Endogenous Endogenous Erythropoietin Research Articles

The association between endogenous erythropoietin levels and the risk of heart failure in a Chinese community-based population

Abstract Background Patients with heart failure (HF) often have elevated endogenous erythropoietin (EPO) levels, which are associated with disease severity and prognosis. Previous studies have indicated that in the special population elevated endogenous EPO levels are associated with HF and cardiovascular death. However, whether endogenous EPO levels are associated with the risk of HF in the general population remains to be elucidated. Purpose Our study aims to investigate the association between endogenous EPO levels and the risk of HF admission in the general population. Methods We conducted a prospective cohort study on subjects from a Beijing community in China who had no history of stroke or myocardial infarction. Endogenous EPO levels were measured at baseline for all participants. The endpoint of interest was admission with HF. Cox proportional hazard regression models were used to analyze the relationship between endogenous EPO levels and the occurrence of the endpoint. Results A total of 4870 participants were included. Among all participants, the mean (±SD) age was 56.72 ± 8.78 years, with 1802 (37.0%) being men. The median (interquartile range, IQR) EPO level was 13.19 (9.47-18.20) IU/L. During a mean 9.57-year follow-up, a total of 176 (3.6%) subjects experienced heart failure. Subjects were grouped in quintiles according to baseline endogenous EPO levels. Higher and lower endogenous EPO levels were both associated with increased risk of HF (Figure 1A). The Kaplan–Meier curves showed significant differences in cumulative hazards of heart failure among EPO quintiles (log-rank test: P＜0.05) (Figure 1B). After adjusting for covariates, including demographics, traditional risk factors for cardiovascular disease, renal function, and hemoglobin levels, and using the middle quintile (Q3) (11.72-14.94IU/L) of EPO levels as a reference, we found that the highest quintile (Q5) (>19.86 IU/L) was associated with a 159% increased risk of HF admission (HR 2.59, 95% CI 1.57-4.28, P = 0.0002). Similarly, the lowest quintile (Q1) (<8.66 IU/L) was associated with a 94% increased risk (HR 1.94, 95% CI 1.11-3.41, P = 0.0210) (Table 1). Conclusion There exists a "U-shaped" relationship between endogenous EPO levels and HF admission in the general population. Both higher and lower endogenous EPO levels were associated with an increased risk of HF admission in the community population. These findings differ from previous studies, so further research may be needed to explore the underlying pathophysiological mechanisms of endogenous EPO and HF.

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease.

Anemia plays an important role in chronic kidney disease (CKD) progression because it worsens the quality of life and increases the risk of cardiovascular complications in CKD patients. In such cases, anemia is mainly caused by endogenous erythropoietin (EPO) and iron deficiencies. Therefore, KDIGO and ERBP guidelines for anemia treatment in CKD patients focus on recombinant EPO and iron supplementation. A recent new treatment option for anemia in CKD patients involves blocking the hypoxia-inducible factor (HIF) system with prolyl hydroxylase inhibitors (PHIs), what causes increasing endogenous EPO production and optimizing the use of iron. Clinical studies have shown that the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) covered in this manuscript-roxadustat, vadadustat, daprodustat, and molidustat-effectively increase hemoglobin (Hb) levels in both non-dialyzed and dialyzed CKD patients. Moreover, these medicines reduce blood lipid levels and do not accelerate CKD progression. However, blockage of the HIF system by HIF-PHIs may be associated with adverse effects such as cardiovascular complications, tumorogenesis, hyperkalemia. and retinopathy. More extensive and long-term clinical trials of HIF-PHIs-based anemia treatment in CKD patients are needed, and their results will indicate whether HIF-PHIs represent an effective and safe alternative to EPO and iron supplementation for anemia treatment in CKD patients.

Prognostic impact of elevated erythropoietin levels in patients with severe aortic stenosis receiving trans-catheter aortic valve implantation

BackgroundElevated endogenous erythropoietin (EPO) levels are associated with worse clinical outcomes in patients with heart failure (HF). The clinical implication of endogenous EPO levels in patients undergoing trans-catheter aortic valve implantation (TAVI) beyond other conventional risk factors remains unknown. MethodsConsecutive patients with EPO measurements who underwent TAVI for the treatment of their severe aortic stenosis at our institute between May 2015 and December 2020 were included. The association between the endogenous EPO levels and the primary outcome consisting of all-cause mortality and HF hospitalization was evaluated. ResultsA total of 263 patients (85.1 ± 5.1 years old, 74 men) were included and tertiled according to the baseline EPO levels. The high EPO group had more advanced anemia, renal impairment, and hypoalbuminemia than the other two tertiled groups (p < 0.05 for both). Patients with high EPO had a significantly higher cumulative incidence of the primary outcomes compared to the other two groups (p = 0.002) with an adjusted hazard ratio of 6.0 (95 % confidence interval 1.9–18.1) in its logarithmic value (p < 0.001). ConclusionsElevated baseline EPO levels were independently associated with mortality and morbidity following TAVI. The clinical implication of aggressive intervention on the elevated EPO levels in this cohort remains the next concern.

1402-P: Endogenous Erythropoietin Is Protective in Mice during High-Fat Diet to Obesity and Cardiac Function while Exogenous Erythropoietin Exacerbates Cardiac Function

Endogenous Erythropoietin (EPO) provides protection against obesity and heart function. Mice with EPO receptor restricted to erythroid tissue (ΔEPORE mice) become obese, glucose intolerant and insulin resistant. In male mice at 4 months of age, after three weeks of high fat diet feeding, ΔEPORE mice showed an increase in fat mass from to 13 grams compared to fat mass in wild type mice that more than doubled from 4 to grams. EPO treatment (i.p. 3000 U/kg, 3 times/week for three weeks) during high fat diet feeding in wild type mice reduced the increase in fat mass to 3 grams and had a minimal effect on fat mass in ΔEPORE mice. The EPO stimulated increase in hematocrit was comparable in wild type and ΔEPORE mice. Using echocardiography to measure cardiac systolic function and cardiac output after high fat diet feeding, without EPO treatment ejection fraction (%) and fractional shortening (%) of left ventricular contractility were decreased in ΔEPORE mice compared with wild type mice, suggesting that endogenous EPO provided a cardioprotective effect mediated by EPO receptor expression in non-erythroid cells. EPO treatment in wild type mice decreased peak velocity and left ventricular outflow tract velocity but there were no significant changes in ΔEPORE mice, indicating that the decreases in these parameters with EPO administration are independent of EPO stimulated erythropoiesis and mediated by EPO receptor in non-erythroid cells. EPO treatment also decreased ejection fraction and fractional shortening in wild type mice and had no further significant effect in ΔEPORE mice. These data provide evidence that while endogenous EPO may be protective for heart function, high dose EPO administration during high fat diet feeding in wild type mice compromises cardiac function. EPO modulation of heart function requires EPO receptor expression beyond erythroid cells and is distinct from EPO stimulated erythropoiesis. Disclosure J.Lee: None. H.Rogers: None. C.T.Noguchi: None.

Iron deficiency contributes to resistance to endogenous erythropoietin in anaemic heart failure patients.

Abnormal endogenous erythropoietin (EPO) constitutes an important cause of anaemia in chronic diseases. We analysed the relationships between iron deficiency (ID) and the adequacy of endogenous EPO in anaemic heart failure (HF) patients, and the impact of abnormal EPO on 12-month mortality. We investigated 435 anaemic HF patients (age: 74 ± 10 years; males: 60%; New York Heart Association class I or II: 39%; left ventricular ejection fraction: 43 ± 17%). Patients with EPO higher than expected for a given haemoglobin were considered EPO-resistant whereas those with EPO lower than expected - EPO-deficient. ID was defined as serum ferritin <100 µg/L or 100-299 µg/L with transferrin saturation <20%. EPO-resistant patients (22%) had more advanced HF whereas those with EPO deficiency (57%) were more frequently females and had worse renal function. Lower serum ferritin (indicating depleted body iron stores) was related to higher EPO observed/predicted ratio when adjusted for significant clinical confounders, including C-reactive protein. One year all-cause mortality was 28% in patients with EPO resistance compared to 17% in patients with EPO deficiency and 10% in patients with adequate EPO (log-rank test for the comparison EPO resistance vs. adequate EPO: P=0.02). When adjusted for other prognosticators, there was still a trend towards increased 12-month mortality in patients with higher EPO level. Anaemic HF patients with endogenous EPO deficiency vs. resistance have different clinical and laboratory characteristics. In such patients, ID contributes to EPO resistance independently of inflammation.

Erythropoietin Concentration in Boys With p.His63Asp Polymorphism of the HFE Gene.

The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. HFE-related hemochromatosis is characterized by excessive intestinal absorption of dietary iron, in particular cases resulting in pathologically high iron storage in tissues and organs. During childhood, HFE gene homozygosity or heterozygosity manifests exclusively in the form of biochemical abnormalities. Because of their mutual link, bioavailable iron and endogenous erythropoietin (EPO) are indispensable for effective erythropoiesis. We analyzed the impact of p.(His63Asp) polymorphism of the HFE gene on erythropoiesis taking into consideration endogenous EPO production in the developmental age. In the study we performed, we observed a significant, strong and negative correlation between the concentration of EPO, hemoglobin, and red blood cell count. A negative trend was also noted on the impact of iron concentration and transferrin saturation on EPO production. In conclusion, this preliminary study demonstrates an impaired impact of endogenous EPO on erythropoiesis in the presence of increased iron content in carriers of p.(His63Asp) (heterozygotes) variant of the HFE gene in developmental age.

Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents.

Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which have raised great expectations. On the one hand, a novel family of drugs has been developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These agents induce, among other effects, an increase in the production of endogenous EPO, improve iron availability and reduce hepcidin levels. Some of them have already received marketing authorization. On the other hand, recent clinical trials have elucidated important aspects of iron supplementation, which may change the treatment targets in the future. This article reviews the current knowledge of the pathophysiology CKD-related anemia, current and future therapies, the trends in patient management and the unmet goals.

Оценка эффективности препарата Гамавит при коррекции ренальной анемии у кошек с ХБП: контролируемое рандомизированное исследование

Renal anemia is one of the most common complications of chronic kidney disease (CKD) in cats, which significantly reduces their life quality. Most often, the mechanism of renal anemia development is associated with insufficiency of endogenous erythropoietin (EPO), or with a reduction in the life of red blood cells caused by uremic intoxication. Since anemia increases the severity of renal hypertension and other CKD symptoms, the search for effective drugs that can stimulate erythropoiesis in CKD and do not have nephrotoxic properties is particularly relevant. The aim of the work was to study the effectiveness of Gamavit in the treatment regimen for cats with CKD compared with the standard treatment protocol. Active ingredients of Gamavit are sodium nucleinate and denaturated placenta extract. The study included 20 cats of different breeds aged from 5 to 16 years with CKD stage III-IV according to the IRIS classification, accompanied by anemia and a decrease in hematocrit in the range from 25 to 16%. Patients were randomly divided into 2 equal groups - control (n=10) and experimental (n=10) using the block randomization method. In the control group a standard nephroprotective therapy regimen was used. In the experimental group Gamavit was added to the standard regimen. Gamavit was administered at a dose of 0.5 ml/kg 1 time per day, at the same time, during 14 consecutive days (7 days i/v and 7 days s/c). The conditions for feeding and keeping animals of the experimental and control groups were identical. For feeding, we used a standardized serial diet ― Purina CatChow Adult with chicken/turkey/salmon. Access to drinking water ― ad libitum. The initial number of red blood cells, as well as the hematocrit index and hemoglobin level in the experimental and control groups were at the lower limit of the norm or below the reference values. During the study, in the experimental group of the patients, these indicators returned to normal after 2 weeks, while in the control group there were no significant changes. The statistically significant difference between the experimental and control groups remained until the end of the observation (p=0.001). Levels of creatinine and urea in the blood serum of the patients of both groups consistently high throughout the study, but in the experimental group a significant decrease in these indicators was found. The initial level of EPO in both groups was significantly lower than in healthy cats. During the experiment, it was not possible to reach the lower limit of the normal value, which allows us to conclude that the stimulation of erythropoiesis indicators in the experimental group, observed under the influence of Gamavit, is not associated with the stimulation of endogenous EPO production. Thus, the study revealed that Gamavit stimulates erythropoiesis in cats with CKD stage III-IV, significantly increasing the number of red blood cells, and the levels of hematocrit and hemoglobin. This effect, combined with a decrease in uremic intoxication values (creatinine and urea levels), lead to an improvement in the general condition of patients and regression in a number of important clinical manifestations. Since no nephrotoxic effects and undesirable interactions with drugs of standard nephroprotective therapy were detected in the process of this study, Gamavit can be recommended for widespread use in cats as one of the pathogenetic, symptomatic, and therapeutic and prophylactic drugs in the complex therapy of CKD at the preclinical and clinical stages of the disease.

P0860INTRAVENOUS IRON ADMINISTRATION SUPPRESSES ENDOGENOUS ERYTHROPOIETIN SECRETION IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Iron therapy may induce inflammatory response that may indirectly affect endogenous erythropoietin (EPO) production. We postulated that increased secretion of FGF-23 may provide a link between intravenous iron administration and suppression of endogenous EPO secretion. Evaluation of a short-term effect of intravenous iron sucrose administration on the secretion of endogenous EPO in patients with chronic kidney disease (CKD). Method 35 non-dialysed patients with G3b-5 CKD were included. All patients received 100 mg of intravenous iron infusion (iron (III)-hydroxide sucrose complex) daily for 5 days. Plasma concentration of EPO, iFGF-23, cFGF-23, PTH, bone alkaline phosphatase (BAP), phosphorus (PO4) and calcium (Ca) were measured before and two hours after the first and third iron infusion and at the end of iron therapy. Results EPO concentration at the end of iron treatment was significantly lower compared to 2 h after the first iron infusion (p&amp;lt;0.001) and before the third dose (p&amp;lt;0.001) (12.6 [31.2] mIU/mL, 30.9 [38.3] mIU/mL, 33.4 [41.3] mIU/mL and, respectively). Conversely, serum iFGF-23 increased significantly after the third dose (61.1 [401.5] pg/mL; p&amp;lt;0.05) and after the treatment (92.1 [849.7] pg/mL; p&amp;lt;0.01) compared to pre-treatment value (48.4 [403.8] pg/mL). cFGF-23 concentration decreased significantly after the first dose of iron (491.8 [828.6] vs. 339.2 [875.8] RU/mL; p&amp;lt;0.01) and after the completion of the therapy (398.7 [931.9]) vs. baseline (p&amp;lt;0.05). There was no linear correlation between EPO and FGF-23. Conclusion Intravenous iron therapy increases the secretion of FGF-23 and supresses endogenous EPO production but these two effects do not seem to be related.

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF\u2013PH inhibitor for the treatment of renal anaemia

PurposeThe present studies assessed the drug–drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD).MethodsForty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12–15 participants per study). Molidustat AUC and Cmax were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics.ResultsDepending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and Cmax by 50–75% and 46–84%, respectively, and EPO AUC(0-24) and Cmax by 31–44% and 36–48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and Cmax of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and Cmax by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated.ConclusionsIn contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.

Roxadustat (FG4592; ASP1517; AZD9941) in the Treatment of Anemia in Patients with Lower Risk Myelodysplastic Syndrome (LR-MDS) and Low Red Blood Cell (RBC) Transfusion Burden (LTB)

Background: Roxadustat (FG-4592) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. Transient, intermittent HIF activation by roxadustat mimics a physiological response that increases endogenous erythropoietin (EPO) production to near physiologic range and stimulates EPO receptor synthesis. In addition, roxadustat promotes iron metabolism by reducing serum hepcidin to allow absorption of iron from the gut and mobilize iron from cellular storage making more iron available for erythropoiesis. Roxadustat corrected and maintained hemoglobin (Hb) in chronic kidney disease patients in multiple Phase 3 trials irrespective of underlying inflammation. In these studies, roxadustat-treated patients required less IV iron to correct and maintain Hb compared to erythropoiesis-stimulating agent (ESA)-treated patients. MDS is characterized by symptomatic anemia and many patients require RBC transfusion and/or ESA treatment. As response to ESAs varies across sub-populations with limited durability, there is an unmet need for treatment of anemia in LR-MDS. This is the first study to evaluate the effect of roxadustat in treating anemia in primary MDS patients. Methods: This is a two-part study; an open-label (OL), dose-finding segment (N=24) followed by a randomized double-blind (DB) placebo-controlled segment (N=156, 3:2 ratio of roxadustat to placebo). The primary goal of the OL segment is to identify the starting roxadustat dose-level for the DB segment. A total 24 patients in the OL segment have been enrolled in three sequential cohorts with 8 patients in each starting dose cohort (1.5, 2.0, or 2.5 mg/kg). RBC transfusion has been allowed per institutional criteria. Eligible patients were very low, low or intermediate risk primary MDS patients based on the International Prognostic Scoring System Revised classification with &amp;lt;5% bone marrow blasts; had baseline Hb &amp;lt; 10.0 g/dL; were &amp;gt;18 years old; and had LTB defined as receiving 1-4 RBC units per 8 week period. Patients were ineligible if they used an ESA within 8 weeks of the study start; had endogenous EPO levels &amp;gt;400 mIU/mL, or had a del(5q) cytogenetic abnormality. Roxadustat was administered TIW with doses titrated every 8 weeks per a dosing algorithm based on Hb response and transfusion need. Data from the OL segment were evaluated to identify the starting dose for the DB segment (currently enrolling). The primary endpoint is transfusion independence (TI) for ≥56 consecutive days during the first 28 weeks of treatment. The proportion of patients who achieve ≥50% reduction in RBC transfusion over any 8 weeks compared to baseline (8 weeks prior to Day 1) and proportion of patients who achieve TI for ≥20 consecutive weeks are evaluated. Safety and tolerability are assessed by adverse event reporting, percentage of patients progressing to acute myeloid leukemia (AML), and clinical laboratory values. Results: Twenty-four transfusion dependent, LR-MDS patients were enrolled in the OL segment of this global Phase 3 trial. Nine patients (38%) achieved TI for at least 56 consecutive days within the first 28 weeks.Three of 9 patients started at 1.5 mg/kg dose, 1 patient started at 2.0 mg/kg dose and 5 patients started at 2.5 mg/kg dose. At the time of achieving TI, 7 of 9 patients (78%) were on 2.5 mg/kg dose, 1 patient (11%) was on 2.0 mg/kg dose (started with 1.5 mg/kg dose) and one patient (11%) was on 1.5 mg/kg dose. Four patients remained TI for &amp;gt;20 weeks (one at 1.5 mg/kg dose level and three at 2.5 mg/Kg dose-level). One additional patient achieved TI after the initial 28-week dosing period at a dose-level of 3.5 mg/kg (starting dose 2.0 mg/kg). A total of 14 patients (58%) achieved a ≥50% reduction in RBC units in any 8-week period compared to baseline (range of 2-4 RBC units in 8 weeks before dosing); 12 of these patients were at ≥ 2.5 mg/kg dose level when achieving a 50% reduction in transfusion without need for IV iron. The overall safety profile observed is consistent with the patient population under study. Six patients reported 8 treatment-emergent SAEs with none being fatal. No patient has progressed to AML. Full results from the OL segment of the study will be presented. Conclusion: Based on the observed response (TI and transfusion reduction) and safety profile in LR-MDS patients, 2.5 mg/kg was selected as the starting dose for the ongoing 156-patient DB portion of the trial. Disclosures Harrup: Cooperative Trial Group for NeuroOncolog: Other: Collaborative Clinical Trials Group; Cancer Council of Tasmania: Membership on an entity's Board of Directors or advisory committees. Mittelman:Novartis: Honoraria, Research Funding, Speakers Bureau. Bradley:FibroGen Inc.: Employment, Equity Ownership. Saha:FibroGen Inc.: Employment, Equity Ownership. Bartels:FibroGen Inc.: Employment, Equity Ownership. Robert:FibroGen Inc.: Employment, Equity Ownership. Yu:FibroGen Inc.: Employment, Equity Ownership.

Are prolyl-hydroxylase inhibitors potential alternative treatments for anaemia in patients with chronic kidney disease?

Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.

Thermal injury of the skin induces G-CSF-dependent attenuation of EPO-mediated STAT signaling and erythroid differentiation arrest in mice

Inflammation-mediated impairment of erythropoiesis plays a central role in the development of the anemia of critical illness (ACI). ACI develops despite elevation of endogenous erythropoietin (EPO), does not respond to exogenous erythropoietin (EPO) supplementation, and contributes significantly to transfusion requirements in burned patients. We have reported previously that the reduction of red blood cell mass in the bone marrow of a burn-injured ACI mouse model is granulocyte colony-stimulating factor (G-CSF) dependent. Given that elevated G-CSF levels also have been associated with lower hemoglobin levels and increased transfusion requirements in trauma victims, we postulated that G-CSF mediates postburn EPO resistance. In ACI mice, we found that bone marrow erythroid differentiation, viability, and proliferation are impaired after thermal injury of the skin. These changes in the marrow were associated with attenuated phosphorylation of known EPO-responsive signaling nodes, signal transducer and activator of transcription 5 (STAT5) Y694 and STAT3 S727, in bone marrow erythroid cells and developed despite highly elevated levels of endogenous EPO. Severely blunted STAT5 Y694 phosphorylation in bone marrow erythroid cells after exogenous EPO supplementation confirmed that EPO signaling was impaired in ACI mice. Importantly, parenteral administration of anti-G-CSF largely rescued postburn bone marrow erythroid differentiation arrest and EPO signaling in erythroid cells. Together, these data provide strong evidence for a role for G-CSF in the development of ACI after burn injury through suppression of EPO signaling in bone marrow erythroid cells.

Endogenous Erythropoietin.

We sought to briefly describe current models of endogenous erythropoietin (EPO) pleiotropic properties to make four points clear. First, endogenous EPO regulates erythroid cell apoptosis so that red blood cell production is balanced against the number of cells destroyed in order to maintain optimal tissue oxygen levels (i.e., consistent with provision of homeostatic functional signaling information). Second, preclinical and clinical studies alike provide additional evidence of other (i.e., extraerythropoietic) immune-related and growth/trophic properties. Third, EPO might also be increased as an antiinflammatory response to other proinflammatory cytokines, and not because it is an inflammatory protein, in which case, it would make the association between EPO and these other proteins an epiphenomenon. Fourth, on the other hand, EPO might also act as a tissue protector or it could reflect immaturity/vulnerability of the brain or of the systems responsible for protecting it. Each of these scenarios is plausible, and all are probably true in certain circumstances.

Endogenous Erythropoietin Protects Neuroretinal Function in Ischemic Retinopathy

Because retinal ischemia is a common cause of vision loss, we sought to determine the effects of ischemia on neuroretinal function and survival in murine oxygen-induced retinopathy (OIR) and to define the role of endogenous erythropoietin (EPO) in this model. OIR is a reproducible model of ischemia-induced retinal neovascularization; it is used commonly to develop antiangiogenic strategies. We investigated the effects of ischemia in murine OIR on retinal function and neurodegeneration by electroretinography and detailed morphology. OIR was associated with significant neuroretinal dysfunction, with reduced photopic and scotopic ERG responses and reduced b-wave/a-wave ratios consistent with specific inner-retinal dysfunction. OIR resulted in significantly increased apoptosis and atrophy of the inner retina in areas of ischemia. EPO deficiency in heterozygous Epo-Tag transgenic mice was associated with more profound retinal dysfunction after OIR, indicated by a significantly greater suppression of ERG amplitudes, but had no measurable effect on the extent of retinal ischemia, preretinal neovascularization, or neuroretinal degeneration in OIR. Systemic administration of recombinant EPO protected EPO-deficient mice against this additional suppression, but EPO supplementation in wild-type animals with OIR did not rescue neuroretinal dysfunction or degeneration. Murine OIR offers a valuable model of ischemic neuroretinal dysfunction and degeneration in which to investigate adaptive tissue responses and evaluate novel therapeutic approaches. Endogenous EPO can protect neuroretinal function in ischemic retinopathy.

Treatment with Erythropoietic Stimulating Agents in IPSS Lower Risk MDS: Outcome Comparison Between 5q- and Non 5q- MDS Cases

Abstract 2799 Background.In IPSS lower-risk Myelodysplastic Syndromes (MDS), anemia is the main therapeutic challenge. Erythropoietin stimulating agents (ESAs) can frequently correct anemia, but not all patients respond, and median response duration to ESAs is around 2 years (Park, Blood 2008;111:574). Patients with deletion of chromosome 5q are usually considered refractory to ESAs. Endogenous serum erythropoietin levels have been demonstrated in only one study to be higher in patients carrying del5q than in patients with Lower-Risk MDS and different abnormalities in karyotypes. Aims. We wanted to further analyze differences in management, efficacy and tolerability of ESAs therapy between MDS with and without del5q. Patients and Methods. We studied 239 MDS patients affected by IPSS low and intermediate 1 risk disease. 82 patients carried deletion of 5q, 12/82 in association with other anomalies. MDS patients with del 5q were WHO diagnosed as 9 RA, 9 RCMD, 13 RAEB-1, 47 5q minus syndrome and 2 unclassifiable MDS and divided by IPSS risk: 49 low risk and 33 INT-1. Patients without del5q were diagnosed as follows: 59 RA, 24 RARS, 43 RCMD, 17 RAEB-1, 4 CMML and 10 unclassifiable MDS. When subdivide per IPSS risk: 90 low risk and 67 INT-1. 75% of patients with del5q were female against 37% of patients without del5q. Medical record of patient were collected and reviewed, statistical analysis were perform with SPSS software. IWG criteria for response to ESA treatment were applied. Results. Endogenous erythropoietin (EPO) level at diagnosis were significant higher in patients with del 5q (mean 599,6 mU/ml) than in others (mean 99,3 mU/ml)(p=0.002). There was no significant difference, in terms of endogenous EPO levels, either stratifying by WHO classification (p=0.996) or by IPSS score (INT-1 325.8 mU/ml, low 138.6 mU/ml, p=0.120), or blast % (p>0.05). Serum creatinine levels were correlated with endogenous EPO levels (p=0.003 Spearman’s rho −0.258). Serum Epo was also correlated to age (p=0.026 Spearman’s rho −0.183). No correlation was seen between number of transfusions at diagnosis and serum EPO levels and between hemoglobin levels and serum EPO levels. 18 patients (22%) with deletion of 5 q responded to ESAs treatment versus 56,8% of responding patients without del 5q (p<0.001). Erythroid response was shorter p<0.05 in MDS with del5q. ESA response was inversely correlated with endogenous serum EPO levels (p=0.000). In all of our cohort rate of response to ESA was lower in patients with excess of blast than the others (32% vs 49% p=0,022). Conclusion. ESAs treatment has to be considered first line therapy for IPSS lower risk MDS patients with syntomatic anemia, also when carrying del5q. Endogenous EPO levels are constantly higher, throughout disease history, in del5q MDS cases. This could account for worse ESA response. Anemia and WHO classification do not seem to influence ESA response. Excess of blasts was an adverse prognostic factor to ESA response with or without del5q. A deeper insight into mechanisms of resistance to ESAs is needed. Disclosures:No relevant conflicts of interest to declare.

An Increase in Endogenous Erythropoietin Concentrations Has No Cardioprotective Effects in Patients Undergoing Coronary Artery Bypass Graft Surgery

Preliminary data showed an increase in endogenous erythropoietin (EPO) concentrations after acute normovolemic hemodilution (ANH) in patients undergoing coronary artery bypass graft (CABG) surgery. Numerous studies have shown the organ protective properties of EPO. The aim of this study was to investigate the cardioprotective effects of these increased EPO concentrations that resulted from ANH during cardiac surgery. A prospective, randomized, blind study. A university hospital. A total of 93 patients undergoing isolated CABG surgery with or without cardiopulmonary bypass (CPB). Subjects with CPB were randomized into the control (C) or ANH group. Those in the off-pump coronary artery bypass group underwent no treatment. In the ANH group, a precalculated amount of blood was withdrawn and replaced by colloids after the induction of anesthesia. Hemodynamic parameters were recorded intra- and postoperatively. Troponin concentrations were measured as a routine parameter postoperatively. Upon intensive care unit arrival, the EPO levels were higher in the ANH group than in the C group. There was no significant difference between the troponin values of the C and the ANH groups at 4 hours postoperatively. In patients undergoing CABG surgery on CPB, an increase in endogenous EPO concentrations in the physiologic range has no cardioprotective effects.

Endogenous Erythropoietin and the Association with Inflammation and Mortality in Diabetic Chronic Kidney Disease

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

Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use

Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use

Erythropoietin exerts anti-epileptic effects with the suppression of aberrant new cell formation in the dentate gyrus and upregulation of neuropeptide Y in seizure model of rats

We explored the effects of exogenous and endogenous erythropoietin (EPO) in a seizure model of rat. Adult male Fischer 344 rats received continuous intraventricular infusion of EPO dissolved in saline containing 1 mg/ml of rat serum albumin, anti-EPO antibody, saline containing 1 mg/ml of rat serum albumin or combined EPO and neuropeptide Y (NPY) Y2-receptor antagonist. Animals were behaviorally evaluated for seizure development over 6 h after kainic acid injection followed by immunohistochemical assays. Mortality rate, seizure severity, apoptotic cell death and abnormal cell proliferation in the hippocampus of EPO-treated epileptic rats were significantly attenuated, compared to control rats. Anti-EPO antibody in non-EPO-treated animals worsened seizures and CA1 neuronal cell death, while NPY Y2-receptor antagonist cancelled the therapeutic effects of exogenous EPO. Both exogenous and endogenous EPO might modulate seizure severity and protect the hippocampal neurons in epileptic rats, via novel mechanistic pathways involving blockade of epileptogenic cell formation coupled with NPY receptor modulation in the hippocampus.