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Cigarette smoking continues to be one of the major risk factors for increased morbidity and mortality worldwide. Among many adverse health effects, smoking can induce erythrocytosis, which is commonly believed to result from elevated serum erythropoietin (EPO) levels. Currently, however, this notion is only alleged, without data available to substantiate it. Hence, we analyzed data from the Prevention of Renal and Vascular End-Stage Disease study, a prospective population-based cohort study. Smoking behavior was quantified as number of cigarettes smoked per day and as 24-hour urinary cotinine excretion levels, an objective and quantitative measure of nicotine exposure. In 6808 community-dwelling participants, the prevalence of nonsmokers, former smokers, and current smokers were 29%, 43%, and 28%, respectively. Hematocrit levels were higher in current smokers (41.4%±3.6%) than in nonsmokers (40.3%±3.6%) (P<.001). In contrast, median EPO levels were lower in current smokers (7.5 IU/L; interquartile range [IQR], 5.7-9.6 IU/L) than in nonsmokers (7.9 IU/L; IQR, 6.0-10.7 IU/L) (P<.001). In multivariate linear regression analysis, current smoking, compared with nonsmoking, was independently positively associated with hematocrit levels (β=.12; P<.001) and hemoglobin levels (β=.11; P<.001), but inversely associated with EPO levels (β=-.09; P<.001). In sensitivity analyses, we observed a dose-dependent inverse association of smoking exposure reflected by 24-hour urinary cotinine excretion levels with EPO levels. Contrary to common belief, we identified that in the general population, smoking is inversely associated with EPO levels. Future mechanistic insight is needed to unravel the currently identified association, and if reproduced in other studies, guidelines for diagnosis of secondary erythrocytosis may need to be revisited., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

To date, good experimental animal models of renal anemia are not available. Therefore, the purpose of this study was to establish a novel approach to induce chronic kidney disease (CKD) with severe anemia by oral administration of adenine in rodents. Adenine was administered to 6-week-old male C57BL/6 mice (25 and 50 mg/kg body weight) by oral gavage daily for 28 days. Serum creatinine and BUN as well as hematocrit, hemoglobin (Hb) and plasma erythropoietin (EPO) levels were monitored to assess renal function and anemia, respectively. Adenine at 25 mg/kg for 28 days slightly increased plasma creatinine levels, but did not induce anemia. In contrast, 50 mg/kg of adenine daily for 28 days showed severe renal dysfunction (plasma creatinine 1.9 ± 0.10 mg/dL) and anemia (hematocrit 36.5 ± 1.0% and EPO 28 ± 2.4 pg/mL) as compared with vehicle-treated mice (0.4 ± 0.02 mg/dL, 49.6 ± 1.6% and 61 ± 4.0 pg/mL, respectively). At the end of experiment, level of Hb also significantly reduced in 50 mg/kg adenine administration group. Remarkable histological changes of kidney tissues characterized by interstitial fibrosis and cystic appearance in tubules were observed in 50 mg/kg of adenine treatment group. These results have demonstrated that oral dosing with adenine at 50 mg/kg for 28 days is suitable to induce a stable anemia associated with CKD in mice.

Purpose: Various hypoxia-related proteins are differentially expressed in the retina and secreted to the vitreous and/or aqueous humor of patients affected by dry or neovascular age-related macular degeneration (nAMD). To determine whether these conditions alter concentrations of cytokines also in the systemic circulation, we measured plasma levels of six hypoxia-related proteins., Methods: Plasma was prepared from EDTA blood that was collected from patients affected by dry AMD (n = 5), nAMD (n = 11), proliferative diabetic retinopathy (PDR; n = 9), and patients with an epiretinal membrane (ERM; n = 11). ERM samples served as negative controls, PDR samples as positive controls. Protein concentrations of vascular endothelial growth factor (VEGF), erythropoietin (EPO), angiopoietin-like 4 (ANGPTL4), placental growth factor (PlGF), tumor necrosis factor alpha (TNF-α), and pigment epithelium-derived factor (PEDF) were determined by enzyme-linked immunosorbent assay (ELISA)., Results: The concentration of PlGF was significantly increased in plasma of patients affected by nAMD. Although no statistically significant differences were found for EPO, ANGPTL4, PlGF, TNF-α, and PEDF, the mean concentration of VEGF was lowest in the nAMD group. Plasma concentrations of the six factors did not correlate with gender or age of patients., Conclusions: nAMD may increase plasma concentrations of PlGF, making it a candidate as a biomarker for the neovascular form of AMD. Other factors, however, were not differentially regulated, suggesting that their systemic concentrations are not generally increased in hypoxia-related retinal diseases.

Introduction: Chronic kidney disease (CKD) is a global health problem with an increasing prevalence worldwide. Anemia is one of its consistent and severe hematological complications although its mechanism is not fully elucidated. The primary defect could manifest as serum erythropoietin (sEPO) deficiency or EPO resistance. We set out to determine the erythropoietic response to anemia of patients with CKD and its relationship with their iron status in a cross-sectional descriptive study of 91 patients in various stages of CKD. Materials and Methods: Soluble transferrin receptor (sTfR), sEpo, and serum ferritin levels were determined using ELISA method (Diagnostic Automation Inc and WKEA med supplies corp.). Data generated were analyzed using Epi Info version 3.5.3 and level of statistical significance was set at ≤0.05. Results: Participants comprised of 50 females (54.9%) and 41 (45.1%) males with an overall mean age of 47 ± 15 years. The major causes of CKD were hypertension (HTN) (50.54%), diabetes mellitus (DM) (6.59%), and HTN + DM (19.78%). The mean hemoglobin (Hb) concentration of the participants was 10.97 ± 2.28 g/dl; the red cell indices were within normal ranges except for Red cell distribution width-Coefficient of variation (%) which was elevated (16.29%). The mean serum ferritin, sTfR, and sEpo were 70.58 ± 46.44 ng/ml (interquartile range [IQR] 82.00), 22.9 ± 49.7 ng/ml (IQR 15.00), and 12.49 ± 33.47 IU/L (IQR 6.00), respectively, with a high variance. Serum ferritin and sTfR are consistently low across the stages of CKD (range between 54.54 ng/ml and 88.64 ng/ml), but sEPO for stage 3 and 4 showed a 2-fold increase when compared to normal level at Hb 10.97 g/dl (29.54 IU/L and 38.83 IU/L, respectively). Correlation between sTfR and sEpo (r 2 = 0.96, P = 0.001), while between sEpo and serum ferritin (r 2 = 0.02, P = 0.185), and between Hb and stage of CKD undulating (r 2 = 0.41, P = 0.001)., Conclusion: In contrast to some existing literature, this study has demonstrated that EPO resistance and iron deficiency contributes to anemia in CKD and serum ferritin can be used to assess the iron level of dialysis naïve CKD patients at every stage of the disease., Competing Interests: There are no conflicts of interest.

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

Thalassemias are a heterogeneous group of red blood cell disorders, considered a major cause of morbidity and mortality among genetic diseases. However, there is still no universally available cure for thalassemias. The underlying basis of thalassemia pathology is the premature apoptotic destruction of erythroblasts causing ineffective erythropoiesis. In β-thalassemia, β-globin synthesis is reduced causing α-globin accumulation. Unpaired globin chains, with heme attached to them, accumulate in thalassemic erythroblasts causing oxidative stress and the premature cell death. We hypothesize that in β-thalassemia heme oxygenase (HO) 1 could play a pathogenic role in the development of anemia and ineffective erythropoiesis. To test this hypothesis, we exploited a mouse model of β-thalassemia intermedia, Th3/ + We observed that HO inhibition using tin protoporphyrin IX (SnPP) decreased heme-iron recycling in the liver and ameliorated anemia in the Th3/ + mice. SnPP administration led to a decrease in erythropoietin and increase in hepcidin serum levels, changes that were accompanied by an alleviation of ineffective erythropoiesis in Th3/ + mice. Additionally, the bone marrow from Th3/ + mice treated with SnPP exhibited decreased heme catabolism and diminished iron release as well as reduced apoptosis. Our results indicate that the iron released from heme because of HO activity contributes to the pathophysiology of thalassemia. Therefore, new therapies that suppress heme catabolism may be beneficial in ameliorating the anemia and ineffective erythropoiesis in thalassemias., (© 2018 by The American Society of Hematology.)

Background: Red cell distribution width (RDW) is a cardiac marker for risk stratification and prognostic evaluation of coronary artery disease (CAD); however, the underlying mechanism remains unclear. Erythropoietin (EPO), a crucial factor affecting erythropoiesis, has been reported to be a protective molecule regulating the process of myocardial ischemia and relevant damage. No study has as yet reported the relationship between RDW and endogenous EPO in CAD patients. This cross-sectional study aimed to establish the association between endogenous EPO levels and increases in RDW in CAD patients., Patients and Methods: Two hundred participants who underwent coronary arteriography were recruited from July 2015 to October 2015. The participants were divided into CAD and non-CAD groups on the basis of angiography diagnosis. Demographic data were obtained through personal interviews and general clinical methods., Results: RDW and EPO levels in the CAD group were higher than those in the non-CAD group. The correlation between RDW and EPO levels was statistically significant among CAD patients (r=0.411, P<0.001). The increases in EPO and RDW were related to the prevalence of CAD. The levels of RDW were correlated to endogenous EPO levels in CAD patients., Conclusion: Increased EPO and RDW might be risk factors for CAD. Endogenous EPO levels are associated with increases in RDW in CAD patients.

he concentration of erythropoietin (EPO) in serum was studied. The study included 122 people divided into two groups. The main group (group 1) consisted of 102 patients with chronic obstructive pulmonary disease (COPD). The control group (group 2), comparable in age and sex, was 20 surveyed, with no signs of respiratory failure. The concentration of EPO was determined by the method of solid-phase enzyme immunoassay (ELISA) using the test system "Erythropoietin-EIA-BEST" (ZAO Vector-Best, Russia). The concentration of EPO in the serum of the patients of the main group significantly exceeded its content in the control group, the median and interquartile range were respectively 12.0 (7.4 - 16.1) mIU / ml in the main group and 7.5 (5.65-8 , 1) mIU / ml in the control group (p = 0.000454). The degree of increase in EPO correlated with the severity of COPD on the GOLD scale. In a pair comparison of the results obtained, significant differences were established between the control group and the G grade subgroup (p (control and C) = 0.021578), and the control group and subgroup D according to the GOLD classification (p (control and D) = 0,000721). An increase in the content of EPO in the blood is probably due to the reaction of the juxtaglomerular nephron apparatus to the formation of hypoxia due to a violation of the function of external respiration. Thus, the study of the concentration of EPO can be used to assess the severity of COPD, and in interpreting the results of this laboratory test, the possibility of increasing its concentration due to impairment of the function of external respiration should be considered., Competing Interests: The authors declare no conflict of interest.

The study was carried out at Concordia Station (Antarctic Plateau). The aim was to investigate the respiratory and haematological responses to hypoxia in healthy subjects living at constant altitude. Thirteen men and women (34.1 ± 3.1 years) were exposed for 10 months to hypobaric hypoxia (oxygen level equivalent to 3800 m asl). These unique conditions enable a greater accuracy of monitoring human responses to chronic hypoxia than can be achieved elsewhere. Blood haemoglobin and erythropoietin concentrations were determined at sea level (Pre), and after 3, 7, 20, 90 and 300 days at altitude. Blood gas analysis, base excess and arterial oxygen saturation were measured at Pre, and after 150 and 300 days at altitude. Erythropoietin returned quickly to baseline level after a transient increase in the first days. Blood haemoglobin concentration started increasing at day 7 and remained markedly higher for the entire duration of the mission. At day 150 the blood carbon dioxide partial pressure was markedly reduced, and consequently blood pH remained higher at negative base excess until day 300. The arterial oxygen saturation remained lower than Pre throughout. In conclusion, humans display little capacity of hypoxia acclimatization even after ten months of constant exposure to low oxygen partial pressure.

Lower risk myelodysplastic syndromes (MDS), defined as MDS with a Revised International Prognostic Scoring System score ≤3.5 points, will remain a challenging entity in 2018. Supportive care continues to be the linchpin of treatment, although the options to reduce transfusion needs are broadening. To achieve red blood cell transfusion independence in non-del(5q) patients, erythropoiesis-stimulating agents remain a mainstay of therapy as long as endogenous erythropoietin levels are <500 U/L (and preferably <200 U/L). Experimental strategies for patients ineligible for erythropoiesis-stimulating agents or relapsing after gaining transfusion independence include immunosuppressive agents, transforming growth factor β inhibitors, and lenalidomide. All these alternatives have shown reasonable response rates in selected patient populations with lower risk MDS. Patients with del(5q) disease can derive long-term benefit from lenalidomide, and some patients remain transfusion free for extended periods even after discontinuation of the drug. In rare cases in which thrombocytopenia is the main clinical problem leading to clinically significant bleeding events, thrombopoietin receptor analogues may alleviate bleeding, increase platelet counts, and rarely lead to trilineage responses. It seems prudent to use these drugs only in patients with confirmed bone marrow blast counts <5%. Allogeneic stem cell transplantation is reasonable for patients with high molecular risk of progression and those failing several lines of treatment with signs of progression toward higher-risk MDS., Competing Interests: Conflict-of-interest disclosure: The author has received honoraria from Novartis, Celgene, and Acceleron., (© 2016 by The American Society of Hematology. All rights reserved.)

Objective: To explore the protective effects of Tibetan medicine Zuo-Mu-A Decoction (, ZMAD) on the blood parameters and myocardium of high altitude polycythemia (HAPC) model rats., Methods: Forty male Wistar rats were randomly divided into 4 groups by a random number table, including the normal, model, Rhodiola rosea L. (RRL) and ZMAD groups (10 in each group). Every group was raised in Lhasa to create a HAPC model except the normal group. After modeling, rats in the RRL and the ZMAD groups were administered intragastrically with RRL (20 mL/kg) and ZMAD (7.5 mL/kg) once a day for 2 months, respectively; for the normal and the model groups, 5 mL of distilled water was administered intragastrically instead of decoction. Then routine blood and hematologic rheology parameters were taken, levels of erythropoietin and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were tested, and ultrastructural change in the left ventricular myocardium was observed using transmission electron microscopy., Results: Compared with the model group, ZMAD significantly reduced the red blood cell count, hemoglobin levels, whole blood viscosity at low/middle shear rates, plasma viscosity, erythrocyte electrophoretic time, erythropoietin and 8-OHdG levels, and also increased the erythrocyte deformation index (P<0.05). There was no difference in all results between the RRL and the ZMAD groups. The cardiac muscle fibers were well-protected, mitochondrial matrix swelled mildly and ultrastructure changes were less prominent in the ZMAD group compared with the model group., Conclusion: ZMAD has significant protective effects on the blood parameters against HAPC, and also has the beneficial effect in protecting against myocardial injury.

Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.

Background: Anaemia is a very common problem in patients with end-stage kidney disease (ESKD) and the use of erythropoietin-stimulating agents (ESA) has revolutionised its treatment. Residual renal function (RRF) is associated with a reduction in ESA resistance and mortality in chronic dialysis. The primary aim was to establish whether RRF has an association with ESA dose requirements in ESKD patients receiving chronic dialysis., Methods: A single center, cross-sectional study involving 100 chronic dialysis patients was conducted from December 2015 to May 2016. Participants were divided into two groups depending on presence of RRF, which was defined as a 24-h urine sample volume of ≥ 100 ml. Erythropoietin resistance index [ERI = total weekly ESA dose (IU)/weight (kg)/haemoglobin concentration (g/dL] was used as a measure of ESA dose requirements., Results: There was no difference in ERI between those with RRF as compared to those without (9.5 versus 11.0, respectively; P = 0.45). Also, ERI did not differ between those receiving haemodialysis as compared with peritoneal dialysis (10.8 versus 10.2, respectively; P = 0.84) or in those using renin-angiotensin system (RAS) blockers as compared with no RAS blocker use (11.6 versus 9.2, respectively; P = 0.10). Lower ERI was evident for those with cystic kidney disease as compared to those with other causes of ESKD (6.9 versus 16.5, respectively; P = 0.32) although this did not reach statistical significance. Higher ERI was found in those with evidence of systemic inflammation as compared to those without (16.5 versus 9.5, respectively; P = 0.003)., Conclusions: There was no association between RRF and ESA dose requirements, irrespective of dialysis modality, RAS blocker use, primary renal disease or hyperparathyroidism.

According to the World Anti-Doping Agency (WADA) technical document for erythropoiesis stimulating agents (ESA) analysis (TD2014EPO), double-blotting of serum/plasma samples is mandatory for all analysis by isoelectric focusing (IEF) and for the confirmation procedures (CP) performed by SDS-PAGE or SAR-PAGE. The goal is to prevent potential cross-reactions of the secondary antibody with remaining proteins in the purified samples. To this end, we have developed an immunopurification method of ESA in serum/plasma samples using a combination of streptavidin-coated immunomagnetic beads and biotinylated anti-EPO polyclonal antibodies. Here we report that this immunomagnetic bead-based purification allows the analysis of serum/plasma samples by single-blotting. Serum and plasma samples, either intact or spiked with different ESAs, were immunopurified and analyzed by single-blotting, after SAR-PAGE or IEF using a cross-reaction minimized secondary antibody coupled to HRP. The results show that when samples are immunopurified according to this strategy, there is no non-specific binding when single-blotting is performed after SAR-PAGE. With IEF, we observe a faint smearing, however, in the pH gradient outside the ESA detection region. These interferences did not alter ESA profiles of spiked urinary samples or of samples received for routine testing. This approach was compared to the MAIIA monoliths purification or to the isolation of ESAs with other combinations of immunomagnetic reagents (ie, anti-Mouse IgG-coated magnetic beads and anti-EPO mAb). The recovery of ESAs was shown to be significant for serum/plasma samples. Our results suggest that single-blotting could be performed on serum/plasma samples without non-specific interferences. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Erythropoiesis Stimulating Agents (ESAs) were developed for therapeutic purposes to stimulate red blood cell (RBC) production. Consequently, tissue oxygenation is enhanced as athlete's endurance and ESAs misuse now benefits doping. Our hypothesis is that most of ESAs should have similar mechanisms and thus have the same effects on metabolism. Studying the metabolome variations could allow suspecting the use of any ESAs with a single method by targeting their effects. In this objective, a metabolomic study was carried out on 3 thoroughbred horses with a single administration of 4.2μg/kg of Mircera ® , also called Continuous Erythropoiesis Receptor Activator (CERA). Blood and urine samples were collected from D -17 to D +74 and haematological parameters were followed throughout the study as plasmatic CERA concentration (ELISA). Urine and plasma metabolic fingerprints were recorded by Liquid Chromatography coupled to High Resolution Mass Spectrometry (LC-HRMS) in positive and negative mode. After preprocessing steps, normalized data were analyzed by multivariate statistics to build OPLS models. Hemoglobin concentration and hematocrit showed a significant increase after CERA administration unlike reticulocytes. CERA concentration showed a high intensity peak and then a slow decrease until becoming undetectable after D +31 . Models built with multivariate statistics allow a discrimination between pre and post-administration plasma and urine samples until 74days after administration, i.e. 43days longer than ELISA method. By reducing and studying variables (ions), some potential candidate biomarkers were found., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The patients with severe aplastic anemia (SAA) usually rely on red cell transfusion which lead to secondary iron overload. Transforming growth differentiation factor-15 (GDF-15) plays an important role in erythropoiesis and iron regulation. In this study, we investigated the level of GDF-15 and other indexes of iron metabolism in SAA patients to explore the correlation with GDF-15 and iron overload in SAA., Methods: The levels of serum GDF-15, hepcidin (Hepc), and erythropoietin (EPO) were determined by ELISA. The levels of serum iron (SI), ferritin, TIBC, and transferrin saturation (TS) were measured by an auto analyzer. Iron staining of bone marrow cells was used for testing extracellular and intracellular iron., Results: The GDF-15 level in the experimental group was higher than that of the case-control group and normal control group (all p < 0.05). The Hepc level in the experimental group and case-control group were both higher than that of healthy controls (all p < 0.05). The Hepc level was significantly lower in the experimental group patients who had excessive GDF-15 (r = -0.766, p = 0.000). There was a positive correlation between the level of GDF15 and EPO in the experimental group (r = 0.68, p < 0.000). The level of GDF15 in SAA patients was positively correlated with SI levels (r = 0.537, p = 0.008), TS levels (r = 0.466, p = 0.025), and sideroblasts (%) (r = 0.463, p = 0.026). Moreover, there was a positive correlation between GDF-15 level and blood transfusion-dependent time (r = 0.739, p = 0.000)., Discussion: Our data indicated that GDF-15 plays an important role in iron metabolism in SAA. GDF-15 might be a novel target for SAA therapy.

Background: The pathogenesis of post-transplantation erythrocytosis (PTE) is not well understood and appears to be multifactorial. Our hypothesis in this study was that several factors, including toxicity of calcineurin inhibitor, immunologic factors, and chronic allograft nephropathy, can trigger local tissue hypoxia in peritubular interstitium, which is where production of erythropoietin (EPO) takes place. This local interstitial tissue hypoxia can cause an increase in renal EPO production, which induces the development of PTE., Methods: This cross-sectional study included 15 renal transplant recipients, in whom polycythemia developed after kidney transplantation, with elevated hematocrit level to >51%. Forty-eight age- and gender-matched renal transplant recipients with normal hematocrit level were included as the renal transplant control group. In addition, 13 age- and gender-matched healthy subjects were also included as the healthy control group. We used urine hypoxia-inducible factor-2 alpha (HIF-2α) levels to evaluate whether there is local tissue hypoxia in renal allograft. HIF-2α levels were measured by double antibody sandwich enzyme-linked immunosorbent assay (ELISA). Serum EPO and insulin-like growth factor-1 (IGF-1) levels were also measured., Results: HIF-2α levels were significantly lower in the polycythemia group than the other two groups, but there was no significant difference between the healthy control group and the renal transplant control group with regard to HIF-2α levels. There was no significant difference among the 3 study groups in terms of levels of serum EPO and IGF-1., Conclusion: Local tissue hypoxia in renal allograft does not seem to play an important role in the development of PTE., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45-52% of plasma level) and brain (1-4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47-64%), cognitive dysfunction (60-75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

Objective: To determine the adverse pregnancy outcomes associated with maternal pre-pregnancy overweight and obesity and we measure cord blood erythropoietin and NRBC count as indices of hypoxia and predictors of neonatal outcome., Study Design: This prospective cohort study was done in Minia University Hospital, carried out from May 2015 to April 2016. Two hundred and seventy full-term neonates born to mothers of various body mass indices were included. Excluded were neonates with major factors known to be associated with a potential increase in fetal erythropoiesis. Pre-pregnancy maternal BMI was calculated from maternally reported weight and height. Cord blood erythropoietin and nucleated red blood cells were measured., Results: There is a significant increase of various adverse pregnancy outcomes as cesarean section. Postpartum hemorrhage and macrosomia with the increase of maternal pre-pregnancy BMI. Significant positive correlations between cord blood erythropoietin and nucleated red blood cells with maternal BMI., Conclusion: The increase in the maternal pre-pregnancy BMI is associated with poor pregnancy outcomes. Cord blood erythropoietin and nucleated red blood cells can predict the poor neonatal outcome.

Objective  This study aims to investigate the changes of serum erythropoietin (EPO) in premature infants with retinopathy of prematurity (ROP) after birth. Method  The premature infants were divided into two groups, the first were infants with ROP, and the rest were infants without ROP. The peripheral blood of these infants after birth was collected, aiming to identify the correlation of serum EPO with ROP in the first 8 weeks after birth and before 38 weeks' postconceptual age. Results  A total of 299 infants without ROP and 107 infants with ROP were recruited into our study. It was suggested that serum the EPO level in ROP group was significantly lower than it is in the group without ROP on the 28th day after birth. The median value of serum EPO in the group with and without ROP at day 28 of life were 0.44 mIU/mL and 0.62 mIU/mL, respectively ( p  = 0.017). These data indicated that there was no significant association between serum EPO and the clinical factors. Multivariate analysis identified only EPO serum level on the 28th day after birth and gestational age as independent predictors of ROP ( p was 0.025 and 0.021, respectively). Conclusion  EPO serum level may serve as a surrogate marker for the development of ROP., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Intraventricular hemorrhage (IVH) is an important cause of death in premature infants. This study aimed to assess the association of the umbilical cord plasma levels of interleukin-6 (IL-6) and erythropoietin (EPO) with the occurrence and severity of IVH in premature infants., Methods: Fifty premature newborns of mothers with chorioamnionitis risk factor were selected via nonprobability sampling. The concentration of the cord plasma's IL-6 and erythropoietin were measured by enzyme-linked immunosorbent assay (ELISA) for 3 days. Finally, all samples underwent sonography for the diagnosis of IVH. Results analyzed statistically., Results: Among the samples, 68.98% of them were diagnosed with IVH grade 1. The most severe IVH cases were detected on the second day. The mean and standard deviation of IL-6 level was 74.71 ± 50.53 in the case group and 24.10 ± 46.10 in the control group. There was a correlation between IL-6 levels and IVH (p = 0.0005). The mean and standard deviation of EPO level was 18.38 ± 15.23 in the IVH group and 6.45 ± 13.48 in samples without IVH. A correlation was detected between EPO level and IVH (p = 0.005)., Conclusion: The concentration of IL-6 and EPO levels of the cord plasma was higher in the premature newborns with IVH.

Erythropoietin (EPO) rapidly decreases on return to sea level (SL) after chronic altitude exposure. Acute hypoxia may provide an additional stimulus to prevent the decline in EPO. Proinflammatory cytokines, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) have been shown to inhibit EPO production. Optimal normobaric hypoxic exposure has not been established; therefore, investigation of methods eliciting the greatest response in EPO to limit physiological stress is required. Eight men (age 27 ± 4 years, body mass 77.5 ± 9.0 kg, height 179 ± 6 cm) performed four passive exposures to different normobaric hypoxic severities [FiO 2 : 0.209 (SL), FiO 2 : ~0.135 (3600 m), FiO 2 : ~0.125 (4200 m) and FiO 2 : ~0.115 (4800 m)] in a hypoxic chamber for 2 h. Venous blood was drawn pre-exposure and then at 1, 2, 4, 6, and 8 h to determine EPO concentration ([EPO]), IL-6, and TNFα. During 4200 and 4800 m, [EPO] increased from 5.9 ± 1.5 to 8.1 ± 1.5 mU/mL (P = 0.009) and 6.0 ± 1.4 to 8.9 ± 2.0 mU/mL (P = 0.037), respectively, with [EPO] increase peaking at 4 h (2 h post-exposure). There were no differences in IL-6 or TNFα during or post-exposure. Increased [EPO] was found 2 h post hypoxic exposure as result of 2 h of normobaric hypoxia ≥4200 m. There was no dose-response relationship in [EPO] between simulated hypoxia severities., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O 2 availability. Specifically, a reduction in skin-surface PO 2 attenuates transcutaneous O 2 diffusion, and hence epidermal O 2 supply. In response, epidermal HIF-1α expression increases and facilitates initial cutaneous vasoconstriction and subsequent nitric oxide-dependent vasodilation. Here, we investigated whether the same mechanism exists in humans., Methods: In a first experiment, eight males rested twice for 8 h in a hypobaric chamber. Once, barometric pressure was reduced by 50%, while systemic oxygenation was preserved by O 2 -enriched (42%) breathing gas (Hypoxia Skin ), and once barometric pressure and inspired O 2 fraction were normal (Control 1 ). In a second experiment, nine males rested for 8 h with both forearms wrapped in plastic bags. O 2 was expelled from one bag by nitrogen flushing (Anoxia Skin ), whereas the other bag was flushed with air (Control 2 ). In both experiments, skin blood flux was assessed by laser Doppler on the dorsal forearm, and HIF-1α expression was determined by immunohistochemical staining in forearm skin biopsies., Results: Skin blood flux during Hypoxia Skin and Anoxia Skin remained similar to the corresponding Control trial (P = 0.67 and P = 0.81). Immunohistochemically stained epidermal HIF-1α was detected on 8.2 ± 6.1 and 5.3 ± 5.7% of the analysed area during Hypoxia Skin and Control 1 (P = 0.30) and on 2.3 ± 1.8 and 2.4 ± 1.8% during Anoxia Skin and Control 2 (P = 0.90) respectively., Conclusion: Reductions in skin-surface PO 2 do not affect skin perfusion in humans. The unchanged epidermal HIF-1α expression suggests that epidermal O 2 homoeostasis was not disturbed by Hypoxia Skin /Anoxia Skin , potentially due to compensatory increases in arterial O 2 extraction., (© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

The concentration of hepcidin, a key regulator of iron metabolism, is suppressed during periods of increased erythropoietic activity. The present study obtained blood samples from 109 elite athletes and examined the correlations between hepcidin and markers of erythropoiesis and iron metabolism (i.e., haemoglobin, erythropoietin (EPO), ferritin, erythroferrone (ERFE), and iron concentration). Furthermore, an administration study was undertaken to examine the effect of recombinant human EPO (rhEPO) delta (Dynepo™) on hepcidin concentrations in healthy male volunteers. The effects on hepcidin were then compared with those on reticulocyte percentage (Ret%) and ferritin concentration. There was a significant positive correlation between hepcidin and ferritin, iron, and haemoglobin levels in athletes, whereas hepcidin showed an inverse correlation with ERFE. Administration of rhEPO delta reduced hepcidin levels, suggesting that monitoring hepcidin may increase the sensitivity of the Athlete Biological Passport (ABP) for detecting rhEPO abuse. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs., Case-Diagnosis/treatment: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction., Conclusions: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans., Key Message: Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.

Objective: The study mainly aimed at investigating possible correlations between peripheral blood counts, erythropoietin (EPO), JAK2 V617F mutation, and vascular complications prior to diagnosis of a population-based cohort of newly diagnosed patients with myeloproliferative neoplasms (MPN)., Method: The study comprises 1105 patients with polycythemia vera (PV) and 1284 patients with essential thrombocythemia (ET) registered in the Swedish MPN Registry., Results: Vascular complications, prior to diagnosis, were registered in 37% of PV patients. In multivariate analysis, low hemoglobin was the only significant risk factor (P=.0120). Among ET patients, 35% had encountered a vascular complication. Risk factors for thromboembolic complications in ET were identified as age>65 years, white cell count>12×10 9 /L, and the presence of JAK2 V617F mutation (P=.0004, P=.0038, and P=.0016, respectively). A JAK2 V617F mutation was present in 71% of ET patients with vascular complications, compared to 60% in patients without. A majority of complications were thromboembolic, in both PV and ET., Conclusion: We conclude that vascular complications among newly diagnosed patients had affected more than one-third of our study population. Risk factors for vascular complications prior to diagnosis were lower hemoglobin in PV, and the presence of JAK2 V617F mutation, higher age, and leukocytosis in ET., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes., Research Design and Methods: We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min -1 · 1.73 m -2 ) and in control subjects without diabetes at baseline and following empagliflozin treatment., Results: With chronic (4 weeks) sodium-glucose cotransporter 2 inhibition, baseline fractional glucose excretion (<2%) rose to 38 ± 12% and 46 ± 11% (fasting vs. postmeal, respectively; P < 0.0001) over a range of BMIs (range 23-41 kg/m 2 ) and creatinine clearance (65-168 mL · min -1 · m -2 ). Excretion of β-HB (median [interquartile range]: 0.08 [0.10] to 0.31 [0.43] µmol · min -1 ), lactate (0.06 [0.06] to 0.28 [0.25] µmol · min -1 ), and sodium (0.27 [0.22] to 0.36 [0.16] mEq · min -1 ) all increased ( P ≤ 0.001 for all) and were each positively related to glycosuria ( P ≤ 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro-B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% ( P = 0.0078)., Conclusions: We conclude that the sodium-glucose cotransporter 2 inhibitor-induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism., (© 2017 by the American Diabetes Association.)

Background: Chronic hepatitis C virus (HCV) infection is associated with autoimmune phenomena and is often complicated by anemia. Circulating autoantibodies to endogenous erythropoietin (anti-EPO) have been detected in patients with chronic viral infections and were correlated to anemia. The present study aimed to determine anti-EPO prevalence in patients with chronic HCV infection and investigate its possible association with anemia., Methods: Ninety-three consecutive patients (62 males and 31 females) with chronic HCV infection, who had never received antiviral therapy or recombinant EPO, were enrolled in the study. Circulating anti-EPO were detected in the serum by using an ELISA assay. Quantitative determination of serum EPO levels was done by radioimmunoassay. HCV RNA viral load measurement and genotype sequencing were also performed., Results: Circulating anti-EPO were detected in 10.8% of HCV-infected patients and the prevalence of anti-EPO was significantly higher in patients with anemia (19.4% vs 5.3%, P=0.040) compared to that in those without anemia. Compared to anti-EPO negative cases, anti-EPO positive patients had higher frequency of anemia (70.0% vs 34.9%, P=0.030), lower EPO concentrations (median 16.35 vs 30.65 mU/mL, P=0.005), and higher HCV RNA viral load (median 891.5X10 3 vs 367.5X10 3 IU/mL, P=0.016). In multivariate regression analysis the presence of anti-EPO remained an independent predictor of anemia (adjusted OR: 14.303, 95% CI: 1.417-36.580, P=0.024). EPO response to anemia was less prominent among anti-EPO positive patients (P=0.001)., Conclusions: Circulating anti-EPO are detected in a significant proportion of treatment-naive HCV-infected patients and are independently associated with anemia, suggesting a further implication of autoimmunity in the pathophysiology of HCV-related anemia.

Currently available data regarding the blood levels of erythropoietin (EPO) in sleep apnea (SA) patients are contradictory. The aim of the present meta-analysis was to evaluate the EPO levels in SA patients via quantitative analysis. A systematic search of Pubmed, Embase, and Web of Science were performed. EPO levels in SA group and control group were extracted from each eligible study. Weight mean difference (WMD) or Standard mean difference (SMD) with 95% confidence interval (CI) was calculated by using fixed-effects or random effect model analysis according to the degree of heterogeneity between studies. A total of 9 studies involving 407 participants were enrolled. The results indicated that EPO levels in SA group were significantly higher than that in control group (SMD 0.61, 95% CI 0.11-1.11, p = 0.016). Significantly higher EPO levels were found in patients with body mass index <30 kg/m 2 , and cardiovascular complications in the subsequent subgroup analysis (both p < 0.05). High blood EPO levels were found in SA patients in the present meta-analysis.

Epidemiological studies report an association between chronic arsenic (As) exposure and anemia in men, and women who are predisposed to anemia. The purpose of these studies was to determine whether a 60 d drinking water exposure of adult male C57BL/6J mice to 0, 100, and 500ppb arsenite (As +3 ) results in anemia due to alterations in erythroid progenitor cell development in the bone marrow. Exposure to 500ppb As +3 for 60 d resulted in a reduction of mean corpuscular hemoglobin (MCH) levels, but did not significantly alter red blood cell (RBC) counts, hemoglobin (Hgb) levels, mean corpuscular Hgb concentrations (MCHC), or mean corpuscular volumes (MCV). Attenuation of burst-forming unit-erythroid (BFU-E) colony formation was observed in bone marrow cells of mice exposed to 500ppb As +3 . The differentiation of late-stage bone marrow erythroblasts as defined by CD71 and Ter119 surface marker expression was reduced with the 500ppb As +3 exposure. Mice exposed to 500ppb As +3 also had elevated serum levels of erythropoietin (EPO). Collectively, these results show that exposure to low levels of As +3 attenuate the development of early BFU-E cells and reduce the differentiation of late-stage erythroblasts. This suppression of bone marrow erythropoiesis may be a contributing factor to the mild hypochromic anemia observed in 500ppb As +3 exposed mice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Experimental data have shown that Erythropoietin (EPO) stimulates angiogenesis and neovascularization which may result in improved collateral development. The aim of this study was to investigate the association between serum EPO levels and the extent of coronary collaterals. Patient characteristics possibly related with coronary collaterals were also sought., Methods: A total of 256 patients with high grade coronary stenosis or occlusion were evaluated for the extent of coronary collaterals using Rentrop classification. Patients with grade 0 or 1 collaterals were grouped as poor collaterals, while grade 2 or 3 collaterals were grouped as good collaterals., Results: Mean age of the study population was 63 years, 77% were males. Subjects with good collaterals were significantly more likely to have anemia (p=0.038) and stable angina pectoris as clinical presentation (p=0.40). Serum EPO levels were not different among good and poor collateral groups (10.4±9.4 mU/mL vs. 9.7±11 mU/mL, p=0.397). The prevalence of all other cardiovascular risk factors, medications, and angiographic characteristics were similar between the two groups. After adjusting for age, gender, and clinical presentation with stable angina pectoris, presence of anemia persisted to be a significant correlate of the good collateral formation (OR: 1.95; 95%; CI: 1.07-3.54, p=0.029)., Conclusion: There has been conflicting results from trials studying the effects of serum EPO on coronary collateral development. The present study, with the largest patient population studying this topic, suggests that presence of anemia, but not serum EPO level, is associated with good collateral development.

Background: Erythropoietin seems to play an important role in the regulation of fetal hypoxemia. The present prospective study was designed to determine if changes in erythropoietin levels can be found in fetuses with severe early-onset growth restriction and hemodynamic compromise., Methods and Results: Erythropoietin, hemoglobin, hematocrit, platelet counts, normoblasts, lacate, arterial and venous blood gasses in the umbilical cord were determined in 42 fetuses with fetal growth restriction (IUGR) with absent (zero-flow) and 26 IUGR fetuses with retrograde end-diastolic flow (reverse-flow) in the umbilical artery. Color Doppler measurements were performed on the middle cerebral artery (PI) and ductus venosus [(S-a)/D and (S-a)/Vmean]. Erythropoietin concentrations were significantly lower in the zero-flow group (median: 128.0 mU/mL; range: 60.3-213 mU/mL) compared with the reverse-flow group (median: 202.5 mU/mL; range: 166-1182 mU/mL). Significant differences in median lactate concentrations were observed between the zero-flow group: 3.28 mmol/L (range; 2.3-4.7 mmol/L), and reverse-flow group: 5.6 mmol/L (range: 3.8-7.5 mmol/L). Fetuses with reverse-flow had significantly lower median platelet counts than fetuses with zero-flow (74 vs. 155/μL) and significantly lower normoblast counts (63 vs. 342/100 WBC)., Conclusions: Fetuses with severe IUGR due to chronic placental insufficiency and absent or reversed flow in the umbilical artery show increased erythropoietin levels.

Whole blood donation has immunomodulatory effects, and most of these have been observed at short intervals following blood donation. This study aimed to investigate the impact of whole blood donation on lymphocyte subsets over a typical inter-donation interval. Healthy male subjects were recruited to study changes in complete blood count (CBC) (n = 42) and lymphocyte subsets (n = 16) before and at four intervals up to 106 days following blood donation. Repeated measures ANOVA were used to compare quantitative variables between different visits. Following blood donation, changes in CBC and erythropoietin were as expected. The neutrophil count increased by 11.3% at 8 days (p < .001). Novel changes were observed in lymphocyte subsets as the CD4/CD8 ratio increased by 9.2% (p < .05) at 8 days and 13.7% (p < .05) at 22 days. CD16-56 cells decreased by 16.2% (p < .05) at 8 days. All the subsets had returned to baseline by 106 days. Regression analysis showed that the changes in CD16-56 cells and CD4/CD8 ratio were not significant (Wilk's lambda = 0.15 and 0.94, respectively) when adjusted for BMI. In conclusion, following whole blood donation, there are transient changes in lymphocyte subsets. The effect of BMI on lymphocyte subsets and the effect of this immunomodulation on the immune response merit further investigation.

Objective: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited., Methods: Results of ESA therapy were analyzed in 163 MF patients with severe anemia, most of whom had inadequate erythropoietin (EPO) levels (<125 U/L) at treatment start., Results: According to the revised criteria of the International Working Group for Myelofibrosis Treatment and Research, anemia response was achieved in 86 patients (53%). Median response duration was 19.3 months. In multivariate analysis, baseline factors associated with a higher response rate were female sex (P=.007), leukocyte count ≥10×10 9 /L (P=.033), and serum ferritin <200 ng/mL (P=.002). Patients with 2 or 3 of the above features had a significantly higher response rate than the remainder (73% vs 28%, respectively; P<.001). Over the 373 patient-years of follow-up on ESA treatment, nine patients developed thrombotic complications (six arterial, three venous), accounting for 2.41 events per 100 patient-years. Survival time from ESA start was longer in anemia responders than in non-responders (P=.011)., Conclusion: Besides the already established predictive value of EPO levels, these data can help to identify which MF patients are more likely to benefit from ESA treatment., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of 'relative hypoxia' which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients., Methods: In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO 2 ) ≤0.5 and PaO 2 /FiO 2  ≥ 200 mmHg underwent a 2-hour exposure to hyperoxia (FiO 2 1.0). A further 20 patients acted as controls. Serum EPO was measured at baseline, 24 h and 48 h. Serum glutathione (antioxidant) and ROS levels were assessed at baseline (t0), after 2 h of hyperoxia (t1) and 2 h after returning to their baseline FiO 2 (t2). The microvascular response to hyperoxia was assessed using sublingual sidestream dark field videomicroscopy and thenar near-infrared spectroscopy with a vascular occlusion test., Results: EPO increased within 48 h in patients exposed to hyperoxia from 16.1 [7.4-20.2] to 22.9 [14.1-37.2] IU/L (p = 0.022). Serum ROS transiently increased at t1, and glutathione increased at t2. Early reductions in microvascular density and perfusion were seen during hyperoxia (perfused small vessel density: 85% [95% confidence interval 79-90] of baseline). The response after 2 h of hyperoxia exposure was heterogeneous. Microvascular perfusion/density normalized upon returning to baseline FiO 2 ., Conclusions: A two-hour exposure to hyperoxia in critically ill patients was associated with a slight increase in EPO levels within 48 h. Adequately controlled studies are needed to confirm the effect of short-term hyperoxia on erythropoiesis., Trial Registration: ClinicalTrials.gov ( www.clinicaltrials.gov ), NCT02481843 , registered 15th June 2015, retrospectively registered.

Physical inactivity and a low maximal aerobic capacity (VO 2max ) strongly predict morbidity and mortality in patients with type 2 diabetes (T2D). Patients with T2D have a reduced VO 2max when compared with healthy individuals of similar age, weight, and physical activity levels, and this lower aerobic capacity is usually attributed to a reduced oxygen delivery to the working muscles. The oxygen carrying capacity of the blood, as well as increases in cardiac output and blood flow, contribute to the delivery of oxygen to the active muscles during exercise. Hemoglobin mass (Hb mass), a key determinant of oxygen carrying capacity, is suggested to be reduced in patients with T2D following the observation of a lower blood volume (BV) in combination with normal hematocrit levels in this population. Therefore, a lower Hb mass, in addition to a reported lower BV and impaired cardiovascular response to exercise, likely contributes to the reduced oxygen delivery and VO 2max in patients with T2D. While exercise training increases Hb mass, BV, and consequently VO 2max , the majority of patients with T2D are not physically active, highlighting the need for alternative methods to improve VO 2max in this population. Exposure to hypoxia triggers the release of erythropoietin, the hormone regulating red blood cell production, which increases Hb mass and consequently BV. Exposure to mild intermittent hypoxia (IH), characterized by few and short episodes of hypoxia at a fraction of inspired oxygen ranging between 10 and 14% interspersed with cycles of normoxia, increased red blood cell volume, Hb mass, and plasma volume in patients with coronary artery disease or chronic obstructive pulmonary disease, which resulted in an improved VO 2max in both populations. We hypothesize that 12 exposures to mild IH over a period of 4weeks will increase Hb mass, BV, cardiac function, and VO 2max in patients with T2D. Therefore, exposures to mild IH may increase oxygen delivery and VO 2max without the need to perform exercise in patients with T2D., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To compare maternal, cord blood erythropoietin (EPO), and copeptin levels in low-risk term deliveries which are complicated by meconium-stained amniotic fluid (MSAF) to those with clear amniotic fluid. Also, to evaluate the relations between these markers and cord blood pH values., Methods: Low-risk term pregnant women with MSAF at an active phase of labor were defined as the study group (n = 39). Pregnant women with clear amniotic fluid were selected for the control group (n = 41). The two groups were matched for age, body mass index and gestational age. Maternal, cord blood EPO and copeptin levels with cord blood pH values were also measured., Results: Maternal, cord blood EPO, and copeptin levels of study and control groups were 42.6 ± 9.0 versus 40.7 ± 9.2, 134.2 (20.5-834.6) versus 38.4 (10.3-114.2), 4.9 (0.1-31.1) versus 4.0 (3.1-28.4), and 4.7 (2.6-25.5) versus 3.6 (2.0-23.2), respectively. The differences were statistically significant for cord blood EPO, maternal and cord blood copeptin levels (p < 0.001, p = 0.004, p < 0.001, respectively). The study group had a statistically and significantly lower cord blood pH values (7.25 ± 0.05 versus 7.34 ± 0.04, p < 0.001). Moreover, cord blood EPO and maternal and cord blood copeptin levels were inversely correlated with cord blood pH values in the study group (p < 0.001, p = 0.005, and p = 0.009, respectively)., Conclusion: We suggest that higher cord blood EPO and maternal and cord blood copeptin levels may be an indicator of fetal acidosis in low-risk term deliveries complicated by MSAF.

Background: The role of inflammation in the development and progression of chronic kidney disease (CKD) in cats is not well characterized. Hepcidin is a recently discovered acute-phase protein (APP) that plays an important role in iron metabolism and contributes to the development of anemia in humans with CKD., Objectives: To compare serum APP concentrations, iron status, and erythropoietin (EPO) concentrations in healthy cats and cats with naturally occurring CKD., Animals: A total of 18 healthy control cats and 38 cats with CKD., Methods: Prospective study. After complete physical examination and routine blood analysis, the following tests were performed: serum amyloid A (SAA), haptoglobin (HAP), EPO, serum iron and ferritin concentration as well as total iron-binding capacity (TIBC). Serum hepcidin-25 concentration was measured by ELISA kit designed for use in humans., Results: Mean SAA and hepcidin concentrations were significantly higher and mean total iron and TIBC were significantly lower in the CKD group (P < .05). There was a significant positive correlation between serum creatinine concentration (CRT) and 2 of the APPs (SAA and hepcidin; P < .05). Increases in SAA and hepcidin were associated with decreases in TIBC and hematocrit in the CKD group. Fourteen (37%) of the cats with CKD were anemic, and these cats had significantly lower TIBC (P < .05), suggesting a functional iron deficiency. There was no association between survival time and APP, iron status, or EPO concentrations., Conclusions: Our data suggest that CKD in cats is associated with systemic inflammation and altered iron metabolism. With further validation in cats, hepcidin assays may help better characterize these relationships., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)