Use Of Recombinant Human Erythropoietin Research Articles

Exogenous erythropoietin aggravates retinal neovascularizationin a murine model of proliferative retinopathy

Background/aim: Erythropoietin (EPO) has been proven recently to be a critical mediator in retinal neovascularization (RNV). Previous studies have indicated that the use of recombinant human EPO (rEPO) is a high risk factor in the development of retinopathy of prematurity. In this study, we aimed to investigate the effect of rEPO administration on RNV and its underlying mechanism in a mouse model of oxygen-induced retinopathy (OIR). Materials and methods: A murine model of OIR was used to generate RNV. After daily intraperitoneal injection of rEPO from postnatal day 12 (P12), mice were euthanized at P17. Whole-mount retina staining was used to indicate the nonperfused area and neovascularization tufts. Preretinal neovascular cells were calculated through hematoxylin and eosin staining. The expression levels of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) were detected via western blot analysis. Results: We found that injection of rEPO promoted the severity of RNV. The areas of neovascular tufts and preretinal neovascular cells were increased after administration of rEPO. When mice were injected with rEPO, a dose-dependent upregulation in VEGF and iNOS was observed. Conclusion: The study indicates the proangiogenic role of EPO, suggesting that rEPO contributes to the pathogenesis of RNV.

Treatment with erythropoietin in neonatology

The article presents the basics and con-trol of erythropoiesis in the fetus and the newborn, the development of anaemia of prematurity and its treatment, with an em-phasis on the use of human recombinant erythropoietin. The Intensive Care Unit of the Paediatric Clinic Maribor began treat-ing anaemia of prematurity with eryth-ropoietin in 2000. After introducing the treatment, the clinic found that the num-ber of blood product transfusions and the needed blood volume decreased. In addi-tion to erythropoietin, this was the result of stricter criteria for applying transfusion of concentrated erythrocytes.

Anti-Rh(c), “Little C,” Isoimmunization

The overall prevalence of non-Rh-D isoimmunization seems to lie between 0.15% and 1.1%. Anti-Rh(c) alloimmunization, "little c," occurs in 0.07% of pregnancies and shows a quite broad clinical presentation. Late anemia is a frequent problem occurring in the setting of isoimmunization. It occurs more frequently after intrauterine blood transfusions or exsanguinotransfusion, and it can be thought as a hyporegenerative anemia. The authors describe the use of human recombinant erythropoietin in preventing late anemia in a case of anti-Rh(c) isoimmunization. The use of human recombinant erythropoietin is a valid tool for preventing late-onset anemia due to either anti-Rh-D or non-anti-Rh-D isoimmunization.

Functional significance of erythropoietin in renal cell carcinoma

One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion.

Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10(-4) mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10(-5) mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm(2) (1 dyn = 10(-5) N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.

Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid

The use of human recombinant erythropoietin (EPO) as a neuroprotective agent is limited due to its hematological side effects. An erythropoietin along with a low content of sialic acid (rhEPO b), similar to that produced in the brain during hypoxia, may be used as a neuroprotective agent without risk of thrombotic events. The objective of this investigation was to assess the toxicological potential of a nasal formulation with rhEPO b in acute, subacute and nasal irritation assays in rats. Healthy Wistar rats (Cenp:Wistar) were used for the assays. In an irritation test, animals received 15 μl of rhEPO b into the right nostril. Rats were sacrificed after 24 h and slides of the nasal mucosa tissues were examined. Control and treated groups showed signs of a minimal irritation consisting of week edema and vascular congestion in all animals. In the acute toxicity test, the dose of 47,143 UI/kg was administered by nasal route. Hematological patterns, body weight, relative organ weight, and organ integrity were not affected by single dosing with rhEPO b. In the subacute toxicity test, Wistar rats of both sexes received 6,600 UI/kg/day for 14 days. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, selected tissue weights, and histopathological examinations. An increase of lymphocytes was observed in males that was considered to reflect an immune response to treatment. Histopathological examination of organs and tissues did not reveal treatment-induced changes. The administration of rhEPO b at daily doses of 6,600 UI/kg during 14 days did not produce hematological side effects. These results suggest that rhEPO b could offer the same neuroprotection as EPO, without hematological side effects.

The Erythropoietin NeuroProtective Effect: Assessment in CABG Surgery (TENPEAKS)

Neurocognitive dysfunction complicates coronary artery bypass surgery. Erythropoietin may be neuroprotective. We sought to determine whether human recombinant erythropoietin would reduce the incidence of neurocognitive dysfunction after surgery. We randomly assigned 32 elective first-time coronary artery bypass graft patients to receive placebo or 375 U/kg, 750 U/kg, or 1500 U/kg of recombinant human erythropoietin divided in 3 daily doses, starting the day before surgery. Primary outcomes were feasibility and safety, and secondary outcomes were neurocognitive dysfunction at discharge and 2 months. All subjects were male, mean age 60 years (range 46 to 73). No significant differences were found in pump time, cross-clamp time, or hospital length of stay. Mortality and pure red cell aplasia were not observed. One patient in the 375 U/kg group had ST changes compatible with myocardial injury immediately postoperative, but no other thrombotic complications were observed. Neurocognitive dysfunction occurred in 21/32 (66%) of patients at discharge and 5/32 (16%) at 2 months. Neurocognitive dysfunction at discharge by group was: placebo 6/8 (75%), 375 U/kg 4/8 (50%), 750 U/kg 6/8 (75%), and 1500 U/kg 5/8 (63%). Neurocognitive dysfunction at 2 months by group was: placebo 3/8 (38%), 375 U/kg 1/8 (13%), 750 U/kg 1/8 (13%), and 1500 U/kg 0/8 (0%). Neurocognitive dysfunction at 2 months for erythropoietin at any dose was 2/24 (8.3%) versus 3/8 (38%) for placebo (P=0.085). This study demonstrates feasibility and safety for the use of human recombinant erythropoietin as a neuroprotectant in coronary artery bypass graft surgery. A trend in the reduction of neurocognitive dysfunction at 2 months was associated with erythropoietin use. A multicenter randomized controlled trial is warranted.

Potential mechanisms of adverse outcomes in trials of anemia correction with erythropoietin in chronic kidney disease

Advanced chronic kidney disease (CKD, stages 3–5) is almost invariably associated with anemia that is primarily caused by depressed production of erythropoietin (EPO), oxidative stress and inflammation [1,2]. This can be compounded by iron deficiency that is caused by loss of blood from repetitive laboratory tests, residual blood remaining in the hemodialysis circuits, fistula puncture site bleeding and uremic platelet dysfunction. In addition, when present, hemolytic disorders, bone marrow suppression, nutritional deficiencies, drug toxicities and hereditary diseases exacerbate the CKD-associated anemia. The EPO-deficiency and iron-deficiency components of anemia are routinely corrected with the use of recombinant human EPO and iron preparations. However, presence of severe oxidative stress and inflammation hampers efficacy of EPO and iron in promoting erythropoiesis. In this context, severe persistent anemia despite high doses of EPO and iron is commonly due to oxidative stress and inflammation that may actually be intensified by intravenous iron and EPO administration [3–5]. Observational studies have revealed a strong association between severity of anemia and risk of morbidity and mortality from cardiovascular disease and other causes in CKD patients [6–10]. These findings have been widely interpreted as evidence for the causal role of anemia in the pathogenesis of adverse outcomes in this population. Contrary to expectations, randomized clinical trials of anemia correction revealed either no effect or increased morbidity and mortality in patients assigned to normal hemoglobin (Hb) targets [11–13]. In fact, meta-

Neuroprotective Properties of Erythropoietin in Cerebral Ischemia

Since the human erythropoietin (EPO) gene was cloned in 1983, use of recombinant human EPO (rh-EPO) has become widespread for treating anemia in patients with end stage renal failure. Rh-EPO has a direct effect on haematopoiesis, reflected by increased hemoglobin levels. However, recent studies have shown that nerve cells also have erythropoietin receptors and that this cytokine is made in the nervous system and can function as a neuroprotective agent. In the last decade, it has been shown that EPO exerts general tissue protection including anti-apoptotic, antioxidant and angiogenesis effects. Perhaps best characterized is the mechanism whereby EPO inhibits apoptosis, with the effect believed to occur mostly by activation of the PI-3K-Akt axis or JAK2-STAT5 axis. This anti-apoptotic mechanism is not only important for erythropoiesis, but also appears to play an important role in other processes with high apoptotic activity, such as in stroke, retinal diseases and possibly chronic heart failure and myocardial infarction. Experimental studies in rats have shown that administration of EPO after six hours of arterial occlusion of the middle cerebral artery provided a 50% reduction in infarct size. Moreover, a recent phase 1-2 clinical trial has suggested that EPO can ameliorate neural damage in patients who have had a stroke. In this review, we discuss the neuroprotective properties and the future of rh- EPO therapy in patients with ischaemic stroke.

Routine once-weekly darbepoetin alfa administration is cost-effective in lung cancer patients with chemotherapy-induced anemia: A Markov analysis

Despite the clinical efficacy of recombinant human erythropoietin (RHE) on chemotherapy-induced anemia, most cost-effectiveness studies have given unfavorable results. To determine the cost of managing anemia in unselected patients receiving chemotherapy for lung cancer, and the efficacy and cost-effectiveness of RHE. We constructed Markov models of two cohorts of patients who received (n=94) or did not receive (n=89) darbepoetin (one weekly injection when the hemoglobin level fell below 11 g/dl), focusing on changes in hemoglobin levels, transfusion requirements, anemia management costs, and the cost-effectiveness ratios of the two management strategies. The use of RHE significantly reduced the proportion of patients needing transfusions (from 33.6% to 19.1%, p<0.05) and the number of red cell units used by transfusion (from 2.97+/-1.47 to 2.11+/-0.47, p<0.01). Markov modeling showed that the RHE strategy significantly increased the mean Hb level (13+/-0.5 g/dl versus 11.9+/-1g/dl, p<0.001), at the price of an increase in the main cost (respectively, US$ 1732+/-897 and 996+/-643; p<0.01). The cost-effectiveness ratio favored the RHE strategy (7.02 versus 9.04). Sensitivity analysis showed that the RHE strategy remained dominant in most situations. Routine use of RHE appears to be cost-effective in patients receiving chemotherapy for lung cancer.

A Common Cause of Anemia in Inflammatory Disorders: Anemia of Chronic Disease

Anemia of chronic disease (ACD), one of the most common syndromes in medicine, is observed in patients with chronic infections, inflammatory and neoplastic disorders. All of the factors involved in the development of ACD can be attributed to effects of 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. Tumor Necrosis Factor-alpha (TNF! ), which is important for the pathophysiology of ACD, may act directly on bone marrow erythroid precursors. Hepcidin is a liver-made peptide, and its synthesis is greatly stimulated by inflammation. The plasma level of erythropoietin (EPO) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Interleukin 1 and TNF! suppress EPO gene expression. ACD is most effectively treated via approaches directed against the underlying cause. There are also some reports addressing that iron supplementation and iron chelation therapy may be useful. If this is not possible, supportive care is given through red cell transfusions or use of recombinant human EPO. Patients with inflammatory disorders showed remarkable hematologic responses to recombinant EPO, although a significant change in rheumatologic picture was not seen.

Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity.

Human recombinant erythropoietin has been studied extensively as treatment for a variety of anemias. Since in vitro studies showed the primary etiology of the anemia of prematurity to be insufficient serum erythropoietin concentrations, clinical trials have evaluated the administration of human recombinant erythropoietin to preterm infants to treat this indication. These studies were followed by pharmacokinetic determinations in animal models and preterm infants, which revealed that preterm infants required greater doses of human recombinant erythropoietin because of a more rapid clearance and greater volume of distribution. Recent studies have focused on the administration of human recombinant erythropoietin in the first weeks of life to alleviate the anemia caused by excessive phlebotomy losses, and to prevent the anemia of prematurity. In addition, human recombinant erythropoietin has been tried clinically in a variety of neonatal populations in an attempt to decrease or eliminate transfusions. Although much information has been accumulated about the clinical use of human recombinant erythropoietin in preterm infants over the last 15 years, many questions remain unanswered. The evolution of clinical practice in the care of extremely low birthweight infants continues to affect the number of transfusions. It is likely that human recombinant erythropoietin administration in combination with instituting rigorous transfusion guidelines and decreasing phlebotomy losses will have the greatest impact in decreasing transfusion requirements in all preterm and term neonates, regardless of the etiology of their anemia.

Practice Trends in the Management of Low Hematocrit in the Acute Rehabilitation Setting

To examine current clinical practice regarding the management of anemic patients in the acute rehabilitation setting. Ninety-four medical directors of inpatient rehabilitation units were surveyed on their use of transfusion thresholds and human recombinant erythropoietin. Factors affecting their clinical decision making were assessed. The majority of physicians responded that they recommend red cell transfusion in patients with a hematocrit <25%. When a history of cardiovascular disease and advanced age was present, more physicians were likely to transfuse at higher hematocrit levels. Forty-six percent of physicians reported recommending the use of human recombinant erythropoietin in anemic patients. Only 30% of respondents classified their clinical management of anemia as evidence based. Clinical practice guidelines should be developed to aid the rehabilitation medicine specialist in the management of anemic patients in the acute rehabilitation setting. Further study of the relationship between hematocrit level, tolerance for therapeutic exercise, and long-term functional outcome is indicated.

Erythropoietin response is inadequate in cancer patients receiving chemotherapy.

The level of serum erythropoietin (EPO) is inappropriately decreased in cancer patients and has been advocated as the main cause of their anemia. In cancer patients, chemotherapy results in a cumulative anemia severe enough to require transfusion. We investigated the changes in serum EPO, hemoglobin, ceruloplasmin, and copper levels in cancer patients receiving chemotherapy. There was a weak but significant inverse relationship between hemoglobin and log[EPO] (r = -0.41; P < .001). Observed/expected serum EPO ratios decline with repeated chemotherapy indicating inadequate EPO response for the degree of anemia. There was no difference in the severity of anemia and in the degree of EPO response between platinum- and non-platinum-treated patients. Ceruloplasmin, copper, and ferritin levels did not change during chemotherapy. Our results suggest that the EPO response is inadequate for the degree of anemia and justifies the use of recombinant human EPO in cancer patients receiving chemotherapy.

Erythropoietin.

Maintenance of the red cell volume is a fundamental aspect of ensuring oxygen supply to the tissues. The balance between the very dynamic processes of erythropoiesis and erythrocyte loss is precarious and yet normal individuals experience a remarkably constant haematocrit. This is achieved by a very elegant and sensitive homeostatic mechanism which links tissue oxygen delivery to red cell production. The glycoprotein hormone erythropoietin (EPO) is the principle controller of this process. It is now clear that even minor underproduction of EPO will result in anaemia. The most widespread example of this is the anaemia of end-stage renal failure. The pharmacological use of recombinant human EPO (rHuEPO) in this setting is now well established and has had a dramatic impact on the quality of life of patients with renal disease. With the more widespread use of EPO in other clinical conditions and the advent of novel therapeutic approaches, this is an opportune moment to review the physiology and patho-physiology of this fascinating and essential hormone.

Transfusion malgré érythropoïétine recombinante : échec ou limite du traitement ? Étude d’une cohorte annuelle de poids de naissance inférieur à 1 500 g

Despite early use of human recombinant erythropoietin, blood transfusions did not disappear during the neonatal period. Study. – Prospective, observative study. Setting. – Neonatal intensive care unit in a university tertiary care hospital. Aims. – 1) Assessment of blood transfusion requirement. 2) Demonstration of haematocrit and hemoglobin level difference at birth between transfused and non-transfused infants. 3) Assessment of iron mass before and after early iron supplementation. Population. – All premature infants without cardiopathy, surgical diseases, hemolysis or haemorrhage, at less than 30 weeks of gestational age or less than 32 weeks, weighing less than 1,500 grams, with respiratory distress syndrome admitted into the unit during the year 1998, were included in the study. Each received erythropoietin (750 U·kg –1·wk –1) with intravenous iron supplements from day 5 (0.017 mmol·kg –1·d –1), then orally (0.17 mmol·kg –1·d –1). Results. – Seventy-nine premature infants were included in this study. 1) Sixty-seven percent of the transfusions occurred during the first 14 days of life. 2) Haematocrit and hemoglobin levels at birth were significantly different between transfused and non-transfused infants (P < 0.001) and remained different for infants of less than 28 weeks (P < 0.01). 3) After six weeks of iron supplementation (mean 0.31 mmol/kg), the ferritin level had significantly decreased in the non-transfused (P < 0.001) and transfused population (P < 0.01). Conclusion. – Increasing the haematocrit and the hemoglobin levels at birth, for example by placento-fetal transfusion, could decrease the number of early transfusions. Early intravenous iron supplementation had no side effects but did not maintain iron levels.

Use of human recombinant erythropoietin and prednisone for treatment of myelodysplastic syndrome with erythroid predominance in a dog

Use of human recombinant erythropoietin and prednisone for treatment of myelodysplastic syndrome with erythroid predominance in a dog

Maternal and Perinatal Implications of the Use of Human Recombinant Erythropoietin

Background. The use of human recombinant erythropoietin (rHuEPO) in pregnant patients has been limited by the fear of eventual maternal and fetal repercussions (either direct or indirect).Methods. The authors present their experience with the use of rHuEPO during pregnancy, with two pregnant women with kidney transplants and in three others with chronic renal insufficiency (one with diabetic nephropathy, another dialysis dependent), all with hematocrit below 30% and adequate iron reserves.Results. Three of the patients had needed blood transfusions before beginning therapy, and another needed transfusion after significant metrorrhagia. The length of the treatment varied between 2 and 23 weeks and the hematocrit at delivery varied between 26% and 36%. Secondary effects (appearance or worsening of hypertension and seizures) were nil. There was one fetal death at 23 weeks of pregnancy (following an abruptio placentce), two neonates weighing between the 5th and the 10th percentiles, and three needing photothe...

Experience in the use of human recombinant erythropoietin (rHuEPO) in cancer patient with anemia

Experience in the use of human recombinant erythropoietin (rHuEPO) in cancer patient with anemia

Relationships between plasma ferritin and aminotransferase profile in haemodialysis patients with hepatitis C virus

HCV infection is a major complication among patients undergoing dialysis therapy throughout the world. In the years prior to the use of human recombinant erythropoietin (rHuEpo), patients undergoing haemodialysis were subjected to an excessive iron load as a consequence of frequent blood transfusions. Recent data in the non-dialysis population have shown a positive correlation between iron deposits and the severity of HCV hepatitis and between iron deposition and an impaired response to interferon therapy. One hundred and five haemodialysis patients were studied. Every patient was screened for HCV infection by ELISA II and HCV RNA. Serum biochemistries were analysed by SMAC20. Ferritin was measured by radioimmunoassay. The aminotransferase levels for the HCV positive (n = 39) and negative patients (n = 66) were below the normal levels for the general population. The mean values of aminotransferases and plasma ferritin were, however, higher in the HCV-positive patients than in the HCV-negative patients. A positive correlation between aminotransferases and plasma ferritin was evident in HCV-positive patients, which was absent in the HCV-negative individuals. The histological severity of liver disease (n = 7) was, however, not statistically related with the levels of either ferritin or aminotransferases. HCV infection is a relevant variable when estimating iron deposits by measuring plasma ferritin. Accordingly, a misinterpretation of the actual amount of iron deposits may occur in HCV-positive patients, which should be taken into account at the time of planning their iron reposition therapy. On the other hand, the level of iron deposits might have a significant role in the evolution of HCV-related liver disease.