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BackgroundAnemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise.MethodsWe included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4–5 (2009–15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb ≥10 g/dL 91–120 days after HD start (Month 4).ResultsAbout 53% of these patients had Hgb ConclusionsEven among patients with Hgb ≥10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed.

WOS: 000437352100014, PubMed ID: 29843153, Background/Aims: Hypertension is the leading cause of death worldwide. Chronic high blood pressure induces inflammation. Tumor necrosis factor (TNF)-alpha plays a major role in inflammation and also depresses the synthesis of erythropoietin, which exerts protective effects on tissue; however, the mechanism is still unclear. We investigated the protective effect of erythropoietin against tissue damage caused by hypertension in the kidney and whether this effect was suppressed by TNF-alpha. Methods: First, we detected the optimum chronic dose for darbepoetin-alpha (Depo), which is a long-acting erythropoietin analog for rats. We separated 60 female adult rats into 6 groups: control, AP-nitro-L-arginine methyl ester hydrochloride (L-NAME), L-NAME+Depo, L-NAME+Remicade (an anti-TNF-alpha antibody), L-NAME+Depo+Remicade, Depo, and control. After 1 month of treatment, we measured cardiovascular parameters, took blood samples, sacrificed the rats, and removed kidneys for analyses. Results: The apoptotic index and the plasma and kidney mRNA levels of TNF-alpha increased in the L-NAME group and decreased in all other treatment groups. Macrophage accumulation increased in the L-NAME and L-NAME+Remicade groups, while it decreased in the Depo group. The mRNA abundance of TNF receptor 1 (TNFR1) decreased slightly in the Depo group and TNFR2 increased significantly in the same group. Conclusion: Erythropoietin protects kidney tissue against hypertension by preventing the apoptotic effects of TNF-alpha by blocking macrophage accumulation, decreasing TNF-alpha levels, and switching the TNF-alpha receptors from the apoptotic receptor TNFR1 to the proliferative receptor TNFR2, Eskisehir Osmangazi University Scientific Research Projects Committee, Turkey [2013-84], We thank Professor Wolfgang Jelkmann (University of Luebeck, Institute of Physiology) for his support. This study was supported by a grant (no: 2013-84) from the Eskisehir Osmangazi University Scientific Research Projects Committee, Turkey.

Pure red cell aplasia (PRCA) is a rare normochromic, normocytic anemia with a near-to-complete absence of erythroblasts in the bone marrow. Erythropoiesis-stimulating agents have been used widely to improve anemia in patients with chronic kidney disease. We present a case of a 38-year-old woman who was detected to have anemia (hemoglobin: 10 g/dl) and renal dysfunction (creatinine: 3 mg/dl) on a routine health check in December 2016. Her kidney biopsy showed chronic interstitial nephritis. She received intravenous (IV) iron and was started on darbepoetin-alpha. Her hemoglobin after 3 months of treatment was 12 mg/dl. She underwent preemptive one haplomatch renal transplantation on June 2017. She was discharged with serum creatinine of 0.9 mg/dl and hemoglobin of 8 g/dl. She was not on any Erthropoietin stimulating agents (ESA) at discharge. In the 4th week after transplant, her hemoglobin dropped to 7 g/dl, and she was restarted on darbepoetin-alpha 40 μg subcutaneously once a week. In the 6th week posttransplant, her hemoglobin dropped to 6 g/dl. Her peripheral smear showed normocytic normochromic anemia with no evidence of hemolysis. Transferrin saturation was 81%, serum ferritin levels were 1812 ng/ml, and reticulocyte count was 0.1%. Bone marrow biopsy showed suppression of erythroid precursors with myeloid-to-erythroid ratio of 8:1, adequate iron stores, and normal white blood cell and platelet precursors with no dysplastic cells. Paroxysmal Nocturnal hemoglobinuria (PNH) workup; antinuclear antibody; and screening for hepatitis B, hepatitis C, HIV, CMV, and human parvovirus B19 were negative. Anti-erythropoietin (EPO) antibody by enzyme-linked immunosorbent assay was positive. She was diagnosed to have PRCA secondary to anti-EPO antibodies. She was managed with pulse doses of methylprednisolone, adequate dose of tacrolimus, IV immunoglobulin of 125 g (2 g/kg) over 5 days, and two packed red cell transfusions. Darbepoetin-alpha was stopped. At present, her hemoglobin is 12.5 g/dl with serum creatinine of 1 mg/dl on triple immunosuppression with no requirement of ESA.

INTRODUCTION: Chronic heart failure (HF) is frequently accompanied by one or more co-morbidities. The presence of co-morbidities in chronic HF is strongly correlated to HF severity and impaired outcome.AREAS COVERED: This review will address several co-morbidities with high prevalence and/or high impact in patients with chronic HF, including diabetes, anemia, hematinic deficiencies, and hyperkalemia. The background and subsequent pharmacotherapeutic options of these co-morbidities will be discussed. For this review, a MEDLINE search was performed.EXPERT OPINION: Heart failure is increasingly considered a multimorbid syndrome, including metabolic derangements and chronic inflammation. Persistent metabolic derangements and low-grade inflammation might lead to progression of HF and the development of co-morbidities. Although several co-morbidity-specific drugs became available in the past decade, most of these therapies are studied in relatively small cohorts using surrogate end-points. Therefore, larger studies are needed to address whether treating these co-morbidities will improve patient outcome in chronic HF.

Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

Background: Anemia is a serious and highly prevalent co-morbidity in chronic heart failure (HF) patients. Its influence on health-related quality of life (HR-QoL) has rarely been studied, and no data is available regarding the role it plays in hospitalized HF patients.Methods: Baseline data from the COACH study (Coordinating study evaluating Outcomes of Advising and Counselling in Heart Failure) were used. HR-QoL was assessed by means of generic and disease-specific questionnaires. Analyses were performed using ANOVA and ANCOVA, with covariates of age, gender, eGFR, diabetes, and NYHA class.Results: In total, 1013 hospitalized patients with a mean age of 71 (SD 11) years were included; 70% of these patients had no anemia (n=712), 14% had mild anemia (n=141), and 16% had moderate-to-severe anemia (n=160). Independent associations were found between anemia and physical functioning (p=0.019), anemia and role limitations due to physical functioning (p=0.002), anemia and general health (p=0.024), and anemia and global well-being (p=0.003).Conclusion: In addition to the burden of HF itself, anemia is an important factor which influences HR-QoL in hospitalized HF patients, and one that is most pronounced in the domain related to physical functioning and general health. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Anemia and iron deficiency are common in patients with heart failure (HF), and are associated with worse symptoms and adverse outcomes in this population. Although the two can occur together, anemia in HF is often not caused by iron deficiency, and iron deficiency can be present without causing anemia. Erythropoiesis-stimulating agents have been investigated extensively in the past few years and might be of benefit in patients with HF and anemia. However, concerns have arisen regarding the safety of erythropoiesis-stimulating agents in patients with chronic kidney disease and so the results of a large mortality trial are eagerly awaited to provide information on safety in patients with HF. Iron supplementation or replacement is a much older treatment option for patients with HF and anemia, but questions about the safety of intravenous iron, and absorption problems with oral formulations have prevented its widespread use to date. In the past few years, however, new data on the importance of iron deficiency in HF have become available, and a number of studies with intravenous iron have shown promising results. Therefore, this treatment approach is likely to become an attractive option for patients with HF and iron deficiency, both with and without anemia.

Anemia is a common comorbidity in heart failure (HF) patients. Its occurrence and severity are associated with worse prognosis. Although the etiology of anemia is multifactorial, inappropriate erythropoietin (EPO) production and/or bone-marrow resistance to EPO appear crucial in majority of anemic HF patients. Consequently, treatment based on this pathophysiological background may prove to be most effective and beneficial. In a number of smaller clinical studies, administration of erythropoiesis-stimulating agents (ESAs) to anemic HF patients improved a number of surrogate endpoints, including left ventricular function, exercise capacity, renal function, and different quality of life parameters. However, two larger, phase II studies, did not fully confirm these promising results. Furthermore, many concerns have been raised on the safety of ESAs after the recent publication of studies correcting anemia in patients with chronic kidney disease (CKD). On the other hand, chronic HF population varies significantly from CKD patients, with different comorbidities, renal function, and etiology of anemia. Moreover, ESAs have been shown to possess robust nonhematopoietic effects in the heart, namely inhibition of apoptosis and stimulation of neovascularization. Therefore, large-scale trials with ESAs are required to examine the effect and safety of anemia treatment in HF patients.

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. Kidney International (2010) 77, 239-246; doi:10.1038/ki.2009.415; published online 4 November 2009

Chronic heart failure (HF) and renal dysfunction are often seen together, and in both diseases the presence of anaemia is common and associated with an impaired outcome. This article focuses on the interaction between the heart and kidneys and the role of anaemia in this process. We will discuss the aetiology, consequences and treatment of anaemic patients with heart failure and renal dysfunction. Anaemia is frequently observed in patients with chronic HF. The prevalence of anaemia depends both on the severity of chronic HF and the diagnostic criteria used to define it, but may be as high as 50% in selected patient cohorts. The criteria of the World Health Organization (haemoglobin

Background: 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.Objective: To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality.Data sources: A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed.Study selection: Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included.Results: 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.Conclusions: 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.

Objectives The aim of this study was to assess the effect of anemia on mortality in chronic heart failure (CHF). Background Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated with an increased mortality. Methods A systematic literature search in MEDLINE ( through November 2007) for English language articles was performed. In addition, a manual search was performed. We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 patients. Information on study design, patient characteristics, outcome, and potential confounders were extracted. Results Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic. After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic patients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p

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. (C) 2008 Elsevier B.V. All rights reserved.

Background Preclinical studies have consistently shown that erythropoietin (EPO), administered after an acute myocardial infarction (AMI), reduces infarct size and improves left ventricular function. Furthermore, EPO promotes endothelial progenitor cell growth, which increases angiogenesis. A recent pilot study in patients with AMI suggested that a single bolus of EPO was safe and well tolerated.Methods The HEBE III is a multicenter, prospective, randomized, open-label trial with blinded evaluation of the primary end point. The primary objective is to study the effect on left ventricular ejection fraction (LVEF) of a single bolus of EPO, administered directly after a primary percutaneous coronary intervention (PCI) for a first AMI. A total of 466 patients with thrombolysis in myocardial infarction 0/1 flow before the PCI procedure and 2/3 flow after a successful PCI are randomly assigned to either receive standard medical care or a single bolus with 60,000 IU of EPO on top of standard medical care within 3 hours of the PCI procedure. Primary end point of the study is LVEF after 6 weeks, assessed by planar radionuclide ventriculography.Implications If an improvement of LVEF with a single bolus of EPO is demonstrated, this simple approach might further improve clinical outcome of patients with AMI.

Purpose We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function. Methods Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 μg/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery. Results In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R=0.7, p< 0.01). However, additional EPCs preferentially homed to the ischemic MI borderzone (p

Purpose of reviewAnemia 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 findingsRecent 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.SummaryAlthough 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.

Amaç: Çalışmamızda Epo'nun böbreklerden sentezlenmesinin nedeninin Epo'nun böbrekler için yaşamsal bir doku koruyucu olduğunu öne sürdük ve hipertansiyonda oluşan böbrek hasarının başlıca nedeni olan TNF-α'nın blokajı ve TNF-α tarafından sentezi baskılanan Epo'nun L-NAME modeli ile hipertansiyon oluşturulmuş dişi sıçanlarda böbrek dokusu harabiyeti üzerindeki etkilerini sistemik, moleküler ve histolojik düzeyde araştırmayı amaçladık.Materyal Metod: a) Doz çalışması: yetişkin dişi sıçanlara 20 mg/kg/gün L-NAME ile birlikte 10, 2,5, 0,5, 0,25, 0,1 µg/kg dozlarında Depo'yu 3 günde 1 vererek gerçekleştridiğimiz doz çalışmasında kan parametrelerini değiştirmeyen en yüksek doz olarak 0,25 µg/kg Depo'yu tedavi dozu olarak belirledik.b) Tedavi grupları için altmış adet dişi sıçan rastgele 6 gruba ayrıldı, enjeksiyonlar otuz gün boyunca devam etti; Kontrol: günlük intraperitoneal (i.p.) 1 ml/kg serum fizyolojik (SF) enjeksiyonu yapıldı; L: günlük yirmi mg/kg ip L-NAME enjeksiyonu yapıldı; L+Depo: aynı dozda yapılan L-NAME ile birlikte 3 günde 1 ip 0,25 µg/kg Depo enjeksiyonu yapıldı; L+Rem: aynı dozda yapılan L-NAME ile birlikte TNF-α antikoru olan Remicade 5 mg/kg dozunda ip enjeksiyonu yapıldı; L+Depo+Rem: aynı dozlarda hem L-NAME hem Depo hem de Remicade yapıldı; Depo: aynı dozda Depo tek başına yapıldı. 30 günlük enjeksiyonların ardından yapılan femoral arter kateterizasyonu ile kardiyovasküler parametreler ölçüldü ve arteryel kandan kan sayım cihazı kullanılarak kan değerleri ve plazma Epo ve TNF-α miktarları ELISA yöntemi kullanılarak ölçüldü. Sağ böbrek çıkartılarak ağırlığı ölçüldü, sol böbrek çıkartılarak uzun hattan ikiye bölündü, yarısı immunhistokimya tekniği ile TUNEL, ED-1 ve NfKappaB boyamalarının yapılması için formolde diğer yarısı ise PCR tekniği ile TNF-α, TNF-α reseptörleri olan TNFR1 ve TNFR2, Epo reseptörü olan EpoR mRNA ölçümleri için tripure solüsyonu içinde saklandı. Bulgular: L-NAME verilen tüm gruplarda sistolik kan basıncı, diyastolik kan basıncı, nabız basıncı ve ortalama arter basıncı artmıştır. L-NAME ile yükselen apoptotik hücre oranı tüm tedavi gruplarında kontrol grubu seviyesine düşmüştür. ED-1 ile ölçülen makrofaj birikimi L ve L+Rem gruplarda yükselmiştir. NfKappaB L+Rem grubu hariç tüm gruplarda kontrole göre artmıştır. ELISA sonuçlarına göre ise, gruplar arasında istatistiksel bir farklılık görülmese de Epo seviyeleri, L grubunda kontrole göre yarı yarıya düşmüş fakat L+Rem grubunda TNF-α'nın blokajı Epo seviyesini tekrar kontrol düzeyine yükseltmiştir. Kan plazma TNF-α miktarı ve TNF-α mRNA değerleri L grubunda kontrole göre yaklaşık 3 kat artarken, L+Depo grubunda kontrol değerlerinin bile altına düşmüştür. TNF-α'nın apoptotik etkilerine aracılık eden TNFR1'in mRNA miktarı gruplar arasında istatistiksel bir farklılık göstermese de, L+Depo grubunda kontrole göre yarıyarıya düşmüştür. Diğer yandan TNF-α'nın antiapoptotik etkilerine aracılık eden TNFR2'nin mRNA miktarı ise L+Depo grubunda kontrole göre anlamlı derecede yükselmiştir. EpoR mRNA miktarları istatistiksel olarak anlamlı olmasa da L grubunda kısmen artarken, Depo erilen gruplarda düşmüştür. Sonuç: Depo injeksiyonu, L-NAME ile oluşturulmuş kronik hipertansiyonda böbrekte oluşan apoptozisi, yükselmiş kan basıncı düzeyini ve kontrol değeri düzeyindeki kan parametrelerini etkilemeden engellemiştir. Bulgularımız Depo'nun bu etkisini makrofaj birikimini engelleyerek, apoptotik plazma TNF-α seviyesini ve TNF-α mRNA düzeyini ve TNFR1 reseptörünü azaltarak fakat antiapoptotik TNFR2 ifadelenmesini uyararak gerçekleştirdiğini göstermektedir.Sunulan çalışmanın sonuçları ve son yıllarda yayınlanan çalışmaların ışığında Epo ve vücutta hematopoetik bir organ olmasa da majör Epo üreticisi böbrek dokusu ile Epo arasında şu hipotezi ileri sürüyoruz: L-NAME verilerek sıçanlarda oluşturulan kronik hipertansiyonda ortaya çıkan böbrek dokusu hasarı (apoptozis), artan TNF-α aktivitesine bağlı olarak kritik doku koruyucu seviyelerinin altına düşen endojen Epo yetersizliğindendir. Epo'nun hematopoetik etkisi çok düşük konsantrasyonlarda bile gerçekleşirken, doku koruyucu etkisi Epo'ya daha düşük affiniteli bir sitokin reseptörü ile Epo reseptörü arasında heterodimerik bir bağlantı yolağının aktivasyonunu gerektirmektedir. Böbrek dokusunun fizyolojik koşullarda fonksiyonlarının sürdürebilmesi doku koruyucu ve hematopoetik etki seviyelerinin üzerinde Epo varlığına bağlıdır. Böbrek dokusunda üretildiği için böbreklerde doku koruyucu düzeyinde Epo sağlanabilirken kan yoluyla kemik iliğine ulaşabilen pikomolar seviyelerine düşmüş Epo hematopoietik etki için yeterli olabilmektedir. Sunulan çalışmada dışarıdan takviye edilen Epo hipertansiyonda azalan endojen Epo'nun azalan doku koruyucu etkisini telafi ederek böbrek dokusunda hipertansiyonun yol açtığı TNF-α aktivitesine bağlı apoptozisi engellemiştir. Aim: We hypothesis that Epo is secreted by kidneys because it has an important protector role for kidneys and we aimed to study the effect of TNF-alpha blockage that is the main cause of kidney damage in hypertension and effect of Epo treatment which the synthesis of it is depressed by TNF-alpha on kidney tissue damages by using histological, and molecular techniques in L-NAME induced hypertensive female rats.Material Method: a) Dose study: To detect the dose of Darbepoetin-alpha (Depo), a long acting Epo analog, we randomly divided 60 female adult rats into six groups; L-NAME alone, L-NAME+10 µg/kg Depo, L-NAME+2,5 µg/kg Depo, L-NAME + 0,5 µg/kg Depo, LNAME+0,25 µg/kg Depo, L-NAME+0,1 µg/kg Depo. According to survival and blood parameters we detected 0,25 µg/kg Depo dose as the highest dose that is not changing the blood parameters and used it as treatment dose. b) Treatment study: We randomly separated 60 female adult rats into 6 groups and we injected drugs for 30 days, according to the group protocol; Control: Daily i.p. (intra-peritoneal) 1ml/kg/day physiologic serum injected; L-NAME: daily IP 20 mg/kg/day L-NAME injected; L-NAME +Depo: the same dose of L-NAME and 0,25 µg/kg dose of Depo injected once in 3 days i.p; L-NAME+REM: the same dose of L-NAME and Daily 5 mg/kg/day dose of Remicade (REM, TNF-alpha antibody) i.p injected; L-NAME+Depo+REM: the same doses of each agent in the same way injected; Depo: the same dose of Depo alone injected. After 30 days of injection period, rat cardiovascular parameters were recorded under anesthesia (50mg/kg Ketamine HCl+10 mg/kg Xylazine HCl) via PE 50 tip intra-femoral catheterization and at the end of the experiment, arterial blood samples were taken from CBC (all blood cell parameters) via cell counter system and to measure TNF-alpha and Epo levels in the plasma via ELISA technique. We removed right kidney and weighted. Then we removed the left kidney, divided longitudinally into two pieces, half of it was stored in formaldehyde for TUNEL, ED-1 and NfKappaB staining, , the other half was stored in Tri pure solution for TNFalpha, TNFR1, TNFR2 and EpoR MRNA detection. The results: Systolic, diastolic, mean arterial and pulse pressures increased in all the LNAME given groups and heart rate decreased in only Depo treated with L-NAME groups. Apoptotic index increased in the L - NAME group but decreased in all the treatment groups. Macrophage accumulation, as measured by ED-1 staining, that causes TNF-alpha increase, increased in L and L+ REM groups. NfKappaB increased in all groups except L+REM group. Although ELISA results show no significant difference among the groups, Epo decreased in half in the L group compared with that of the control. However, TNF-alpha blockade in the L REM group increased endogenous Epo up to the control level. The lack of Epo increase in Depo treated groups may be because of the insensitivity of the Epo antibody used to Depo. TNF-alpha in the blood plasm value detected by ELISA and the TNF-alpha MRNA amount detected by PCR increased up to 3 folds in the L group compared with that of the control and decreased even below the control level in the L Depo group. MRNA amount of TNFR1 that stimulates apoptosis decreased to half in L-NAME treated with Depo groups compared with that of the control group but this result is not statistically significant. On the other hand MRNA amount of TNFR2 that stimulates antiapoptotic pathways, increased significantly in LNAME treated with Depo group. Apr MRNA amount increased partly in the L group may due to increased Epo demand, but this demand was not seen in Depo treated groups that EPOR MRNA also decreased although it is not statistically significant. Our results suggest that Epo shows its tissue protective activity by blocking the accumulation of macrophages, depressing plasma TNF-alpha level and kidney TNF-alpha mRNA amount, suppressing TNFR1, and stimulating antiapoptotic TNFR2 expression. Apoptosis in the kidney tissue resulted in L-NAME induced hypertension decreased endogenous EPO levels below to the is induced by rising TNF-alpha activity and decreasing below critical tissue protective levels of endogenous Epo during chronic tissue injury.Conclusion: The presented study is the first in-vivo data indicating that the depo injection or TNF-alpha inhibition prevented apoptosis in rat kidney occurred in L-NAME induced chronic hypertension without affecting rat blood pressures and rat blood cell counts. We suggest that given exogenous DEPO substituted TNF-alpha induced decrease in endogenous renal tissue alpha production below of the critical tissue protective concentrations even it may still enough for the hematopoietic actions. Since Epo can show its hematopoietic influences, even in very low concentrations via the homo dimeric Epo receptors, however its tissue protective effects may depend on tissue-protective erythropoietin receptor (EPOR– common receptor (CR) a currently defined another receptor that requires higher Epo concentrations to activate heterodimeric tissue protective receptor pathways that is a lower affinity to Epo. 105

Background Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events.Methods A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with >= 30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality.Results Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (+/- 131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06).Conclusions Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.

Introduction: Erythropoiesis-Stimulating Agents (ESA) are hypothesized to increase cardiovascular mortality in patients with chronic kidney disease. One of the proposed mechanisms is the elevation of blood pressure (BP) by ESA. Therefore, we aimed to determine whether the use of ESA was associated with antihypertensive treatment and higher BP.Materials and Methods: In this cohort 502 incident pre-dialysis patients were included who started specialized pre-dialysis care in 25 clinics in the Netherlands. Data on medication including ESA use and dose, co-morbidities and BP were routinely collected every 6 months. Antihypertensive treatment and BP were compared for patients with and without ESA at baseline. Differences in antihypertensive medication and BP during pre-dialysis care were estimated with linear mixed models adjusted for age, sex, body mass index, cardiovascular disease, diabetes mellitus and estimated glomerular filtration rate.Results: At baseline, 95.6% of patients with ESA were treated with antihypertensive medication and 73.1% of patients without ESA. No relevant difference in BP was found. During pre-dialysis care patients with ESA used 0.77 (95% CI 0.63; 0.91) more classes of antihypertensive drugs. The adjusted difference in systolic blood pressure (SBP) was -0.3 (95% CI -22.7;2.0) mmHg and in diastolic blood pressure (DBP) was -1.0 (95% CI -2.1; 0.3) mmHg for patients with ESA compared to patients without ESA. Adjusted SBP was 3.7 (95% CI -1.6; 9.0) mmHg higher in patients with a high ESA dose compared to patients with a low ESA dose.Conclusions: Our study confirms the hypertensive effect of ESA, since ESA treated patients received more antihypertensive agents. However, no relevant difference in BP was found between patients with and without ESA, thus the increase in BP seems to be controlled for by antihypertensive medication.

Purpose: The HEBE III trial showed that epoetin alfa administration in patients with a first ST-elevation myocardial infarction (STEMI) did not improve left ventricular function at 6 weeks after primary percutaneous coronary intervention (PCI). The long term effects of erythropoiesis- stimulating agents on cardiovascular morbidity and mortality are unknown, therefore we evaluated clinical events at 1 year after PCI. Methods: A total of 529 patients with a first STEMI and successful primary PCI were randomized to standard optimal medical treatment (N = 266) or an additional bolus of 60,000 IU epoetin alfa administered intravenously (N = 263) within 3 h after PCI. Analyses were performed by intention to treat. Results: At 1 year after STEMI, 485 patients had complete follow-up. The rate of the composite end point of all-cause mortality, re-infarction, target vessel revascularization, stroke and/or heart failure was 6.4 % (N = 15) in the epoetin alfa group and 9.6 % (N = 24) in the control group (p = 0.18). Thromboembolic events were present in 1.3 % (N = 3) of patients in the epoetin alfa group and 2.4 % (N = 6) in the control group. There was no evidence of benefit from epoetin alfa administration in subgroups of patients. Conclusions: Administration of a single bolus of epoetin alfa in patients with STEMI does not result in a reduction of cardiovascular events at 1 year after primary PCI. There was a comparable incidence of thromboembolic complications in both treatment groups, suggesting that epoetin alfa administration is safe at long term. © 2013 Springer Science+Business Media New York.

Aims Cardioprotective effects of erythropoietin (EPO) have been shown in experimental and smaller clinical studies. We performed a prospective, multicentre, randomized trial to assess the effects of a single high dose of EPO after primary coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods and results Patients with a successful PCI for a first STEMI were randomized to receive either standard medical care alone, or in combination with a single bolus with 60 000IU i.v. of epoetin alfa within 3 h after PCI. Primary endpoint was left ventricular ejection fraction (LVEF) after 6 weeks, assessed by planar radionuclide ventriculography. Pre-specified secondary endpoints included enzymatic infarct size and major adverse cardiovascular events. A total of 529 patients were enrolled (EPO n = 263, control n = 266). At baseline (before EPO administration), groups were well-matched for all relevant characteristics. After a mean of 6.5 (±2.0) weeks, LVEF was 0.53 (±0.10) in the EPO group and 0.52 (±0.11) in the control group ( P = 0.41). Median area under the curve (inter-quartile range) after 72 h for creatinine kinase was 50 136 (28 212–76 664)U/L per 72 h in the EPO group and 53 510 (33 973–90 486)U/L per 72 h in the control group ( P = 0.058). More major adverse cardiac events occurred in the control than in the EPO group (19 vs. 8; P = 0.032). Conclusion A single high dose of EPO after a successful PCI for a STEMI did not improve LVEF after 6 weeks. However, the use of EPO was related to less major adverse cardiovascular events and a favourable clinical safety profile. Clinical Trial Registration Information: [NCT00449488][1]; [http://www.clinicaltrials.gov/ct2/show/[NCT00449488][1]?term=voors&rank=2][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00449488&atom=%2Fehj%2F31%2F21%2F2593.atom [2]: http://www.clinicaltrials.gov/ct2/show/NCT00449488?term=voors&rank=2

BackgroundChronic heart failure (CHF) is a leading cause of morbidity and mortality worldwide. Anaemia is a common (12-55%) co-morbid condition and is associated with worsening symptoms and increased mortality. Anaemia is treatable and can be targeted in the treatment of patients with CHF. Erythropoiesis-stimulating agents (ESA), supplemented by iron therapy, are used to treat anaemia in chronic kidney disease and cancer, however safety concerns have been raised in these patients. The clinical benefit and safety of these agents in CHF remains unclear.ObjectivesTo assess the benefits and risks of ESA for CHF patients with anaemia.Search strategyWe searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to October 2008), EMBASE (1980 to October 2008) and reference lists of articles. No language restrictions were applied.Selection criteriaRandomised controlled trials of any ESA, with or without iron therapy, in CHF patients were eligible for inclusion.Data collection and analysisThree reviewers independently assessed study quality and extracted data. Original authors were contacted for additional information. The outcomes of interest were: exercise tolerance, haemoglobin level, New York Heart Association (NYHA) functional class, quality of life, left-ventricular ejection fraction, B-type natriuretic peptide, CHF-related hospitalisations, all-cause mortality and adverse effects. Risk ratios (RR) were calculated for dichotomous data and weighted mean difference (WMD) for continuous data.Main resultEleven studies (794 participants) were included. Overall quality of studies was moderate with nine studies being placebo-controlled but only five double-blinded. Compared to control, ESA treatment significantly improved exercise duration by 96.8 seconds (95% CI 5.2 to 188.4, p = 0.04) and 6-minute walk distance by 69.3 metres (95% CI 17.0 to 121.7, p = 0.009). Benefit was also noted in terms of peak VO2 (+2.29 mL/kg/min, p=0.007), NYHA class (-0.73, pAuthors' conclusionsMeta-analysis of small RCTs suggests that ESA treatment in patients with symptomatic CHF and mild anaemia (haemoglobin more than 10g/dL) can improve anaemia and exercise tolerance, reduce symptoms and have benefits on clinical outcomes. Confirmation requires well-designed studies with careful attention to dose, haemoglobin treatment target and associated iron therapy.

The efficacy of human recombinant erythropoietin (rEPO) in myelodysplastic syndromes (MDS) has generally been best in untransfused patients with 'refractory anaemia' according to the World Health Organization (WHO). We treated 63 MDS patients [excluding refractory anaemia with excess blasts, type 2 (RAEB2)] with a previously tested combination of 13-cis-retinoic acid and dihydroxylated vitamin D3 +/- 6-thioguanine in addition to rEPO. Most patients were categorized as refractory cytopenia with multilineage dysplasia and RAEB1, with intermediate 1 International Prognostic Scoring System (IPSS) score; all had Hb

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. (C) 2008 Elsevier B.V. All rights reserved.

Chronic heart failure (CHF) is a leading cause of morbidity and mortality worldwide. Anaemia is a common (12-55%) co-morbid condition and is associated with worsening symptoms and increased mortality. Anaemia is treatable and can be targeted in the treatment of patients with CHF. Erythropoiesis-stimulating agents (ESA), supplemented by iron therapy, are used to treat anaemia in chronic kidney disease and cancer, however safety concerns have been raised in these patients. The clinical benefit and safety of these agents in CHF remains unclear.To assess the benefits and risks of ESA for CHF patients with anaemia.We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to October 2008), EMBASE (1980 to October 2008) and reference lists of articles. No language restrictions were applied.Randomised controlled trials of any ESA, with or without iron therapy, in CHF patients were eligible for inclusion.Three reviewers independently assessed study quality and extracted data. Original authors were contacted for additional information. The outcomes of interest were: exercise tolerance, haemoglobin level, New York Heart Association (NYHA) functional class, quality of life, left-ventricular ejection fraction, B-type natriuretic peptide, CHF-related hospitalisations, all-cause mortality and adverse effects. Risk ratios (RR) were calculated for dichotomous data and weighted mean difference (WMD) for continuous data.Eleven studies (794 participants) were included. Overall quality of studies was moderate with nine studies being placebo-controlled but only five double-blinded. Compared to control, ESA treatment significantly improved exercise duration by 96.8 seconds (95% CI 5.2 to 188.4, p=0.04) and 6-minute walk distance by 69.3 metres (95% CI 17.0 to 121.7, p=0.009). Benefit was also noted in terms of peak VO2 (+2.29 mL/kg/min, p=0.007), NYHA class (-0.73, p0.001), ejection fraction (+5.8%, p0.001), B-type natriuretic peptide (-226.99 pg/mL, p0.001) and quality-of-life indicators, with a mean increase in haemoglobin of 1.98 g/dL (p0.0001). There was also a significantly lower rate of heart failure related hospitalisations (RR 0.62, 95% CI 0.44 to 0.87) and lower all-cause mortality (RR 0.61, 95% CI 0.37 to 0.99). No increase in adverse events with ESA therapy was observed, however studies were of small sample sizes and limited duration.Meta-analysis of small RCTs suggests that ESA treatment in patients with symptomatic CHF and mild anaemia (haemoglobin more than 10g/dL) can improve anaemia and exercise tolerance, reduce symptoms and have benefits on clinical outcomes. Confirmation requires well-designed studies with careful attention to dose, haemoglobin treatment target and associated iron therapy.