Erythropoietin Deficiency Research Articles

An update on the controversies in anemia management in chronic kidney disease: lessons learned and lost.

Background. Erythropoietin deficiency and anemia occur in Chronic Kidney Disease (CKD) and may be treated with Erythropoietin Stimulating Agents (ESAs). The optimal hemoglobin, in non-End Stage Renal Disease CKD, is controversial. Methods. We review three recent randomized trials in anemia in CKD: CHOIR, CREATE, and TREAT. Results. CHOIR (N = 1432) was terminated early with more frequent death and cardiovascular outcomes in the higher Hb group (HR 1.34: 95% C.I. 1.03–1.74, P = .03). CREATE (N = 603) showed no difference in primary cardiovascular endpoints. Stroke was more common in the higher Hb group (HR 1.92; 95% C.I. 1.38–2.68; P < .001) in TREAT (N = 4038). Conclusions. There is no benefit to an Hb outside the 10–12 g/dL range in this population. To avoid transfusions and improve Quality of Life, ESAs should be used cautiously, especially in patients with Diabetes, CKD, risk factors for stroke, and ESA resistance.

Complete correction of anemia by erythropoiesis-stimulating agents is associated with insulin resistance in hemodialysis patients

Insulin resistance and anemia secondary to erythropoietin deficiency characterize patients with end-stage kidney disease. In a cross-sectional analysis, we examined the relationship between erythropoietin-mediated correction of anemia and insulin sensitivity in nondiabetic hemodialysis patients. Insulin sensitivity (euglycemic-hyperinsulinemic clamp) and endogenous glucose production (primed-continuous infusion of [6,6-(2)H(2)]glucose) were determined in two groups of patients with normal hemoglobin (n:8; mean hemoglobin: 14.0±0.3g/dl) or with mild anemia (n:10; mean hemoglobin: 12.1±0.9g/dl). The patients with normal hemoglobin were receiving higher (P<0.05) erythropoietin doses than those with mild anemia (171±73 and 91±39Ukg(-1)wk(-1), respectively). The two groups were matched for all other potential determinants of insulin resistance. Endogenous glucose production was similar in the two groups of patients in the postabsorptive state and was completely suppressed by insulin infusion. During the hyperinsulinemic clamp, the rate of glucose infusion to maintain euglycemia was significantly lower (P<0.01) in the patients with normal hemoglobin levels [166±31mg(m(2))(-1)min(-1)] than in those with mild anemia [251±49mg(m(2))(-1)min(-1)] and in a group of matched controls [275±68mg(m(2))(-1)min(-1)]. In pooled patients, individual values of hemoglobin concentrations inversely correlated with the rates of insulin-mediated glucose infusion, both as absolute values (r=-0.58; P<0.05) and as values normalized by steady-state plasma insulin concentration (r=-0.74; P<0.001). In conclusion, this exploratory study indicates that complete correction of anemia by erythropoietin treatment in patients with end-stage kidney disease on hemodialysis is associated with impaired insulin sensitivity.

A mouse model for an erythropoietin-deficiency anemia

In mammals, the production of red blood cells is tightly regulated by the growth factor erythropoietin (EPO). Mice lacking a functional Epo gene are embryonic lethal, and studying erythropoiesis in EPO-deficient adult animals has therefore been limited. In order to obtain a preclinical model for an EPO-deficient anemia, we developed a mouse in which Epo can be silenced by Cre recombinase. After induction of Cre activity, Epo(KO/flox) mice experience a significant reduction of serum EPO levels and consequently develop a chronic, normocytic and normochromic anemia. Furthermore, compared with wild-type mice, Epo expression in Epo(KO/flox) mice is dramatically reduced in the kidney, and expression of a well-known target gene of EPO signaling, Bcl2l1, is reduced in the bone marrow. These observations are similar to the clinical display of anemia in patients with chronic kidney disease. In addition, during stress-induced erythropoiesis these mice display the same recovery rate as their heterozygous counterparts. Taken together, these results demonstrate that this model can serve as a valuable preclinical model for the anemia of EPO deficiency, as well as a tool for the study of stress-induced erythropoiesis during limiting conditions of EPO.

Anemia in Chronic Kidney Disease: New Advances

Anemia resulting from iron and erythropoietin deficiencies is a common complication of advanced chronic kidney disease (CKD). This article covers major advances in our understanding of anemia in patients with CKD, including newly discovered regulatory molecules, such as hepcidin, to innovative intravenous iron therapies. The use of erythropoiesis-stimulating agents (ESA) in the treatment of anemia has undergone seismic shift in the past 3 years as a result of adverse outcomes associated with targeting higher hemoglobin levels with these agents. Potential mechanisms for adverse outcomes, such as higher mortality, are discussed. Despite the disappointing experience with ESAs, there is a tremendous interest in other novel agents to treat anemia in CKD. Lastly, while awaiting updated guidelines, the authors outline their recommendations on how to best manage patients who are anemic and have CKD.

Future Directions in Management of Anemia in Heart Failure

Anemia in patients with heart failure (HF) may be caused by several factors, including hemodilution, iron or erythropoietin deficiency, and chronic kidney disease. Published pilot studies of erythropoiesis-stimulating agents (ESAs) and intravenous iron therapy in anemic heart failure patients demonstrate improvement in surrogate markers of functional capacity and quality of life, and reasonable safety profile during short-term use. However, the long-term safety of ESA in treatment of anemia in patients with HF remains a concern due to documented harmful side effects of ESA in anemic patients with advanced chronic kidney disease and cancer. Ongoing prospective clinical outcomes studies of ESA and intravenous iron therapies will provide important data that may pave the way for new avenues in the treatment of anemia in the future.

Deficiência de ferro na doença renal crônica

Anemia é uma complicação quase universal nos pacientes em estágios avançados de doença renal crônica (DRC). Ela está associada com maior número de internações hospitalares, maior mortalidade e pior qualidade de vida dos pacientes. Ela tem várias causas, sendo deficiência de eritropoetina e ferro as duas principais causas. A condição inflamatória presente na DRC interfere com a ação da eritropoetina e com a absorção intestinal de ferro e mobilização de ferro dos estoques, devido ao aumento de hepcidina. A correção parcial (não completa) da anemia promove melhores resultados nos pacientes com DRC.

Prevalence and nature of anaemia in a prospective, population‐based sample of people with diabetes: Teesside anaemia in diabetes (TAD) study

Anaemia occurs in 25% of people attending hospital diabetes clinics, but this may not be representative of all people with diabetes. We aimed to determine the prevalence of anaemia in a prospective population-based sample stratified by estimated glomerular filtration rate (eGFR) using the 4-point Modification of Diet in Renal Disease (MDRD) formula. All 7331 patients on our district register were stratified by eGFR. Seven hundred and thirty were approached by letter on two occasions. Two hundred and thirty-four (32%) returned questionnaires and blood samples. Responders (R), non-responders (NR) and the whole cohort (C) were similar: mean +/- sd age R 61.7 +/- 12.7 years; NR 61.3 +/- 15.1 years; C 61.8 +/- 14.2 years; diabetes duration R 8.8 +/- 8.6 years; NR 8.2 +/- 7.9 years; C 7.5 +/- 7.8 years, Type 1 diabetes R 10.1%, NR 10.8%, C 9.4%. Anaemia was defined using World Health Organization criteria: haemoglobin < 13 g/dl for men, < 12 g/dl for women. Previously undiagnosed anaemia was present in 15% of the whole group, 36% with eGFR < 60 ml/min per 1.73 m(2) and 9% of those with eGFR > 60 ml/min per 1.73 m(2). Anaemia was as a result of erythropoietin deficiency in 34%, abnormal haematinics in 40% and was unexplained in 26% of patients. Five per cent of the patients had anaemia below the treatment threshold of 11 g/dl. The prevalence of unrecognized anaemia in population-based cohorts is lower than that in hospital-based studies. Current clinical surveillance in the UK is failing to detect anaemia in stage 3-5 chronic kidney disease (eGFR < 60 ml/min per 1.73 m(2)) and current guidelines will not detect 9% of diabetic patients with anaemia and an eGFR > 60 ml/min per 1.73 m(2).

Prolonged anemia in an intrauterine‐transfused neonate with Rh‐hemolytic disease: no evidence for anti‐D–related suppression of erythropoiesis in vitro

Rh-hemolytic disease may be complicated in some cases by a prolonged postnatal anemia with an extended need for postnatal red blood cell (RBC) transfusion. Besides ongoing hemolysis, marrow suppression and erythropoietin (EPO) deficiency are discussed as underlying mechanisms of this so-called "late hyporegenerative anemia." We present a case of a newborn with Rh-hemolytic disease caused by anti-D who received several intrauterine RBC transfusions. After birth, no reticulocytes or D+ RBCs were detectable in peripheral blood of the infant; thus further RBC transfusions were necessary. Administration of intravenous immunoglobulins had no obvious effect. Reticulocytes first became detectable 15 weeks after birth, when anti-D titer had decreased to 16. A few days later, hemoglobin started to increase and no further treatment was necessary. To investigate whether anti-D is able to cause maturation arrest of erythroid progenitors, maternal serum was added to an in vitro assay of erythropoiesis, induced from human CD34+ cells. In this case, no variables of hemolysis (e.g., elevated bilirubin) were observed. The EPO level was normal and a marrow sample showed increased erythropoiesis. The in vitro erythropoiesis assay revealed no influence of anti-D on RBC proliferation and differentiation. Anemia in our patient seemed to be mainly caused by ongoing intramedullar hemolysis due to persistent high anti-D titers. In such cases, variables for hemolysis are not necessarily found. Release of patient's own RBCs into the circulation may become sufficient when anti-D has declined to a very low level of approximately 16.

Posttransplant anemia in solid organ recipients

Posttransplantation anemia (PTA) is a prevalent sequela of solid organ transplantation and a potential independent risk factor for cardiovascular morbidity and mortality in kidney transplant recipients. There are multiple causes of PTA, some of which are associated with early phase anemia (<6 months), whereas others more often induce anemia in the late posttransplant phase (>6 months). Although impaired kidney function contributes to PTA, it is only one of many factors that result in anemia in transplant recipients. Other causes include iron deficiency, medications, infections, acute rejection, inflammation, and erythropoietin deficiency. Unlike in the predialysis chronic kidney disease population, the impact of anemia after kidney transplantation outcomes is unknown. This is in large part due to the absence of controlled trials that address whether correction of anemia improves allograft function or patient morbidity and mortality. Current guidelines recommend evaluation for hemoglobin level of less than 12 g/dL and treatment when the value falls less than 11 g/dL and a target of 11 to 12 g/dL. Additional treatments may entail removing the cause of the anemia, nutritional supplementation, and/or an erythrocyte stimulating agent.

Recombinant Human Erythropoietin Therapy in Predialysis Patients of Chronic Kidney disease

Renal anemia is a well recognized complication of chronic kidney disease with erythropoietin deficiency being the primary cause. Erythropoiesis-stimulating agents (ESAs), introduced almost two decades ago, have replaced blood transfusions as first line therapy for anemia. They have been shown to markedly improve the quality of life but the effects on blood pressure and rate of progression of disease are still a matter of controversy. This prospective interventional study aimed to determine the efficacy and safety of recombinant human erythropoietin therapy (rHuEPO) in correction of renal anemia, ascertain its effect on progression of renal excretory function and assess the quality of life in predialysis patients of chronic renal failure. We prospectively studied 50 anemic (hemoglobin levels &lt;10.0 g/dL) predialysis patients of chronic renal failure (GFR between 15–90 mL/min/1.73 m2). The children, under 14 years of age, and were randomly selected in the outpatient clinic at The Children's Hospital and Institute of Child Health Lahore, Pakistan between July 2007 to June 2008. These patients were treated with rHuEPO for 48 weeks. The maintenance dose of subcutaneous rHuEPO used was 100 U/kg/week given twice weekly along with oral iron and folate supplementation. Patients underwent clinical and laboratory evaluation during the trial period. GFR was calculated using the Schwartz formula. The mean age of the children enrolled in the study was 7.68 years at presentation with male to female ratio of 1.63. Hemoglobin and GFR values before initiation of rHuEPO treatment were 8.20∓1.28 g/dL and 29.82∓12.00 mL/min/1.73 m2 as compared to the final results of 10.94∓1.04 g/dL and 32.36∓11.24 mL/min/1.73 m2, respectively. Only 4 (8%) patients developed end – stage renal disease by the end of the study period and had to begin dialysis while others continued with the conservative management of chronic renal failure. No significant side – effects were seen in any of the study population like hypertension, seizures or hyperviscosity syndrome, except 3 (6%) children who required increase in dose of antihypertensive medication. The health – related quality of life improved in terms of physical performance and sense of well being in the majority of subjects. Our study provides conclusive evidence that rHuEPO therapy is beneficial for correction of renal anemia with substantial retardation of maintenance dialysis in the majority of predialysis patients with chronic kidney disease.

Potential for erythropoietin synthesis in kidney of uraemic rat alters depending on severity of renal failure

Renal anaemia is a common early complication of chronic renal failure (CRF) that is characterized by relative erythropoietin (EPO) deficiency. Although a lowered renal function is considered to induce limited EPO production, potential EPO production capacity in CRF remains unclear. The aim of this study was to determine the mechanisms underlying this relative deficiency. Male Sprague-Dawley rats were underwent 5/6 nephrectomy with different severities of CRF. These rats were assigned to two groups - mild CRF or advanced CRF - and subjected to haemodilution by exchange of blood with Ringer's solution or haemoconcentration by blood transfusion. Serum EPO and EPO transcript levels in remnant kidney were examined. Expression levels of hypoxia-related genes, including heme oxygenase-1 (HO-1) and glucose transporter-1 (Glut-1), were also examined. Haemodilution increased both serum EPO and EPO transcript levels in mild CRF, as observed in sham-operated controls, whereas the extents of such increases were significantly smaller in advanced CRF. HO-1 and Glut-1 transcript levels also increased by haemodilution in mild CRF, but not in advanced CRF. Haemoconcentration markedly decreased serum EPO and EPO transcript levels in mild CRF as in controls. Rats with advanced CRF did not survive after blood transfusion. Potential EPO regulation capacity in mild CRF is as conserved as that in normal control, whereas that in advanced CRF is impaired, suggesting that underlying mechanisms of low EPO production alters according to the stage of CRF.

Anemia in renal disease: Diagnosis and management

Chronic kidney disease (CKD) is a widespread health problem in the world and anemia is a common complication. Anemia conveys significant risk for cardiovascular disease, faster progression of renal failure and decreased quality of life. Patients with CKD can have anemia for many reasons, including but not invariably their renal insufficiency. These patients require a thorough evaluation to identify and correct causes of anemia other than erythropoietin deficiency. The mainstay of treatment of anemia secondary to CKD has become erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and these agents need to be used judiciously. Iron deficiency often co-exists in this population and must be evaluated and treated. Correction of iron deficiency can improve anemia and reduce ESA requirements. Partial, but not complete, correction of anemia is associated with improved outcomes in patients with CKD.

Erythroid-Stimulating Agents in Cancer Therapy: Potential Dangers and Biologic Mechanisms

Erythropoietin-stimulating agents (ESAs) were originally designed to replace endogenous erythropoietin in patients with anemia secondary to renal failure. Their use has subsequently been expanded to include patients with anemia of other causes, including cancer patients, in whom deficiency of erythropoietin, per se, is not the primary cause of anemia. Although early studies showed promise of ESA administration in reducing the need for transfusions and improving the quality of life in cancer patients, several large randomized clinical trials have recently shown a potential detrimental effect of ESA administration on tumor progression and survival in these patients. These studies have called into question the safety of ESAs as supportive therapy in patients being treated for oncologic conditions. However, numerous questions remain to be addressed regarding the design of these studies, the effect of various targeted hemoglobin levels, and the potential biologic mechanisms proposed to explain promotion of tumor progression and reduced survival.

Resolved

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Disease-Related Anemia in Chronic Lymphocytic Leukemia Is Not Due to Intrinsic Defects of Erythroid Precursors: A Possible Pathogenetic Role for Tumor Necrosis Factor-Alpha

Background/Aims: Disease-related anemia in chronic lymphocytic leukemia (CLL) occurs when the obvious causes are excluded while its pathogenesis is still obscure. We investigated its underlying mechanisms in 56 untreated patients with CLL. Methods: Bone marrow (BM) lymphocytic infiltration was estimated in trephine biopsies. Serum erythropoietin (EPO) and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. The potential of BM CD34+ to differentiate into erythroid cells was evaluated by methylcellulose-based assays and in liquid cultures supplemented with EPO, SCF, IL-3 ± TNF-α. The response of erythroid precursors to EPO ± TNF-α was assessed by detecting activated key proteins of EPO-EPO receptor signalling pathway using Western Blot and EMSA. Results: Bone marrow lymphocytic infiltration was not exclusively responsible for disease-related anemia and CD34+ cells were intrinsically capable of generating erythroid precursors. Also, no deficiency of serum erythropoietin (EPO) or defective intracellular response of erythroid precursors to EPO ± TNF-α stimulation was observed. Serum TNF-α levels were found increased in anemic CLL patients and TNF-α appeared to directly inhibit the erythroid development in early stages of erythropoiesis. Conclusion: We concluded that CLL-related anemia was not due to intrinsic defects of erythroid precursors, but might result from the direct suppressive effect of TNF-α on the erythroid production.

Drug safety profile of darbepoetin alfa for anemia of chronic kidney disease

Anemia of chronic kidney disease due to deficiency of erythropoietin is common and has clinical consequences. Erythropoiesis stimulating agents including darbepoetin alfa (DA) are effective in correcting anemia. DA is generally well tolerated and has side effect profile similar to recombinant human erythropoietin. It has a long half-life permitting infrequent dosing. DA has been tested extensively in preclinical and clinical studies and significant experience has accumulated in clinical practice. Global safety profile of DA must consider recent data indicating worse survival, poor cardiovascular outcomes and thrombotic risks of targeting near normal hemoglobin levels and administering high doses of erythropoiesis stimulating agents. Strategies to achieve and maintain a reasonable, individualized target hemoglobin level with minimal variations in hemoglobin level are needed.

Casting Doubt on the Safety of “Off-the-shelf” Mesenchymal Stem Cells for Cell Therapy

Mesenchymal stem cells (MSCs) show promise for gene delivery to treat various diseases such as anemia and stroke, as well as other oncological and neural disorders.1,2 In this issue of Molecular Therapy, Campeau et al.3 report on an experimental model that compares the responses of allogeneic and syngeneic hosts to the transfer of erythropoietin (EPO)-expressing MSCs. The studies were based on the premise that EPO could be delivered using genetically modified MSCs to treat anemia or myocardial infarction. The treatment of anemia with expanded autologous MSCs seems plausible, in that the chronic nature of anemia is compatible with the time needed to expand bone marrow−derived MSCs to sufficient numbers. However, in the case of acute disorders such as myocardial infarction and stroke,4,5 gene delivery interventions would have to be immediate, thereby eliminating autologous gene-modified MSCs as an option. Because MSCs have been reported to suppress allogeneic responses, in particular graft-versus-host disease,6,7,8 “off-the-shelf” sources of such cells have been proposed to treat various clinical disorders that require intervention at early time points.

En 50 år gammel kvinne med høyt hemoglobinnivå og jernmangel

Elevated haemoglobin and erythrocytosis are frequent causes for investigation. A 50-year-old woman with elevated haemoglobin and erythrocytosis was referred to our hospital for investigation. She had elevated serum erythropoietin and iron deficiency. Mutational status of the JAK2 gene was negative with respect to polycythemia vera, and no secondary reasons for polycythemia - including tumours - were revealed. A bone marrow biopsy and bone marrow smear showed a moderately increased number of lambda- positive monoclonal plasma cells, and small amounts of lambda light chains were detected in the urine. Serum electrophoreses showed no gammopathy. The reason for her elevated haemoglobin could be an erythropoietin-producing tumour or an idiopathic erythrocytosis based on a mutation in exon 12 of the JAK2 gene. Investigation of her plasma cells revealed a 10-fold increase in erythropoietin mRNA expression, indicating the reason for her elevated serum erythropoietin and haemoglobin values.

Treatment of Anemia Associated with Chronic Kidney Disease with Methoxy Polyethylene Glycol-Epoetin Beta

Anemia resulting from a relative deficiency of erythropoietin commonly complicates chronic kidney disease (CKD). With the introduction of recombinant erythropoietin two decades ago, there has been a dramatic reduction in the need for blood transfusions in CKD patients. Epoetin alpha is a first generation erythropoiesis stimulating agent (ESA) that needs to be administered frequently because of its short half-life. Methoxy ethylene glycol-epoetin beta is a longer acting ESA that acts as a continuous erythropoietin receptor activator and is given once every 2 to 4 weeks. In short term clinical studies, Methoxy polyethylene glycol-epoetin beta has been observed to be comparable with other ESAs with regard to safety and efficacy in maintaining hemoglobin levels in the target range. However, hemoglobin is no longer a clinically valid surrogate for safety i.e. correction of anemia does not translate into better clinical outcome. Long term studies evaluating hard end-points such as death and cardiovascular events are lacking. Methoxy polyethylene glycol-epoetin beta has been approved for use in the European Union since 2007 while its use in the United States is prohibited on legal grounds.

Significance of, and Difficulty in Diagnosing, Erythropoietin Deficiency in Sickle Cell Anemia

The clinical diagnosis of erythropoietin deficiency is usually prompted by new onset anemia on a background of elevated serum creatinine, and is then confirmed by measurement of serum erythropoietin. In patients with sickle cell anemia (SCA), who are already anemic, and in whom base-line creatinine and erythropoietin levels tend to run low, it is easy to miss this diagnosis. We demonstrate the clinical significance of erythropoietin deficiency in SCA and suggest alternative criteria for considering this diagnosis. Compensatory reticulocytosis maintains hemoglobin levels compatible with life in the chronic hemolytic anemia of SCA. Relative reticulocytopenia (RR) has been defined by the Multi-Center Study of Hydroxyurea Follow-Up Study (MSH-FU) as reticulocytes <250×109/L despite hemoglobin <9g/dl and is associated with decreased survival. However, to effectively address RR as a possible cause of early death, its underlying cause(s) must be defined. In a population of 433 SCA adult patients followed in our outpatient clinic between 1997 and 2008, 47 patients had consecutive out-patient laboratory values that met the MSH-FU definition of RR. In these patients, the mortality rate for those with RR was 55% compared to 7% in the patients without RR. Median survival from the initial clinic visit was 383 weeks for patients with RR but was not reached for patients without RR. Despite their increased risk for mortality, patients with RR did not have more frequent vaso-occlusive crises or emergency room (ER) visits (ie., ER visit frequency was a poor indicator of this population at risk).SCA causes multi-organ damage, therefore, RR could result from decreased bone marrow function, from renal damage causing a decrease in erythropoietin levels, or from both processes. In univariate analyses, RR was significantly associated with thrombocytopenia, leucopenia, elevated serum creatinine and proteinuria (p<0.001 Chi-Square). This suggested that both global bone marrow function and renal damage causing erythropoietin deficiency could be contributing to RR. This was confirmed in multi-variate analyses, in which both platelet counts and proteinuria were significantly associated with RR (p<0.0001, logistic regression). Erythropoietin levels, and the erythropoietin/reticulocyte ratio, were especially low in RR patients with hemoglobin levels <8g/dl, suggesting that erythropoietin deficiency was the major cause of RR in patients with the greatest declines in hemoglobin.Importantly, the erythropoietin/reticulocyte ratios that implicated erythropoietin deficiency in the etiology of RR were mostly noted in patients who did not meet standard clinical definitions of chronic renal failure: < 30% of the patients with RR had serum creatinine levels >1.1 or calculated creatinine clearance <60ml/min. However, 87% of the patients with RR had proteinuria as evidence of renal damage. Therefore, early renal damage, sufficient to cause proteinuria, but insufficient to cause azotemia, was associated with clinically significant erythropoietin deficiency in SCA.In conclusion, RR in adult SCA is not associated with more frequent vaso-occlusive crises but nonetheless has a major association with mortality. An important and potentially correctable cause of RR is erythropoietin deficiency, which can be diagnosed in patients with early renal damage manifest by proteinuria but without azotemia. This sub-set of SCA patients requires more study, including evaluation for the causes of death, and the possible benefits of erythropoietin replacement therapy, using end-point criteria such as survival or progression of chronic organ damage (for eg., left-ventricular dysfunction) rather than vaso-occlusive crisis frequency.