r-HuEpo associated PRCA cases. This association may be used in identifying the risk of the patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Anemia; Antibodies, Anti-Idiotypic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Risk Factors; Young Adult

There are no investigations demonstrating that body size-adapted doses of erythropoietin (EPO) are as equally effective in children as in adults. A treatment starting with 150 IU/kg body weight per week leads to an insufficient rise in hemoglobin levels in anemic children with chronic kidney disease (CKD). Nevertheless, this strategy is widely used and seems to be the reason for a high percentage of young anemic children in spite of EPO treatment. In children and in adults, 1,000 IU EPO intravenously increases the hemoglobin level equally by 0.04 g/l. This strongly argues for specifying the EPO dose in the treatment of children with CKD in absolute amounts. A prediction model exists which allows the determination of the EPO dose which is expected to raise hemoglobin from a given pretreatment level to a desired steady state level.

Topics: Adult; Anemia; Body Size; Child; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Kidney Diseases

Anaemia is frequently found in patients with diabetes, in whom it is associated with increased morbidity and mortality. Low testosterone levels are also common in men with type 2 diabetes. We hypothesized that low testosterone levels are also associated with anaemia in men with type 2 diabetes, over the effects of chronic kidney disease.. Cross-sectional cohort study, performed in 2005 in a tertiary diabetes clinic. Patients 464 men with type 2 diabetes.. Anaemia (haemoglobin (Hb) < 13.7 g/dl in men aged < 60, or < 13.2 g/dl in men aged 60 and older).. About 24% of study participants had anaemia, which was associated with the presence and severity of chronic kidney disease, systemic inflammation, increased age, and reduced iron availability. In addition, testosterone levels were independently associated with reduced Hb levels, determining between 6 and 8% of the total variability in raw Hb levels in this population after adjusting for these other factors. Individuals with total testosterone level < 10 nmol/l (43% of the cohort) were more likely to have anaemia (adjusted odds ratio 1.7; 95% CI 1.1-2.8). Similarly, anaemia was twice as common in individuals with a calculated free testosterone of < 0.23 nmol/l (adjusted odds ratio 2.0, 95% CI 1.2-3.1).. These findings suggest that testosterone deficiency may contribute to the increased frequency of anaemia in men with type 2 diabetes. However, the appropriate clinical response to testosterone deficiency in anaemic patients remains to be established by prospective clinical trials.

Topics: Aged; Anemia; C-Reactive Protein; Chronic Disease; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Regression Analysis; Severity of Illness Index; Testosterone

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Hematinics; Humans; Kidney Diseases

Anemia is a well known complication of chronic kidney disease (CKD); however, the prevalence of anemia within CKD stages in the pediatric population has not been established. Additionally, the associated morbidity of anemia in the pediatric CKD population has not been elucidated.. 2,779 patients ages 2 yr and older in the North American Pediatric Renal Trials and Collaborative Studies database with CKD stage II to V (excluding dialysis or previous transplant patients) were identified. Descriptive statistics and multivariate modeling using logistic regression was performed to determine the prevalence of anemia and to evaluate the correlation between baseline anemia and hospitalization.. The prevalence of anemia (hematocrit < 33%) increased from 18.5% in CKD stage II to 68% in CKD stage V (predialysis). Anemic children were 55% more likely to be hospitalized when compared with nonanemic children (odds ratio 1.55; 95% confidence interval 1.23 to 1.94). Similar results were obtained using hematocrit cutoffs of 36 and 39%.. In this pediatric predialysis CKD population, anemia increases with increasing CKD stage and is significantly associated with hospitalization risk. Hematocrit levels above 36 and 39% were not associated with increased risk of hospitalization. Further examination into the effect of correcting anemia on hospitalization rates may provide additional useful information.

Topics: Adolescent; Anemia; Canada; Child; Child, Preschool; Chronic Disease; Erythropoietin; Female; Hematinics; Hematocrit; Hospitalization; Humans; Kidney Diseases; Logistic Models; Male; Odds Ratio; Prevalence; Registries; Retrospective Studies; Risk Assessment; Risk Factors; United States

Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAg(h)) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAg(h) mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1alpha, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAg(h) mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1alpha, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAg(h) mice developed cerebral angiogenesis through the HIF-1alpha/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAg(h), the decrease in HIF-1alpha, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.

Topics: Anemia; Animals; Body Weight; Brain; Cerebral Cortex; Chronic Disease; Erythropoietin; Hemoglobins; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoassay; Immunohistochemistry; Male; Mice; Mice, Inbred CBA; Mice, Knockout; Nitric Oxide; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA; STAT5 Transcription Factor; Vascular Endothelial Growth Factor A

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

Topics: Acute Disease; Anemia; Blood Transfusion; Chronic Disease; Erythropoietin; Hemodynamics; Humans; Perioperative Care; Recombinant Proteins

Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis (EE) secondary to hypoventilation. Erythropoietin (Epo) and testosterone regulate erythrocyte production. Low thyroid hormone levels are also associated to hypoventilation. Hence, these hormones can play a role in etiopathogeny of EE. The purpose of this study was to elucidate the effect of sexual and thyroid hormones and Epo in residents from Lima (150 m) and Cerro de Pasco (4,340 m), Peru, and the response to human chorionic gonadotrophin stimulation (hCG). Three groups, one at low altitude and two at high altitude [1 with hemoglobin values >16-21 g/dl and the second with Hb >or=21 g/dl (EE)], were studied. hCG was administered intramuscularly in a single dose (1,000 IU), and blood samples were obtained at 0, 6, 12, 24, 48, and 72 h after injection. High-altitude natives present similar levels of gonadotropins and thyroid hormones but lower dehydroepiandrosterone sulphate (DHEAS) levels (P < 0.01) and greater Epo (P < 0.01), 17alpha-hydroxyprogesterone (P < 0.01), and testosterone levels (P < 0.01) than those at 150 m. Serum testosterone levels (524.13 +/- 55.91 microg/dl vs. 328.14 +/- 53.23 ng/dl, means +/- SE; P < 0.05) and testosterone/DHEAS ratios are higher (7.98 +/- 1.1 vs. 3.65 +/- 1.1; P < 0.01) and DHEAS levels lower in the EE group (83.85 +/- 14.60 microg/dl vs. 148.95 +/- 19.11 ug/dl; P < 0.05), whereas Epo was not further affected. Testosterone levels were highest and DHEAS levels lowest in the EE group at all times after hCG stimulation. In conclusion, high androgen activity could be involved in the etiopathogeny of CMS. This evidence provides an opportunity to develop new therapeutic strategies.

Topics: 17-alpha-Hydroxyprogesterone; Adult; Aged; Altitude; Altitude Sickness; Chronic Disease; Dehydroepiandrosterone Sulfate; Erythrocytes; Erythropoietin; Estradiol; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Peru; Polycythemia; Testosterone

Topics: Anemia; Chronic Disease; Cohort Studies; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Erythropoietin level was studied in blood plasma of humans from different age groups and in patients with chronic hearts failure of ishemic genesis. It was determined that there was no statistically significant difference of erythropoietin level among the age groups. Erythropoietin level in patients with chronic heart failure was 16-fold greater (102.86 +/- 29.04 mU/ml) than in the studied elder aged groups (6.38 +/- 1.82 mU/ml). The data obtained indicate that elderly (60 to 85 years) persons' organisms retain the ability of response to hypoxia by intensive erythropoietin production.

Topics: Adult; Aged; Aged, 80 and over; Aging; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Ischemia

The blood plasma erythropoietin content, erythropoietin content, erythropoietin and cellular renovation markers expression in exocervical epithelium in reproductive aged women with normal peripheral red blood values were studied. It was determined that erythropoietin expression increased in exocervical epithelium activity (cervical intraepithelial neoplasia 1 and 2), combined with the increase of blood plasma erythropoietin level, activation of pro- and antiapoptosis programs and cellular proliferation processes in cervical epithelium.

Topics: Adolescent; Adult; Apoptosis; Cell Proliferation; Cervix Uteri; Chronic Disease; Epithelium; Erythropoietin; Female; Humans; Middle Aged; Uterine Cervical Dysplasia; Uterine Cervicitis

Sialic acids (SA) located in erythrocyte membranes (EM) play an important role in the survival of circulating red blood cells.. The aim of the present study was to evaluate the SA content in EM obtained from patients on chronic hemodialysis (HD) and to examine the relationships between SA and hematological parameters. Moreover, the effects of HD, treatment with human recombinant erythropoetin (epoetin), and some biochemical and hematological parameters were analyzed.. The total protein (TP) and total sialic acids (TSA), together with SA bound with proteins (PBSA) and lipids (LBSA), were determined in EM of 72 HD patients and compared with the control group of healthy individuals (CG; n=25). The adequacy of HD, weekly epoetin doses, mean arterial pressure (MAP), comorbidity score, serum levels of albumin, intact parathyroid hormone (iPTH), low-density lipoprotein cholesterol (LDL-cholesterol) were estimated in patients.. Compared to the CG, HD patients had higher levels of TSA (p < 0.001), PBSA (p < 0.001), LBSA (p <0.001) and decreased TP levels (p < 0.001). The TP (p < 0.045) and PBSA (p < 0.05) levels were higher in patients with diabetic nephropathy than in non-diabetic HD patients. In HD patients there were correlations between TSA, PBSA in EM and some hematologial parameters. There were no relationships between the TSA, PB content in EM and variables such as HD, epoetin treatment, MAP comorbidity score, albumin, iPTH, and LDL-cholesterol.. The results of the current study demonstrated there are significantly higher levels of TSA, PBSA, LBSA and lower TP levels in EM obtained from HD patients compared to healthy subjects. Comorbidity score, epoetin and HD treatment, MAP, iPTH, albumin and LDL cholesterol had no influence on SA levels in EM of patients.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Chronic Disease; Comorbidity; Diabetic Nephropathies; Erythrocyte Membrane; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; N-Acetylneuraminic Acid; Recombinant Proteins; Renal Dialysis; Smoking

We aimed in this study to assess the opinion of medical directors of dialysis centers in the Kingdom of Saudi Arabia (KSA) about updates of strategies for treatment of anemia in patients with chronic kidney disease (CKD). A questionnaire was sent to the medical directors of the 174 active dialysis centers in the KSA including centers under the Ministry of Health (MOH) (67 %), the governmental non-MOH sector (12%) and private hospitals (21 %) that together care for a population of more than 11,300 chronic dialysis patients. The study was performed between November 2008 and March 2009. A total of 143 of the 174 (82.1%) medical directors answered the questionnaire. This covered 9563 (84%) dialysis patients in the KSA. There were 95 (68.8%) respondents who believed that the mechanism of action of ESAs is due to both blood concentration and direct action on the stem cells that form red cells. Only 81 (57%) respondents believed that the half-life of the short-acting ESAs is less than one day, 67 (46.9%) believed the half-life of darbepoetin is 2-4 days, and 52 (36.6%) believed the half-life of CERA is 5-10 days; 79 (55.6%) respondents believed that the interval of dosing of darbepoetin is once biweekly, and 92 (71.9%) believed that the interval of dosing of CERA is once a month. There were 110 (76.9%) respondents who believed the CKD should receive a long-acting than short-acting ESAs for the more stable hemoglobin levels, 64 (44.8%) believed that pharmacodynamics of the CERA are better than other ESAs and warrant its use over all of them, and 115 (80.6%) believed that the target hemoglobin is 11-13 g/dL in CKD patients is well established. Finally, 65 (51.5%) respondents would request more than 30% of the stock of ESAs in the future as short-acting ESAs vs 71 (55%) for darbepoetin and 40 (37.4%) for CERA. There were no statistically significant differences among the respondents according to their affiliations (MOH, non MOH and private sector) on any of the issues in the questionnaire. We conclude that our results showed inadequate awareness of the medical directors of the dialysis centers in the KSA of the mechanisms of action of ESAs and the new agents such as the CERA. However, they were well informed about the limits of the targeted hemoglobin levels and showed a trend toward using the long-acting ESAs.

Topics: Anemia; Attitude of Health Personnel; Awareness; Biomarkers; Chronic Disease; Darbepoetin alfa; Erythropoietin; Guideline Adherence; Health Care Surveys; Health Knowledge, Attitudes, Practice; Hematinics; Hemoglobins; Humans; Kidney Diseases; Perception; Physician Executives; Polyethylene Glycols; Practice Guidelines as Topic; Practice Patterns, Physicians'; Recombinant Proteins; Renal Dialysis; Saudi Arabia; Surveys and Questionnaires; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Risk Factors

Some time has passed since the torrent of discussion surrounding the cardiovascular risk of pushing up hemoglobin concentrations in dialysis patients with erythropoietin. The debate here reflects a look back on the tension produced by confusing data and outcomes. Is it the target hemoglobin per se or the high doses of erythropoietin in subsets of resistant patients that is the problem? You decide.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Risk Factors

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with increased rates of mortality and diminished quality of life in patients with CKD. Although extended dosing with darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), has been shown to be effective in maintaining haemoglobin (Hb) levels in CKD patients, little information is published on the use of darbepoetin alfa in the correction and maintenance of Hb levels in elderly CKD patients naive to ESA therapy.. This post hoc subanalysis of data from two clinical trials was conducted to investigate the efficacy and safety profile of de novo every-other-week (q2w) darbepoetin alfa in elderly patients with CKD-associated anaemia (not on dialysis), as compared with that of a younger (aged <65 years) patient cohort.. This analysis was based on data obtained from two open-label, single-arm, multicentre studies of similar design. Patients were aged >or=18 years and naive to previous ESA therapy. Darbepoetin alfa administration was initiated at 0.75 microg/kg and titrated according to individual patient requirements to achieve and maintain Hb levels between 11.0 and 13.0 g/dL. The proportion of patients who achieved the primary endpoint, Hb >or=11.0 g/dL (study 1), and an Hb level between 11.0 and 13.0 g/dL (study 2) at weeks 4, 8 and 12 weeks and at the end of the study were determined. The results of this subanalysis were stratified by age (<65, 65-74 and >or=75 years).. A total of 203 patients were enrolled in the two studies; 60% were female, 84 (41%) were aged <65 years, 57 (28%) were aged 65-74 years and 62 (31%) were aged >or=75 years. The proportion of patients who achieved Hb levels of >or=11.0 g/dL in study 1 and 11.0-13.0 g/dL in study 2 at week 20 were 93%, 96% and 92%, respectively, for the three age groups. Weight-adjusted q2w darbepoetin alfa doses were similar between the age groups and stable throughout the study period. The mean (standard deviation) Hb levels at week 21 were 12.0 (1.2), 12.7 (1.1) and 12.6 (1.0) g/dL in subjects aged <65, 65-74 and >or=75 years, respectively. The median (standard error) time to reach the primary endpoint was 5.0 (4.7), 5.0 (5.7) and 5.0 (5.7) weeks for subjects aged <65 years, 65-74 years and >or=75 years, respectively. The safety profiles of q2w darbepoetin alfa in both the older and younger age-groups were consistent with those expected for patients with CKD not receiving dialysis.. The results of this study suggest that ESA-naive subjects aged <65, 65-74 and >or=75 years of age with CKD (not receiving dialysis) who received q2w darbepoetin alfa were able to achieve and maintain Hb levels at 11.0-13.0 g/dL. The de novo q2w treatment regimen with darbepoetin alfa described in the present report may help optimize anaemia management in CKD-associated anaemia patients, including those in the older adult population.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Treatment Outcome; Young Adult

Topics: Adrenergic beta-Antagonists; Anemia; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Drug Resistance; Erythropoietin; Heart Failure; Humans; Kidney Diseases

Topics: Anemia; Chronic Disease; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Meta-Analysis as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

To determine the optimal range of increase in haemoglobin concentration with treatment with erythropoietins that is safe and is not associated with mortality.. Retrospective cohort study. The analysis was adjusted for several covariables with Cox regression analysis with spline functions. Use of erythropoietins, haemoglobin concentration, and covariables were included in a time varying manner; variable selection was based on the purposeful selection algorithm.. Transplantation centres in Austria.. 1794 renal transplant recipients recorded in the Austrian Dialysis and Transplant Registry who received a transplant between 1 January 1992 and 31 December 2004 and survived at least three months.. Survival time and haemoglobin concentration after treatment with erythropoietins.. The prevalence of use of erythropoietins has increased over the past 15 years to 25%. Unadjusted extended Kaplan-Meier analysis suggests higher mortality in patients treated with erythropoietins, in whom 10 year survival was 57% compared with 78% in those not treated with erythropoietins (P<0.001). In the treated patients there were 5.4 events/100 person years, compared with 2.6 events/100 person years in those not treated (P<0.001). After adjustment for confounding by indication, comorbidities, comedication, and laboratory readings, haemoglobin concentrations >125 g/l were associated with increased mortality in treated patients (hazard ratio 2.8 (95% confidence interval 1.0 to 7.9) for haemoglobin concentration 140 g/l v 125 g/l), but not in those not treated (0.7, 0.4 to 1.5). When haemoglobin concentrations were 147 g/l or above, patients treated with erythropoietins showed significantly higher mortality than those who were not treated (3.0, 1.0 to 9.4).. Increasing haemoglobin concentrations to above 125 g/l with erythropoietins in renal transplant recipients is associated with an increase in mortality. This increase was significant at concentrations above 140 g/l.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Retrospective Studies

The prognosis in elderly patients with advanced chronic heart failure (CHF) and cardio-renal anemia syndrome (CRAS) is ominous, and treatment alternatives in this subset of patients are scarce.. To assess the long-term influence of combined therapy with intravenous (IV) iron and erythropoietin (rHuEPO) on hemoglobin (Hb), natriuretic peptides (NT-proBNP), and clinical outcomes in elderly patients with advanced CHF and mild-to-moderate renal dysfunction and anemia (CRAS) who are not candidates for other treatment alternatives, 487 consecutive patients were evaluated. Of them, 65 fulfilling criteria for entering the study were divided into 2 groups and treated in an open-label, nonrandomized fashion: intervention group (27, combined anemia therapy) and control group (38, no treatment for anemia). At baseline, mean age was 74 +/- 8 years, left ventricular ejection fraction was 34.5 +/- 14.1, Hb was 10.9 +/- 0.9 g/dL, creatinine was 1.5 +/- 0.5 mg/dL, NT-proBNP was 4256 +/- 4952 pg/mL, and 100% were in persistent New York Heart Association (NYHA) Class III or IV. At follow-up (15.3 +/- 8.6 months), patients in the intervention group had higher levels of hemoglobin (13.5 +/- 1.5 vs. 11.3 +/- 1.1; P < .0001), lower levels of natural log of NT-proBNP (7.3 +/- 0.8 vs. 8.0 +/- 1.3, P = .016), better NYHA functional class (2.0 +/- 0.6 vs. 3.3 +/- 0.5; P < .001), and lower readmission rate (25.9% vs. 76.3%; P < .001). In the multivariate Cox proportional hazards model, combined therapy was associated with a reduction of the combined end point all-cause mortality or cardiovascular hospitalization (HR 95%CI 0.2 [0.1-0.6]; P < .001).. Long-term combined therapy with IV iron and rHuEPO may increase Hb, reduce NT-proBNP, and improve functional capacity and cardiovascular hospitalization in elderly patients with advanced CHF and CRAS with mild to moderate renal dysfunction.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Cohort Studies; Drug Evaluation; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Follow-Up Studies; Glucaric Acid; Heart Failure; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Neurotransmitter Agents; Pilot Projects; Prospective Studies; Recombinant Proteins; Survival Rate; Syndrome; Time Factors; Treatment Outcome

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Patient Selection; Recombinant Proteins; Treatment Outcome

Anemia is frequently observed in patients with chronic heart failure (CHF) and is related to an impaired outcome. The origin of anemia in CHF is diverse and is associated with several factors including renal failure, resistance of the bone marrow to erythropoietin (EPO), hematinic deficiencies, and medication use. Recently, several small-scale clinical trials have shown that EPO treatment might improve clinical parameters in anemic heart failure patients. In addition, several preclinical studies have shown that EPO possesses non-hematopoietic effects. This current review focuses on the etiology, consequences, and treatment of anemia in heart failure patients. The pleiotropic effects of EPO in an experimental setting will also be discussed. Heart Fail Monit 2008;6(1):28-33.

Topics: Anemia; Bone Marrow; Chronic Disease; Epoetin Alfa; Erythropoietin; Heart Failure; Humans

Topics: Age Factors; Anemia; Antineoplastic Agents; Chronic Disease; Disease Progression; Disease-Free Survival; Drug Antagonism; Erythropoietin; Humans; Janus Kinase 2; Neoplasms; Neovascularization, Pathologic; Polypharmacy; Receptors, Erythropoietin; RNA, Messenger

We evaluated the relation between serum erithropoietin level and the severity of disease and mortality in patients with chronic heart failure (CHF).. We enrolled 96 CHF patients and 50 age- and sex-matched control subjects. Haemoglobin, haemotocrit, N terminal pro-B type natriuretic peptide (NT-proBNP) and erythropoietin levels and echocardiographic parameters were measured. The patients were contacted 1 year after the evaluations to determine survival.. The patients had lower haemoglobin and haematocrit but higher serum erythropoietin and NT-proBNP levels than the control subjects. Serum erythropoietin and NT-proBNP levels increased with worsening functional class. The serum erythropoietin level correlated negatively with left ventricular ejection fraction (r = -0.404, P < 0.001), haemoglobin (r = -0.530, P < 0.001) and haematocrit (r = -0.496, P < 0.001) levels. The patients who died (n = 17) had lower haemoglobin and haematocrit levels and significantly higher erythropoietin and NT-proBNP levels. However, multivariate logistic regression analysis showed that only NT-proBNP level was an independent predictor of mortality (P = 0.002).. Anaemia and resistance to erythropoietin develop proportionately to disease severity and left ventricular systolic dysfunction in patients with CHF. Although serum erythropoietin level seems related with mortality, this observation needs to be confirmed by studies with more patients and longer follow-up.

Topics: Biomarkers; Chronic Disease; Echocardiography; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Hematocrit; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Severity of Illness Index; Survival Rate; Time Factors; Turkey

Aims Chronic heart failure (CHF) is frequently associated with a decreased haemoglobin level, whereas the mechanism remains largely unknown. Methods and results One hundred consecutive CHF patients without anaemia or renal dysfunction based on non-cardiac reasons were enrolled. We explored determinants of anaemia (as iron parameters, erythropoietin, hepcidin and kidney function) including red cell volume (RCV) (by a 51 Cr assay) as well as related markers and plasma volume. The influence of each factor on haemoglobin concentrations was determined in a multiple regression model. Mean haemoglobin concentrations were 11.7 +/- 0.8 mg/dL in anaemic CHF patients and 14.4 +/- 1.2 mg/dL in non-anaemic patients. Corrected reticulocytes were lower in anaemic patients (35.1 +/- 15.7 vs. 50.3 +/- 19.2 G/L, P = 0.001), but the RCV was not reduced (1659.3 +/- 517.6 vs. 1826.4 +/- 641.3 mL, P = 0.194). We found that plasma volumes were significantly higher in anaemic CHF patients (70.0 +/- 2.4 vs. 65.0 +/- 4.0%, P < 0.001). Plasma volume was the best predictor of haemoglobin concentrations in the regression model applied (B = -0.651, P < 0.001, R(2) = 0.769). Conclusion Haemodilution appears to be the most potent factor for the development of low haemoglobin levels in patients with CHF. Our data support an additional independent, but minor influence of iron deficiency on haemoglobin concentrations in CHF patients.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Cross-Sectional Studies; Erythrocyte Volume; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Iron; Male; Middle Aged; Plasma Volume

High doses of human recombinant erythropoietin (rHuEPO) to achieve hemoglobin levels greater than 13 g/dL in patients with chronic kidney disease appear to be associated with increased mortality.. We conducted logistic regression and survival analyses in a retrospective cohort of long-term hemodialysis patients to examine the hypothesis that the induced iron depletion with resultant relative thrombocytosis may be a possible contributor to the link between the high rHuEPO dose-associated hemoglobin level of 13 g/dL or greater and mortality.. The national database of a large dialysis organization (DaVita) with 40,787 long-term hemodialysis patients during July to December 2001 and their survival up to July 2004 were examined.. Hemoglobin level, platelet count, and administered rHuEPO dose during each calendar quarter.. Case-mix-adjusted 3-year all-cause mortality and measures of iron stores, including serum ferritin and iron saturation ratio.. Higher platelet count was associated with lower iron stores and greater prescribed rHuEPO dose. Compared with a hemoglobin level of 12 to 13 g/dL, a hemoglobin level of 13 g/dL or greater was associated with increased mortality in the presence of relative thrombocytosis, ie, platelet count of 300,000/microL or greater (case-mix-adjusted death-rate ratio, 1.21; 95% confidence limits, 1.02 to 1.44; P = 0.03) as opposed to the absence of relative thrombocytosis (death-rate ratio, 1.04; 95% confidence limits, 0.98 to 1.08; P = 0.1). A prescribed rHuEPO dose greater than 20,000 U/wk was associated with a greater likelihood of iron depletion (iron saturation ratio < 20%) and relative thrombocytosis (case-mix-adjusted odds ratio, 2.53; 95% confidence limits, 2.37 to 2.69; and 1.36; 95% confidence limits, 1.30 to 1.42, respectively; P < 0.001) and increased mortality during 3 years (death-rate ratio, 1.59; 95% confidence limits, 1.54 to 1.65; P < 0.001).. Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different mortality predictability than targeted hemoglobin level.. Iron depletion and associated relative thrombocytosis might contribute to increased mortality when administering high rHuEPO doses to achieve hemoglobin levels of 13 g/dL or greater in long-term hemodialysis patients. Randomized trials are needed to test these observational associations.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Chronic Disease; Cohort Studies; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney Diseases; Logistic Models; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Factors; Survival Analysis; Thrombocytosis

Topics: Aged; Anemia; Causality; Chronic Disease; Cross-Over Studies; Double-Blind Method; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobinometry; Humans; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

The objective of this study was to investigate the expressions of hematopoietic cytokines EPO, SCF and GM-CSF in bone marrow cells of patients with chronic aplastic anemia (CAA) and their significance. The mRNA expressions of EPO, SCF and GM-CSF from 35 CAA patients and 10 healthy individuals were detected by semi-quantitative RT-PCR. The results showed that the levels of EPO, SCF and GM-CSF in CAA patients were obviously lower than those in the healthy individuals (p < 0.01). It is concluded that the immunity disorder mediated by hematopoietic cytokines is one of the pathogenesis in the CAA patients, it provided theoretical basis for guiding clinical treatment.

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Bone Marrow; Child; Chronic Disease; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Middle Aged; RNA, Messenger; Stem Cell Factor; Young Adult

Topics: Anemia; Black or African American; Chronic Disease; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Recombinant Proteins; White People

The response to erythropoietin-stimulating agents (ESA) can vary among different patients and according to the different circumstances over time within a given individual. The aim of this study was to analyze the factors that can modify the response to epoetin in patients on hemodialysis (HD) and its influence on early mortality. Prospective and observational study including 1710 patients from 119 HD units in Spain with a follow-up of 12 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI), calculated as the weekly weight-adjusted dose of EPO divided by the hemoglobin level. Patients were stratified in three groups according to ERI: group A, ERI <5; group B, ERI=5-15; group C, ERI>15 U/kg/week/g per 100 ml. Mean ERI for the entire group was 10.2+/-7.3 U/kg/week/g per 100 ml. ERI was directly related with incident comorbidity (Charlson Index), age, female gender and low body mass index with no relationship with etiology of chronic kidney disease. Patients with antecedents of heart failure, acute infection or malignant neoplasm had significantly higher ERI than those without. Transferrin saturation index, but not serum ferritin, was inversely related with ERI. Serum levels of albumin and cholesterol were related with lower ERI, but no relation was found with normalized protein catabolic rate. Patients with a permanent catheter for HD had significant higher values of ERI than those with native fistula (P=0.012). One year survival in all three groups of patients according to ERI was 0.916 in group A, 0.877 in group B and 0.788 in group C (log-rank=20.7, P<0.001). The resistance to ESA is directly related with incident comorbidity in patients on hemodialysis and it can be interpreted as a useful marker of early mortality.

Topics: Aged; Biomarkers; Cholesterol; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renal Dialysis; Serum Albumin; Spain; Survival Analysis; Transferrin

Maintenance of target hemoglobin (Hb) values in hemodialysis patients treated with erythropoiesis-stimulating agents (ESAs) remains difficult. We examined Hb variability in the clinical setting in hemodialysis patients. Hemodialysis patients treated with ESAs who maintained the recommended Hb range of 11-13 g per 100 ml over 3 months and were not admitted to hospital, did not require transfusion, and did not experience any major clinical event during this period were followed prospectively for 1 year. Anemia events, Hb variation events (any value out of +/-1.5 g per 100 ml of the median Hb level in the total follow-up period for the individual patient), risk factors for anemia, and Hb variation events were assessed. We studied 420 patients (63% males, mean age 61 years), 222 received short-acting erythropoietin (EPO) and 198 long-acting darbepoetin. A total of 4654 blood samples (mean 11.1 per patient-year) were analyzed. Only 3.8% of patients were maintained within the target Hb levels (11-13 g per 100 ml) during 1 year. Hb variation events occurred in 20.8% of laboratory values and anemia events in 14.7%, with a median time to the first event of 3 months. Treatment with short-acting EPO (vs long-acting darbepoetin), change of ESA dose in the previous visit, resistance index, and hospitalization were significant risk factors for both anemia events and Hb variation events. Our results show that Hb values are rarely maintained within the recommended guidelines even in more stable hemodialysis patients. Hb variability is frequently associated with clinical events or ESA dose changes. Long-acting darbepoetin achieved better Hb stability than short-acting EPO.

Topics: Adult; Aged; Anemia; Chronic Disease; Cohort Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Renal Dialysis; Risk Factors; Spain

Recent studies have showed that erythropoietin (EPO) is a neuroprotectant for central nerve system neurons in addition to being a hematopoietic cytokine in response to hypoxia. In this study, we investigate the role of the EPO/EPO receptor (EPOR) system in the rat retina after ocular hypertension injury that mimics glaucoma.. Elevated intraocular pressure was induced by laser coagulation of the episcleral and limbal veins. Expression of EPO and EPOR in the normal and glaucomous retinas was investigated by immunohistochemistry and Western blot. To examine the effects of endogenous EPO on the survival of retinal ganglion cells (RGCs) subjected to hypertensive injury, soluble EPOR was directly injected into the vitreous body. Recombinant human EPO was both intravitreally and systemically administrated to study the effect of exogenous EPO on the survival of RGCs after ocular hypertension injury.. Immunohistochemistry studies identified Müller cells as the main source of EPO in the normal retina. Expression of EPO and EPOR proteins was increased significantly 2 weeks after ocular hypertension. RGCs, amacrine and bipolar cells all demonstrated an increased expression of EPOR after ocular hypertension. Neutralization of endogenous EPO with soluble EPOR exacerbated ocular hypertensive injury, suggesting a role of the EPO/EPOR system in the survival of RGCs after injury. Similarly, topical and systemic administration of recombinant human EPO rescues RGCs after chronic ocular hypertension.. These results indicate that an endogenous EPO/EPOR system participates in intrinsic recovery mechanisms after retina injury and RGCs might be rescued by exogenous administration of EPO.

Topics: Animals; Cell Survival; Chronic Disease; Erythropoietin; Female; Neuroprotective Agents; Ocular Hypertension; Optic Nerve Injuries; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Retinal Ganglion Cells; Solubility; Up-Regulation

Erythropoietin is the treatment of the anaemia in chronic kidney disease. A target rate of haemoglobin higher than 11 g/dl was usually proposed, but recent recommendations stated that higher limit of haemoglobin was to be reached, with the aim to improve the quality of life of the patients and to reduce their risks of cardiovascular diseases. These objectives are to be revised, according to the results of recently published clinical trials.. Patients treated to reach a high rate of haemoglobin (between 13 and 14,5 g/dl) have an improved quality of life, but a 30% higher mortality rate, compared to patients treated with a lower objective of haemoglobin rate (10-12 g/dl). Hypertension and vascular access thromboses were also more frequent in the patients with the highest haemoglobin rate. Two to three times more erythropoietin was necessary to reach the higher rate of haemoglobin. These results favour a target rate of haemoglobin not higher than 12 g/dl. A polemic followed the results of these clinical trials, mostly in the United States, questioning the way in which the higher limit had been fixed whereas precise data were unavailable. The role of pharmaceutical industry and of for profit dialysis centres was underlined.. The next step is now to explain if the excess in cardiovascular morbimortality is related to the haemoglobin rate or to a direct effect of the erythropoietin. Such an understanding is important, the more so as new erythropoiesis-stimulating agents are being developed.

Topics: Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins

Anaemia and hypertension are common in patients with chronic renal insufficiency. The correction of anaemia with erythropoiesis stimulating agents (ESA) can improve survival and decrease the decline of renal function. Angiotensin converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (AIIRA) can also slow the progression of renal failure, but the blockade of the renin-angiotensin system can worsen anaemia. The aim of our study was to assess the impact of antihypertensive therapy (ACEI plus AIIRA) in the requirements of darbepoietin in a group of elderly predialysis patients. We included 71 patients (m = 39, f = 32), mean age of 76.3 years with a mean creatinine clearance of 17.5 ml/min. Patients were divided in two groups according to their antihypertensive therapy: G-I patients under ACEI or AIIRA therapy and G-II normotensive patients or hypertensive patients under antihypertensive drugs other than ACEI or AIIRA. The groups were compared regarding demographic, nutritional, biochemical and inflammatory parameters. We also compared the mean darbepoietin dose. In GI the mean dose of darbepoietin was higher than in GII (0.543 vs. 0.325 microg/kg/week, P = 0.032). We did not find any difference regarding other parameters analysed. We conclude that ACEI and AIIRA can increase the needs of darbepoietin in predialysis elderly patients. However, when formally indicated to treat hypertension in a specific patient, they should not be switched to another antihypertensive agent. Instead, in such cases, higher doses of ESA should be used, if necessary.

Topics: Aged; Aged, 80 and over; Anemia; Antihypertensive Agents; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Hypertension; Kidney Diseases; Male

Hypocholesterolemia of unknown etiology has been previously described in various chronic anemias. Few small studies also suggested that those patients have a lower incidence of atherosclerotic events. The aim of our study was to determine the extent of hypocholesterolemia in various types of anemias. We studied 59 patients with chronic anemias associated with high-erythropoietic activity (thalassemia intermedia, congenital dyserythropoietic anemia type I, congenital spherocytosis), 8 patients with low-erythropoietic activity anemias (acquired aplastic anemia, Fanconi anemia, and Diamond Blackfan anemia), and 20 healthy controls. Mean serum cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, hemoglobin, serum ferritin, soluble transferrin receptor (STR), and serum erythropoietin levels were determined in each patient. All patients with chronic anemia and increased erythropoietic activity had hypocholesterolemia, whereas none of those with low erythropoietic activity was hypocholesterolemic. Mean serum cholesterol, HDL cholesterol, and LDL cholesterol levels were found to be significantly lower in the high-erythropoietic activity group (80+/-19 mg/dl; 31+/-10 mg/dl; 35+/-14 mg/dl, respectively) compared with the control group (P<0.001; 0.001; 0.001, respectively) and the low-erythropoietic activity group (P<0.001; 0.001; 0.01, respectively). Significant inverse correlation (R2=0.507) was observed between serum cholesterol and STR levels, which in the absence of iron deficiency reflect bone marrow activity. Taken together, our results imply that hypocholesterolemia accompanies anemias with high-erythropoietic activity. We suggest that the high-erythropoitic activity-associated hypocholesterolemia is due to increased cholesterol requirements by the proliferating erythoid cells. Further studies are needed to elucidate the exact mechanism and the possible clinical consequences of this phenomenon.

Topics: Anemia; Child; Cholesterol; Chronic Disease; Erythropoiesis; Erythropoietin; Ferritins; Humans; Lipids; Receptors, Transferrin

Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients.. We studied 97 patients with CHF, of which 15 had anaemia (Hb<13.0 g/dL in men and Hb<12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused 125I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of 131I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P=0.002), ERPF (P=0.005) and EPO production (P=0.001), and an elevated ECV (P=0.015). Multivariable analysis demonstrated that lower GFR (P=0.003), lower ERPF (P=0.004), lower EPO production (P=0.006), and a higher ECV (P=0.001) were significant independent predictors of lower haemoglobin levels.. Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cell Size; Chronic Disease; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Circulation; Renal Plasma Flow, Effective; Water-Electrolyte Imbalance

Topics: Adult; Chronic Disease; Disease Progression; Erythropoietin; Female; Glomerulonephritis, IGA; Humans; Kidney; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Recombinant Proteins; Renal Dialysis

We aimed in this study to evaluate the attitude of physicians in the Kingdom of Saudi Arabia (KSA) towards strategies for treatment of anemia in patients with chronic kidney disease (CKD). A questionnaire was sent to 153 physicians in 148 active dialysis units in the KSA including centers under the Ministry of Health (MOH) (73.6%), centers in the governmental non-MOH sector (12.2%) and centers in private hospitals (14.2%) that together care for a population of more than 7900 chronic dialysis patients. The study was performed between April and June 2006. A total of 137 physicians (89.5%) answered the questionnaire from 129 (87.1%) dialysis centers that catered to 7052 (89.2%) dialysis patients. There were 104 respondents (75.9%) who staged their CKD patients according to the level of glomerular filtration rate (GFR). The estimated mean prevalence of each stage of CKD in the respondents' clinics was 15%, 19%, 29%, 22%, and 29% for the stages 1, 2, 3, 4, and 5, respectively. The estimated prevalence of anemia [hemoglobin (Hb) < 110 g/L] in the different stages of CKD were 11%, 17%, 38%, 59%, and 78% in stages 1, 2, 3, 4, and 5, respectively. However, only 69 respondents (48%) answered these two questions. Sixty-seven respondents (50.4 %) believed that any patient with Hb < 110 g/L should receive r-HuEPO irrespective of the CKD stage, and 133 (99.3%) believed that correction of anemia in the CKD patients has documented impact on morbidity and mortality. In case of availability of a long acting r-HuEPO such as darbepoetin, 88 (66.2%) respondents would use it as their first choice other than the current short acting drug. Our survey suggests that the current practices concerning anemia management in CKD patients in the KSA may not be satisfactory. There are many centers that do not have data on the prevalence of CKD or anemia in their units. More studies are required to explore the quality of services rendered to the CKD patients and guidelines need to be outlined for the management of anemia in the CKD patients.

Topics: Anemia, Hypochromic; Attitude of Health Personnel; Chronic Disease; Darbepoetin alfa; Drug Utilization; Erythropoietin; Glomerular Filtration Rate; Guideline Adherence; Health Care Surveys; Health Knowledge, Attitudes, Practice; Hematinics; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prevalence; Recombinant Proteins; Saudi Arabia; Severity of Illness Index; Surveys and Questionnaires

Topics: Aged; Anemia; Antibodies; Chronic Disease; Cyclophosphamide; Darbepoetin alfa; Erythropoietin; Fatal Outcome; Hematinics; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Opportunistic Infections; Prednisolone; Red-Cell Aplasia, Pure

To determine the prevalence of anemia in an outpatient heart failure clinic, describe the type of anemia in patients treated there, and evaluate the potential costs associated with epoetin therapy in this cohort.. Single-center, retrospective cohort analysis (part 1) and a literature-based economic decision analysis (part 2).. Medical records from a multidisciplinary, outpatient, heart failure clinic, and published hospitalization and drug-use data.. We evaluated 170 adults with chronic heart failure who were enrolled in the clinic and for whom at least one complete blood count was recorded between January 1, 2003, and April 15, 2006.. In part 1, demographic and clinical data were extracted from electronic medical records. The overall prevalence of anemia was 47.6% or 47.1%, as based on World Health Organization or National Kidney Foundation definitions, respectively. Normocytic anemia was characterized in 75.0% of patients. In part 2, heart failure hospitalization rates and costs, drug acquisition, and drug administration were estimated by using the published literature. In a hypothetical cohort of 100 patients with heart failure and comorbid anemia, the costs associated with outpatient epoetin and intravenous iron therapy exceeded savings in hospitalization costs by $83,070. Results of 1-way sensitivity analyses generally confirmed robustness of the model.. Anemia is a common comorbidity in patients with chronic heart failure treated in the outpatient clinic. Although the current evidence is insufficient to support the use of epoetin in this population, initial findings indicate that epoetin and intravenous iron therapy may be associated with positive clinical outcomes. From a pharmacoeconomic standpoint, however, a reduction in the cost of heart failure-related hospitalization does not offset the cost of epoetin and intravenous iron therapy.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care Facilities; Anemia; Cardiac Output, Low; Chronic Disease; Cohort Studies; Cost-Benefit Analysis; Costs and Cost Analysis; Decision Support Techniques; Epoetin Alfa; Erythropoietin; Female; Health Care Costs; Hematinics; Hospitalization; Humans; Iron; Male; Middle Aged; Prevalence; Recombinant Proteins; Retrospective Studies

Nucleated red blood cells (NRBCs) in fetal circulation have been proposed as a marker of chronic hypoxia in fetuses with intrauterine growth restriction (IUGR). We sought to determine the effects of chronic hypoxia, chronic nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME), or both on NRBC counts, erythropoietin levels, and pathologic changes in an animal model of IUGR.. We assigned timed pregnant adult Sprague Dawley rats to the following groups: (1) 21% oxygen + saline solution (n = 7); (2) 21% oxygen + L-NAME (n = 8); (3) 10% oxygen + saline solution (n = 6); and (4) 10% oxygen + L-NAME (n = 6). We inserted osmotic pumps that were prefilled with saline solution or L-NAME subcutaneously on day 17 of gestation. The animals were placed in a Plexiglas hypoxic chamber, which ensured a constant hypoxic environment. The animals were killed on day 21 of gestation before the onset of spontaneous labor. We collected maternal and fetal blood for measurement of NRBC and erythropoietin levels. The results were interpreted in relationship to maternal arterial blood gases and hemoglobin and hematocrit levels. Fetuses were examined for gross abnormalities and histological abnormalities that are characteristic of vascular disruptions by a blind examiner to experimental manipulation.. Nitric oxide inhibition induced IUGR with maximal effect when both L-NAME and hypoxia treatments were combined. Inhibition of nitric oxide synthesis, but not chronic hypoxia, increased the number of fetal NRBCs and generalized hemorrhagic diathesis in utero. These features were aggravated significantly when the treatments were combined. Moreover, chronic hypoxia induced significant maternal metabolic acidosis and increased hematocrit and erythropoietin levels in maternal and fetal blood. Nitric oxide inhibition increased maternal hematocrit levels while decreasing maternal erythropoietin levels without significantly altering the maternal acid-base status. In contrast with chronic hypoxia, nitric oxide inhibition increased fetal NRBCs without affecting erythropoietin levels.. Our findings indicate that the number of NRBCs in fetal circulation does not serve as a specific marker of chronic hypoxia that accompanies IUGR or of elevated erythropoietin levels but are an epiphenomenon that is related to the inhibition of nitric oxide.

Topics: Animals; Chronic Disease; Disease Models, Animal; Erythroblasts; Erythrocyte Count; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Hypoxia; Nitric Oxide Synthase; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley

The hypoxia-inducible factor (HIF) pathway is crucial in mitigating the deleterious effects of oxygen deprivation. HIF-alpha is an essential component of the oxygen-sensing mechanisms and under normoxic conditions is targeted for degradation via hydroxylation by HIF-prolyl hydroxylases. Several HIF-prolyl hydroxylase inhibitors (PHIs) induced erythropoietin (epo) expression in vitro and in mice, with peak epo expression ranging from 5.6- to 207-fold above control animals. Furthermore, several PHIs induced fetal hemoglobin (HbF) expression in primary human erythroid cells in vitro, as determined by flow cytometry. One PHI, FG-2216, was further tested in a nonhuman primate model without and with chronic phlebotomy. FG-2216 was orally bioavailable and induced significant and reversible Epo induction in vivo (82- to 309-fold at 60 mg/kg). Chronic oral dosing in male rhesus macaques was well tolerated, significantly increased erythropoiesis, and prevented anemia induced by weekly phlebotomy. Furthermore, modest increases in HbF-containing red cells and reticulocytes were demonstrated by flow cytometry, though significant increases in HbF were not demonstrated by high-pressure liquid chromatography (HPLC). HIF PHIs represent a novel class of molecules with broad potential clinical application for congenital and acquired anemias.

Topics: Administration, Oral; Animals; Carcinoma, Hepatocellular; Chronic Disease; Enzyme Inhibitors; Erythrocytes; Erythroid Cells; Erythroid Precursor Cells; Erythropoietin; Fetal Hemoglobin; Flow Cytometry; Humans; Hypoxia; Liver Neoplasms; Macaca mulatta; Male; Mice; Oxygen; Phlebotomy; Polycythemia; Procollagen-Proline Dioxygenase; Reticulocytes

Topics: Anemia; Chronic Disease; Erythropoietin; Hematinics; Humans; Kidney Diseases; Legislation, Drug; Neoplasms; Recombinant Proteins; United States; United States Food and Drug Administration

Patients with chronic kidney disease (CKD) are frequently complicated by renal anemia as renal function declines. However, clinical guidelines on erythrocyte stimulating agents (erythropoietin : EPO) for such patients have not been established. Current clinical practice for EPO administration is based on the recommendations of the Japanese health insurance regulations, which have not always been supported by clinical evidence.. The study subjects were 49 patients with CKD staged above 3 who had developed renal anemia requiring EPO. These patients were treated with EPO S. C. at the dose of 6,000 IU/week together with iron supplementation as deemed necessary for more than 24 weeks.. The hemoglobin (Hb) value was 9.2 +/- 1.0 g/dL at the start, 10.9 +/- 1.6 g/dL at the peak (n = 49, p < 0.001 the start vs. the peak), and 9.0 +/- 1.6 g/dL at the commencement of dialysis (n = 49, p < 0.001 the peak vs. the commencement of dialysis). Seventy-one percent (35/49) of the patients achieved Hb levels over 10 g/dL, and 51% (25/49) achieved Hb levels over 11 g/dL. Conversely, 28% (14/49) of the patients failed to reach an Hb level over 10 g/dL. Factors explaining the good response to EPO (good responders were defined as those achieving Hb levels over 11 g/dL) had shown high Hb levels at the start (Logistic multiple regression analysis, p = 0.03) along with low creatinine concentration at the start (Cox's proportional hazard models, p = 0.015). Transferrin saturation (TSAT) at the start was 33.6 +/- 13.6%, 34.0 +/- 19.9% at the peak, and 24.7 +/- 11.6% at the commencement of dialysis, showing a significant reduction in TSAT at the commencement of dialysis compared to that at the start (n = 49, p = 0.0383, the start vs. the commencement of dialysis). Serum ferritin concentration was 140.7 +/- 139.5 pg/mL at the start, 107.9 +/- 110.8 pg/mL at the peak, and 131.9 +/- 112.4 pg/mL at the commencement of dialysis, indicating an absence of significant differences among the three time points.. The current health insurance regulations in Japan seem to be inappropriate in that the permitted EPO dosage of 6,000 IU/week might not be sufficient to achieve the target Hb level of more than 11 g/dL in most patients with CKD. To more efficiently achieve renoprotection, both early and timely initiation of EPO and reconsideration of the recommended EPO dosage appear to be warranted.

Topics: Aged; Anemia; Chronic Disease; Dialysis; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged

There are limited data suggesting that initiation of epoetin alfa at extended dosing intervals of every 2, 3, or 4 wk may be efficacious for treating anemia in patients who have chronic kidney disease and are not on dialysis (CKD-NOD). This open-label, multicenter, single-arm study investigated the efficacy of administration of 20,000 IU of epoetin alfa once every 2 wk as initiation therapy in these patients. Adults with CKD-NOD were eligible when they had hemoglobin (Hb) <11 g/dl, GFR of 10 to 60 ml/min per 1.73 m2, and stable serum creatinine for the past 6 mo. Patients received 20,000 IU of epoetin alfa subcutaneously every 2 wk for up to 27 wk, with dosage adjustments permitted after 4 wk of treatment. The primary efficacy end point was the proportion of patients with Hb response, defined as achievement of the target Hb range of 11 to 12 g/dl for at least two consecutive visits. Sixty-seven patients were enrolled; >88% (59 of 67) of patients achieved an Hb response. Mean Hb increased to the targeted range by week 6 and remained in the range through week 28. Hb increases of 1 and 2 g/dl were observed in 91 and 78% of patients, respectively. Epoetin Alfa was well tolerated; most adverse events were mild or moderate in nature and typical of the CKD patient population. In this study, results demonstrated that epoetin alfa can be initiated safely and effectively at an extended dosing interval of 20,000 IU every 2 wk in patients with CKD-NOD.

Topics: Aged; Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Recombinant Proteins

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Recombinant Proteins

Forty-one percent of UK patients commence RRT with an Hb < 10.0 g/dl. The mean Hb at commencement of RRT is 10.3 g/dl. Eighty-five percent of patients on dialysis in the UK have an Hb > or = 10.0 g/dl by 6 months after commencement of RRT. The median Hb on haemodialysis in the UK is 11.8 g/dl with an IQR of 10.7-12.8 g/dl. Eighty-six percent of haemodialysis patients in the UK have a Hb > or = 10.0 g/dl. The median Hb on peritoneal dialysis in the UK is 12.0 g/dl with an IQR of 11.0-12.9 g/dl. Ninety percent of peritoneal dialysis patients in the UK have an Hb > or = 10.0 g/dl. In the UK, 49% of patients on PD and 48% of patients on haemodialysis have an Hb between 10.5-12.5 g/dl. The median ferritin in UK haemodialysis patients is 413 microg/l (IQR 262-623), 95% of UK haemodialysis patients have a ferritin > or =100 microg/l. The median ferritin in UK PD patients is 256 microg/l (IQR 147-421), 86% of UK peritoneal dialysis patients have a ferritin > or = 100 microg/l. A higher proportion of HD patients than PD patients receive ESA therapy (88% vs 76%). The ESA dose is higher for HD than PD patients (9204 vs 6080 IU/week).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Female; Ferritins; Guideline Adherence; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Registries; Renal Dialysis; United Kingdom

Instability of hemoglobin levels during epoetin therapy is a new problem in hemodialysis. We evaluated extent and correlates of time in target, that is, the time spent with hemoglobin > or = 11 g/dl during the first year of epoetin and its association with renal survival.. Data were collected in 917 visits for 12.0 mo in 119 patients with chronic kidney disease; thereafter, patients started renal survival analysis for 10.1 mo. At baseline, hemoglobin was 10.0 +/- 0.8 g/dl and GFR was 22.1 +/- 14.2 ml/min per 1.73 m2.. Hemoglobin target, reached in 1.5 mo, was steadily maintained in only 24% of patients. Time in target was not merely due to differences in time to target; after first achievement of target, in fact, a reduction of hemoglobin < 11 g/dl occurred in 51% of patients. At multivariate analysis, male gender, basal GFR and hemoglobin levels, first epoetin dose, and iron supplementation were directly associated with length of time in target. A lower risk for renal death (dialysis n = 53; death n = 8) was detected in the higher tertile of time in target (11.3 mo) versus lower tertile (3.2 mo). This difference persisted at Cox analysis after adjustment for age, gender, GFR, BP, and proteinuria.. In chronic kidney disease, time in target during the first year of epoetin therapy is frequently short depending not only on time to target but also on post-target hemoglobin reductions, correlates with male gender, timing, and intensity of initial therapy and is coupled with better renal survival.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Time Factors

Anemia is a common complication of chronic kidney disease (CKD). The approved dosing interval for currently available erythropoiesis-stimulating agents (ESAs) is 2 to 3 times weekly for epoetin alfa (EPO) and every 1 to 2 weeks for darbepoetin alfa (DARB). However, clinicians sometimes use less frequent dosing in the interest of convenience.. This study investigated patterns of actual ESA use (doses and dosing intervals) and hemoglo- bin (Hb) control in adult outpatients with CKD not requiring dialysis at the Cleveland Clinic Foundation anemia clinic. The distribution of and variability in Hb levels in these patients were also examined.. The clinical charts and electronic records of adult outpatients with CKD who initiated ESA therapy before March 2005 were reviewed to identify the initial, dominant (used for the longest consecutive period), and final dosing intervals and mean weekly doses of EPO and DARB. Hb control was examined in terms of maximum deviations >12 g/dL and <11 g/dL, and the proportions of measurements outside these values.. The analysis included data from 111 outpatients (mean [SD] age, 65.9 [14.4] years; 53.2% male; 66.7% white, 29.7% black, 2.7% other, 0.9% unknown ethnicity). Twenty-one patients received EPO only, 74 received DARB only, and 16 switched ESAs. The mean duration of follow-up was 20.5 months. The most common initial dosing intervals were qwk for EPO (66.7%) and q2wk for DARB (90.5%). The dominant dosing intervals were q2wk in 61.9% of EPO patients and q3wk in 62.3% of DARB patients. However, 80.0% of those who received EPO q2wk and 63.2% of those who received DARB q3wk eventually returned to their initial dosing intervals. The largest proportions of Hb mea- surements <11 g/dL occurred at dominant dosing intervals of qwk for EPO and q2wk for DARB (both, 46.0%; 11 and 26 patients, respectively), whereas the largest proportions of measurements >12 g/dL occurred with EPO dosed at q2wk (44.0%; 5 patients) and DARB dosed at >q4wk (62.0%; 5 patients).. The patterns of ESA usage in adult outpatients with CKD at this center indicated that clinicians extended dosing intervals beyond those in the approved prescribing information. However, variations in Hb concentrations occurred during maintenance therapy administered at extended dosing intervals, resulting in the resumption of shorter dosing intervals in the majority of patients.

Topics: Aged; Anemia; Chronic Disease; Cohort Studies; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Recombinant Proteins; Retrospective Studies

The anemia of chronic disease (ACD) results from 3 major processes: slightly shortened red cell survival, impaired reticuloendothelial system iron mobilization, and impaired erythropoiesis. Hepcidin is an acute-phase protein with specific iron regulatory properties, which, along with the anemia seen with increased hepcidin expression, have led many to consider it the major mediator of ACD. However, if hepcidin is the major factor responsible for ACD, then it should also contribute to the impaired erythropoiesis observed in this syndrome. Erythroid colony formation in vitro was inhibited by hepcidin at erythropoietin (Epo) concentrations less than or equal to 0.5 U/mL but not at Epo 1.0 U/mL. At Epo concentrations of 0.3 U/mL, HCD57 erythroleukemia cells exposed to hepcidin exhibit decreased expression of the antiapoptotic protein pBad compared with controls. These studies suggest that hepcidin may contribute to anemia in ACD not only through effects on iron metabolism, but also through inhibition of erythroid progenitor proliferation and survival.

Topics: Anemia; Antimicrobial Cationic Peptides; Bone Marrow Cells; Cell Division; Cell Line; Chronic Disease; Colony-Forming Units Assay; Erythropoiesis; Erythropoietin; Hepcidins; Humans

Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum dosing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 microg/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR2)-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR2. CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-alpha, IL-1beta and IL-1Ra in the spinal cord, and IFN-gamma by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis.

Topics: Analysis of Variance; Animals; Body Weight; Chronic Disease; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Glycoproteins; Hematocrit; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Peptide Fragments; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Spinal Cord; Spleen; Statistics, Nonparametric; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Goals; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Thrombophilia

Anemia of chronic disease (ACD) is frequently found in patients with chronic immune activation. Since most studies on ACD pathophysiology were performed with cell culture or animal models but not in humans, we examined 37 ACD patients suffering from autoimmune diseases or infections, 10 subjects with iron-deficiency anemia (IDA), 10 anemic patients with hereditary spherocytosis (HS), and 27 age-matched controls. Although hemoglobin concentrations were comparable between ACD and IDA patients, the latter presented with significantly higher serum erythropoietin concentrations than ACD patients. The significant negative correlation between erythropoietin and hemoglobin levels observed in IDA patients was also found in a group of anemic but not hypoferremic hereditary spherocytosis subjects, but not in ACD patients. Increased serum concentrations of the hepcidin precursor prohepcidin were paralleled by a decreased expression of the iron exporter ferroportin in circulating monocytes of ACD patients. In the latter cells, increased amounts of the iron storage protein ferritin and a reduced activity of iron-regulatory protein indicated monocyte iron accumulation. Our data indicate that hypoferremia in ACD may result from downregulation of ferroportin expression by hepcidin and cytokines with subsequent iron retention in monocytes. Together with a diminished erythropoietin formation, the impaired iron recirculation from monocytes may be central in the pathophysiology of ACD in humans.

Topics: Aged; Anemia; Base Sequence; C-Reactive Protein; Chronic Disease; Cytokines; DNA Primers; Erythropoietin; Female; Homeostasis; Humans; Iron; Male; Middle Aged; Monocytes; Polymerase Chain Reaction; RNA, Messenger

Apart from its well-known stimulation of erythropoiesis, erythropoietin (EPO) exhibits angiogenic and anti-apoptotic effects. These cellular protective effects have also been described in experimental acute myocardial infarction models. We investigated the effects of EPO in a porcine model of chronic progressive myocardial ischaemia.. At weeks 2 and 6 after implantation of a circumflex ameroid constrictor, endocardial electromechanical NOGA system (Biosense Webster, Inc., California, USA) mapping of the left ventricle, coronary and ventricular angiography, as well as echocardiography were performed. Two weeks after ameroid placement, 13 pigs were randomized with 7 pigs receiving 10.000 U EPO and 6 pigs receiving placebo into the ischaemic region using a NOGA guided percutaneous transendocardial injection catheter, MYOSTAR. After 6 weeks, histology (Masson's Trichrome) was analyzed.. Endocardial electromechanical mapping showed an increase of mean unipolar voltage (UV) amplitude in the ischaemic myocardial segments in the EPO-treated animals (8.5 mV pre and 10.6 mV post treatment) and a significantly reduced ischaemic surface area compared to the control group (19% vs. 41%) suggesting a decline in ischaemic injury. Echocardiography revealed 2,2 hypokinetic segments of the lateral wall in the EPO group vs. 3,3 in the control groups. The mean ejection fraction was 64% in the EPO group and 55% in the placebo group. Quantitative histological analysis of the ischaemic regions revealed a reduction of myocardial fibrosis (8% vs. 28%) in the EPO group.. Endocardial EPO injection may induce cardioprotective effects in hibernating myocardium and may attenuate the progression of ischaemic tissue damage.

Topics: Animals; Chronic Disease; Coronary Circulation; Disease Models, Animal; Disease Progression; Electrophysiologic Techniques, Cardiac; Endocardium; Erythropoietin; Image Processing, Computer-Assisted; Myocardial Contraction; Myocardial Ischemia; Myocardial Stunning; Swine; Ultrasonography

Recent studies have suggested that endogenous erythropoietin (Epo) plays an important role in the mobilization of bone marrow-derived endothelial progenitor cells (EPCs). However, it remains to be elucidated whether the Epo system exerts protective effects on pulmonary hypertension (PH), a fatal disorder encountered in cardiovascular medicine.. A mouse model of hypoxia-induced PH was used for study. We evaluated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice lacking the Epo receptor (EpoR) in nonerythroid lineages (EpoR(-/-) rescued mice) after 3 weeks of exposure to hypoxia. Those mice lack EpoR in the cardiovascular system but not in the hematopoietic system. The development of PH and pulmonary vascular remodeling were accelerated in EpoR(-/-) rescued mice compared with wild-type mice. The mobilization of EPCs and their recruitment to the pulmonary endothelium were significantly impaired in EpoR(-/-) rescued mice. By contrast, reconstitution of the bone marrow with wild-type bone marrow cells ameliorated PH in the EpoR(-/-) rescued mice. Hypoxia enhanced the expression of EpoR on pulmonary endothelial cells in wild-type but not EpoR(-/-) rescued mice. Finally, hypoxia activated endothelial nitric oxide synthase in the lungs in wild-type mice but not in EpoR(-/-) rescued mice.. These results indicate that the endogenous Epo/EpoR system plays an important role in the recruitment of EPCs and prevents the development of PH during chronic hypoxia in mice in vivo, suggesting the therapeutic importance of the system for the treatment of PH.

Topics: Animals; Bone Marrow Transplantation; Cell Movement; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelium; Endothelium, Vascular; Enzyme Activation; Erythroid Precursor Cells; Erythropoietin; GATA1 Transcription Factor; Heart Failure; Hematopoietic Stem Cells; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type III; Organ Specificity; Radiation Chimera; Receptor, TIE-2; Receptors, Erythropoietin; Systole; Ventricular Dysfunction, Right

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Practice Guidelines as Topic; Recombinant Proteins

Arteriovenous grafts (AVG) and tunneled permanent catheters (TPC) are increasingly being used in hemodialysis (HD) patients. However, their role in baseline inflammatory status has not been fully evaluated. Aim of the study was to evaluate the influence of the current kind of vascular access on the baseline inflammatory status, marked by serum C-reactive protein (CRP), and the response to epoetin therapy in a group of iron-replete HD patients, under steady clinical conditions, without evidence of acute infections and/or inflammatory diseases.. We studied 79 patients who had been on bicarbonate HD for 8-410 months and were receiving epoetin therapy. They all had adequate iron stores and stable hemoglobin (Hb) levels. Exclusion criteria were fever, signs of infection, white blood cell count (WBC) > 10 x 1,000/microl, for at least 4 weeks before study. 48 patients (group A) had arteriovenous fistula (AVF), 18 patients (group B) AVG, 13 patients (group C) TPC. CRP, Hb, transferrin saturation, serum ferritin, WBC, serum albumin, protein catabolic rate, Kt/V, and epoetin dose (U/kg body weight/week) were measured. CRP values were log-transformed to normalize the distribution.. Log-transformed CRP values among the 3 groups were significantly different: group A 1.81 +/- 0.48; group B 2.12 +/- 0.50, and group C 3.00 +/- 0.25 (group A vs. B p < 0.003; group B vs. C p < 0.001; group A vs. C p < 0.0001). CRP and the epoetin dose were directly correlated (r = 0.519; p < 0.0001). The epoetin doses among the 3 groups were significantly different. Multiple regression analysis confirmed AVG and TPC as factors independently influencing CRP levels.. AVG and TPC have a higher degree of chronic inflammation than AVF. The epoetin requirement is increased in TPC and AVG compared with AVF.

Topics: Aged; Analysis of Variance; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis; C-Reactive Protein; Chi-Square Distribution; Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Linear Models; Male; Middle Aged; Renal Dialysis; Statistics, Nonparametric

A 40-year-old black male with scleroderma lung disease presented with blurry vision and headache. His presenting hemoglobin was 22.3 g/dL and his serum erythropoietin level was surprisingly low. Although nocturnal hypoxemia was evident, his daytime resting arterial oxygen saturation was normal. The patient's symptoms of hyperviscosity improved after phlebotomy, as his hemoglobin gradually decreased to 18.3 g/dL. Repeat serum erythropoietin levels were in normal and high ranges. Patients with chronic interstitial lung disease and erythrocytosis could have normoxemia at rest and a normal or low serum erythropoietin level at the peak of erythrocytosis. A repeat sampling of serum erythropoietin and monitoring of oxygen saturation during sleep and exertion may help in diagnosis. Physicians should prescribe continuous oxygen therapy for patients with chronic interstitial lung disease and erythrocytosis, even if diurnal resting hypoxemia is absent.

Topics: Adult; Chronic Disease; Erythropoietin; Headache; Humans; Lung Diseases, Interstitial; Male; Oxygen Inhalation Therapy; Polycythemia; Scleroderma, Systemic; Vision, Low

Our aim is to study the effect of improvement in anemia on event-related potentials (ERPs; P300) as markers of cognitive dysfunction in predialysis and dialysis patients of chronic kidney disease (CKD). Thirty anemic patients of CKD (hemoglobin [Hb] < 9 g%), 15 in the predialysis group (Group A), and 15 patients on biweekly hemodialysis (Group B) were recruited for the study. Patients of uremic encephalopathy, dyselectrolytemia, and those with hearing problems were excluded. Both groups were given recombinant human erythropoietin (rhuEPO) 100 IU/kg biweekly for 6 weeks by the subcutaneous route. No intervention was performed in the third control group (Group C), which consisted of 30 normal healthy volunteers. The improvement in Hb was assessed every 2 weeks, and the amplitude and latency of the P300 component of the ERPs were studied before initiating treatment and after 6 weeks of rhuEPO administration. There was a significant increase in Hb in both the study groups without any significant alteration in kidney functions. A significant reduction in P300 latency was noted in both the study groups after intervention. Similarly, the amplitude of P300 also increased in both study groups, but attained statistical significance for the dialysis group only. No significant changes were observed in the control group. Administration of EPO in patients of anemia with CKD resulted in a significant improvement in the electrophysiological markers of cognitive function in the form of increased amplitudes and decreased latencies of P300 in both predialysis and dialysis patients.

Topics: Anemia; Chronic Disease; Cognition Disorders; Erythropoietin; Event-Related Potentials, P300; Hemoglobins; Humans; Kidney Diseases; Reaction Time; Recombinant Proteins

To evaluate the relationship between hemoglobin (Hb) level and quality of life (QOL) in anemic patients with non-dialysis chronic kidney disease receiving epoetin alfa.. A post-hoc analysis using data from a multicenter, open-label, prospective study of epoetin alfa for anemia in patients with chronic kidney disease not on dialysis was conducted. The relationship between Hb and QOL was analyzed using correlation and longitudinal analyses, the latter adjusting for sample selection bias. The Linear Analog Scale Assessment (LASA) and the Kidney Disease Questionnaire (KDQ) subscales were used to measure QOL. The impact of an incremental 1 g/dL increase in Hb level on LASA and KDQ scores was determined using an incremental analysis.. A total of 1183 and 1044 patients formed the study populations for the LASA and KDQ analyses, respectively. There was a positive and significant relationship between Hb levels and QOL (p < 0.05). Using non-linear regression analysis, we characterized the sigmoid-shape of the relationship between Hb levels and QOL scores. Hemoglobin change was a statistically significant determinant of QOL improvement for both LASA and KDQ scales (p < 0.05). The model predicted that, based on a 2 unit change in Hb, the greatest incremental QOL improvement per unit of Hb increase occurred when Hb was in the range of 11 to 12 g/dL.. This study demonstrates that, beyond the well-known relationship between Hb increases and QOL improvements, the maximal incremental gain in QOL occurred when Hb reached 11 to 12 g/dL. This suggests that treating anemic patients with non-dialysis chronic kidney disease until their Hb level reaches 12 g/dL will result in the greatest QOL improvement per Hb unit increase. The analyses were conducted based on an open-label study of epoetin alfa and could be further validated using a randomized, controlled trial, comparing incremental gains in QOL associated with treatment initiation at varying levels of Hb across arms.

Topics: Aged; Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Quality of Life; Recombinant Proteins

The prevalence of iron deficiency and its contribution to the anemia of end stage renal disease has been extensively studied, but much less is known about the role of iron deficiency in the pathogenesis of the anemia of chronic kidney disease in predialysis patients. All new hemodialysis patients entering a single hemodialysis unit between July 1999 and April 2002 were included in the study. The admission laboratory tests and the Health Care Financing Administration (HCFA) 2728 form were examined to determine the prevalence of erythropoietin use, anemia (Hb<11 g/dl), and iron deficiency (ferritin<100 ng/ml and transferrin saturation %<20%). In a second part of the study, the effect of intravenous iron gluconate replacement in patients with stage III & IV chronic kidney disease was examined. Anemia was present in 68% of all patients starting hemodialysis. Iron deficiency was a common feature occurring in 29% of patients taking erythropoietin (49% of all patients) and 26% of patients without erythropoietin (51% of all patients). Following the administration of intravenous iron gluconate to four patients, there was a significant rise in hemoglobin levels from 10.6+/-0.19 to 11.7+/-g/dl (p=0.02).. Iron deficiency is common in predialysis patients. Replenishing iron stores in anemic patients with chronic kidney disease significantly increases hemoglobin levels and should be considered as an integral part of the therapy for treating anemia in the predialysis population.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Ferric Compounds; Gluconates; Humans; Kidney Diseases

To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W).. This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa.. Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure.. The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects.. Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.

Topics: Administration, Oral; Aged; Anemia; Chronic Disease; Colony-Stimulating Factors; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Male; Middle Aged; Treatment Outcome

Anaemia is frequently found in patients with chronic heart failure (CHF) and has been associated with an increase in mortality and morbidity, impaired cardiac and renal function and a reduced quality of life (QoL) compared with non-anaemic CHF patients. Correction of anaemia with recombinant human erythropoietin (epoetin) has been associated with an improvement in CHF in both controlled and uncontrolled studies. The present study describes our findings in a series of 78 consecutive patients with symptomatic CHF and anaemia (haemoglobin (Hb) level <12.0 g/dl) treated with epoetin beta and, if necessary, intravenous iron sucrose. Over a mean observation period of 20.7 +/- 12.1 months, mean Hb levels increased from 10.2 +/- 1.1 to 13.5 +/- 1.2 g/dl, p < 0.01. New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) were significantly improved and the number of hospitalizations was significantly reduced with the period before treatment (all p < 0.01). Serum creatinine and creatinine clearance (CCr) were 2.2 +/- 0.9 mg/dl and 32.5 +/- 26.5 ml/min, respectively, at baseline, and remained stable over the observation period. Interestingly, >90% of the patients had concomitant mild-to-moderate chronic kidney disease at baseline and study end (CKD), as defined by the accepted diagnostic criterion of a CCr <60 ml/min.. The correction of the anaemia with epoetin beta together with initial intravenous iron supplementation, resulted in significant improvements in NYHA class and cardiac function, and a reduction in hospitalization rate. Moreover, renal function was maintained stable in most patients.

Topics: Aged; Aged, 80 and over; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Heart Failure; Hospitalization; Humans; Kidney Diseases; Male; Recombinant Proteins

Despite an increase in the use and average dose of recombinant human EPO (rh-EPO) over the last 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. The definition of rh-EPO resistance has been introduced to identify those patients in whom the target hemoglobin level is not attained despite a greater-than-usual dose of erythropoietin-stimulating agent (ESA). In recent years, increasing attention has been paid to the relationship between dialysis, increased inflammatory stimulus, malnutrition, and ESA response. About 35% to 65% of hemodialysis patients show signs of inflammation that could be a cause of anemia through the suppression of bone marrow erythropoiesis by a number of cytokines. A large proportion of chronic kidney disease patients also have protein-energy malnutrition and wasting; low serum albumin levels, together with other more specific nutritional markers, are predictors of rh-EPO response. A diminished nutritional state could then be a feature of patients who are resistant to ESA treatment, with malnutrition probably being a consequence of a chronic inflammatory state. Starting from the hypothesis that anemia, partially attributable to a reduced response to ESA, could be the link among malnutrition, inflammation, and the poor outcome of chronic kidney disease patients, we designed a multicenter observational study, the Malnutrition-Inflammation-Resistance-Treatment Outcome Study (MIRTOS), aimed at evaluating the impact and possible causes of resistance to ESA in a large sample of hemodialysis patients. We hope the results of MIRTOS will represent a step forward toward a better understanding of the factors influencing the response to ESA in hemodialysis patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Drug Resistance; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Malnutrition; Protein-Energy Malnutrition; Recombinant Proteins; Renal Dialysis

Patients with chronic kidney disease (CKD) stages 2-5 are known to suffer numerous complications and co-morbidities associated with kidney disease. The medication prescription patterns in this population are not well understood. We report on prescription data collected as part of a multicentre longitudinal study in patients with CKD, with a focus on medications with cardiovascular or cardioprotective effects.. Patients were recruited from four academic nephrology centres in the USA, with patient recruitment from June 2000 to March 2002. Medication data were captured at the time of first enrollment into the study. Individual medications were classified into medication groups, and those with predominant cardioprotective effects or for prevention of progression of kidney disease (e.g. medications for treatment of anaemia, lipid-lowering agents, antihypertensives, statins, etc.) were recorded for analysis. Descriptive statistics were used for medication prescription according to baseline demographics and co-morbidities. Predictors of epoetin and iron use were determined by logistic regression adjusting for age, race, sex, diabetes, glomerular filtration rate (GFR), haemoglobin and serum albumin.. Medication data were available for 619 patients with stages 2-5 CKD. Patients were 60.6+/-16.0 years of age, and were prescribed 8+/-4 (range 1-28) medications. Overall, the proportion of patients prescribed different classes of medications included epoetin (20%), intravenous iron (13%), HMG-CoA reductase inhibitors (16%), angiotensin-converting enzyme (ACE) inhibitors (44%), angiotensin receptor blockers (13%), beta-blockers (46%), calcium channel blockers (52%) and aspirin (37%). There was a low use of epoetin (45%) and iron (20%) in patients with anaemia. Only 24% of patients with coronary artery disease were prescribed statins, and ACE inhibitors and angiotensin receptor blockers were used in only 58 and 23% of diabetic patients with proteinuria. Positive predictors of epoetin and iron therapy included white race and diabetes. Higher GFR and higher serum albumin were associated with lower odds of being prescribed epoetin. White race and diabetics were more likely to be prescribed iron.. This study provides an overview of prescription practices in a cohort of CKD patients. Substantial underutilization of certain classes of cardioprotective medications is apparent, and systematic educational efforts in this direction may well prove worthwhile to impact outcomes.

Topics: Aged; Cardiovascular Diseases; Chronic Disease; Drug Utilization; Epoetin Alfa; Erythropoietin; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Logistic Models; Middle Aged; Recombinant Proteins

Reducing the dosage frequency of subcutaneous epoetin in peritoneal dialysis (PD) patients is convenient and should improve patient satisfaction and, possibly, compliance. We investigated if a weekly dosage of epoetin beta in PD patients safely maintained haemoglobin (Hb) concentrations equivalent to those obtained with previous twice- or thrice-weekly administration. In addition, we investigated if a fortnightly dosage of epoetin beta was safe and as effective as previous weekly administration.. After a 4 week run-in period, PD patients were switched to either weekly or fortnightly epoetin beta administration, depending on their previous treatment schedules, for 25 weeks.. The per-protocol cohort included 128 patients, of whom 54 received epoetin beta once weekly and 74 once fortnightly. The mean change in Hb concentration from baseline over weeks 13-25 and the 90% confidence intervals (CIs) remained within the target range (10-12 g/dl) and specified equivalence (+/-0.75 g/dl) limits in the weekly (-0.34 g/dl; 90% CI: -0.14 to -0.54 g/dl) and fortnightly (-0.39 g/dl; 90% CI: -0.24 to -0.55 g/dl) cohorts. The mean change from baseline in the epoetin beta dose was 1.4 IU/kg/week (90% CI: -3.8 to 6.6 IU/kg/week; 2%) in the weekly cohort and 4.4 IU/kg/week (90% CI: 1.7-7.2 IU/kg/week; 13%) in the fortnightly cohort. Both treatment regimens were well tolerated.. In stable PD patients switched from twice- or thrice-weekly to weekly epoetin beta treatment, Hb concentrations could be maintained within the specified range over 25 weeks without significant change in their mean epoetin beta doses. In patients switched from weekly to fortnightly treatment, Hb concentrations could also be maintained over 25 weeks. There was a small increase in the mean dose during this period, but >/=50% of patients could be maintained without dose increase. Reducing dosage frequency may improve compliance in PD patients who self-administer their epoetin.

Topics: Adult; Aged; Anemia; Chronic Disease; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Peritoneal Dialysis; Recombinant Proteins

Topics: Biomarkers; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Liver Cirrhosis; Male; Prognosis; Reference Values; Sensitivity and Specificity

Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.. The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Humans; Kidney Diseases; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Reduction Behavior

We describe a 41-year-old woman with chronic idiopathic thrombocytopenic purpura who received recombinant human thrombopoietin (rhTPO) therapy. rhTPO was administrated subcutaneously at a dosage of 1.0 mug/kg daily for a maximum of 14 days until the platelet count was more than 50 x 10/l. The patient received three cycles (six, 13, and eight doses each) of rhTPO, each initiated when the platelet counts was less than 10 x 10/l. The platelet count increased to above 50 x 10/l on days 5, 11 and 8, and peaked at 456 x 10/l, 130 x 10/l and 82 x 10/l on days 9, 15 and 13 in the three respective cycles, each followed by a gradual decline. The durations of platelet counts at more than 50 x 10/l in the three cycles were 13, 7 and 10 days, respectively. rhTPO was well tolerated with no adverse event observed. Antibodies to rhTPO by enzyme-linked immunosorbent assay were not detected. Our observations suggested that rhTPO could transiently increase the peripheral platelet count in patients with chronic refractory idiopathic thrombocytopenic purpura. The reasons why the peak platelet counts decreased and the duration of response shortened after successive cycles of treatment were unclear.

Topics: Adult; Antibodies; Blood Platelets; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Salvage Therapy

Anemia is an important cause of morbidity in patients suffering from chronic renal failure, and erythropoietin is a milestone of anemia treatment. Various factors may cause erythropoietin resistance. Herein, we describe the case of 32-year-old man who presented with anemia and weakness. He developed progressive renal failure secondary to recurrent kidney stones. One year before admission, he developed anemia for which he had been treated with erythropoietin. However, the anemia persisted. Examination of bone marrow biopsy specimen showed that the marrow was extensively replaced with oxalate crystals and fibrous connective tissue with severe decrease of hematopoietic cells. To the best of our knowledge, our patient represents the first case in the literature describing the association between the oxalate deposition and EPO resistance.

Topics: Adult; Anemia; Biopsy, Needle; Bone Marrow Diseases; Chronic Disease; Drug Resistance; Erythropoietin; Follow-Up Studies; Humans; Hyperoxaluria; Immunohistochemistry; Kidney Calculi; Kidney Failure, Chronic; Male; Oxalates; Renal Dialysis; Risk Assessment; Severity of Illness Index; Treatment Failure

Ten-day-old rat pups (P10) subjected to acute hypoxia (down to 4% O2) had as adults increased aggression (handling test), memory impairment (water maze test), and decreased CA1 cell counts. Pups subjected to chronic hypoxia (10% O2 from P0 to P21) had increased aggression, hyperactivity (open-field test), and decreased CA1 cell counts. Chronic hypoxia with superimposed acute hypoxia resulted in consequences that were not different from those of chronic hypoxia.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Cell Count; Cell Death; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Exploratory Behavior; Hippocampus; Hypoxia; In Situ Nick-End Labeling; Maze Learning; Rats; Rats, Sprague-Dawley; Time; Time Factors

Anaemia is often observed in patients with chronic heart failure (CHF), and it may be associated with a worse prognosis. Aim of this study was to identify the individual mechanisms of anaemia in CHF patients.. One hundred and forty-eight consecutive patients with haemoglobin concentration <13 g/dL (if males) or <12 g/dL (if females) were enrolled. Factors responsible for anaemia were investigated by evaluating endogenous erythropoietin (Epo) production, serum cytokines levels, body iron status, and iron supply for erythropoiesis. Most patients (57%) presented anaemia of chronic disease and among them, 92% showed evidence of a defective endogenous Epo production. This was indicated by an observed/predicted log(serum Epo) ratio less than 0.8 and/or a defective iron supply for erythropoiesis diagnosed by low transferrin saturation and/or increased value of soluble transferrin receptor. According to regression analysis sex, renal failure, and serum Epo were correlated with anaemia.. According to our study, about half of anaemic CHF patients showed anaemia of chronic disease with blunted endogenous Epo production and/or a defective iron supply for erythropoiesis. Determination of the individual mechanisms of anaemia in CHF could justify a rational therapeutic approach to anaemia.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Female; Heart Failure; Humans; Iron Deficiencies; Male; Middle Aged; Receptors, Transferrin

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

Topics: Autoantibodies; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Immunosuppression Therapy; Kidney Diseases; Kidney Transplantation; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Aged; Animals; Chronic Disease; Disease Models, Animal; Erythropoietin; Humans; Injections, Intravenous; Male; Mice; Mice, Transgenic; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary Wedge Pressure; Recombinant Proteins

To determine if prenatally measured cardiac troponin T in the amniotic fluid (Am-TnT) could be used as a marker of fetal myocardial hypoxia and necrosis in pathological pregnancy characterized by increased concentration of amniotic fluid erythropoietin (Am-EPO) as a sign of chronic fetal hypoxia.. We measured Am-TnT and Am-EPO in 29 pathological and 5 uncomplicated pregnancies. Samples of amniotic fluid were collected prospectively during elective amniocentesis (n=15), cesarean sections (n=17), and before elective induction of labor in two pregnancies with stillbirth. Am-TnT and Am-EPO were determined by chemiluminescent immunological method.. Am-TnT was undetectable in normal pregnancies, but it was detectable in 9 of 29 amniotic fluid samples from pathological pregnancies, with a median value of 0.030 microg/L (range, 0.010-111.6 microg/L). Am-EPO values were above normal values (>11 U/L) in all pathological pregnancies. Am-EPO concentration showed positive correlation with the Am-TnT concentration (r=0.526, P=0.003). Median concentration of Am-EPO in 9 pregnancies with detectable Am-TnT was 198 U/L (range, 16-3,378 U/L). In 20 pathologic pregnancies with undetectable Am-TnT, the median concentration of Am-EPO was 39 U/L (range, 12-293 U/L). There was no statistically significant difference between the groups (P=0.051).. Am-TnT is measurable in some pathological pregnancies with signs of fetal chronic hypoxia and myocardial involvement and could be potentially used as a biochemical marker of fetal myocardial injury.

Topics: Amniocentesis; Amniotic Fluid; Biomarkers; Cardiomyopathy, Hypertrophic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Fetal Growth Retardation; Fetal Hypoxia; Humans; Pregnancy; Prospective Studies; Troponin T

Erythropoiesis-stimulating proteins, such as erythropoietin alfa and darbepoetin alfa, have positively impacted anemia management. These medications improve patient outcomes and quality of life. Their costs, however, remain a major barrier for health systems.. To evaluate the development, implementation, and cost-effectiveness of an inpatient therapeutic interchange protocol for erythropoiesis-stimulating proteins at a large, tertiary care, university-affiliated health system.. Virginia Commonwealth University Health System (VCUHS) developed and implemented a therapeutic interchange program to convert therapy for all inpatients undergoing dialysis from erythropoietin alfa to darbepoetin alfa for treatment of chronic kidney disease-related anemia. An evaluation of the economic impact of this program on drug expenditures over a fiscal quarter (2003) was conducted using historical comparator data (2002).. Preliminary evaluation of the program demonstrated cost-savings and reduced drug utilization of erythropoiesis-stimulating proteins in hospitalized dialysis patients. For the first quarter of 2003 compared with the first quarter of 2002, VCUHS realized a cost-savings of nearly 10,000 US dollars, which was related to the program's aggressive screening procedure. When these data were normalized for equal numbers of patients in each group receiving one of the drugs, the actual cost-savings was over 2000 US dollars. These cost-savings are largely due to reduced utilization of these expensive biotechnology products with implementation of a dosing protocol.. VCUHS has successfully developed and implemented a darbepoetin alfa therapeutic interchange protocol for hospitalized dialysis patients. This has translated into reduced use of erythropoiesis-stimulating proteins, resulting in cost-savings for the health system.

Topics: Anemia; Chronic Disease; Clinical Protocols; Costs and Cost Analysis; Darbepoetin alfa; Drug Administration Schedule; Drug Utilization Review; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Hospitals, University; Humans; Injections, Intravenous; Kidney Diseases; Length of Stay; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Therapeutic Equivalency; Virginia

Topics: Anemia; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Heart Failure; Humans; Iron; Recombinant Proteins

Topics: Anemia; Bias; Biomarkers; Chronic Disease; Epoetin Alfa; Erythropoietin; Goals; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Research Design; Treatment Outcome

Topics: Adult; Anemia, Hypochromic; Arthroplasty, Replacement, Hip; Chronic Disease; Colitis; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Ferric Compounds; Folic Acid; Humans; Intestinal Polyps; Leucovorin; Malabsorption Syndromes; Male; Methotrexate; Osteoarthritis, Hip; Preoperative Care; Recombinant Proteins; Rectal Diseases; Remission Induction; Spondylitis, Ankylosing; Time Factors; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amniocentesis; Amniotic Fluid; Chronic Disease; Erythropoietin; Fetal Hypoxia; Humans; Immunoassay; Troponin I; Troponin T

The National Kidney Foundation has developed guidelines for the diagnosis and classification of chronic kidney disease (CKD) but it is not known whether these are applicable to renal transplant recipients. This study determined the prevalence of CKD according to the stages defined in the guidelines, the complications related to CKD and whether the prevalence of complications was related to CKD stage in 459 renal transplant recipients. CKD was present in 412 patients (90%) and 60% were in CKD Stage 3 with a glomerular filtration rate (GFR) between 30 and 59 mL/min/1.73 m2. The prevalence of anemia increased from 0% in Stage 1 to 33% in Stage 5 (p<0.001). Hypertension was present in 86% and increased from 60% in Stage 1 to 100% in Stage 5 (p=0.02). The number of anti-hypertensives per patient increased from 0.7 in Stage 1 to 2.3 in Stage 5 (p<0.001). The number of CKD complications per patient increased from 1.1 in Stage 1 to 2.7 in Stage 5 (p<0.001). We conclude that CKD and the complications of CKD are highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians identify patients at increased risk and target appropriate therapy to improve outcomes.

Topics: Blood Pressure; Chronic Disease; Creatinine; Cross-Sectional Studies; Erythropoietin; Ferritins; Glomerular Filtration Rate; Hemoglobins; Humans; Hypocalcemia; Kidney Diseases; Kidney Transplantation; Ontario; Postoperative Complications; Prevalence; Renal Replacement Therapy; Retrospective Studies; Transferrin

The anemia of chronic disease (ACD) is usually defined as mild to moderate anemia occurring during the chronic infection, inflammation, neoplasm or trauma. It is the most common anemia among in-hospital adults. The insufficient endogenous erythropoietin (EPO) production is probably one of the pathogenic mechanisms of ACD. Inflammatory cytokines play an important role in the ACD pathogenesis. But nowadays there are few published papers on the childhood ACD in the world. This study aimed to detect the EPO levels in children's ACD, to explore the relationship between EPO and tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) and, to evaluate the effect of recombinant human TNF alpha (rhTNF-alpha) on EPO gene expression.. Sixty children were divided into ACD group (20 children), non-anemia (NA) group (19 children) and iron deficiency anemia (IDA) group (21 children) according to clinical diagnosis. Serum TNF alpha and IL-6 levels were detected with ELISA method. The EPO level was detected by chemical immulite method. The effect of rhTNF alpha on the expression of EPO gene was studied by culturing Hep G2 cell line and RT-PCR method.. Serum EPO levels were different among the 3 groups (F = 44.68, P < 0.01). Serum EPO levels in ACD group were higher than those in NA group, while the hemoglobin levels were similar between the two groups. Serum EPO levels in ACD patients were lower than those in IDA patients. Serum TNF alpha levels were different among the 3 groups (F = 25.15, P < 0.01), and serum IL-6 levels were also different among the 3 groups (F = 13.16, P < 0.01). Serum TNF alpha and IL-6 levels in ACD group were higher than those in NA group. In ACD group, serum levels of both TNF alpha and IL-6 were not correlated to the serum level of EPO (r = -0.35, P > 0.05 and r = -0.05, P > 0.05, respectively). In vitro, rhTNF alpha inhibited the expression of EPO mRNA in hypoxia, and the inhibitory effects became stronger with the increase of rhTNF alpha (F = 64.20, P < 0.01).. EPO levels increased incompensatively in ACD children, which may be a cause of ACD. TNF alpha may cause anemia by inhibiting EPO production.

Topics: Anemia; Cell Line, Tumor; Child; Child, Preschool; Chronic Disease; Erythropoietin; Gene Expression; Humans; Interleukin-6; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Dysregulated erythropoietin (EPO) plasma levels may play a role in the pathophysiology of chronic liver disease (CLD) because chronic anaemia is frequently observed in patients with liver cirrhosis. We aimed to identify the factors contributing to EPO regulation in patients with CLD.. Plasma EPO concentrations were correlated with clinical and laboratory parameters in 111 CLD patients and 220 healthy controls.. Anaemia, though generally mild, was common in CLD patients, and thrombocytopenia and previous bleeding episodes were observed in two-thirds of the patients. Plasma EPO levels were significantly elevated in CLD patients (P < 0.001). EPO increased according to Child's stages of cirrhosis, independently of the aetiology of CLD. EPO correlated with haemoglobin (r= -0.498, P < 0.001). Additionally, EPO independently correlated with markers of liver dysfunction, e.g. prothrombin time, albumin concentration or cholinesterase activity, and platelet count. EPO was also significantly elevated in patients with a current bleeding tendency and with prior gastrointestinal haemorrhages. EPO levels were increased in patients with impaired pulmonary function, e.g. decreased diffusion capacity, vital capacity or hyperventilation. Interestingly, plasma interleukin-6 (IL-6) concentrations positively correlated with EPO (r=0.277, P = 0.003), suggesting a possible mechanism of EPO upregulation in patients with CLD through IL-6 dependent pathways, e.g. binding of STAT transcription factors in the putative EPO promoter region.. EPO is upregulated in patients with chronic liver diseases in response to anaemia, bleeding complications, impaired pulmonary function, thrombocytopenia and liver dysfunction. IL-6 dependent pathways could be involved in mediating elevated EPO levels in CLD patients.

Topics: Adolescent; Adult; Aged; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemorrhage; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Respiratory Function Tests; Severity of Illness Index; Thrombocytopenia; Up-Regulation

In patients with cirrhosis, anemia is common and is likely to be multifactorial, including decreased erythrocyte production, sequestration due to hypersplenism, hemolysis, and increased blood loss from gastrointestinal bleeding. Renal dysfunction is also common in liver disease and this may also cause anemia. However, an association between anemia and renal dysfunction has not been reported in patients with cirrhosis. Our objective was to determine whether anemia in cirrhotic patients is independently related to renal dysfunction. We conducted a retrospective chart review of patients in our institution listed for liver transplantation. We collected simultaneous data on age, hemoglobin, creatinine, albumin, liver enzymes, prothrombin time, and bilirubin. We excluded patients who were hospitalized or deceased to avoid confounding variables. Two hundred eighty-six (female n = 130) patients with a mean age of 52.8 +/- 9.7 (range, 18-73) years were studied. Renal dysfunction (creatinine > 1.2 mg/dL) was present in 55 (19%) patients, and anemia (hemoglobin < 12 g/dL) was seen in 115 (40%) patients. Anemia was more common in patients with renal dysfunction (64 versus 34%; P < 0.001) compared to those with normal renal function. Creatinine, prothrombin time, and bilirubin showed an inverse relationship (all P's < 0.001) with hemoglobin, and albumin showed a positive correlation with hemoglobin (P < 0.001). Multivariate analysis showed that creatinine (OR, 2.4; 95% CI, 1.05-5.3; P = 0.038), prothrombin time (P = 0.026), bilirubin (P = 0.035), and albumin (P = 0.001) were independent predictors of anemia. Renal dysfunction is an important cause of anemia in patients with cirrhosis. The role of erythropoietin in the management of anemia in patients with cirrhosis and renal dysfunction should be explored in prospective studies.

Topics: Adolescent; Adult; Age Distribution; Aged; Analysis of Variance; Anemia; Chronic Disease; Comorbidity; Confidence Intervals; Erythropoietin; Female; Follow-Up Studies; Humans; Incidence; Kidney Function Tests; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Odds Ratio; Probability; Renal Insufficiency; Retrospective Studies; Risk Assessment; Sex Distribution; Waiting Lists

Topics: Anemia; Anemia, Sickle Cell; Arteriovenous Shunt, Surgical; Blood Transfusion; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Disease Progression; Erythropoiesis; Erythropoietin; Europe; Evidence-Based Medicine; Ferritins; Hematocrit; Hematologic Tests; Hemoglobinometry; Hemoglobins; Hemorheology; Humans; Iron; Kidney Failure, Chronic; Nutritional Physiological Phenomena; Oxidative Stress; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Review Literature as Topic; Transferrin; Treatment Failure; Vitamin E

This study aimed to investigate the prognostic importance of plasma erythropoietin (EPO) levels in chronic heart failure (CHF) patients.. Anemia is common and is associated with an impaired survival in patients with CHF. Erythropoietin is a hematopoietic growth factor, upregulated in anemic conditions. Little is known about the pathophysiology of anemia in CHF and the prognostic importance of plasma EPO levels in CHF patients.. In 74 patients with CHF (age, 61 +/- 2 years; left ventricular ejection fraction, 0.31 +/- 0.01; peak oxygen consumption, 19.1 +/- 0.6 [mean +/- SEM]) and in 15 control patients, hemoglobin levels and plasma concentrations of EPO and brain natriuretic peptide were measured.. During a mean follow-up of 3.0 years (range, 2.3 to 5.3 years), 22 patients (30%) died. Anemia was present in 24% of the patients. Multivariate analysis showed that plasma EPO (p = 0.026) and hemoglobin levels (p = 0.005) were independent predictors of survival in this CHF population. We observed only a mild inverse correlation between the logarithm of EPO and hemoglobin levels (r2 = 0.08, p = 0.02) in CHF patients, whereas the control group showed a clear significant inverse correlation (r2 = 0.44, p = 0.007).. Elevated plasma EPO levels are associated with an impaired prognosis independent of hemoglobin levels and other established markers of CHF severity. Furthermore, in the CHF patients, EPO levels poorly correlate with the hemoglobin levels, in contrast with the control group.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Netherlands; Prognosis; Retrospective Studies; Severity of Illness Index; Statistics as Topic; Survival Analysis

Chronic inflammation is a major cause of morbidity and mortality in end-stage renal disease. The associated anemia in these patients due to renal cortical atrophy and erythropoietin deficiency is treated with recombinant erythropoietin. Recent reports suggest a growing incidence of symptomatic venous thrombosis in cancer patients treated with recombinant erythropoietin. Several investigators have reported on different mechanisms of thrombosis in these patients. We hypothesize that thrombosis in patients with end-stage renal disease due to increased expression of C-reactive protein (CRP) as a result of chronic inflammation promotes the release of thrombin activatable fibrinolytic inhibitor causing fibrinolytic deficit and eventually thrombosis. Furthermore, because endothelial nitric oxide is responsible for the maintenance of the normal vascular function, the decreased levels of nitric oxide in chronic inflammation cause endothelial damage and result in thrombosis. To test this hypothesis, blood samples were collected from 106 patients (49 male and 57 female, aged 59.8+/-15.7 years) with end-stage renal disease undergoing hemodialysis and treated with recombinant erythropoietin at a mean dose of 201.8 U/kg/week. Blood samples were drawn in 5-mL tubes containing 3.2% sodium citrate just before the hemodialysis procedure. These blood samples were immediately centrifuged to obtain platelet-poor plasma, which was aliquoted and frozen at -70 degrees C until further analysis. Erytropoietin antibodies were measured using an anti-EPO enzyme-linked immunosorbent assay (ELISA) method developed in our laboratory. Nitric oxide was measured using a NO analyzer (Sievers 280I, Ionics, Boulder, CO). Plasma CRP levels were measured with a highly sensitive ELISA method IMUNOCLONE CRP ELISA (American Diagnostica, Greenwich, CT). TAFI antigen levels in plasma were analyzed with an IMUCLONE TAFI ELISA kit (American Diagnostica, Greenwich, CT). TAFI functional activity was assayed with an ACTICHROME TAFI activity kit. The measured levels of nitric oxide, CRP, TAFI antigen, and TAFI functional were 37.36+/-36.8 (normal value, 37.49+/-18.96; range, 19.3-102 microM), 12.27+/-10.6 (normal value, < 1 microg/mL), 146.9+/-28.4% NHP (normal, 100% NHP), and 102.55+/-37% NHP (normal range, 22.3-165.7; mean, 89.5% NHP), respectively. The erythropoietin antibody was detected in 9.4% of the patient group. While 20% of the erythropoietin antibody-positive and 27.1% of the erythropoietin ant

Topics: Adult; Aged; Aged, 80 and over; Anemia; Autoantibodies; C-Reactive Protein; Carboxypeptidase B2; Chronic Disease; Complement Activation; Cytokines; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Induction; Erythropoietin; Female; Fibrinolysis; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Recombinant Proteins; Renal Dialysis; Thrombin; Thrombophilia; Thrombosis

Topics: Anemia; Cardiac Output, Low; Chronic Disease; Erythropoietin; Humans

Patients returning to hemodialysis (HD) after failure of their kidney transplant suffer from high morbidity and mortality rates. It is common practice to keep failed kidney transplants in place. It is not known if these failed kidney transplants induce an inflammatory state that contributes to morbidity and mortality. In a single facility, patients starting on HD with failed kidney transplant were identified (Group A) and screened for the presence of chronic inflammatory state. Those with clinical symptoms attributed to the failed allograft (Group A1) were not offered transplant nephrectomy unless deemed necessary during follow-up. Their clinical and laboratory data were followed up for 6 months. Similar data were obtained from a group of incident HD patients (Group B). Forty-three patients had a failed Kidney transplant (Group A). Of these, 29 comprised Group A1 and 14 Group A2. Group B comprised 121 patients. In comparison with Group B, Group A exhibited worse anemia and erythropoietin resistance index (ERI), had lower serum albumin and prealbumin, and higher CRP. Group A1 had lower Hb and higher ferritin, CRP, and ESR in comparison with Group A2. Following transplant nephrectomy, Group A1 had improvement in ERI, serum albumin, prealbumin, ferritin, fibrinogen, CRP, and ESR. At 6 months, Group A1 had higher Hb and serum albumin levels, and lower CRP and ERI in comparison with Group A2. Group B parameters showed no change during follow-up. Patients returning to HD following failure of their kidney transplant suffer from a chronic inflammatory state. Resection of failed transplants in symptomatic patients is associated with amelioration of markers of chronic inflammation. Transplant nephrectomy should be considered a treatment option for patients with failed kidney transplants, especially if they exhibit signs and symptoms of chronic inflammatory state.

Topics: Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Kidney Transplantation; Male; Middle Aged; Nephrectomy; Postoperative Complications; Renal Dialysis; Treatment Failure

Patients with hemoglobin greater than or equal to 100 g/L may have difficulty healing pressure ulcers because of impaired tissue oxygenation. Decreased hemoglobin is often anemia of chronic disease and may be due to the effects of inflammatory cytokines on erythroid progenitor cells. Recombinant human erythropoietin has been found to reverse anemia of chronic disease and may act as a growth factor in wound healing. To review the effect of 6 weeks of subcutaneous recombinant human erythropoietin 75 IU/kg administered 3 times weekly to resolve refractory anemia of chronic disease and heal Stage IV pressure ulcers, a retrospective chart review was conducted of four spinal cord injured patients (all men, mean age 59 years +/- 19) with Stage IV pressure ulcers and multiple comorbid conditions. The patients received recombinant human erythropoietin either through an inpatient spinal cord rehabilitation unit or an outpatient wound management clinic as part of interdisciplinary care. Mean hemoglobin increased from 88 +/- 7.4 g/L to 110 +/- 3.7 g/L. Mean ulcer surface area decreased from 42.3 cm2 (+/- 40.2) to 37.3 cm2 (+/- 44.3) despite extensive deroofing of one ulcer and subsequent increase in size. Mean ulcer depth decreased from 2.3 cm (+/- 1.2) to 1.2 cm (+/- 1.0). Human recombinant erythropoietin shows promise in resolving the refractory anemia of chronic disease associated with Stage IV pressure ulcers. Further study is suggested.

Topics: Adult; Aged; Anemia; Chronic Disease; Cost-Benefit Analysis; Drug Administration Schedule; Drug Costs; Erythropoietin; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Pressure Ulcer; Recombinant Proteins; Retrospective Studies; Risk Factors; Severity of Illness Index; Spinal Cord Injuries; Treatment Outcome; Wound Healing

Topics: Anemia, Iron-Deficiency; Bone Marrow; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Hematologic Tests; Humans; Inflammation; Iron; Neoplasms

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative disease in which autonomous, clonal proliferation of eosinophilic precursors results in persistent increase of eosinophils in the blood and bone marrow. A case of CEL spontaneous oscillation of white blood cell (WBC) count is presented. The cycle of WBC variation comprised about 60 days. Similar cyclic variations were noted in his platelet count, hemoglobin level and bone marrow cellularity, as well as in the spleen size, which was directly correlated with the WBC count. The numbers of bone marrow erythroid colony-forming units (CFU-E), granulocyte-macrophage colony-forming units (CFU-GM) and the serum level of colony-stimulating factors (CSFs) were also regularly changed during the oscillation of WBC. Bone marrow hyperplasia was accompanied with the increase in peripheral WBC count, suggesting that the variation of cell production caused the cyclic oscillation.

Topics: Bone Marrow; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Hypereosinophilic Syndrome; Hyperplasia; Interleukin-1; Interleukin-2; Interleukin-6; Leukocyte Count; Leukocytosis; Male; Middle Aged; Periodicity; Platelet Count; Thrombocytosis; Tumor Necrosis Factor-alpha; Tumor Stem Cell Assay

The Predialysis Survey on Anemia Management was designed to assess the care given to predialysis patients within 3 months of the start of hemodialysis or peritoneal dialysis (PD) therapy. In this presentation, we focus on demographic data and patient referral practices of patients who enter kidney centers.. We conducted a retrospective chart review of patients who had started hemodialysis or PD therapy between August 1999 and April 2000. All patients (age, 16 to 99 years) who entered 1 of the 779 centers in 21 European countries, Israel, or South Africa were included, except those for whom dialysis therapy was only started during an acute episode. Demographic characteristics, referral to kidney centers, comorbidities, drug treatments, major clinical events, and use of epoetin were documented.. Mean creatinine clearance rate at the first visit to the kidney center was 18.2 mL/min (0.303 mL/s). Of all patients, greater than 35% had a creatinine clearance less than 10.0 mL/min (<0.167 mL/s) at their first visit. Overall, 87% of patients were initiated on hemodialysis therapy, and 13% were started on PD therapy. PD was used more often the longer a patient was under the care of a nephrologist. Of 4,333 new dialysis patients, 68% had a hemoglobin concentration of 11.0 g/dL or less (< or =110 g/L) at the first visit.. The majority of patients in the survey had been under the care of a nephrologist for more than 12 months before the start of dialysis therapy. Nevertheless, most of these patients were anemic, and only a minority were on epoetin treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; European Union; Female; Health Care Surveys; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Practice Guidelines as Topic; Recombinant Proteins; Referral and Consultation; Renal Dialysis; Retrospective Studies

One of the complications of hemodialysis (HD) therapy is anemia caused by erythropoietin (EPO) deficiency. Recombinant EPO (rEPO) has been used routinely as a supplemental treatment. Erythrocyte expression of the complement regulatory proteins decay accelerating factor (DAF) and CD59 restricts complement activation and inhibits hemolysis. We hypothesized that the efficacy of rEPO treatment may be caused in part by the ability of rEPO to increase erythrocyte expression of DAF and CD59.. DAF, CD59, and complement receptor 1 (CR1) levels were analyzed for a group of 95 HD patients and compared with those of a control group. To evaluate effects of discontinuation of rEPO therapy, rEPO therapy was stopped for 12 HD patients until hematocrits decreased to less than 25%. DAF and CD59 levels then were reanalyzed.. In the 95 HD patients, three factors correlated significantly: DAF and CD59 (r = 0.642), DAF and CR1 (r = 0.503), and CD59 and CR1 (r = 0.324), whereas no correlations were found in the group of 42 healthy controls. In the experiment in which rEPO therapy was discontinued, 8 of 12 patients reached the defined level of anemia 4 to 7 weeks after rEPO treatment had been withheld. Both DAF and CD59 levels decreased significantly after discontinuation of rEPO therapy (P < 0.01). DAF and CD59 levels increased in all 8 patients after rEPO treatment was reinitiated (P < 0.01), and CR1 levels increased in 5 of 8 patients. Four of 12 patients showed no evidence of anemia after discontinuation of rEPO treatment. In these patients, DAF, CD59, and CR1 levels did not change before or after withholding rEPO therapy.. One of the mechanisms mediating the efficacy of EPO therapy is increased DAF and CD59 expression.

Topics: Anemia; CD55 Antigens; CD59 Antigens; Chronic Disease; Complement C3; Diabetes Mellitus; Erythrocytes; Erythropoietin; Glomerulonephritis; Humans; Middle Aged; Receptors, Complement; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Topics: Anemia; Chronic Disease; Contraindications; Darbepoetin alfa; Erythropoietin; Humans; Kidney Diseases

Decreased expression of c-MPL protein in platelets, increased expression of polycythemia rubra vera 1 (PRV-1) and nuclear factor I-B (NFIB) mRNA in granulocytes, and loss of heterozygosity on chromosome 9p (9pLOH) were described as molecular markers for myeloproliferative disorders (MPDs). To assess whether these markers are clustered in subgroups of MPDs or represent independent phenotypic variations, we simultaneously determined their status in a cohort of MPD patients. Growth of erythropoietin-independent colonies (EECs) was measured for comparison. We observed concordance between EECs and PRV-1 in MPD patients across all diagnostic subclasses, but our results indicate that EECs remain the most reliable auxiliary test for polycythemia vera (PV). In contrast, c-MPL, NFIB, and 9pLOH constitute independent variations. Interestingly, decreased c-MPL and elevated PRV-1 also were observed in patients with hereditary thrombocythemia (HT) who carry a mutation in the thrombopoietin (TPO) gene. Thus, altered c-MPL and PRV-1 expression also can arise through a molecular mechanism different from sporadic MPD.

Topics: Chronic Disease; Cohort Studies; Erythropoietin; GPI-Linked Proteins; Humans; Isoantigens; Loss of Heterozygosity; Membrane Glycoproteins; Microsatellite Repeats; Myeloproliferative Disorders; Neoplasm Proteins; NFI Transcription Factors; Proteins; Proto-Oncogene Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Thrombopoietin

The mean arterial pressure (MAP) usually serves as an expression of blood pressure in patients on chronic haemodialysis (PCHD), instead of using solely systolic or diastolic pressure. Pulse pressure (PP) has been recognized as an important correlate of mortality in PCHD. We conducted this study in order to demonstrate clinical and biochemical determinants and variability of predialysis and postdialysis MAP and PP values. A total of 136 single haemodialysis (HD) treatments in 23 subjects (PCHD, 11 male and 12 female patients) were processed during 15 months. MAP before HD was in negative correlation with haemoglobin (P<0.001) and body mass index (BMI) (P<0.001), and in positive correlation with weekly erythropoietin dosage (P=0.017). MAP after HD was in negative correlation with haemoglobin (P<0.001), ultrafiltration per HD (P=0.015), and BMI (P=0.001), and in positive correlation with weekly erythropoietin dosage (P=0.003). PP before HD was in negative correlation with parathyroid hormone (PTH) level (P=0.020), haemoglobin (P<0.001), ultrafiltration per HD (P=0.001), and years on the chronic HD treatment (P=0.001), and in positive correlation with weekly erythropoietin dosage (P<0.001) and age (P<0.001). PP after HD was in significant negative correlation with PTH (P=0.015), haemoglobin (P=0.005), ultrafiltration per HD (P<0.001), BMI (P=0.003), and in positive correlation with weekly erythropoietin dosage (P<0.001) and age (P=0.004). Multiple regression analyses unveiled the strongest and negative correlations between MAP before HD and BMI (beta=-0.37, P=0.01); MAP after HD and haemoglobin (beta=-0.36, P=0.01); PP after HD and ultrafiltration/body weight ratio (beta=-0.41, P<0.001). The strongest and positive correlation was found between PP before HD and erythropoietin dosage per week (beta=0.51, P&<0.001). In conclusion, our findings support the assumption that PP and MAP are associated with different clinical parameters. PP values have advantages as the method of blood pressure expression.

Topics: Alkaline Phosphatase; Biomarkers; Blood Pressure; Blood Proteins; Body Mass Index; Cholesterol, HDL; Chronic Disease; Diabetic Nephropathies; Erythropoietin; Female; Glomerulonephritis; Humans; Male; Phosphorus; Pyelonephritis; Regression Analysis; Renal Dialysis; Sex Factors; Statistics as Topic; Time Factors; Treatment Outcome; Ultrafiltration

Patients undergoing chronic hemodialysis have an increased risk of acquiring hepatitis B infection. Only 43-66% of dialysis patients develop effective anti-HBs titers after vaccination.. To evaluate the effect of recombinant erythropoietin (rEPO) therapy and basal hemoglobin levels on the outcome of the immune response to four doses of IM 40 microg Engerix-B vaccination in hemodialysis and chronic kidney disease (CKD) patients before starting replacement therapy.. One hundred and three patients were included in the study: 34 hemodialysis patients treated with rEPO (Group A), 36 predialytic patients who did not treated with rEPO (Group B) and 33 predialytic patients treated with rEPO (Group C). Plasma creatinine in predialytic patients was 2-7 mg/dL. All patients' HBsAg and anti-HBs antibodies were negative. Patients were immunized with IM 40 microg Engerix-B at 0, 1, 3, and 6 months. Anti-HBs titers were measured at 7th month.. Eighty seven point one percent of patients from group C developed protective anti-HBs titers compared with 69.4% from group B and 44.1% from group A (p = 0.001). Patients from all groups with baseline hemoglobin levels above 11 gr/dL developed protective anti-HBs titers significantly more than patients with baseline hemoglobin levels below 11 gr/dL (p < 0.05).. Predialytic patients treated with rEPO and with hemoglobin levels higher than 11 gr/dL had significantly better immune response outcomes to Engerix-B vaccination. Immunization against hepatitis B infection should be considered at early stages of CKD prior to the deterioration in kidney functions and the development of renal anemia.

Topics: Aged; Chronic Disease; Complement Hemolytic Activity Assay; Erythropoietin; Female; Hemoglobins; Hepatitis B Vaccines; Hepatitis C Antibodies; Humans; Immunity; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Treatment Outcome; Vaccination; Vaccines, Synthetic

We report the case of a patient with a severe chronic radiation enteropathy. She had been dependent on red cell transfusions for many years. On admission, she displayed anemia (8.6 g/dL) resulting from both inadequate EPO production and a functional iron deficiency. A 3-wk IV iron sucrose treatment (200 mg once weekly) resulted in an increased reticulocyte count, but did not raise the hemoglobin (Hb) level. The adjunction of epoetin alpha (10,000 IU three times a week) made it possible to reach the normal range (12.9 g/dL) after a 17-wk treatment. As the anti-anemic treatment discontinued, the Hb level decreased to 11.1 g/dL within 2 wk. Giving EPO again (10,000 IU twice a week) failed to maintain the Hb level, which dropped under basal values (7.8 g/dL). In contrast, a second combination EPO/iron sucrose did restore a normal Hb level and maintained it. This case report supports the combination of EPO and IV iron supplementation in patients with anemia of chronic disease and either an impaired iron absorption or intolerance to oral iron.

Topics: Anemia; Chronic Disease; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Middle Aged; Radiation Injuries; Recombinant Proteins; Reticulocyte Count

PURE RED CELL APLASIA: Designated by the acronym PRCA or the term erythroblastopenia, pure red cell aplasia is characterised by severe anaemia with reticulocytopenia. It may occur in acute form induced by infectious agents, following drug toxicity or transplantation of allogeneic haematopoietic cells, associated with autoimmune haemolytic anaemia. The chronic form is rarely constitutional but can be acquired and is usually associated with blood or idiopathic diseases. IMMUNOLOGICAL INHIBITION OF ERYTHROPOIESIS: Among the mechanisms responsible for PRCA is immunological erythropoiesis inhibition. This may be of lymphocyte T cell origin or due to the presence of antibodies in the patient's serum. Although observations of PRCA with presence of neutralising antierythropoietin antibodies in patient's serum have multiplied over the past 5 years, they still remain extremely rare. From a therapeutic point of view, they require withdrawal of epoetin and often the administration of immunosuppressors and transfusion for symptomatic treatment. GROWTH FACTORS: The role of growth factors in restoring aplastic anaemia appears to be only partial, at random and temporary.

Topics: Acute Disease; Anemia, Aplastic; Autoantibodies; Chronic Disease; Erythropoietin; Humans; Immunosuppressive Agents; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors

Rare cases of unexplained sudden severe anemia or red cell aplasia and resistance to recombinant human erythropoietin (rHuEPO) in patients with chronic renal failure (CRF) have been attributed to the development of anti-EPO antibodies. The development and validation of a radioimmunoprecipitation (RIP) assay to detect human anti-EPO antibodies in serum or plasma has been hampered by the lack of purified antibody to fully characterize and validate the assay. We have prepared an affinity-purified human antibody to EPO and used the antibody to characterize and validate a sensitive and reproducible RIP assay that can qualitatively measure anti-EPO antibody in serum or plasma samples. The lower limit of detection of the assay is 8 ng/ml of purified antibody. The threshold for detecting antibody is > or =0.9% cpm bound. The precision of the assay using purified antibody standards ranges from 5.8% to 15.3% and the precision of the assay using dilutions of the positive control ranges from 15.9% to 18.7%. EPO in the samples did not interfere with detection of the anti-EPO antibody except at high concentrations.

Topics: Antibodies; Chronic Disease; Dose-Response Relationship, Immunologic; Erythropoietin; Humans; Iodine Radioisotopes; Precipitin Tests; Recombinant Proteins; Reproducibility of Results; Sensitivity and Specificity

Recent investigation has shown that on-line hemodiafiltration (HDF) can reduce the amount of recombinant human erythropoietin (rhEPO) deemed necessary to reach the target hematocrit. The aim of this study was to analyze the potential effect of on-line HDF on rhEPO resistance in relation to iron utilization and anemia-related parameters, when compared to conventional hemodialysis (HD).. Ninety-two chronic uremic patients were treated with conventional HD and then shifted to on-line HDF. Measurements of various erythropoiesis-related parameters were collected during HD and on-line HDF periods for statistical analysis for erythropoietin resistance.. Patients treated with on-line HDF switching from conventional HD significantly contributed to the reduction of EPO dose to reach a higher mean hematocrit level (31.8 +/- 4.4% vs. 29.5 +/- 3.9%, p < 0.001) and a reduction of the serum ferritin level (322.5 +/- 268.4 vs. 544.9 +/- 642.4, p < 0.001). The median EPO/Hct ratio was greater in the HD period (504.6 +/- 310.1) than in the on-line HDF period (307.6 +/- 334.4) (p < 0.001). These results indicated a reduced EPO resistance and improved iron utilization by on-line HDF. By multiple regression analysis, the significant predictors of EPO resistance are ferritin, transferrin, albumin, and TACurea (Time average concentration of urea) in HD treatment. In on-line HDF modality, in addition to ferritin and albumin, the duration of on-line HDF is a negative predictor in EPO resistance.. When on-line HDF is recommended to chronic dialysis patients, long-term use of this technique provides an efficient means of achieving the goal of an elevated hemoglobulin by reducing EPO resistance, improved iron utilization and may further improve the quality of life.

Topics: Chronic Disease; Drug Resistance; Erythropoietin; Female; Ferritins; Hematocrit; Hemodiafiltration; Humans; Iron; Male; Middle Aged; Online Systems; Recombinant Proteins; Serum Albumin; Transferrin; Uremia

Topics: Anemia, Iron-Deficiency; Ascorbic Acid; Bacteremia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Humans; Kidney Diseases

Increased fetal plasma erythropoietin concentration is an indicator of chronic fetal hypoxia. Amniotic fluid erythropoietin levels correlate highly significantly with fetal erythropoietin levels before labor. We studied AF erythropoietin levels after fetal death in order to determine whether this could differentiate between stillbirths from acute or chronic causes.. Amniotic fluid was obtained after fetal death for erythropoietin measurement following fetal death in 21 pregnancies. Two of the pregnancies had twins, of which one infant was born alive. All 22 stillborn fetuses had an autopsy. None had malformations. Without prior knowledge of the results of the erythropoietin analyzes, the causes of fetal death were divided into acute, chronic or unknown groups.. Eight pregnancies had an acute cause of fetal death (e.g. cord complication or placental abruption), eight pregnancies had a chronic cause (intrauterine growth restriction or erythroblastosis) and in five pregnancies the cause of fetal death could not be determined. In all eight pregnancies with an acute cause of fetal death, AF erythropoietin levels were normal (< 20 mU/mL). In contrast, six of the eight pregnancies with a chronic cause had AF erythropoietin levels above normal (range from 49.9 mU/mL to 391 mU/mL). In the five pregnancies with an unknown cause of fetal death, AF erythropoietin levels were normal in three and elevated in two.. Elevated AF erythropoietin levels, identified after fetal death, suggest that the fetus died from a chronic hypoxic event, whereas normal AF erythropoietin levels suggest that the fetus died from an acute event.

Topics: Acute Disease; Amniotic Fluid; Body Temperature; Cause of Death; Chronic Disease; Erythropoietin; Female; Fetal Death; Fetal Diseases; Humans; In Vitro Techniques; Pregnancy; Time Factors

Occult infection of old nonfunctioning arteriovenous grafts (AVGs) is frequent among hemodialysis patients. It is a recognized cause of bacteremia and other infectious complications. Additionally, old nonfunctioning AVGs may be harbingers of other noninfectious complications. The aim of this study was to investigate whether occult infection of old nonfunctioning AVGs is a cause of a chronic inflammatory state in hemodialysis patients.. This study was performed in two phases: In the first phase (study 1), 22 patients with clinically proven occult infection of old nonfunctioning AVG were identified, and data on hemoglobin, weekly erythropoietin dose, and albumin levels were collected retrospectively. Comparisons were made between values obtained pre- and post-AVG resection. In the second phase (study 2), we examined whether the presence of a chronic inflammatory state is associated with occult AVG infection in old nonfunctioning AVGs. Twenty hemodialysis patients were identified with chronic inflammatory state based on erythropoietin dose (units/wk)/hematocrit ratio>470, serum albumin <3.3 g/dL, and CRP>25 mg/L. Among these patients, we found eight with old nonfunctioning AVGs. We then performed indium-labeled white blood cell (WBC) scans on the eight patients to screen for occult infection of old nonfunctioning AVGs. The AVGs with positive indium scan were resected and cultured. Data on hematocrit, erythropoietin dosing, serum albumin, ferritin, and CRP were obtained at 2 months following AVG resection and compared to pre-resection values.. In study 1, the 22 patients with occult infection of old nonfunctioning AVG exhibited profound anemia and hypoalbuminemia. Their mean hemoglobin was 9.2 +/- 1.2 g/dL which improved to 11.6 +/- 0.8 g/dL (P < 0.05) 3 months after AVG resection. Their mean serum albumin was 3.3 +/- 0.5 g/dL which improved to 3.8 +/- 0.2 g/dL (P < 0.05) 3 months after AVG resection. Their mean erythropoietin dosages (units/patient/wk) fell from 14,240 +/- 350 to 6,675 +/- 455 (P < 0.05). In study 2, among the 8 patients with chronic inflammatory state and old nonfunctioning AVG, 6 (75%) had positive indium scans and underwent surgical resection that proved bacterial infection. Upon follow-up, the 2-month data showed a remarkable improvement in the following parameters: weekly erythropoietin dose/hematocrit ratio from 622 +/- 137 to 254 +/- 28 (P < 0.05), plasma ferritin values from 690 +/- 126 ng/mL to 247 +/- 42 ng/mL (P < 0.01), and plasma CRP from 56.7 +/- 9.0 to 14.5 +/- 3.8 mg/L (P < 0.01). Serum albumin values also improved from 3.07 +/- 0.08 g/dL to 3.34 +/- 0.14 g/dL (P = 0.13). Percent plasma iron saturation did not appreciably differ from baseline (20.5% +/- 4.4% to 19.8 +/- 1.9%, P = 0.89).. Occult infection of old nonfunctioning AVG is a common cause of erythropoietin resistance and chronic inflammatory state among hemodialysis patients. Resection of old nonfunctioning AVGs with occult infection is associated with resolution of markers of chronic inflammatory state.

Topics: Algorithms; Anemia; Blood Vessel Prosthesis; Chronic Disease; Drug Resistance; Erythropoietin; Follow-Up Studies; Humans; Inflammation; Prosthesis-Related Infections; Renal Dialysis; Retrospective Studies; Time Factors

Liver dysfunction is a frequent complication that arises in the period following kidney transplantations, often resulting in death. We reported a case proving hemosiderosis as a cause of prolonged liver dysfunction after cadaveric kidney transplantation.. A 47-year-old man, who had been undergoing hemodialysis, was referred to our hospital on 2 November 1999. On the same day, cadaveric kidney transplantation was performed, and serum creatinine level reached a normal level within 2 weeks after surgery. However, serum transaminase gradually increased in the postoperative period. Serum ALT rose up to 116 IU/L on day 20 after the operation and 215 IU/L on day 30. Microscopic examination by needle biopsy revealed hemosiderosis of the liver. Recombinant human erythropoietin was administered and phlebotomy was performed. Liver function improved as a result.. Early histological diagnosis can be a useful marker in predicting the course of chronic liver disease.

Topics: Cadaver; Chronic Disease; Erythropoietin; Hemosiderosis; Humans; Kidney Transplantation; Liver Diseases; Male; Middle Aged; Recombinant Proteins

Chronic inflammation, the associated cardiovascular disease, and attendant high mortality remain huge problems in the HD population. Determining the predominant causal factors in the triggering and maintenance of this inflammatory state is of paramount importance in formulating treatment strategies for individuals and for centers. In most cases, causation is multifactorial and several different areas of the HD process need to be considered. In this respect, the water system in HD centers is certainly one parameter that demands careful design, rigorous monitoring and strict adherence to effective disinfection protocols. In this way it may be possible not only to reduce levels of inflammatory markers, but to improve performance in other clinical areas, such as EPO therapy, and perhaps outcomes in the HD population.

Topics: Acute-Phase Reaction; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Quality Control; Quality of Life; Renal Dialysis; Water; Water Purification; Water Supply

The most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span.

Topics: Age Factors; Animals; Blood Vessels; Cardiovascular Diseases; Chronic Disease; Death; Electrocardiography; Erythropoietin; Exercise Tolerance; Female; Hematocrit; Hemodynamics; Humans; Male; Mice; Mice, Transgenic; Microscopy, Electron; Models, Animal; Organ Size; Polycythemia; Sex Factors; Survival Rate

It has been suggested that calcitriol (C) could improve anemia in chronic renal failure. However it remains debatable whether vitamin D has a specific effect on erythropoiesis, or it acts via suppression of hyperparathyroidism.. We enrolled 29 patients with chronic renal failure, free from malignancies, iron deficiency or other chronic or hematological diseases. Aluminium accumulation was also excluded by DFO test. 22 were on hemodialysis and 7 on conservative management, creatinine clearance ranging 22-48 ml/min. Their mean age was 62+/-28 years and duration of renal disease was 98+/-51 months. No patient under-went rHu-Epo or Vitamin D treatment. 4 subjects were enrolled as controls. Samples of peripheral blood were drawn for the Burst Forming Unit-Erythroid (BFU-E) assay. After isolation of mononuclear cells by density gradient centrifugation with Fycoll-Hypaque, a 15-day incubation was set up with four different conditions: a) adding standard dose, 3 U/ml, of r-HuEpo (Dompè Biotec), standard colture; b) combined doses of r-HuEpo, 3 U/ml, and C (Abbott), 30 pg; c) standard dose, 3 U/ml, of r-HuEpo and high dose, 300 pg, of C; and lastly d) combined high doses of r-HuEpo, 30 U/ml, and C, 300 pg.. In the b colture (combined low doses) a higher BFU-E proliferation was found vs standard (a) colture (33.2+/-15.5 vs 17.1+/-9.2, p<0.02); interestingly, either in the c and d studies BFU-E showed an even higher proliferation (52.3+/-24 and 86.3+/-37.8 respectively, p<0.01 vs a). No difference was found when evaluating separately preterminal and hemodialysis patients. In control subjects only colture d showed an increased BFU-E proliferation.. C has a direct effect on erythroid precursors proliferation in vitro, acting in a sinergystic manner with rHuEpo. C may be useful as adjuvant therapy for renal anemia.

Topics: Calcitriol; Calcium Channel Agonists; Cell Division; Cells, Cultured; Chronic Disease; Drug Synergism; Erythroid Precursor Cells; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Uremia

This study describes the frequency and the type of anemia seen in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). We found that NI-CINA patients had low hemoglobin levels and increased serum concentrations of erythropoietin (EPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The hemoglobin levels correlated positively with the number of circulating neutrophils and inversely with the levels of EPO and TNF-alpha but not of IL-1beta. Anemia, defined as the reduction of the hemoglobin below 12.0 g/dl for women and 13.3 g/dl for men, was found in 23 out of 148 patients studied, a proportion of 15.5%. Two of the anemic patients had iron deficiency anemia (8.7%), 11 had anemia of chronic disease (ACD; 47.8%) presenting with normal or slightly reduced erythrocytic indices, low serum iron, and increased serum ferritin, and the remaining ten had anemia of undefined pathogenesis (AUP; 43.5%) with normal or slightly decreased erythrocytic indices, serum iron ranging from 43 to 88 microg/dl, and ferritin values ranging from 12 to 50 ng/ml. We conclude that ACD is the more frequent type of anemia seen in patients with NI-CINA, and that pro-inflammatory cytokines, notably TNF-alpha, may be involved in the pathogenesis of both ACD and AUP, given that serum levels of the cytokine were significantly increased and that the EPO response to anemia was blunted in these patients. These findings further support our previously reported suggestion for the possible existence, in NI-CINA patients, of an unrecognized low-grade chronic inflammatory process that may be involved in the pathogenesis of the disorder.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Interleukin-1; Iron; Male; Middle Aged; Neutropenia; Reticulocyte Count; Tumor Necrosis Factor-alpha

To evaluate the pattern of erythropoietin (EPO) and some proinflammatory cytokines in the anemia of chronic disorders (ACD) secondary to infection.. Sequential determination in serum of interleukin-1 beta (IL-1 beta), necrosis tumoral factor alpha (TNF-alpha), gamma interferon (IFN-gamma), interleukin-6 (IL-6), and erythropoietin (EPO) in 25 patients with chronic bacterial infectious diseases and ACD criteria. We evaluated the relationship of these mediators with the anemia and the iron metabolism.. Serum EPO levels significatively decreased compared with initial values, and the last control was in normal rank (18.04 +/- 19.10 vs. 8.56 +/- 4.72 UI/mL; p < 0.001; normal rank: 4-15 mUI/mL). In the first control, there was a negative and non significative correlation between the EPO levels and the hemoglobin concentration (r = -0.115, NS), reaching significance in the last control (r = -0.446; p < 0.05). There was negative correlation between the hematocrit and TNF-alpha levels (r = 0.467; p < 0.05) and between the haemoglobin values and the log of serum TNF-alpha (r = 0.424; p < 0.001). An inverse correlation between the IL-6 levels and both, the hemoglobin concentration and the serum iron was found, and there was a direct correlation between this cytokine values and the EPO levels.. Blunted response of erythropoietin and the action of TNF may contribute to the pathogenesis of ACD secondary to infection. Positive correlation between IL-6 and EPO suggest a proerythropoietic action of IL-6 in response to the anemia.

Topics: Adult; Aged; Anemia; Bacterial Infections; Chronic Disease; Cytokines; Erythropoietin; Female; Fever; Hematocrit; Hemoglobinometry; Humans; Interferon-gamma; Interleukin-1; Interleukin-6; Male; Middle Aged; Tumor Necrosis Factor-alpha

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Cytokines; Erythropoietin; Humans; Inflammatory Bowel Diseases; Intestinal Absorption; Quality of Life; Vitamin B 12 Deficiency

Long-term loss of fetal blood can occur with fetomaternal hemorrhage, vasoprevia, or placental previa. Our objective was to determine the effects of progressive fetal blood loss over 10 days on fetal plasma erythropoietin (EPO) concentration and its relationship to arterial PO(2), hematocrit, and the volume of blood loss. Late-gestation fetal sheep (n = 8) were hemorrhaged daily at a rate of 1 ml/min over 10 days. The extent of hemorrhage differed in each fetus and ranged from 30 to 80 ml/day, with the cumulative volume removed ranging from 78 to 236 ml/kg estimated fetal weight. Four fetuses served as time controls. EPO concentration measurements were by radioimmunoassay. Statistical analyses included regression, correlation, and analysis of variance. We found that EPO and arterial PO(2) were unchanged until the cumulative hemorrhage volume exceeded 20-40 ml/kg. Once this threshold was exceeded, plasma EPO concentration increased progressively throughout the study and averaged 14.3 +/- 3.2 times basal values on day 10. EPO concentration, arterial PO(2), and hematocrit changes were related curvilinearly to cumulative hemorrhage volume (P < 0.01), whereas the relationship between plasma EPO and arterial PO(2) was log linear (P < 0.001). We conclude that 1) fetal plasma EPO concentration and arterial PO(2) are insensitive to a slow, mild-to-moderate blood loss over several days; 2) unlike the rapid return of EPO to normal within 48 h after acute hemorrhage, fetal EPO concentration undergoes a progressive increase with moderate-to-severe blood loss over several days; 3) the long-term hemorrhage-induced changes in EPO are best correlated with arterial PO(2); and 4) the fetal EPO response to hemorrhage does not appear to be limited by the fetus's ability to produce EPO.

Topics: Animals; Arteries; Blood Gas Analysis; Blood Volume; Chronic Disease; Disease Models, Animal; Erythropoietin; Female; Fetomaternal Transfusion; Fetus; Hematocrit; Iron; Multivariate Analysis; Oxygen; Pregnancy; Sheep

Advanced glycation end products (AGE), growth factors, and nitric oxide contribute to alterations of the peritoneum during peritoneal dialysis (PD). These mediators are also involved in chronic uremia, a condition associated with increased permeability of serosal membranes. It is unknown whether chronic uremia per se modifies the peritoneum before PD initiation. A rat model of subtotal nephrectomy was used to measure peritoneal permeability after 3, 6, and 9 wk, in parallel with peritoneal nitric oxide synthase (NOS) isoform expression and activity and structural changes. Uremic rats were characterized by a higher peritoneal permeability for small solutes and an increased NOS activity due to the up-regulation of endothelial and neuronal NOS. The permeability changes and increased NOS activities correlated with the degree of renal failure. Focal areas of vascular proliferation and fibrosis were detected in uremic rats, in relation with a transient up-regulation of vascular endothelial growth factor and basic fibroblast growth factor, as well as vascular deposits of the AGE carboxymethyllysine and pentosidine. Correction of anemia with erythropoietin did not prevent the permeability or structural changes in uremic rats. Thus, in this rat model, uremia induces permeability and structural changes in the peritoneum, in parallel with AGE deposits and up-regulation of specific NOS isoforms and growth factors. These data suggest an independent contribution of uremia in the peritoneal changes during PD and offer a paradigm to better understand the modifications of serosal membranes in uremia.

Topics: Anemia; Animals; Chronic Disease; Creatine; Erythropoietin; Growth Substances; Kidney Failure, Chronic; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Peritoneum; Permeability; Rats; Rats, Sprague-Dawley; Reference Values; Urea; Uremia

We developed a rodent model of noninfectious systemic inflammation to examine the pathogenesis of the associated anemia of chronic disorders (ACD), to evaluate the similarity of this ACD model to human ACD, and to evaluate the potential efficacy of novel erythropoiesis stimulating protein (darbepoetin alfa) as an ACD therapy.. Lewis rats were immunized with peptidoglycan-polysaccharide polymers (PG-APS), the chronic inflammation and associated ACD were characterized, and the effects of darbepoetin alfa treatment on complete blood counts (CBC), red blood cell (RBC) indices, and iron metabolism were analyzed weekly.. Acutely inflamed rats had reduced peripheral blood (PB) RBC counts and hemoglobin (Hb) concentrations and increased reticulocyte counts. PB RBC numbers normalized during chronic inflammation, but RBC remained hypochromic and microcytic. Consequently, the rats remained chronically anemic. Anemic rats had fluctuating serum erythropoietin (EPO) concentrations, but mean EPO concentrations never varied significantly from baseline control levels. Histology of anemic rat spleen sections revealed reticuloendothelial siderosis. Total serum iron concentrations were chronically low. Peritoneal exudate cells (PEC) isolated from anemic rats and stimulated with PG-APS in vitro produced more interleukin (IL)-1alpha and interferon (IFN)-gamma, and significantly more tumor necrosis factor (TNF)-alpha and IL-10 than control cultures. Darbepoetin alfa restored Hb concentrations to baseline levels within 2 to 7 weeks, depending on dosage. A refined treatment strategy restored Hb to baseline and maintained those levels with reduced dosing.. ACD in this rodent model closely replicates human ACD. Darbepoetin alfa treatment reversed ACD in this model by increasing RBC production and RBC hemoglobinization while reducing siderosis and hypoferremia.

Topics: Anemia; Animals; Ascitic Fluid; Blood Cell Count; Chronic Disease; Disease Models, Animal; Erythrocyte Count; Erythropoietin; Female; Hemoglobins; Inflammation; Mononuclear Phagocyte System; Peptidoglycan; Polysaccharides; Rats; Rats, Inbred Lew; Reticulocyte Count; Siderosis

Mild chronic anemia following heart transplantation (HTX), with hemoglobin (Hb) values of 10-14 g/dL in men and 10-12 g/dL in women, is frequent. It has continued to be of uncertain etiology yet clinical relevance. Nonetheless, therapeutic immunosuppression has been regarded as a major cause of chronic anemia in HTX patients.. Sixty outpatients were observed over a period of 5 yr after HTX. Laboratory values related to anemia such as Hb, erythropoietin (EPO), ferritin, transferrin, iron, and vitamin levels were obtained and analyzed monthly. Patients were divided into two groups retrospectively. Patients with persistent anemia for more than 1 yr were compared with non-anemic patients.. Forty-three (72%) of the 60 patients were anemic. Anemia was normochromic, normocytic, and slightly anisocytic. Anemic and non-anemic patients showed EPO levels within the expected range as defined by Erslev (Erythropoietin. N Engl J Med 1991: 324: 1339). Reticulocyte counts were found to be normal in all patients. Iron deficiency and deficiency of vitamin B12 or folic acid were not observed. Patients with persistent anemia showed a significantly shorter survival period than non-anemic patients (p<0.02).. Mild anemia following HTX shows the same characteristics as anemia in chronic diseases. Persisting mild anemia used to be associated with a shorter life expectancy. There is no evidence that standard immunosuppression causes anemia.

Topics: Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Ferritins; Heart Transplantation; Hemoglobins; Humans; Iron; Male; Middle Aged; Retrospective Studies; Risk Factors; Statistics, Nonparametric; Survival Analysis; Transferrin; Vitamins

The regulation of transferrin receptor (RTF) is related to intracellular iron stores and with the soluble receptor is present in plasma. It has already been demonstrated that in iron deficiency anemia (IDA), receptor expression increases when iron stores decrease. In anemia of chronic diseases (ACD) it is difficult to establish the real iron status because of the influence exerted by inflammatory or infectious diseases on iron metabolism. We studied 30 healthy normal subjects and 42 anemic patients (hemoglobin less than 120 g/L) affected with ACD divided into two groups with and without iron deficiency, in order to establish the diagnostic value of measuring the soluble transferrin receptor (sRTF). We correlated erythropoietin (EPO) (as an erythropoietic stimulating factor) with the decreased hemoglobin values observed in both groups. The results were analysed with an ANOVA statistic test of one way analysis of variance, and there were no significant differences in sRTF values between the ACD groups with or without iron deficiency. The ratio log EPO vs hemoglobin showed a remarkably significant inverse correlation in both groups. We can conclude that sRTF levels are within the normal reference values in these patients and are not related to organic iron. Consequently, sRTF cannot be considered a good parameter for making a diagnosis of iron deficiency in chronic diseases.

Topics: Adult; Aged; Analysis of Variance; Anemia; Anemia, Iron-Deficiency; Biomarkers; Chronic Disease; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Male; Middle Aged; Receptors, Transferrin

The aim of the work has to assess the effects of L-carnitine therapy on erythropoiesis and whole blood platelet aggregation. The studies were performed in 28 patients divided into 3 groups: I-group was given erythropoietin, II-group was given erythropoietin and L-carnitine, III-group was given L-carnitine. After 22 month of the therapy a statistically significant rise in hematocrit was observed in group III, improvement in muscle strength, a rise in free and total carnitine concentration was found in group II and III. There were no significant changes in urea concentration, platelet count and iron metabolism. Whole blood platelet aggregation induced by ADP, collagen and ristocetin was impaired relative to healthy volunteers. After 2 month of L-carnitine treatment of significant rise in collagen induced platelet aggregation was observed in group II.

Topics: Adult; Carnitine; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Platelet Aggregation; Renal Dialysis; Renal Insufficiency

Topics: Adult; Anemia; Blood Transfusion; Chronic Disease; Delayed-Action Preparations; Epidermolysis Bullosa Dystrophica; Erythropoietin; Female; Ferrous Compounds; Folic Acid; Hematinics; Humans; Recombinant Proteins

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Recombinant Proteins; Uremia

The impairment of function of human T lymphocytes, leading to an inappropriate cytokine production, is partially responsible for defective immunological response in hemodialysis patients (HD). Recent data suggest that recombinant human erythropoietin (rhEPO) may exert immunological effects. The aim of this study was to find out whether rhEPO treatment of the HD patients may have an effect on the interleukin 2 (IL-2) production by their whole blood cell cultures. The study was carried out in 10 HD patients receiving rhEPO for 6 months. Compared with the levels seen before the treatment, the concentration of IL-2 increased in the phytohemagglutinin-stimulated whole blood cell cultures of 7 of 10 patients under study. Addition of rhEPO in vitro to the whole blood cell cultures of the HD patients before implementation of erythropoietin confirmed that rhEPO is able to directly stimulate IL-2 production. Our studies show that the therapy with rhEPO affects IL-2 secretion.

Topics: Adjuvants, Immunologic; Adult; Blood Cells; Cells, Cultured; Chromogenic Compounds; Chronic Disease; Colorimetry; Coloring Agents; Erythropoietin; Female; Glomerulonephritis; Humans; Interleukin-2; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Phytohemagglutinins; Recombinant Proteins; Renal Dialysis; T-Lymphocytes; Tetrazolium Salts; Thiazoles

In the present study, the relationship between the blood erythropoietin level and cardiac function was investigated in 15 patients on chronic hemodialysis who developed chronic heart failure. Another 45 patients without cardiac dysfunction were selected as a control group that was matched for gender, age, and the duration of dialysis. The erythropoietin level was 256.3 +/- 481.8 mU/ml in the heart failure group, which was significantly higher than that in the control group (17.0 +/- 10.0 mU/ml, P < 0.01). Eight of the 15 patients in the heart failure group maintained a hematocrit of more than 30% without receiving recombinant human erythropoietin therapy, whereas 29 of the 45 patients in the control group required erythropoietin. In the heart failure group, the erythropoietin level was significantly correlated with the levels of atrial natriuretic peptide and brain natriuretic peptide (P < 0.01). These results suggest that heart failure can increase the erythropoietin level in proportion to the severity of cardiac dysfunction, even in patients on long-term dialysis.

Topics: Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Dialysis

To determine if umbilical cord plasma erythropoietin (EPO) levels in combination with cord blood gases and Apgar scores can distinguish between subacute and chronic uteroplacental insufficiency.. A total of 184 neonates delivered between 1993 and 1997 at Tampa General Hospital were studied. Cord plasma EPO levels, cord blood gases, and Apgar scores were determined prospectively and compared in four subgroups that were defined based on the presence or absence of fetal growth restriction (FGR; chronic fetal hypoxia), abnormal fetal heart rate tracings during labor (FHR; subacute/acute fetal hypoxia), or both.. Both growth-restricted and appropriately grown newborns with abnormal intrapartum FHR tracing had elevated umbilical cord plasma EPO (183.5 and 135.2 mIU/ml, respectively; normal = 20.7 mIU/ml) and base deficit, whereas pH, Po2, and 1-minute and 5-minute Apgar scores were significantly lower, compared with appropriately grown newborns with a normal intrapartum course. Among newborns with normal heart rate tracings and FGR, the mean plasma EPO levels were elevated (89.5 mIU/ml), whereas the other parameters were not different from normal.. Our findings suggest that, although cord blood gases and Apgar scores may reflect subacute and acute events, they are not good predictors of chronic uteroplacental insufficiency. The supplemental use of umbilical cord plasma EPO levels may improve our ability to identify chronic uteroplacental insufficiency.

Topics: Apgar Score; Blood Gas Analysis; Chronic Disease; Erythropoietin; Female; Fetal Blood; Fetal Growth Retardation; Heart Rate, Fetal; Humans; Infant, Newborn; Placental Insufficiency; Pregnancy

We examined erythropoietin (EPO) gene expression and EPO production during hypoxia in two Sprague-Dawley rat strains with divergent polycythemic responses to hypoxia. Hilltop (H) rats develop severe polycythemia, severe hypoxemia, and pulmonary artery hypertension. The H rats often die from a syndrome indistinguishable from chronic mountain sickness (CMS) in humans. Madison (M) rats develop polycythemia and pulmonary artery hypertension that is modest and suffer no excess mortality. We tested the hypothesis that these rat strains have different stimulus-response characteristics governing EPO production. Rats of each strain were exposed to hypoxia (0.5 atm, 73 Torr inspired PO2), and renal tissue EPO mRNA and EPO levels, plasma EPO, ventilation, arterial and renal venous blood gases, and indexes of renal function were measured at fixed times during a 30-day hypoxic exposure. During extended hypoxic exposure, H rats had significantly elevated renal EPO mRNA, renal EPO, and plasma EPO levels compared with M rats. Ventilatory responses and indexes of renal function were similar in the strains during the hypoxic exposure. H rats had greater arterial hypoxemia from the onset of hypoxia and more severe renal tissue hypoxemia and greater polycythemia after 14 days of hypoxic exposure. When EPO responses were expressed as functions of renal venous PO2, the two strains appeared to lie on the same dose-response curves, but the responses of H rats were shifted along the curve toward more hypoxic values. We conclude that H rats have significantly greater polycythemia secondary to poorer renal tissue oxygenation, but the stimulus-response characteristics governing EPO gene expression and EPO production do not seem to differ between M and H rats. Finally, the regulation of EPO levels during hypoxia occurs primarily at the transcriptional level.

Topics: Altitude Sickness; Animals; Blood Gas Analysis; Blotting, Northern; Chronic Disease; Cobalt; Erythropoietin; Feedback; Gene Expression Regulation; Hypoxia; Kidney; Kidney Function Tests; Male; Polycythemia; Rats; Rats, Sprague-Dawley; Ribonucleases

To determinate the erythropoietin concentration in amniotic fluid in normal pregnancies and pregnancies with suspected hypoxia.. The erythropoietin concentration of 164 samples of amniotic fluid was determined by ELISA. The samples were taken by amniotomy during birth, as well as amniocentesis conducted during prenatal care.. A distribution of 1.07-7.29 U/l (10th-90th percentile) within the normal group (n = 106) was determined. Significantly elevated erythropoietin levels in amniotic fluid were determined in maternal hypertension (P = 0.039) and low birth-weight children (P = 0.0032). A correlation with the child's sex could be excluded.. Elevated erythropoietin levels in amniotic fluid indicated chronic fetal hypoxia.

Topics: Adolescent; Adult; Amniotic Fluid; Biomarkers; Chronic Disease; Erythropoietin; Female; Fetal Hypoxia; Humans; Pregnancy; Prenatal Diagnosis; Risk Factors

Augmented endogenous nitric oxide (NO) production may ameliorate derangement of renal functions or glomerular damage in polycythemia. To investigate this possibility, we examined the effect of NO synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME; 50 mg/dl in drinking water) on renal functions and histology in heminephrectomized Sprague-Dawley rats treated for 4 weeks with recombinant human erythropoietin (rh-EP; 500 IU/kg on alternate days). L-NAME elevated the blood pressure which was aggravated by concomitant rh-EP and was ameliorated by treatment with a nonpeptide angiotensin type 1 receptor blocker (CV116; 60 mg/kg in chow). The hematocrit level was prominently increased by rh-EP. The glomerular filtration rate was impaired by L-NAME alone, but was maintained by concomitant administration of rh-EP or CV116. Micropuncture experiments revealed that the glomerular capillary pressure was similarly elevated by L-NAME alone or in combination with rh-EP. L-NAME significantly, although not prominently, aggravated glomerular sclerosis observed with rh-EP alone, and concomitant CV116 ameliorated the glomerular damage. These results suggest that, in polycythemia, enhanced NO production buffers the glomerular damage, and the balance between NO and angiotensin II may play an important role in maintaining renal function and glomerular structure.

Topics: Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Chronic Disease; Enzyme Inhibitors; Erythropoietin; Follow-Up Studies; Glomerular Filtration Rate; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Polycythemia; Prodrugs; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tetrazoles

Topics: Adult; Chronic Disease; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Recombinant Proteins; Renal Dialysis; Time Factors

The clinical relevance of mild chronic anemia in patients after heart transplantation (HTX) has not yet been demonstrated. Forty-five outpatients who had undergone HTX 2-99 months prior to investigation and who had not received blood transfusions or erythropoietin (EPO) before data acquisition were observed over a period of 37 months. Anemia was found in 36 of the 45 patients and was normocytic, normochromic, and slightly anisocytotic (coefficient of variation = 16 +/- 2, normal 11.5-14.5). Anemic patients showed elevated EPO levels, whereas in nonanemic patients EPO levels were normal. Survival after HTX differed significantly in anemic and nonanemic patients (P < 0.02), with 100% survival in the nonanemic and 85% in the anemic group. Chronic anemia in patients after HTX shows a typical pattern. Even when mild, anemia in patients after HTX seems to be of prognostic value and thus might be an indicator of chronic disorders.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Female; Heart Transplantation; Hematocrit; Humans; Iron; Male; Middle Aged; Morbidity; Prognosis; Survival Rate

Topics: Beverages; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Glomerulonephritis; Humans; Middle Aged; Polycythemia; Renal Dialysis; Vegetables

Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) play an important role in decreased erythropoiesis in patients with anemia of chronic disease (ACD) and rheumatoid arthritis (RA). Modulation of quantities of bone marrow erythroid progenitors during chronic inflammation may be one of the pathogenetic mechanisms leading to ACD. We studied bone marrow from patients with ACD with RA by investigating, first, local production of inflammatory cytokines in the bone marrow, and second, the relative fraction of late erythroid progenitors (erythropoietin and transferrin receptor positive cells; EpoR+ TrfR+) in bone marrow. In addition, the effects of TNF-alpha on EpoR+ TrfR+ cells were studied in vitro.. Levels of IL-6 and TNF-alpha were measured by EL ELISA in supernatant of bone marrow and peripheral blood cultures from 14 patients with RA and ACD and 14 patients with RA without anemia. The numbers of EpoR+ TrfR+ cells in bone marrow samples of both groups were assessed by 2 color fluorescence flow cytometry.. Levels of IL-6 and TNF-alpha were significantly higher in the supernatant of bone marrow cultures of patients with ACD compared to controls. No significant differences in the fraction of EpoR+ TrfR+ cells in samples was observed between the 2 groups of patients. Incubation of the samples with TNF-alpha did not result in modulation of the number of EpoR+ TrfR+ cells.. Local production of proinflammatory cytokines in the bone marrow may be associated with the development of ACD in RA.

Topics: Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Bone Marrow; Cells, Cultured; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Erythroblasts; Erythropoietin; Female; Flow Cytometry; Humans; Interleukin-6; Male; Middle Aged; Receptors, Transferrin; Tumor Necrosis Factor-alpha

To define the etiology of anemia post-renal transplantation, we assessed hematologic parameters and EPO levels in 38 anemic and 16 non-anemic control renal transplant recipients (RTRs) with varying degrees of allograft function at periods > 3 months post-transplantation. Significant differences between the two groups were found for serum creatinine (Cr) 291.7 +/- 26.5 vs. 203.3 +/- 26.5 mumol/l, p < 0.01; iron 9.3 +/- 0.92 vs. 13.6 +/- 1.7 mumol/l, p < 0.05; and ferritin 345.5 +/- 90.8 vs. 91.1 +/- 18.5 micrograms/l, p < 0.01. Serum EPO levels were inappropriately low in anemic patients with no significant correlation between EPO and Cr or hematocrit (Hct) levels. Serum iron was the only predictive factor for anemia on regression analysis (p < 0.05). Ferritin levels did not correlate with serum iron or Hct, and may be falsely elevated in iron deficient RTRs. Iron deficiency, poor renal function and inappropriately low EPO levels are major contributors to the 12% of our outpatient renal transplant population who are anemic.

Topics: Anemia; Anemia, Iron-Deficiency; Blood Urea Nitrogen; Chronic Disease; Creatinine; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Follow-Up Studies; Forecasting; Graft Rejection; Hematocrit; Humans; Iron; Iron Deficiencies; Kidney Transplantation; Male; Middle Aged; Regression Analysis; Reticulocyte Count; Transplantation, Homologous

Erythropoietin secretion was evaluated in the anaemia of chronic disorders in elderly patients, since it has been shown that this secretion is impaired in adults. We looked for a possible role of inflammatory cytokines: tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) on erythropoietin production. The influence of nutritional status on the anaemia was also investigated. Erythropoietin secretion was significantly increased in elderly patients with anaemia of chronic disorders (ACD) and inversely correlated with haemoglobin concentrations in infectious and inflammatory diseases. Plasma TNF alpha levels were significantly enhanced only in cancerous patients, but no correlation could be established between TNF alpha and erythropoietin or haemoglobin. No noticeable increase of IL-1 beta levels was observed in ACD. These findings suggest that systemic TNF alpha or IL-1 beta are not involved in the erythropoietin response to ACD. Albumin levels were decreased in anaemic patients. Further investigations of the effects of a nutritional supplementation in elderly patients with ACD may be of interest.

Topics: Aged; Aged, 80 and over; Aging; Anemia; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Interleukin-1; Male; Serum Albumin; Tumor Necrosis Factor-alpha

An 11-year-old castrated male Dachshund was determined to have pancytopenia on the basis of results of CBC and bone marrow cytologic examination. Pancytopenia was believed to have resulted from administration of captopril, which had been administered for treatment of chronic mitral insufficiency, because other causes of pancytopenia were not found. Treatment consisted of discontinuing captopril and stimulating the bone marrow with recombinant human erythropoietin and granulocyte colony-stimulating factor. Although neutralizing antibodies will develop against the heterologous human protein, recombinant human granulocyte colony-stimulating factor should be considered for short-term treatment of neutropenias associated with adverse drug reactions, canine parvovirus infections, and bone marrow suppression from primary bone marrow disease, cancer chemotherapy, or total body irradiation before bone marrow transplantation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biopsy, Needle; Blood Cell Count; Bone Marrow; Captopril; Chronic Disease; Dog Diseases; Dogs; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematocrit; Male; Mitral Valve Insufficiency; Pancytopenia; Recombinant Proteins

Topics: Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Inflammatory Bowel Diseases; Iron; Recombinant Proteins

To investigate the effects of desferrioxamine (DFO) infusion on chronic disease anemia (CDA) of rheumatoid arthritis (RA) by evaluating interleukin-6 (IL-6) and erythropoietin (EPO) production.. Five patients with RA and CDA (group I) were treated with DFO, 500 mg daily, through a continuous 10-h subcutaneous infusion 5 days a week for 4 weeks. One month after withdrawal, DFO was resumed in all five group I patients (group II) with an increase to 1 g daily following the previous treatment schedule. Clinical and laboratory parameters were evaluated weekly during the two study periods. Serum EPO was measured by radioimmunoassay. IL-6 was detected by the enzyme-linked immunoabsorbent assay method.. No significant variations in hematological parameters, IL-6 or EPO levels were observed in group I patients. After 1 week of DFO 1 g daily, reticulocyte counts and EPO improved significantly. Hemoglobin and hematocrit rose significantly after 3 weeks of 1 g daily DFO therapy. Four weeks after DFO withdrawal, EPO, reticulocyte counts, hemoglobin and hematocrit returned to baseline levels. A significant improvement in the clinical parameters of disease activity was observed, particularly in group II patients.. DFO improves CDA in RA patients. The beneficial effects on erythropoiesis seem to be related to improved EPO responsiveness to the anemia.

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Deferoxamine; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Infusions, Parenteral; Interleukin-6; Iron; Male; Middle Aged; Siderophores; Treatment Outcome

In order to better understand the mechanisms affecting erythropoietin (Epo) synthesis and red cell mass increase under chronic hypoxia, we examined Epo production and erythroid progenitors (CFU-E) in rats exposed to normobaric hypoxia for four weeks. Hypoxia induced the rise of hematocrit (Htc), hemoglobin (Hb) concentration and the red blood cell (RBC) number with a plateau in hematocrit values after two weeks. After 24 h of hypoxia, Epo levels were increased 20 fold, followed by a significant decrease. After the first week of hypoxia, the values were still higher than in the controls, but after two weeks Epo levels did not differ significantly from the normal values. The fall of Epo levels coincided with the plateau values of hematocrit. The changes in the CFU-E number followed the changes in Epo concentration: a two fold increase after 24 h of hypoxia; a further increase during the next two weeks reaching a peak on day 14, and then a progressive decrease at the time when Epo concentration was at a normal level. Although decreased, but still higher than normal, the CFU-E number during the last two weeks of hypoxia could be necessary for the maintenance of an achieved steady state under persistent hypoxic conditions with normal Epo concentration sufficient to maintain the existing rate of erythropoiesis.

Topics: Animals; Cell Hypoxia; Chronic Disease; Erythroid Precursor Cells; Erythropoietin; Female; Rats; Rats, Wistar

Topics: Anemia, Refractory; Blood Transfusion; Chronic Disease; Combined Modality Therapy; Erythropoietin; Hepatitis C; Humans; Male; Middle Aged; Pancytopenia; Recombinant Proteins; Recurrence; Remission Induction; Splenectomy

Topics: Adult; Anemia, Sickle Cell; Cell Adhesion; Chronic Disease; Endothelium, Vascular; Erythrocytes; Erythropoietin; Female; Hemoglobins; Humans; Hydroxyurea; Microcirculation; Pain; Pain Management

Topics: Anemia; Chronic Disease; Elective Surgical Procedures; Erythropoietin; Humans; Inflammation; Neoplasms; Preoperative Care; Recombinant Proteins

Topics: Chronic Disease; Erythropoietin; Humans; Liver Diseases; Recombinant Proteins; Thrombocytopenia

To assess the risk for acute and chronic fetal hypoxia in twin pregnancies.. We investigated 50 sets of twins (24-38 weeks' gestation, 660-3200 g birth weight) admitted consecutively to our neonatal intensive care unit. Seventy-six infants were appropriate for gestational age (AGA; tenth to 90th percentile), 20 were small for gestational age (SGA; below the tenth percentile), and four were large for gestational age (above the 90th percentile). Twenty-six singleton AGA term newborns served as controls. Umbilical arterial pH was used as a marker for acute and umbilical venous erythropoietin concentration for chronic fetal hypoxia. The results are given as median followed by quartiles.. We identified 40 sets of diamniotic-dichorionic twins and ten sets of diamniotic-monochorionic twins with transplacental vascular shunts. In the second-born twin, umbilical arterial pH was lower (7.29, 7.23-7.33) than in the firstborn (7.31, 7.25-7.34) (P = .03), and the incidence of a low pH (less than 7.20) was higher (19 versus 11%). Two second-born twins and none of the firstborn twins had an umbilical arterial pH less than 7.05. In SGA twins, the erythropoietin concentration was elevated (34.8, 22.8-325 mU/mL) compared with that in AGA twins (16.2, 8.2-26.6 mU/mL) (P < .01). In AGA twins, erythropoietin concentration did not differ from that in AGA singleton newborns (19.6, 14.7-31.6 mU/mL). In 12 of 17 twin sets with weight discordancy greater than 15% and in all five twin sets with weight difference greater than 25%, erythropoietin concentration was higher in the smaller twin. The proportion of infants and of complete sets with elevated erythropoietin levels was higher (P < .01) in monochorionic than in dichorionic pregnancies.. The second-born twin is at increased risk for acute birth asphyxia. Fetal growth restriction in twin pregnancies is associated with chronic fetal hypoxia. Monochorionic twins are at higher risk for chronic fetal hypoxia than are dichorionic twins.

Topics: Acute Disease; Chronic Disease; Erythropoietin; Fetal Hypoxia; Humans; Infant, Newborn; Infant, Newborn, Diseases; Risk Factors; Twins, Dizygotic; Twins, Monozygotic

Chronic anemia is frequently observed in patients affected by cirrhosis. To investigate the possible role of erythropoietin (Epo) in the pathogenesis of anemia in cirrhosis, we measured the immunoreactive Epo levels and the respective hemoglobin (Hb) concentrations in 48 anemic and nonanemic cirrhotic patients and in a control group of healthy subjects and patients with iron-deficiency anemia. Epo concentrations were determined in serum using a sensitive enzyme immunoassay. The regression curve between Epo values and Hb concentrations showed a significant inverse exponential trend both in cirrhotic patients (r = -.55; P < .0001) and controls (r = -.92; P < .0001). In a semilogarithmic plot, the line slope obtained in cirrhotic patients was significantly lower (P < .005) than that of controls, suggesting a blunt Epo response to anemia in cirrhosis. Moreover, covariance analysis showed that the Epo levels for a given degree of anemia were further reduced in the patients with a more severe disease, suggesting a close relation between cirrhosis and the mechanisms involved in the derangement of the Epo feedback system. Finally, the Epo concentrations measured in the cirrhotic patients without anemia did not significantly differ from Epo values obtained in healthy subjects. An impaired Epo response may play a role in maintaining low Hb concentrations in cirrhotic patients with anemia. However, the evidence of a residual Epo response to anemia in cirrhosis and the presence of normal basal Epo levels in nonanemic cirrhotic patients do not support an inadequate Epo secretion as one of the primary causes of anemia in cirrhosis.

Topics: Adult; Aged; Anemia; Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Feedback; Female; Hemoglobins; Humans; Liver Cirrhosis; Male; Middle Aged; Regression Analysis

We previously found that augmentation of polycythemia by exogenous human recombinant erythropoietin (EPO) failed to worsen the severity of hypoxic pulmonary hypertension in rats. We asked whether this unexpected finding was related to reductions in cardiac output, left ventricular end-diastolic pressure, pulmonary vascular resistance, or some combination of these factors. Four groups of Sprague-Dawley rats were studied over a 3-wk period: hypoxic (0.5 ATM) and normoxic animals each injected with EPO (500 U/kg sc thrice weekly) or saline (control animals). As observed previously, we found that pulmonary arterial (PA) pressures and right ventricular hypertrophy were not increased in EPO-treated rats despite significant increases in hematocrit and blood viscosity. Cardiac outputs, blood volumes, and left ventricular end-diastolic pressures were similar in EPO-treated and control rats. Acute PA pressure responses to acute normoxia in hypoxic rats and to acute hypoxia in normoxic rats were similar, suggesting no differences in vasoreactivity. However, lungs isolated from EPO-treated hypoxic rats had lower pulmonary vascular resistance than saline-treated hypoxic rats when perfused with blood from normocythemic donor rats. PA medial thickness and the percentage of muscularized small PAs were significantly lower in EPO-treated hypoxic rats. These results indicate that augmented polycythemia fails to worsen hypoxic pulmonary hypertension in rats because of a decrease in the severity of structural remodeling.

Topics: Adaptation, Physiological; Animals; Blood Pressure; Blood Vessels; Blood Viscosity; Chronic Disease; Erythropoietin; Hematocrit; Hemodynamics; Humans; Hypoxia; Male; Polycythemia; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Endogenous erythropoietin (EPO) secretion can still be modulated in patients with end-stage renal failure but only in response to strong stimuli. Thus even anephric dialysis patients are able to increase EPO production acutely when exposed to a marked hypoxic stimulus. The present study was designed to test the hypothesis that a decrease of plasma calcium or the administration of various antihypertensive agents might be able to induce acute changes of plasma EPO concentration. Four groups of chronic hemodialysis patients were studied. Eight patients volunteered for the induction of an acute, transient hypocalcemia via a calcium-free dialysate during the initial 60 min of a regular dialysis session of 240 min. Plasma immunoreactive (i) EPO, total calcium, and intact parathyroid hormone (iPTH1-84), as well as blood ionized calcium and blood gases were measured before as well as 30, 60, 120 and 240 min after the start of dialysis. In addition, plasma iEPO was measured 48 h after the session. Patients of group 2 (n = 6), group 3 (n = 6), and group 4 (n = 7) received the day after a hemodialysis session a single dose of either acetazolamide, furosemide, or enalapril, respectively, and their plasma iEPO was determined before and 3, 6 and/or 24 h after drug administration. In group 1, plasma total calcium decreased from 2.39 +/- 0.07 mM (mean +/- SEM) to 1.98 +/- 0.02 and 1.83 +/- 0.03 mM after 30 and 60 min of dialysis, respectively, and blood ionized calcium from 1.28 +/- 0.04 to 1.02 +/- 0.03 and 0.92 +/- 0.04 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Antihypertensive Agents; Calcium; Chronic Disease; Dialysis Solutions; Erythropoietin; Female; Humans; Hypocalcemia; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Uremia

Angiotensin-converting enzyme (ACE) inhibitor therapy has recently been shown to be effective in the treatment of post-renal transplant erythrocytosis (PTE). In an attempt to assess the effect of drug treatment on serum erythropoietin level, glomerular filtration rate, and urinary protein excretion, we prospectively evaluated 8 consecutive cadaveric renal transplant recipients with PTE treated with ACE inhibitor therapy for 3 months. In response to ACE inhibition, the mean hematocrit (HCT) value decreased from 53.7 +/- 0.6% before treatment to 42.7 +/- 2.2% at the conclusion of the study (p = 0.03). However, 1 patient failed to respond to ACE inhibition (HCT > 50%), and 2 patients with PTE developed anemia (HCT < 35%) while maintained on drug treatment. Although the mean serum erythropoietin level decreased during ACE inhibition (from 22.8 +/- 8.4 to 9.4 +/- 5.3 mU/ml; p = 0.06), a consistent change in individual erythropoietin levels was not identified. At the conclusion of the study, the serum erythropoietin levels were undetectable in 4 patients, decreased in 1, unchanged in 2, and increased in the only patient with PTE who failed to respond to drug treatment. All patients tolerated the ACE inhibitor therapy without developing cough or hyperkalemia. In addition, serum creatinine levels, 125I-iothalamate clearances, and mean arterial blood pressures were unchanged throughout the study. Microalbuminuria (spot urinary albumin/creatinine ratio between 30 and 200 mg/g) developed in 5 patients with PTE and coincided with the onset of erythrocytosis (25.2 +/- 7 mg/g before PTE and 76.3 +/- 36.7 mg/g at the time of PTE detection).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Contrast Media; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Iodine Radioisotopes; Iothalamic Acid; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polycythemia; Prospective Studies

In 69 patients on chronic haemodialysis, blood sampled randomly during dialysis was analyzed for carboxyhaemoglobin (COHb). The median value was 1.40% (range 0.9-2.3) in non-smoking patients and (1.4-7.5) in smokers. In non-smokers treated with erythropoietin (EPO) correlation was found between COHb and the weekly EPO dose (r = 0.57, p = 0.007). In smoking patients not given EPO, the COHb correlated well with the number of cigarettes smoked (r = 0.84, p = 0.003). The COHb values did not correlate to the haemoglobin values. It is concluded that COHb levels in uraemic non-smokers are elevated because of increased endogenous CO production from the enhanced erythrocyte turnover. As even low COHb levels may negatively influence the oxygen status of the uraemic patient, the addition of exogenous CO from cigarette smoking should be avoided.

Topics: Adult; Aged; Carbon Monoxide; Chronic Disease; Erythropoietin; Female; Humans; Longitudinal Studies; Male; Middle Aged; Renal Dialysis; Smoking; Uremia

The most common cause of limited response to recombinant human erythropoietin (r-HuEPO) is unrecognized, mild-to-moderate iron deficiency, either at the start of treatment or secondary to enhanced iron utilization by newly formed erythrocytes. Iron stores in patients with chronic renal failure (CRF) are often depleted through gastrointestinal bleeding, blood loss during haemodialysis, and blood sampling. Mobilization of iron stores may be inadequate, especially during rapid haemoglobin regeneration. Aluminium overload may also interfere with gastrointestinal and cellular iron uptake. Overt or unrecognized infection or inflammation is another common cause of hyporesponsiveness, and is a consequence of increased blood concentrations of cytokines such as tumour necrosis factor (TNF), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma), which suppress erythrocyte stem-cell proliferation. Less common causes include severe secondary hyperparathyroidism and myeloma (during chemotherapy). Response to r-HuEPO can be best predicted by baseline fibrinogen (a marker of subclinical inflammation); baseline transferrin receptor (sTfR) concentrations (a marker of functional iron deficiency); and sTfR increment after 2 weeks (a marker of early change in erythropoietic activity).

Topics: Aluminum; Anemia; Chronic Disease; Drug Interactions; Erythropoietin; Humans; Immune Tolerance; Iron Deficiencies; Recombinant Proteins; Sepsis

The role of erythropoietin in the pathogenesis of anaemia associated with inflammatory disorders is unclear. We studied serum erythropoietin levels in patients with inflammatory process of varying aetiologies. Serum erythropoietin levels and reticulocyte counts were prospectively measured in 40 patients with inflammatory syndromes and compared with values obtained in 20 patients with myelodysplastic syndromes. Significant inverse correlation between erythropoietin levels and haemoglobin concentration were noted in the 2 groups. The slope of the regression line for patients with inflammatory disorders was lower as compared with that for the myelodysplastic syndromes. In all cases, when the erythropoietin response in relation to degree of anaemia is compared with that which occurs in patients with myelodysplastic syndromes, the inadequate erythropoietin response in patients with chronic inflammatory process becomes evident. In patients with inflammatory process, a relationship between erythropoietin levels and reticulocyte counts were only noted in patients with mildly anaemia (haemoglobin concentration higher than 10.5 g/dl). This study suggests blunted erythropoietin production and impaired marrow response to this hormone in the anaemia which occurs in inflammatory syndromes and supports the hypothesis that these disorders may contribute to the development of the anaemia associated with inflammatory disorders.

Topics: Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Reticulocyte Count

Since renal allograft rejection is frequently associated with a blunted erythropoiesis, we investigated erythropoietin (EPO) serum concentrations in 17 patients with acute rejection, eight patients with chronic rejection, and 18 transplant recipients with stable graft function. All rejection episodes were proven by biopsy. Erythropoietin serum levels were significantly reduced in patients with chronic rejection (6.2 +/- 3.4 mU/mL; P < 0.01) compared with individuals with acute rejection (35.6 +/- 33.9 mU/mL) or stable graft function (24.0 +/- 19.7 mU/mL). Suppressed EPO levels were associated with marked anemia in chronic rejection patients. In a subgroup of patients with acute rejection and bad responses to an intensified immunosuppressive regimen or with transplant failure, we found significantly suppressed EPO levels (11.6 +/- 6.1 mU/mL) compared with a subgroup of patients with a beneficial acute rejection outcome (57.0 +/- 34.2 mU/mL; P < 0.01). A correlation between histologic parameters of acute rejection and hormone levels showed that signs of moderate glomerulitis were associated with elevated EPO levels, whereas lesions of moderate tubulitis were associated with low values. We conclude that serum EPO may have prognostic value for rejection outcome in renal transplant recipients.

Topics: Acute Disease; Anemia; Biopsy; Chronic Disease; Erythropoietin; Female; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; Prognosis

The aim of our study was to evaluate cardiovascular function at rest and during exercise in dialysis patients before and after treatment with Epo and to examine the changes in left ventricular mass as the consequence of treatment for anaemia. We applied echocardiography and radionuclide ventriculography at rest and after exercise in our research. Following treatment with Epo there was a decrease in the initially high cardiac output (CO) and cardiac index (CI) from 7.5 to 6.31/min and from 4.3 to 3.61/min/m2 respectively. No changes were noted in mean diastolic (DPB) and mean blood pressure (MBP), as well as the initially increased peripheral resistance index (TPRi) of 2582.3 +/- 2097.3 dyn-s-cm-5.m2. Nevertheless, end-diastolic (EDV) and end-systolic (ESV) volume were significantly decreased (P < 0.05), but the ejection fraction (EF) remained unchanged (73.9%). The decrease in the mean values for left ventricular mass (LVM) was significant only within the subgroup of dialysed patients who initially had larger left ventricular mass (P < 0.01). The functional capacity of the CV system measured during exercise increased from four metabolic equivalents (METs) to 6 METs (P < 0.01). A significant increase in blood volume was also observed following treatment of anaemia. The haemodynamic consequences of Epo therapy for the treatment of anaemia were quite positive. However, we would like to point out certain concerns regarding the dialysed patients with initially lower values for left ventricular mass and cardiac output, since the patients within this group developed left ventricular hypertrophy and an increase in cardiac output.

Topics: Adult; Anemia; Chronic Disease; Echocardiography; Erythropoietin; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Radionuclide Ventriculography; Renal Dialysis

Plasma lipid disturbances are common among patients on maintenance haemodialysis and it seems to be important to evalate lipid status on r-Epo since this treatment of anemia is becoming substantial and so often used in that population. It appears more valuable because there are controversial data in the literature concerning this problem. The aim of the present study was to measure changes in serum lipid concentration in two comparable groups: I--11 patients (7f, 4m) aged 47 +/- 8 years receiving r-Epo s.c. during at least 6 months before HD and 2 years of HD with initial dose 3 x 50 u/kg b.w. and II--18 patients (7f, 11m) aged 45 +/- 8 years without r-Epo in that period of time. Following parameters were estimated every two months: total cholesterol (CH-C), HDL cholesterol (HDL-CH), LDL cholesterol (LDL-CH), triglycerides (TG), apolipoprotein B (Apo B).. 1. Subcutaneous therapy with r-Epo is an effective method of treatment of anemia in dialysis patients. 2. Long-term r-Epo treatment does not permanently influence the blood lipid profile in hemodialysed patients.

Topics: Adult; Anemia; Apolipoproteins B; Chronic Disease; Erythropoietin; Female; Humans; Hyperlipidemias; Injections, Subcutaneous; Kidney Diseases; Lipids; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

The most common hematological abnormality associated with HIV infection is anaemia. The aetiology is multifactorial and may include the HIV virus itself; the anaemia of chronic diseases (ACD); infection with other viruses, mycobacteria and fungi; medications, especially zidovudine; and even B12 deficiency. Erythropoietin insufficiency is present in all anaemic AIDS patients, probably as a result of the mechanism of ACD. The studies, performed in patients with PGL, ARC and AIDS stages of disease demonstrate that rHuEPO is safe, and in dose of 100-200 U/kg b.w. three times a week can alleviate the anemia in AIDS patients taking AZT whose baseline EPO levels are less than 500 mU/ml.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Chronic Disease; Erythropoietin; Humans; Zidovudine

This study aimed to assess the effect of anaemia on volume related hormones in dialyzed patients with chronic uraemia. Three groups of subjects were examined. The first one comprised 34 hemodialyzed patients with severe anaemia (haematocrit value < 28%). 17 patients were treated with EPO for 1 year (EPO group) while the other 17 patients did not receive rHuEPO (no-EPO group) but were intensively monitored biochemically and clinically as patients of the EPO group. The second group (HD) consisted of 12 hemodialyzed uraemic patients with a Hct > 30% without rHuEPO treatment, while the third one comprised 15 healthy subjects. In patients of the EPO and no-EPO group plasma renin activity (PRA), plasma concentration of aldosterone (Ald) atrial natriuretic peptide (ANP and vasopressin (AVP) were assessed before (0) and after 3, 6, 9 and 12 months of clinical monitoring, while in patients of the HD group and in normals the above mentioned parameters were estimated only once. EPO treatment improved significantly the Hct value already after three months of therapy. No significant changes in PRA and plasma concentrations of Ald, ANP and AVP in the noEPO group were noticed during 12 months of monitoring. In contrast EPO treatment induced a significant, although transitory decrease of PRA, Ald and AVP, but an increase of plasma ANP. No influence of rHuEPO therapy on blood pressure was noticed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Anemia; Arginine Vasopressin; Blood Pressure; Blood Volume; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

A male patient suffered chronic renal failure due to lupus nephritis and was undergoing hemodialysis. Six years after beginning hemodialysis, anemia developed, which improved by erythropoietin. Unresponsiveness to erythropoietin gradually appeared, and with a suspicion of pure red cell aplasia, he was treated with a high-dose corticosteroid but the unresponsiveness did not improve. Neither his serum nor lymphocytes inhibited erythropoiesis of either normal bone marrow stem cells or his own in vitro. These observations suggest an impaired hematopoietic microenvironment in his bone marrow.

Topics: Adrenal Cortex Hormones; Adult; Chronic Disease; Colony-Forming Units Assay; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Lupus Nephritis; Male; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Adult; Chronic Disease; Cyclosporine; Drug Resistance; Erythropoietin; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male

Topics: Adult; Blood Cell Count; Chronic Disease; Combined Modality Therapy; Drug Therapy, Combination; Erythropoietin; Hemoglobins; Hepatitis C; Humans; Interferon-alpha; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Serum levels of erythropoietin and five other cytokines potentially operational in erythropoiesis were determined in patients with anemia of chronic disease. No correlation between erythropoietin levels and severity of anemia was found. A spectrum of abnormality was encountered among patients in whom there was less than expected erythropoietin response to increased levels of erythropoietin and among others in whom the erythropoietin levels were subnormal for their degree of anemia. Increased serum levels of interleukin-3, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor were encountered in limited numbers of patients, especially those with increased erythropoietin levels. Deficient erythropoietin production is concluded to be the major cause of anemia of chronic disease.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Colony-Stimulating Factors; Cytokines; Erythropoietin; Female; Humans; Interleukins; Male; Middle Aged

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Lung Transplantation; Male; Middle Aged; Recombinant Proteins

To examine the endogenous erythropoietin response in critically ill children with acute anemia or acute hypoxemia.. A prospective case study of critically ill acutely anemic, and acutely hypoxemic pediatric patients compared with control groups of critically ill nonanemic and nonhypoxemic patients and with a hemoglobin and age-matched, chronically anemic patient group.. Multidisciplinary, tertiary, pediatric intensive care unit (ICU).. Critically ill patients admitted to the pediatric ICU during an 11-month period between February 1992 and March 1993 with acute anemia (n = 21), acute hypoxemia (n = 18), or neither anemia nor hypoxemia (n = 10). Outpatients with chronic anemia (n = 21) and no acute illness were also studied as a comparison group.. None.. Ages were equivalent among the groups and averaged 57.4 +/- 47.2 months (range 1 to 144). Acutely hypoxemic and critically ill control patients had normal hemoglobin levels. Acutely anemic patients had a hemoglobin level equivalent to chronically anemic outpatients, but lower (p < .001) hemoglobin levels than acutely hypoxemic and critically ill control patients. The serum erythropoietin concentrations in the acutely anemic group were significantly lower than erythropoietin values in the chronically anemic group (39.3 +/- 62.2 vs. 861 +/- 758 mU/mL, p < .001) and similar to erythropoietin concentrations in the critically ill control (13.5 +/- 10.5 mU/mL) and acutely hypoxemic (5.2 +/- 3.3 mU/mL) patient groups. Only ten of 49 critically ill patients had an erythropoietin concentration above normal, compared with 20 of 21 chronically anemic patients, whose erythropoietin concentrations were above normal.. The erythropoietin response to known physiologic stimuli is blunted in critically ill children. This blunted erythropoietin response may result in increased transfusion requirements.

Topics: Acute Disease; Analysis of Variance; Anemia; Blood Transfusion; Case-Control Studies; Child; Child, Preschool; Chronic Disease; Critical Illness; Erythropoietin; Hemoglobins; Humans; Hypoxia; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Matched-Pair Analysis; Outpatients; Prospective Studies; Severity of Illness Index

In patients with the anemia of chronic diseases, the plasma level of EPO is often low in relation to the blood hemoglobin concentration. Because infectious and inflammatory processes cause activation of cytokine-producing macrophages and lymphocytes, we investigated whether isolated inflammatory cytokines influence the synthesis of EPO in vitro. IL-1 and TNF-alpha were shown to inhibit EPO mRNA levels and EPO formation in the human hepatoma cell cultures HepG2 and Hep3B, and to lower EPO formation in isolated perfused rat kidneys. IFN-alpha and IFN-beta also induced some inhibition of EPO production in HepG2 cultures. IL-3, TGF-beta 2, and IFN-gamma did not inhibit. IL-6 stimulated the production of EPO in Hep3B cells but was ineffective in HepG2 cells and lowered EPO production in isolated perfused rat kidneys. IL-1, TNF-alpha, and possibly other cytokines could contribute to defective EPO production in renal and nonrenal immune responses.

Topics: Anemia; Animals; Carcinoma, Hepatocellular; Cell Line; Chronic Disease; Culture Media, Conditioned; Cytokines; Erythropoietin; Hemoglobins; Humans; Inflammation; Interferon-alpha; Interferon-beta; Kidney; Kinetics; Liver Neoplasms; Macrophages, Peritoneal; Male; Mice; Monokines; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tumor Cells, Cultured

Several factors may contribute to the pathogenesis of uraemic anaemia but there is general agreement that inadequate secretion of erythropoietin is the main cause. Recombinant human erythropoietin (r-Hu EPO) is today widely used in the treatment of patients with renal anaemia. Initial studies were conducted on patients receiving haemodialysis (HD) using intravenous dosing, and number of reports have confirmed the efficacy and safety of the hormone. However, there is still limited information on the use of r-Hu EPO in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The cost of this treatment was initially very high. The optimal way of administration of the drug and optimal dosage is still under discussion. More studies are needed to optimize treatment from a clinical as well as an economic point of view. We therefore present our result on the efficacy and safety of low dose r-Hu EPO given subcutaneously in th treatment of anemia in CAPD patients.

Topics: Adult; Anemia; Chronic Disease; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Quality of Life; Recombinant Proteins; Reticulocyte Count; Treatment Outcome

To analyze the relationship between serum erythropoietin levels and hemoglobin levels in elderly patients with anemia of chronic disorders related to cancer or acute infection when compared with anemic patients with iron deficiency.. Prospective survey with comparison groups.. Tertiary care center.. An elderly group aged 70 and above (mean 84, range 70-96) was divided into subgroups of 45 with anemia of chronic disorders (23 with cancer and 22 with acute infection), 24 with iron-deficiency anemia, and 27 with no anemia. Thirty non-anemic younger adults were also studied.. Serum erythropoietin (radioimmunoassay), complete blood count, serum iron, B12, folate and ferritin, liver and kidney function tests, blood gas analyses, and bacteriological and radiological tests.. The serum erythropoietin levels were significantly lower in the elderly non-anemic hospitalized group than in the healthy younger group. A significant negative relationship between the log serum erythropoietin and hemoglobin levels was found in patients with iron deficiency, but not in the other groups. For any given hemoglobin level, the response of erythropoietin was significantly higher in anemic patients with iron deficiency when compared with the neoplastic and infectious group.. Erythropoietin response to anemia is blunted in elderly patients with anemia of chronic disorders related to cancer or acute infection. Erythropoietin level is lower in non-anemic elderly inpatients than in healthy younger persons.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anemia; Anemia, Hypochromic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemoglobins; Hospitalization; Humans; Infections; Male; Neoplasms; Prospective Studies

This paper describes how Bayesian networks can be used in combination with compartmental models to plan recombinant human erythropoietin delivery in the treatment of anemia of chronic uremic patients. Past measurements of hemoglobin concentration in a patient during the therapy can be exploited to adjust the parameters of a compartmental model of erythropoiesis. This adaptive process provides more accurate patient-specific predictions, and hence a more rational dosage planning. Inferences are performed by using a stochastic simulation algorithm called Gibbs sampling. We describe a drug delivery optimization protocol based on our approach. Some results obtained on real data are presented.

Topics: Adult; Anemia; Bayes Theorem; Chronic Disease; Computer Simulation; Costs and Cost Analysis; Drug Administration Schedule; Drug Therapy, Computer-Assisted; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Male; Models, Biological; Uremia

The effect of recombinant human erythropoietin (rHuEPO) on the lymphocyte subpopulations of maintenance hemodialysis patients has been studied. Peripheral lymphocyte counts, lymphocyte subpopulations (Two color analysis) and PHA-induced proliferative response were measured before and after rHuEPO administration during 8 months in 22 stable hemodialysis patients (mean age 52 years, mean duration of dialysis 48 months). We could find a significant increase in the proportions of CD4+ Leu8- cells, HLA-DR+ cells, CD8+ HLA-DR+ cells, CD14+ HLA-DR+ cells and CD4+ Leu8-/CD8+ CD11b+ cells ratios after rHuEPO therapy. In addition, a significant decrease in the proportions of CD16+ CD57- cells and CD20+ cells could be found after rHuEPO therapy. These results suggest that rHuEPO administration to stable hemodialysis patients induces increases in lymphocytes categorized into helper subset groups and in activated T lymphocytes.

Topics: Adult; Aged; Antigens, CD; Chronic Disease; Erythropoietin; Female; Glomerulonephritis; Humans; Lymphocyte Activation; Lymphocyte Subsets; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

1. To clarify the relationship between nocturnal oxygen desaturation and erythropoietin production in patients with chronic obstructive pulmonary disease, we determined arterial oxygen saturation and serum immunoreactive erythropoietin levels over 24 h in eight patients with chronic obstructive pulmonary disease and in nine normal subjects. 2. In the normal subjects, there was a significant circadian variation in serum erythropoietin levels with the highest mean deviation from the geometric mean at 22.00 hours and the nadir at 05.00 hours. 3. The three patients with chronic obstructive pulmonary disease with the most marked nocturnal desaturation (lowest arterial oxygen saturation < 57%) and most marked daytime hypoxaemia (daytime arterial partial pressure of oxygen < 6 kPa) had raised nocturnal serum erythropoietin levels. In two of these patients, the serum erythropoietin level was raised throughout the 24 h and erythrocyte mass was also raised. In the other patient, the serum erythropoietin level was not raised in five daytime samples and erythrocyte mass was normal. 4. The other five patients with chronic obstructive pulmonary disease with less severe nocturnal hypoxaemia (lowest arterial oxygen saturation range 78-86%) had serum erythropoietin levels (range 14-36 m-i.u./ml) which were indistinguishable from normal (range 12-44 m-i.u./ml) and showed circadian changes which were not significantly different (P = 0.35) from those in the normal subjects. 5. Thus, mild nocturnal oxygen desaturation is not associated with elevation of serum erythropoietin levels, whereas daytime hypoxaemia with associated severe nocturnal desaturation is associated with increased serum erythropoietin levels both by day and by night.

Topics: Aged; Chronic Disease; Circadian Rhythm; Erythropoietin; Female; Humans; Hypoxia; Lung Diseases, Obstructive; Male; Oxygen; Sleep

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Quality of Life; Recombinant Proteins

Neoplasias, especially in their more advanced stages, are often associated with chronic anemia of malignancy which impairs the patient's physical ability and quality of life.. Forty-two patients with chronic anemia associated with hematological malignancies (18 multiple myelomas, 10 myelodysplastic syndromes) or solid tumors (9 breast cancers, 5 colon cancers) were treated with 150-300 units/kg rHuEPO for a median time period of 16 weeks. Response was defined as an increase of the initial hemoglobin level by at least 2 g/dl.. The response rates for solid tumors were comparable (44.4% and 40% for breast cancer and colon cancer, respectively), whilst the response in patients with hematological malignancies depended strongly on the disease entity (77.8% for multiple myeloma, 10% for myelodysplastic syndrome). Pretreatment serum levels of endogenous erythropoietin (EPO) were significantly higher in non-responding patients than in responders. During rHuEPO therapy, EPO levels in non-responders increased even further, while they remained basically unchanged in responding patients. In responders, the WHO performance status before the start of rHuEPO therapy was more favorable and showed impressive improvement during the course of treatment. The median survival time of responders was 28.0 months as compared to only 9.2 months for non-responders. Clinical symptoms of anemia subsided or at least considerably improved under successful rHuEPO therapy. With the exception of occasional flu-like symptoms, no undesirable effects of rHuEPO treatment were observed.. In conclusion, rHuEPO treatment corrected anemia of malignancy both in patients with hematologic disease and in those with solid tumors, but responsiveness varied considerably amongst the different disease entities.

Topics: Aged; Aged, 80 and over; Anemia; Breast Neoplasms; Chronic Disease; Colonic Neoplasms; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Survival Rate; Treatment Outcome

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Humans

Topics: Adult; Bromocriptine; Chronic Disease; Drug Evaluation; Erythropoietin; Humans; Hypogonadism; Kidney Failure, Chronic; Male; Middle Aged; Penile Erection; Recombinant Proteins; Renal Dialysis; Spermatogenesis; Sulfates; Uremia; Zinc; Zinc Sulfate

In all mammalian species studied the haematocrit (hct) declines after birth in the absence of any known nutritional deficiencies. The glycoprotein hormone, erythropoietin (Epo), is essential for normal red blood cell production. The aims of this study were 1) to investigate the changes in plasma Epo during the normal post-natal decrease in hct in lambs; 2) to compare the effects of chronic and acute haemorrhage in neonatal lambs; and 3) to test the hypothesis that the Epo response to haemorrhage is blunted in the neonatal period. Twenty-one lambs (0-9 weeks of age) were studied; group I (n = 8) were used to document normal post-natal changes (98 samples); group II (n = 7) lambs were haemorrhaged repetitively during weeks 3-6 (95 samples); group III (n = 6) lambs were bled once in the first 3-week period. In the group I (control lambs) the hct decreased from 30.6 +/- 1.3 (weeks 1 & 2) to a nadir of 23.2 +/- 0.8 (75.8% of initial value) in the 6th week, and the plasma Epo declined from 25.7 +/- 4.9 (week 1) to 12.3 +/- 1.0 mU/ml (week 6). In group II, the lambs were bled repetitively, a total of 510 +/- 32 ml blood being removed during weeks 3-6, the hct was 18.7 +/- 0.8 (81% of hct at nadir in controls) in week 6, and Epo was 26.9 +/- 13.3 in week 3, 23.4 +/- 3.6 mU/ml in week 6.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adrenocorticotropic Hormone; Animals; Animals, Newborn; Carbon Dioxide; Chronic Disease; Erythropoietin; Globins; Hematocrit; Hemorrhage; Hydrocortisone; Oxygen; Reference Values; Sheep

We have developed a method for directly estimating the secretion rate of endogenous erythropoietin (EPO) in human subjects. Carrier-free recombinant human EPO was labeled with 125I by the chloramine T method. Human serum albumin was then added prior to removal of free iodide. Seven normal subjects and nine patients with chronic uremia and anemia were studied. Each subject received a bolus of 125I-EPO according to body size and then a constant infusion for 5 h. Secretion rate was calculated as the rate of infusion divided by serum EPO specific activity given by the protein-bound counts divided by the EPO concentration. Serum EPO concentration was significantly higher in the patients than the controls (mean 30.9 pg/ml vs. 11.1 pg/ml, P < 0.05), although all values were within the normal range. Mean EPO secretion rate was 255 in the patients (range 68-1,101) and 190 pg.kg-1 x h-1 in the normal group (range 52-382). This difference was not significant. As the subjects were in a steady state, EPO disappearance/degradation was the same in patients compared with controls despite a relatively hypoplastic marrow.

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Osmolar Concentration; Reference Values; Uremia

Chronic mountain sickness, which affects permanent residents of high altitudes, is the outcome of a progressive loss of ventilatory rate which naturally occurs with age and resulting in excessive hypoxemia and polycythemia. A theoretical model predicts the progressive failure of homeostatic control of the hemoglobin concentration when the values increase above those found at sea level. This is confirmed by lack of feedback mechanism between high altitude erythrocytosis and serum erythropoietin. The results of epidemiological studies are in agreement with the physiological findings. In a male population living at 4,300 m, an increase with age of the prevalences of excessive erythrocytosis (Hb > 213 g/l), blood oxygen saturation < 83%, headaches and a high score of symptoms of chronic mountain sickness has been found. The studies suggest the possibility that in addition to an accentuated hypoxemia, the excessive erythrocytosis may also result from an overreaction of the bone marrow to a fixed level of hypoxemia in ageing individuals.

Topics: Adult; Aged; Aging; Altitude Sickness; Chronic Disease; Erythropoietin; Homeostasis; Humans; Hypoventilation; Hypoxia; Male; Middle Aged; Models, Theoretical; Peru; Polycythemia; Prevalence

This study attempts to evaluate the adequacy of the erythropoietin (EPO) response in 42 anaemic patients with advanced human immunodeficiency virus (HIV) infection [30 with acquired immunodeficiency syndrome (AIDS) and 12 with AIDS-related conditions] by comparing their serum EPO levels with those found in a non-HIV reference population consisting of 36 patients with anaemia of chronic disorders (ACD) and 57 with iron deficiency anaemia (IDA). Although the average Hb concentration was similar in the three groups, the EPO level for HIV patients (mean +/- SEM, 64.3 +/- 7.7 mU/ml) did not differ significantly from that in ACD patients (45.3 +/- 8.3 mU/ml, P > 0.1), and both groups had a lower mean EPO level (P < 0.05 and P < 0.01 respectively) than IDA subjects (133.5 +/- 18.7 mU/ml). Thirteen HIV patients on zidovudine therapy showed similar mean Hb and EPO levels to those in the untreated patients. A significant inverse correlation between the log of serum EPO and the Hb values was observed in the three groups. However, this relationship was found to be stronger in IDA patients than in either HIV or ACD subjects (P < 0.001), with no difference between the two latter groups (P > 0.2). These data suggest that the EPO response is blunted in the anaemia associated with advanced HIV infection.

Topics: Acquired Immunodeficiency Syndrome; Acute-Phase Reaction; Adolescent; Adult; Aged; Anemia; Anemia, Hypochromic; Child; Chronic Disease; Erythropoietin; Female; Hemoglobins; HIV Infections; Humans; Male; Middle Aged

Patients with uraemia have a defect haemostasis caused by severe anaemia and disturbances of platelet/vessel wall interactions. Recombinant human erythropoietin (rHuEPO) treatment not only corrects anaemia, but also shortens the bleeding time. There are few reports dealing with changes of haemostasis during the first month of rHuEPO treatment. We studied platelet function after 1, 2, 4, 8, and 12 weeks of rHuEPO treatment. Erythropoietin was given to 19 dialysed patients with chronic uraemia in a dose of 2000 u subcutaneously 3 times a week. Bleeding time showed a significant fall as early as after the first week of rHuEPO treatment (p < 0.05). After the first month the bleeding time became normal in most of the patients. A significant rise in ristocetin-induced platelet aggregation was observed from the first week of therapy. It showed a strong correlation with the shortening of the bleeding time. Collagen-induced aggregation followed the same pattern but the changes were not striking. There was not significant difference in platelet adhesion, platelet aggregation in the whole blood and those induced by ADP and arachidonic acid. Platelet serotonin concentration was also showed to increase during rHuEPO therapy. We conclude that rHuEPO improves haemostasis by influencing platelet aggregation possibly involving a serotoninergic mechanism but on the other hand may increase a tendency to thrombosis.

Topics: Adult; Anemia; Bleeding Time; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Platelet Aggregation; Recombination, Genetic; Renal Dialysis; Uremia

Erythroid alterations were studied in 136 patients with rheumatoid arthritis (RA). Anemia was present in 75 cases. A definite diagnosis was determined in 65. The most frequent anemia was that of chronic disease (ACD) (43 cases); 14 patients with ACD presented with moderate to severe anemia. Prevalence of deficiencies were also high (15 cases had iron deficiency anemia, IDA). Serum erythropoietin levels were different in patients with RA compared with a healthy control group (p < 0.00001). Serum erythropoietin was increased in ACD (49 +/- 28.8 U/l) with respect to both RA (38.6 +/- 12.7 U/l, p = 0.0036) and controls (18.2 +/- 7.6 U/l, p < 0.00001). Although hemoglobin (Hb) was similar in ACD and IDA, serum erythropoietin in ACD was lower than in IDA (p = 0.01). There was a negative relationship between Hb and serum erythropoietin in ACD (r = -0.42, p = 0.005). In conclusion, almost 50% of patients with RA have anemia and ACD is the most frequent. As serum erythropoietin in ACD is blunted, patients with moderate to severe ACD are possible candidates for erythropoietin treatment.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Folic Acid Deficiency; Humans; Male; Middle Aged; Prevalence; Prospective Studies; Vitamin B 12 Deficiency

The hemostatic effects of recombinant human erythropoietin (rHuEP) were investigated in 20 patients with end-stage renal disease (thirteen on hemodialysis, seven without dialysis) receiving this hormone. We studied their hemograms and coagulation profiles before and at 1 month after initiation of rHuEP therapy. One month after rHuEP administration, improvement in anemia (16/20, 80%) and shortening of bleeding time (17/19, 89.5%) were observed. Shortening or correction of bleeding time was achieved in three patients without any increase of the hemoglobin level. This means that factors other than the increased hematocrit level might contribute to shortening bleeding time in uremic patients receiving rHuEP treatment. The platelet count, prothrombin time, partial thromboplastin time, and fibrinogen level did not change over the course of rHuEP therapy. Thrombosis of vascular access was not observed, and heparin doses were not increased in this short-term period. A significant decrease was found in the plasminogen level, from 108.5% to 88.2% (p less than 0.05), in uremic patients on hemodialysis. The antithrombin III level also decreased, from 98.8% to 89.8% (p less than 0.05), and its level dropped to below normal ranges in six of thirteen patients (46%) on hemodialysis after treatment with rHuEP. No significant change was noted in the levels of antithrombin III, plasminogen, and alpha 2-antiplasmin in uremic patients not receiving dialysis. These results suggest that rHuEP administration induces increased extracorporeal dialyzer clotting and consumption coagulopathy, and that this extracorporeal consumption coagulopathy may play a role in the genesis of thrombotic complications.

Topics: Adult; Aged; alpha-2-Antiplasmin; Anemia; Antithrombin III; Bleeding Time; Blood Coagulation Tests; Chronic Disease; Erythropoietin; Female; Hemoglobins; Hemostasis; Humans; Male; Middle Aged; Peptide Fragments; Plasminogen; Platelet Count; Prothrombin; Recombinant Fusion Proteins; Renal Dialysis; Uremia

Eleven patients with chronic inflammatory arthritides and haemoglobin concentrations less than 105 g/l with symptoms from their anaemia were treated with a dose of 250 IU/kg/week of recombinant human erythropoietin for six weeks. The treatment was given as subcutaneous injections five days a week. All patients had active inflammatory disease. Nine patients responded to treatment with an increase in haemoglobin of more than 15 g/l. The mean (SD) haemoglobin concentration increased from 93.0 (8.0) g/l before treatment to 115.0 (12.0) g/l after six weeks. There was no correlation between the initial serum concentration of erythropoietin and the response. It was concluded that anaemia in chronic inflammatory arthritides responds to treatment with subcutaneous injections of recombinant human erythropoietin.

Topics: Administration, Cutaneous; Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged

Anaemia in rheumatoid arthritis (RA) is a common and debilitating complication. The most common causes of this anaemia are iron deficiency and anaemia of chronic disease. Investigations have suggested that interleukin 1 (IL-1) or tumour necrosis factor (TNF), or both, from monocytes associated with chronic inflammation are responsible for the anaemia of chronic disease. On bone marrow examination anaemia of chronic disease is characterised by the diversion of iron from the erythropoietic compartment into marrow macrophages. This phenomenon is termed failure of iron utilisation. In this study, CFU-E (colony forming unit erythroid; late red cell precursors) and BFU-E (burst forming unit erythroid; early red cell precursors) stem cells were cultured from 10 normal marrow samples and 12 marrow samples from patients with RA with iron deficiency anaemia and 10 samples from patients with RA with failure of iron utilisation. All patients with RA were anaemic (haemoglobin less than 100 g/l), Potential accessory or inhibitory cells of erythropoiesis (CD4, CD8, or CD14 positive cells) were removed before culture. Control marrow samples were studied in a similar manner. Normal marrow samples yielded 377 (17) CFU-E and 133 (6) BFU-E (mean (SD)) colonies for each 2 x 10(5) light density cells plated. CD4 ablation caused reductions of 62 and 100% in CFU-E and BFU-E colonies respectively. CD14 removal resulted in considerable but lesser reductions of 46% for CFU-E and 25% for BFU-E. In both groups of patients with RA, CFU-E colony numbers were significantly lower than those seen in normal control subjects, 293 (17) for patients with iron deficiency anaemia and 242 (35) for patients with failure of iron utilisation. BFU-E colony numbers were 102 (13) and 108 (20) respectively. In patients with RA, CD4 removal caused a significantly greater loss of CFU-E colonies compared with normal control subjects. Cytolysis of CD14 positive cells caused a reduction in CFU-E colonies in the two RA groups which was similar to that seen in normal subjects. In conclusion, patients with RA seem to have fewer CFU-E progenitors but essentially normal numbers of BFU-E stem cells. Our data suggest a stimulatory role for marrow CD4 and CD14 cells in erythropoiesis in patients with RA. Monocytes-macrophages (CD14 positive) are known to be producers of IL-1 or TNF, or both, however, the predicted increase in the CFU-E colonies on removal of CD14 cells is not seen. Therefore, if IL-1 or TNF, or bot

Topics: Anemia; Arthritis, Rheumatoid; Bone Marrow; Cells, Cultured; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Interleukin-1; Macrophages

A 55-year-old female patient with hemosiderosis induced by administration of excessive doses of parenteral iron was successfully treated with regular phlebotomy combined with recombinant human erythropoietin (rHuEPO). Ferrokinetic data before therapy showed 28.0 mumol/l of serum iron, 4.1 mumol/l of unsaturated iron-binding capacity, 4,060 ng/ml of serum ferritin, 148 min of plasma iron disappearance time, 45% of red cell iron utilization and 0.4 mg/kg/day of plasma iron turnover rate. She had 300-ml phlebotomies, first every other week then weekly, and subcutaneous injections of rHuEPO twice a week. Two years later, the total volume of phlebotomized blood reached 31 liters and her ferrokinetic data showed: serum iron 8.6 mumol/l, iron-binding capacity 39.6 mumol/l, serum ferritin 277 ng/ml, plasma iron disappearance time 52 min, red cell iron utilization 100% and plasma iron turnover rate 0.5 mg/kg/day. During the phlebotomy therapy, her hemoglobin levels were maintained above 12 g/dl. No adverse effect due to rHuEPO occurred. These findings provide evidence for the efficacy of rHuEPO in multiple phlebotomy therapy for hemosiderosis and may open new avenues for its clinical application.

Topics: Bloodletting; Chronic Disease; Combined Modality Therapy; Erythropoietin; Female; Hemosiderosis; Humans; Iron; Middle Aged; Recombinant Proteins

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Ferritins; Humans; Recombinant Proteins; Renal Dialysis

We treated 5 patients with rheumatoid arthritis (RA) with anemia of chronic disease with recombinant human erythropoietin (rHuEPO) for 11 weeks. An increase in hematocrit (Hct) greater than 5 was seen in 4 patients after 4 weeks of therapy. The 5th patient had a significant rise in Hct when the dosage of rHuEPO was increased to 150 units/kg from the 4th to 7th week. The subcutaneous administration of rHuEPO dose, reduced by one third with respect to initial dose, maintained an effective Hct value in all the 5 patients during the last 4 weeks of therapy. There was no change in disease activity. In one patient Hct normalization completely resolved symptoms of angina pectoris and permitted hip replacement surgery in another. No side effects occurred during rHuEPO therapy. We conclude that HuEPO is an effective, safe and well tolerated therapy for RA patients with severe anemia of chronic disease.

Topics: Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Hematocrit; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins

A 23-year-old man with severe sickle cell disease and a chronic non-healing left leg ulcer was entered into a study in which he received hydroxyurea (HU) and recombinant human erythropoietin (r-HuEPO) in order to modify the severity of his disease. HU 20 mg/kg/day effectively prevented vaso-occlusive crises and improved hematological parameters, but the chronic leg ulcer and chronic mild bone pains remained. Six months later, r-HuEPO 600-800 IU/kg subcutaneously was added at weekly intervals. This led to a rapid and complete healing of the chronic leg ulcer, further improvement in hematological parameters and relief from chronic pains. We conclude that treatment with r-HuEPO may provide an effective therapy for chronic leg ulcers in patients with sickle cell disease.

Topics: Adult; Anemia, Sickle Cell; Chronic Disease; Erythropoietin; Humans; Leg Ulcer; Male; Recombinant Proteins

Consecutive determinations of erythropoietin in serum (s-Epo) were made in ten patients with chronic hypoxia starting domiciliary long-term oxygen therapy (LTO). After 24 h of supplementary oxygen treatment there was a fall in the median s-Epo level from 11.3 to 4.4 IU.l-1 (p less than 0.01). The initial decrease in s-Epo in conjunction with oxygen treatment was not sustained after one and three months of LTO. S-Epo levels above the reference range (3.3-13.5 IU.l-1) were found in three patients before and during LTO and in another two patients during LTO. Markedly elevated s-Epo levels were found in two patients with hypoxia and hypercapnia at the time of blood sampling. A significant negative relationship was found between the arterial oxygen tension and the log value for the s-Epo level (r = 0.40, p less than 0.005). The s-Epo levels were found to be normal in half of the measurements in patients using oxygen less than 15 h daily, a fact that indicates that s-Epo measurements are probably not suitable as indicators of compliance with LTO.

Topics: Aged; Aged, 80 and over; Chronic Disease; Erythropoietin; Home Care Services; Humans; Hypoxia; Long-Term Care; Male; Middle Aged; Oxygen Inhalation Therapy; Patient Compliance

The ability of blood mononuclear cells (MNC) to produce burst promoting activity (BPA) was evaluated in 31 patients with chronic renal failure. The BPA of cells from uremic patients, with or without hemodialysis, was consistently lower than that of 17 normal donors (mean 64%, P less than 0.01). Coculture of MNC with recombinant erythropoietin (rEpo) in vitro did not increase BPA production. Five of 31 patients received in vivo treatment with rEpo (1,500 units x3/week) and showed therapeutic benefit, but in all patients the BPA production remained low. On the other hand, in four patients who were on a hemodialysis protocol and subsequently underwent renal transplantation, impaired BPA production was resolved quickly, and at the same time the number of circulating BFU-E and the hemoglobin level increased toward normal ranges. Furthermore, such impaired BPA production was not observed in patients receiving continuous ambulatory peritoneal dialysis. These observations suggest that decreased production of BPA may play a role in the development of anemia associated with chronic uremic patients, and the correction of BPA production by the improvement of hemodialysis procedure may result in more effective therapy with rEpo for those patients.

Topics: Adult; Aged; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Monocytes; Recombinant Proteins; Reference Values; Renal Dialysis; Uremia

The erythropoietin (EPO) response to anemia was assessed for 244 subjects aged 1-64 years (mean 45.2 years) and 121 subjects aged 65-94 years (mean 68.3 years). Subjects included non-anemic individuals as well as those with anemia of various etiologies, excluding renal disease and pregnancy. Significant inverse correlations between serum immunoreactive EPO and hematocrit were noted for both groups. Regression lines failed to show a significantly lower slope or y-intercept for older compared to younger subjects. EPO levels were not significantly lower for older compared to younger subjects when controlled for hematocrit level. These results suggest that the EPO response to anemia in older subjects is similar to that of younger subjects.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Anemia; Child; Child, Preschool; Chronic Disease; Erythropoietin; Hematocrit; Humans; Infant; Infant, Newborn; Middle Aged; Nutrition Disorders

Eighteen patients on chronic hemodialysis with renal anemia were treated with recombinant human erythropoietin (r-HuEPO). Hemodynamic parameters in the resting state were determined before and after successful treatment. Posttreatment cardiac index was decreased (3.3 v 2.8 L/min/m2), whereas diastolic blood pressure (72 v 79 mm Hg) and calculated peripheral resistance (2,230 v 2,860 dyne.cm.s-5) were increased significantly when compared with the pretreatment period. We conclude from our study that the increase of blood pressure as seen in patients on dialysis, who are effectively treated with r-HuEPO, is due to an increase in peripheral resistance. This increase overrules the decrease of cardiac index and might well be a result of peripheral vasoconstriction due to improved oxygen availability.

Topics: Adult; Anemia, Hypochromic; Chronic Disease; Erythropoietin; Female; Hemodynamics; Humans; Hypotension; Male; Recombinant Proteins; Renal Dialysis

We treated a patient with alcohol-induced cirrhosis, intractable pain from a defective hip prosthesis, and multiple red cell allo-antibodies with recombinant human erythropoietin (EPO) in order to facilitate collection of blood for autologous transfusion during an elective total hip revision. This patient had experienced a delayed transfusion reaction 4 months earlier after receiving least incompatible packed red cells for gastrointestinal bleeding. His blood could not be crossmatched because of the development of multiple antibodies to homologous blood given during previous surgery and several episodes of gastrointestinal hemorrhage. Following initiation of EPO therapy, there was a prompt and persistent increase in the reticulocyte count from a baseline of 1.6% to a maximum of 8.6%. This was accompanied by maintenance of the hematocrit between 32% and 38.5% despite withdrawal of seven units of autologous blood over the 45-day treatment period. Poor venous access and availability of blood bank personnel, not hematocrit level, were the limiting factors that determined how frequently blood could be collected. We conclude that EPO stimulated erythropoiesis in this patient with underlying anemia of chronic disease and facilitated harvest of autologous blood for elective surgery.

Topics: Aged; Anemia; Blood Specimen Collection; Blood Transfusion, Autologous; Chronic Disease; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Hip Prosthesis; Humans; Isoantibodies; Male; Prosthesis Failure; Recombinant Proteins; Reoperation

Defective iron metabolism, mild haemolysis and impaired erythropoiesis contribute to the anaemia of chronic disorders (ACD), but evidence for a deficiency of circulating erythropoietin (Epo) is equivocal. We have examined serum Epo in moderately anaemic patients with Hb less than 10 g/dl--41 patients with ACD (23 associated with rheumatoid disease and 18 with malignancy), 17 with uncomplicated iron-deficiency anaemia and 33 with chronic renal failure (CRF). In ACD the serum Epo (mean (confidence limits] results of 41 (31, 54) mU/ml for the rheumatoid group and 63 (49, 80) mU/ml for the malignancy group, were significantly lower than the Epo of 104 (78, 136) mU/ml for the iron-deficiency group. The CRF group with more severe anaemia had serum Epo of 27 (19, 35) mU/ml. Thus, recombinant human erythropoietin (rHu Epo) should be considered for the treatment of ACD associated with rheumatoid disease and malignancy.

Topics: Adult; Anemia; Anemia, Hypochromic; Chronic Disease; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Rheumatic Diseases

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins

Topics: Anemia; Animals; Arthritis, Rheumatoid; Chronic Disease; Erythrocyte Aging; Erythropoietin; Female; Folic Acid Deficiency; Humans; Lupus Erythematosus, Systemic; Male; Recombinant Proteins; Vitamin B 12 Deficiency

To obtain information on the effects of the correction of uremic anemia on cardiac function and size, nine normotensive dialyzed patients were studied before, during and six months after the start of i.v. treatment with recombinant human erythropoietin (rHuEPO). Pulsed-doppler echocardiographic determinations of the cardiac index (CI) and M-Mode echocardiographic estimations of the indexed left ventricular end diastolic diameter (LVEDDi), interventricular septum (IVSi), left ventricular posterior wall (LVPWi), with calculations of the left ventricular mass index (LVMi), were made on every occasion. Mean (+/- SD) hemoglobin (Hb) concentration before rHuEPO was 5.9 +/- 1.3 g/dl and rose significantly (p less than 0.0001) up to the third month, then remained constant. Baseline CI (3.4 +/- 0.6 l/min/m2bsa) was significantly higher (p less than 0.0001) than in healthy subjects (2.5 +/- 0.5 l), and decreased after the third month to a value (2.8 +/- 0.5 l) no longer different from that of controls. From pooled baseline and third month data, an inverse relationship between Hb and CI was found (p less than 0.0001). Baseline LVEDDi (32.7 +/- 4.3 mm/m2bsa), IVSi (6 +/- 1.1 mm/m2bsa) and LVPWi (5 +/- 0.8 mm/m2bsa) were all significantly higher than in controls. After three months of therapy, the only change was a decrease in LVPWi while after six months all indices, including the LVMi, decreased to values no longer higher than in controls. From pooled baseline and six months data, an inverse relationship between Hb and LVMi was found (p less than 0.0001). We conclude that treatment of uremic patients by rHuEPO is able to renormalize their already increased cardiac output soon after correction of the anemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Blood Volume; Cardiac Output; Chronic Disease; Echocardiography, Doppler; Erythropoietin; Female; Heart Ventricles; Humans; Male; Middle Aged; Norepinephrine; Recombinant Proteins; Renal Dialysis; Renin; Time Factors; Uremia

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Ultrafiltration

Skin microcirculation and regional peripheral resistance were studied in 14 patients with renal anaemia during therapy with recombinant human erythropoietin. Haematocrit was raised from 20.0 to 31.3% after 10-12 weeks of treatment and remained stable over another period of 12 weeks. Antihypertensive treatment had to be intensified in five patients. Regional calf blood flow decreased significantly; accordingly, calculated peripheral vascular resistance was increased by more than 100%. However, transcutaneous oxygen pressure (37 degrees C and 44 degrees C) increased significantly. The pathological vasoconstrictor response of skin capillaries was not influenced. There were no significant differences of any parameter between the patients requiring reinforced antihypertensive therapy and those with stable blood pressure. In conclusion skin oxygenation may be improved by erythropoietin treatment to a large extent despite an increase in calculated total limb vascular resistance.

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Microcirculation; Middle Aged; Oxygen; Skin; Vascular Resistance

Although anemia of chronic disease is a common hematologic disorder, the pathogenesis of the disease is still not well understood. Various workers have demonstrated decreased red cell life span, decreased erythropoietin levels, and inappropriate response of the bone marrow to the degree of anemia. The iron metabolism in the anemia of chronic disease is abnormal in that the macrophages in the bone marrow hold onto iron and do not release it for reutilization by the erythroid precursors. More recent studies have focused attention on cytokines produced by macrophages. These are interleukin-1 and tumor necrosis factor. These cytokines appear to be involved in both red cell production and ferrokinetics. Greater understanding of the biology of the cytokines may be the key to understanding the pathogenesis of anemia of chronic disease.

Topics: Anemia; Bacterial Infections; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Interleukin-1; Neoplasms; Tumor Necrosis Factor-alpha

The effects of repeated administration of recombinant human erythropoietin (rHuEPO) were investigated in mice with haemolytic anaemia. Mice with haemolytic anaemia induced by phenylhydrazine (PHZ mice) were examined as an acute model and New Zealand black mice (NZB mice) at 13 months of age were examined as a chronic model. The plasma erythropoietin (EPO) level in PHZ mice was high and showed a strong inverse correlation with the Hb in the anaemia development period. However, it was relatively low in the recovery period from anaemia. On the other hand, the plasma EPO level in NZB mice showed a simple inverse correlation with the Hb. The rHuEPO was injected every day for a week into these mice. While a high plasma EPO level was maintained in PHZ mice, no significant effect was observed by injection with rHuEPO at dose of 600 IU/kg. However, in the recovery period from anaemia, RBC and haemoglobin in PHZ mice were increased by the rHuEPO treatment and recovered more quickly to their normal levels. In NZB mice, RBC and haemoglobin were also increased by treatment with rHuEPO at dose of 600 IU/kg. Anti-RBC autoantibodies and anti-EPO antibodies did not increase, while RBC and plasma EPO levels were increased by the rHuEPO treatment. These results suggest that some types of haemolytic anaemia are not always combined with high endogenous EPO levels and that exogenous rHuEPO may be effective for use in the treatment of haemolytic anaemia.

Topics: Acute Disease; Anemia, Hemolytic; Animals; Antibodies; Blood Group Antigens; Chronic Disease; Erythropoietin; Female; Hemoglobins; Male; Mice; Mice, Inbred NZB; Phenylhydrazines; Recombinant Proteins

Thirty six patients with rheumatoid arthritis (RA) (25 with anaemia) were studied to establish the role of iron, vitamin B12, and folic acid deficiency, erythropoietin responsiveness, and iron absorption in the diagnosis and pathogenesis of anaemia in RA. Iron deficiency, assessed by stainable bone marrow iron content, occurred in 13/25 (52%), vitamin B12 deficiency in 7/24 (29%), and folic acid deficiency in 5/24 (21%) of the anaemic patients. Only 8/25 (32%) had just one type of anaemia. The iron deficiency of anaemia of chronic disease (ACD) was distinguished by ferritin concentration, which was higher in that group. Mean cell volume (MCV) and mean cell haemoglobin (MCH) were lower in both anaemic groups, but most pronounced in iron deficient patients. Folic acid, and especially vitamin B12 deficiency, masked iron deficiency by increasing the MCV and MCH. Iron absorption tended to be highest in iron deficiency and lowest in ACD, suggesting that decreased iron absorption is not a cause of ACD in RA. No specific causes were found for vitamin B12 or folic acid deficiency. Haemoglobin concentration was negatively correlated with erythrocyte sedimentation rate in the group with ACD. Erythropoietin response was lower in ACD than in iron deficient patients. It was concluded that generally more than one type of anaemia is present simultaneously in anaemic patients with RA. The diagnosis of each type may be masked by another. Studies on pathogenesis of the anaemia are difficult as deficiencies generally coexist with ACD. Disease activity and, possibly, erythropoietin responsiveness are major factors in ACD pathogenesis.

Topics: Aged; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Erythropoietin; Female; Folic Acid Deficiency; Humans; Iron Deficiencies; Male; Middle Aged; Vitamin B 12 Deficiency

Immunoreactive serum erythropoietin concentrations were measured in 35 patients with anaemia associated with active rheumatoid arthritis. Based on an evaluation of stainable iron in the bone marrow (marrow iron grade 0-4) and serum ferritin concentrations (concentrations less than or equal to 60 micrograms/l compatible with iron deficiency) the anaemia was found to be complicated by iron deficiency in 19/35 (54%) of the patients. The mean serum erythropoietin level (57.6 (SD) 27.3) U/l) was sufficiently raised for the degree of anaemia irrespective of the size of the marrow iron stores. Thus the data do not support the contention that suppressed secretion of erythropoietin is involved in the pathogenesis of anaemia of chronic disorders. There was a significant inverse correlation between the haemoglobin concentration and log serum erythropoietin in the patients with rheumatoid arthritis. In the patients with adequate iron stores, but not in the iron depleted patients, there was a tendency for serum erythropoietin concentrations to correlate positively both with C reactive protein and erythrocyte sedimentation rate. Red cell distribution width (mean (SD) 16.3 (1.8)%) was above normal (11.5-14.5%) both in the iron replete and the iron depleted patients, and the mean red cell distribution width values did not differ significantly among the two subpopulations. The plasma lactoferrin concentration (mean (SD) 137.6 (109.9) micrograms/l) was normal and did not differ significantly between the iron deficient patients and those with adequate iron.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythrocyte Indices; Erythrocyte Volume; Erythrocytes; Erythropoietin; Female; Ferritins; Humans; Iron; Male; Middle Aged

It was revealed during examination of 91 patients with chronic nonspecific lung diseases for the blood titers of erythropoietin, erythrocytic chalones, erythrocyte hemolysis products and medium molecules that in the stage I respiratory failure, there were no material changes in the titres of erythrocyte hemolysis products, erythropoietin and medium molecules, whereas the titer of erythrocytic chalones appeared to be high. Stage III of the disease was also marked by no changes in the titer of erythrocyte hemolysis products. However, the titers of erythropoietin and medium molecules rose whereas the titer of erythrocytic chalones was reduced. In the stage II respiratory failure, the above enumerated factors of humoral regulation of erythropoiesis appeared similar to those in stage I. These data evidence that different compensatory reactions to hypoxia associated with chronic respiratory failure are implicated at the molecular, cellular and systemic levels. The up-to-date treatment and diagnostic process is not feasible, provided these reactions are not taken into consideration.

Topics: Adaptation, Physiological; Adult; Aged; Bronchitis; Chronic Disease; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Growth Inhibitors; Humans; Male; Middle Aged; Neurotransmitter Agents; Respiratory Insufficiency

Topics: Anemia; Chronic Disease; Erythropoietin; Graft Rejection; Humans; Hypertension; Kidney Transplantation; Recombinant Proteins

A new cell line of human erythroleukemia cells differentiates spontaneously so that 30% of the cells are always hemoglobinized. Erythropoietin did not affect the percentage of such cells but stimulated the cell growth, indicating that the cells have functioning receptors. Binding of human recombinant radioiodinated erythropoietin to the receptors was specific. The bound ligand was internalized into cells at 37 degrees C but not at 15 degrees C. Scatchard analysis showed two classes of binding sites. Covalent binding of erythropoietin to its receptors yielded two products detected on sodium dodecyl sulfate-polyacrylamide gels electrophoresed under reducing conditions. Under non-reducing conditions, these species disappeared and larger products appeared.

Topics: Cell Differentiation; Cell Division; Cell Line; Chronic Disease; Erythropoietin; Humans; Kinetics; Leukemia; Leukemia, Erythroblastic, Acute; Receptors, Cell Surface; Receptors, Erythropoietin; Recombinant Proteins

The growth of normal burst-forming units (BFU-E) is known to depend on a burst-promoting activity (BPA) produced by T-lymphocytes. Few BFU-E colonies have been observed in cultures of blood mononuclear cells (MNC) of uremic patients. The aim of the present study was to examine the concentration of BFU-E in the blood of uremic patients and to evaluate the ability of uremic T-lymphocytes to produce BPA. We have studied 6 chronic uremic patients treated with maintenance hemodialysis. When 5 X 10(5) blood MNC depleted of T-lymphocytes of uremic subjects were stimulated by 1 X 10(6) normal T-lymphocytes in a methylcellulose culture system we observed the growth of a number of BFU-E colonies that did not differ significantly from normal (29 +/- 11.8 colonies). On the contrary, when 5 X 10(5) blood MNC depleted of T-lymphocytes of normal subjects were stimulated by 1 X 10(6) T-lymphocytes of uremic patients, the number of BFU-E colonies obtained was significantly lower than normal (1.9 +/- 3.1 colonies). These data show that the decreased number of BFU-E colonies obtained from blood MNC of uremic patients is due to a defect of uremic T-lymphocytes. The impairment of T-lymphocytes can be due to inhibitors of T-lymphocyte function or to variations in T cell subsets, leading to a decrease in the OKT4/OKT8 cell ratio. In any case it is a significant pathogenetic mechanism contributing to anemia in chronic uremia.

Topics: Adult; Chronic Disease; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Male; Middle Aged; T-Lymphocytes; Uremia

Topics: Acute Disease; Adult; Anemia; Cell Cycle; Chronic Disease; Erythropoiesis; Erythropoietin; Fetal Hemoglobin; Humans; Recombinant Proteins

The erythropoietin (Ep) plasma titre of 41 anaemic patients with normal renal function or with renal insufficiency (with or without kidney) was measured by RIA and compared to values observed with the polycythaemic mouse assay. A good correlation was found with both methods (r = 0.88). However, about 20% of samples gave higher values with the bioassay. 21 Ep titres measurable by the bioassay ranged from 40 to 4400 mU (mean 717.1 mU) compared to 14.8 to 3788 mU (mean 484.7 mU) measured by the RIA. Low levels of Ep plasma titre have been observed in patients with renal insufficiency and no difference was found between nephric uraemic patients and the anephric group. These results suggest that the increased blood requirements in anephrics are not due to a smaller production of Ep, but ultimately to the presence of an inhibitor of erythropoiesis. The well-known inverse relationship between haematocrit and Ep level was not found in renal insufficiency. However, some humoral regulation of erythropoiesis seems to persist in these patients since the elevation of red blood cells by transfusions was followed by a decrease of the Ep level.

Topics: Biological Assay; Chronic Disease; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Nephrons; Radioimmunoassay; Uremia

Serum erythropoietin (ESF) levels and the numbers of marrow and blood erythroid progenitors (CFU-Es) of patients with chronic myeloproliferative disorders (CMPD) were studied simultaneously. The numbers of marrow and blood CFU-Es per 1 x 10(5) cells were normal or greatly elevated. There was an inverse correlation between the hemoglobin concentration and the serum ESF level in patients with chronic myelogenous leukemia when the hemoglobin concentration ranged from 9.0 to 13.0 g/100 ml. The serum ESF level was closely related to the hemoglobin concentration in CMPD and it was suggested that the negative feedback mechanism might operate in anemic patients with CMPD.

Topics: Adult; Animals; Bone Marrow Cells; Cell Count; Chronic Disease; Erythropoietin; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia, Myeloid; Male; Mice; Middle Aged; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis

Topics: Androgens; Chronic Disease; Endocrine Glands; Erythropoietin; Estrogens; Female; Glucocorticoids; Gonadal Steroid Hormones; Humans; Liver Diseases; Male; Prolactin; Renin-Angiotensin System; Thyroid Hormones; Vitamin D

Topics: Anemia; Chronic Disease; Cobalt; Erythropoietin; Ferritins; Humans; Infusions, Parenteral; Intestinal Mucosa; Iron; Kinetics; Mononuclear Phagocyte System; Protoporphyrins

Topics: Anemia; Autoantibodies; Chronic Disease; Erythropoietin; Hemolysis; Humans; Infections; Iron; Neoplasms

During chronic hypoxia, the number of splenic erythroid progenitor cells in mice, particularly CFU-E, increased dramatically but transiently. Since all three classes of erythroid progenitors in the femoral bone marrow were suppressed, a large part of this increase might be attributed to migration of CFU-E and/or their progenitors from the medullary cavity. The changes in CFU-E were preceded 48-72 hours earlier by an increase in serum erythropoietin (Ep) titers which, in turn, had been preceded by a rapid and marked "shift-to-the-right" in the hemoglobin oxygen dissociation curve. During hypoxia, the mice lost a considerable fraction of their body weight. Computer simulations, using a mathematical model of erythropoietic regulation, suggest that this weight loss, either indirectly by reducing the need for red cells in a smaller-than-control animal or by directly altering the sensitivity of the Ep-producing mechanism, is the major cause of the falling Ep titers despite continuation of the hypoxic stress. Because of high endogenous 59Fe incorporation levels, it was not possible to confirm the thesis that animals with an expanded Erythropoietin Responsive Cell (ERC) compartment would be more sensitive to exogenous erythropoietin than are mice with a normal or reduced ERC population.

Topics: Animals; Bone Marrow Cells; Chronic Disease; Colony-Forming Units Assay; Computers; Disease Models, Animal; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Hypoxia; Mice; Mice, Inbred C3H; Spleen

So far the question has not been elucidated whether latent ESF-deficiency exists in patients with chronic renal disease during initial development of renal anemia. Therefore, ESF was determined in urine and serum of non anemic patients being exposed to acute hypoxia: 8 healthy volunteers and 8 patients who had a Ccreat below 48 ml/min were studied while in a hypobaric chamber for 4 subsequent periods of 10 h each (simulated maximal altitude 4000 m INA = 462 mm Hg). We also determined plasma iron turnover and reticulocyte counts. 10 h after the study began, the patients showed a significantly higher ESF-level than the normal volunteers. In the course of 48 h collection periods of urine under hypoxic conditions the mean ESF excretion in patients corresponded to 9.9 and in healthy persons to 7.3 Units. With regard to plasma iron turnover and reticulocyte count an increase was shown, but no significant differences existed between the two groups. A latent ESF-deficiency as the initial cause of renal anemia does not exist.

Topics: Adult; Chronic Disease; Deficiency Diseases; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypoxia; Iron; Kidney Diseases; Male; Middle Aged

Topics: Anemia; Animals; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hypoxia; Kidney; Lead; Lead Poisoning; Male; Rats

The question of a latent erythropoietin (ESF)-deficiency was studied in incipient renal anemia using a double stimulation technique for ESF. After a 4-week stimulation of ESF production with oral administration of fluoxymesterone (flu) intermittent hypoxic ESF stimulation was performed corresponding to a maximum altitude of 4000 m in 7 patients with chronic renal disease without or with incipient renal anemia (mean hematocrit 40%) and in 11 normal subjects (mean hematocrit 46%). Double stimulation in patients was compared with hypoxic stimulation alone and both were compared with controls. After flu alone only ESF excretion was increased in patients and in normal subjects. After flu plus 10 h of hypoxia serum ESF--titers were higher in healthy subjects than in the patients. The mean ESF titer after double stimulation was 81 mU/ml in patients and 115 mU/ml in normal persons. Forty-eight hour ESF excretion was 11 U and 43 U respectively. Compared to hypoxic stimulation alone double stimulation increased serum ESF titers in patients by 5% versus 80% in controls. Correspondingly, ESF excretion was enhanced by 19% and 49%, respectively. Finally, renal ESF clearance was increased by 42% versus 200%. After hypoxia alone non-anemic patients had higher serum ESF titers than healthy controls excluding a latent ESF deficiency in incipient renal anemia. It is concluded that decreased ESF production after double stimulation in patients was due to a nephrotoxic effect of flu followed by a decreased excretory and ESF-producing function of the damaged kidneys.

Topics: Adult; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Fluoxymesterone; Hematocrit; Humans; Hypoxia; Kidney; Kidney Diseases; Male; Reticulocytes

The serum levels of granulocyte colony-stimulating factor (CSF) and erythropoietin (Ep) were measured in 16 patients with iron-deficiency anemia and 15 patients with the anemia of chronic disease. Levels of both CSF and Ep in the serum of patients with iron-deficiency anemia had an inverse linear relationship to the level of the packed cell volume (PCV). There was no correlation between PCV and the levels of CSF or Ep in the serum of patients with the anemia of chronic disease. The similarity in the behavior of CSF and Ep in iron-deficiency anemia suggests that they may be influenced by similar control mechanisms or have a common cellular or molecular source.

Topics: Anemia; Anemia, Hypochromic; Bone Marrow Examination; Chronic Disease; Colony-Stimulating Factors; Erythropoietin; Female; Glycoproteins; Granulocytes; Hematocrit; Humans; Iron; Male

Two mechanisms are felt to be responsible for the production of anemia in patients with chronic diseases. The first is failure to produce adequate amounts of erythropoietin (EP), and the second is failure to deliver iron to the bone marrow in amounts sufficient to support normal erythropoiesis. In order to evaluate these hypotheses we studied urine and serum EP levels and levels of 2,3-diphosphoglycerate in normal subjects, in patients with the anemia of chronic diseases, in patients with chronic liver disease, and in patients with a variety of other anemias. Based on the results, we propose first that insufficient production of EP is one of the major mechanisms responsible for anemia in patients with chronic diseases. Second, insufficient production of EP is, in part, responsible for anemia seen in patients with chronic liver disease. Third, serum and urine EP levels decrease with aging, and this correlates with the fall of hemoglobin levels seen in older normal subjects.

Topics: Aging; Anemia; Chronic Disease; Diphosphoglyceric Acids; Erythropoietin; Humans; Liver Diseases

Topics: Anemia; Animals; Carcinoma 256, Walker; Chronic Disease; Erythrocyte Aging; Erythropoietin; Inflammation; Iron; Liver; Male; Mononuclear Phagocyte System; Rats; Spleen; Turpentine

Topics: Age Factors; Anemia, Hemolytic; Animals; Child; Chronic Disease; Erythropoietin; Female; Humans; Kidney Diseases; Leukemia; Male; Mice; Mice, Inbred BALB C

Topics: Blood Transfusion; Bloodletting; Bone Marrow; Bone Marrow Cells; Chlorambucil; Chronic Disease; Erythrocytes; Erythropoietin; Female; Humans; Leukemia; Liver; Male; Phosphorus Radioisotopes; Polycythemia; Polycythemia Vera; Spleen; United States

Marrow regulation and iron metabolism were evaluated in 17 patients with mild or moderate anemia associated with chronic disorders. In addition, whole blood P50 and red cell 2,3-diphosphoglycerate (DPG) levels were measured. The study group consisted of seven patients with non-hematologic malignancies, nine with infection or inflammation, and one with idiopathic hypoproliferative anemia. The mean whole blood P50 and DPG levels were elevated to 28.5 +/- 1.9 mm Hg and 7.03 +/- 0.83 mumole/ml packed RBC, respectively, as compared to normal values of 26.6 +/- 0.6 mm Hg and 4.83 +/- 0.33 mumole/ml packed RBC. Erythropoietin (ESF) excretion was variable (1.1-28.7 IRP U, day), clearly elevated above normal in only three patients and, within the study group, bore no relation to hematocrit. While nine of the 17 subjects had ESF excretion rates within the 95% limits predicted by hematocrit, the remaining eight had lower than expected values. No significant differences in ferrokinetics, ESF excretion, or hematologic profile were found between patients with malignancy and those with inflammation. Marrow transit times correlated inversely with both serum and urine ESF activity (r = -0.57, p less than 0.02; and r = -0.63, p less than 0.01, respectively), indicating that the marrow reticulocyte release response to ESF stimulation was unimpaired. Erythroid iron turnovers were unrelated to serum or urinary ESF activity but were significantly correlated with serum iron levels expressed as microgram/100 ml whole blood (r = 0.56, p less than 0.02). These studies suggest that there is an intraerythrocytic response to the anemia in this group of patients, document that reduced ESF production is not a uniform finding with the anemia of chronic disorders, and provide evidence that the marrow proliferative response to anemia is limited in many patients primarily by the availability of iron.

Topics: Anemia; Bone Marrow; Chronic Disease; Diphosphoglyceric Acids; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Iron; Male

Two experimental models for pure red cell aplasia (PRCA) were established. In the first one, administration of PRCA serum IgG in normal mice induced a sustained inhibitory effect on erythropoiesis, a progressive decline of the hematocrit values and an inverse rise of erythropoietin (Ep) levels in serum. Thus, the physiopathological pattern of PRCA type I (or A) was established, In the second model a rabbit producing anti-Ep crossreacting with endogenous Ep was subjected to a booster injection of Ep. The rise of the immune response was associated with decrease of Gct values and disappearance of erythroid precursors from marrow smears, and its subsequent decline with reticulocytosis and regression of the anemia, thus reproducing the physiopathological pattern of PRCA type II (or B).

Topics: Anemia, Aplastic; Animals; Autoantibodies; Autoimmune Diseases; Chronic Disease; Disease Models, Animal; Erythropoietin; Immune Sera; Immunoglobulin G; Mice; Rabbits

Topics: Chronic Disease; Erythropoietin; Glomerulonephritis; Humans; Kidney Failure, Chronic; Leukocyte Count; Pyelonephritis; Renal Dialysis; Reticulocytes

Topics: Aged; Animals; Biopsy, Needle; Carcinoma, Hepatocellular; Chronic Disease; Erythropoietin; Female; Fluorouracil; Hemochromatosis; Humans; Liver Neoplasms; Male; Mice; Polycythemia

Topics: Adult; Chronic Disease; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Glomerulonephritis; Hemoglobins; Humans; Infusions, Parenteral; Kidney Diseases, Cystic; Kidney Failure, Chronic; Male; Middle Aged; Plasmapheresis; Pyelonephritis; Reticulocytes

Topics: Adolescent; Child; Child, Preschool; Chronic Disease; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Humans; Male; Pneumonia

Topics: Acute Disease; Child; Chronic Disease; Erythropoietin; Glomerulonephritis; Humans

Topics: Adult; Anemia, Aplastic; Blood Cell Count; Blood Cells; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Reticulocytes; Uremia

Topics: Anemia; Arthritis, Rheumatoid; Blood Proteins; Bone Marrow; Bone Marrow Cells; Chronic Disease; Erythropoietin; gamma-Globulins; Hematocrit; Humans; Infections; Iron; Neoplasms; Protein Biosynthesis; Serum Albumin; Transferrin; Vitamin B 12

Topics: Adult; Animals; Blood Transfusion; Chronic Disease; Creatinine; Erythrocyte Count; Erythropoietin; Female; Glomerulonephritis; Hemoglobins; Humans; Iron; Iron Isotopes; Male; Mice; Mice, Inbred Strains; Middle Aged; Renal Dialysis; Reticulocytes; Time Factors

Topics: Adolescent; Child; Child, Preschool; Chronic Disease; Erythropoietin; Humans; Nephritis

The serum level of erythropoietin was measured in 31 patients with anemia secondary to chronic infection or malignancy and compared with erythropoietin levels in 23 patients with iron-deficiency anemia and 14 patients with primary hematopoietic diseases. Erythropoietin levels varied directly with the degree of anemia in patients with iron deficiency or primary hematopoietic disorders. There was no correlation of erythropoietin and the degree of anemia in patients with chronic infection or malignancy and the erythropoietin levels were significantly lower than in patients with iron deficiency or primary hematopoietic disease and the same degree of anemia. A major factor in the anemia of chronic disorders is a decrease in levels of erythropoietin.

Topics: Anemia; Anemia, Hypochromic; Animals; Biological Assay; Bone Marrow Diseases; Carcinoma; Chronic Disease; Erythropoietin; Hodgkin Disease; Humans; Infections; Lymphoma, Non-Hodgkin; Male; Mice; Middle Aged; Neoplasms; Neutralization Tests

Topics: Anemia, Aplastic; Animals; Ascites; Blood Transfusion; Chronic Disease; Erythropoietin; Female; Glomerulonephritis; Humans; Hydronephrosis; Immune Sera; Iron Isotopes; Kidney Diseases; Kidney Failure, Chronic; Male; Mice; Phenacetin; Pyelonephritis; Renal Dialysis; Uremia

Topics: Animals; Blood Pressure; Chronic Disease; Erythropoiesis; Erythropoietin; Kidney; Mice; Regional Blood Flow; Renal Artery; Renal Veins; Ureteral Obstruction; Vascular Resistance

Topics: Adult; Aged; Anemia, Aplastic; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Prednisolone