Erythropoietin Concentration Research Articles

Association of gene polymorphism in ERG rs2836411 with anemia and susceptibility to aortic dissection

BackgroundThe erythroblast transformation-specific related gene (ERG) is expressed in hematopoietic stem and progenitor cells and endothelial cells. This study aimed to investigate if ERG rs2836411 is a novel genetic locus associated with anemia and aortic dissection (AD).MethodA case-control trial was conducted to evaluate the association between ERG rs2836411 polymorphism, anemia, and AD risk. The ERG rs2836411 polymorphism was analyzed using Sanger dideoxy chain termination sequencing on genomic DNA extracted from whole blood. Serum erythropoietin (EPO) and interleukin-6 (IL-6) concentrations were measured by enzyme-linked immunosorbent assay (ELISA).Results119 preoperative AD patients and 119 healthy controls were enrolled, with age and sex matched. Anemia was found independently associated with AD presence (Odds ratio (OR) 20.82, p < 0.001). Remarkably, T carriers (CT + TT) of ERG rs2836411 were associated with anemia in AD patients (OR 2.81, p = 0.013) but not in controls. After adjusting for conventional risk factors including age, sex, smoking and hypertension status, T carriers (CT + TT) were independently associated with AD presence (OR 2.20, p = 0.015), but were not associated if anemia was further adjusted. While EPO concentration was higher in AD patients and was associated with AD presence (OR 1.09, p = 0.006), no difference in EPO levels was observed between the ERG genotypes of AD patients.ConclusionsT carriers (CT + TT) of ERG rs2836411 are independently associated with anemia and AD presence. The association between ERG rs2836411 polymorphism and susceptibility to AD may be mediated by anemia. Further studies are warranted to validate whether this association is causal.

Siwu tablet attenuates high fructose-induced glomerular podocyte senescence in rats through increasing Nup155 to promote INO80 mRNA nuclear export

Ethnopharmacological relevanceSiwu tablet (SWT), derived from a traditional Chinese medicinal formula named Siwu decoction, is widely used for blood deficiency syndrome. Siwu decoction and its derived formulas have been proven to improve renal anemia and prevent senescence. Whether SWT prevents glomerular podocyte senescence and the underlying molecular mechanism remains unknow. Aim of the studyTo elucidate the protective effect and possible mechanism of SWT on glomerular podocyte senescence. Material and methodsLiquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to characterize components of SWT. Male Sprague-Dawley rats were given 10% fructose drinking water for 16 weeks. SWT (810 and 1620 mg/kg) was administered orally for the last 8 weeks. The assays of senescence-associated beta-galactosidase (SA-β-gal) staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot as well as enzyme linked immunosorbent assay were performed to evaluate rat glomerular podocyte senescence. The mRNA and protein levels of nucleoporin 155 (Nup155) and inositol requiring mutant 80 (INO80) in rat glomeruli were detected by qRT-PCR, Western blot and immunofluorescence. Foot processes and nuclear pore complexes (NPCs) of rat glomerular podocytes were visualized by transmission electron microscopy. ResultsOne hundred and fifty-nine components were preliminarily identified in SWT. The results of animal experiments showed that SWT decreased the activity of SA-β-gal, protein levels of p16, p21, p53 and phosphorylated histone H2AX (γ-H2AX), and mRNA levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in glomeruli of high fructose-fed rats. As expected, SWT increased renal cortex erythropoietin mRNA expression and serum erythropoietin concentration in this animal model. SWT reduced urine albumin-to-creatinine ratio and serum levels of uric acid, creatinine and blood urea nitrogen, and recovered glomerular structure injury in high fructose-fed rats. It up-regulated mRNA and protein levels of Nup155 and the number of podocyte NPCs, and subsequently reinforced mRNA nuclear export and protein expression of INO80 in rat glomeruli under high fructose stimulation. ConclusionsSWT ameliorates glomerular podocyte senescence in high fructose-fed rats possibly by increasing Nup155 to promote INO80 mRNA nuclear export.

Reaction of young physically active men with early repolarization phenomena on a cycle of inhalations of a hypoxic gas mixture

Aim: To examine a reaction of young physically active men with early repolarization phenomena (ERP) on an inhalation of a hypoxic gas mixture (IHGM).Material and Methods.17 men (6 with ERP &amp; 11 without it) participated in our study. ECG, echocardiography, clinical blood test and erythropoietin blood test were carried out to every of them initially and on the 1-st and 10-th days after the IHGM.Results. It was found that end systolic volume was 13,8% more (р = 0,01) and ejection fraction was 8% less (р = 0,01) in ERP group than in non ERP group. These indicators were not change after IHGM. In ERP group on 1-st day after IHGM erythropoietin concentration was 79% more (р = 0,027) and on a 10-th day was 64% more (р = 0,003) than in non-ERP group. In ERP group high fluorescent reticulocyte count on a 1-st day after IHGM was 69% more (р = 0,03) and middle fluorescent reticulocyte count on a 10-th day after IHGM was 13% more (р = 0,04) than in non-ERP group. On a 10-th day after IHGM hematocrit and hemoglobin concentration were 5% (р = 0,01) and 12% (р = 0,01) less than in non ERP group.Conclusion. Thus, men with ERP have a pronounced reaction of the erythropoiesis system on normobaric hypoxia.

Evaluation of some hormones in patients with major β-Thalassemia in the Nineveh Governorate - Iraq

Thalassemia is one of the most important genetic haemolytic diseases that cause the breakdown of red blood cells (RBCs) in patients with β-Thalassemia major. The body does not produce enough haemoglobin, which is an important part of RBCs. When there is not enough haemoglobin, RBCs do not function properly in the body, so the condition continues for short periods of time. The current studies aimed to determine the extent of the impact of β-Thalassemia major on some hormonal variables in the serum of 80 patients (40 males and 40 females) aged between (1-15) years, in addition to 20 healthy children of the same age range and of both sexes, who were considered as a control group. The results of this study showed a significant increase in the concentration of erythropoietin (EPO) by 187% in the serum of patients with β-Thalassemia major compared to healthy of both sexes, with an increase of 188 in males and 183% in females. The highest significant increase was in the age group of (11-15) years in males and females compared to healthy control. The results also showed a significant decrease in the concentration of hepcidin and growth hormones in the serum of patients with a decrease of 55 and 56% respectively compared to healthy individuals of both sexes, with a highest significant decrease of 56 and 59% in males, and 55 and 52% in females respectively. The highest significant decrease was in the age group of (11-15) years for both hormones in males and females compared to healthy control based on age groups and sex.

Acute exposure to carbon monoxide inhalation and/or hot water immersion transiently increases erythropoietin in females but not in males.

The use of acute carbon monoxide inhalation (COi) and hot water immersion (HWI) are of growing interest as interventions to stimulate erythropoietin (EPO) production. However, whether EPO production is further augmented when combining these stressors and whether there are sex differences in this response are poorly understood. Therefore, we measured circulating EPO concentration in response to acute COi and HWI independently and in combination and determined whether the responses were altered by sex. Participants completed three study visits-COi, HWI, and combined COi and HWI-separated by 1 week in a randomized, balanced, crossover design. Renal blood velocity was measured during all interventions, and carboxyhaemoglobin was measured during and after COi. Serum samples were analysed every hour for 6h post-intervention for EPO concentration. HWI decreased renal blood velocity (46.2cm/s to 36.2cm/s) (P<0.0001), and COi increased carboxyhaemoglobin (1.5%-12.8%) (P<0.0001) without changing renal blood velocity (46.4-45.2cm/s) (P=0.4456). All three interventions increased peak EPO concentration from baseline (COi: 6.02-9.74mIU/mL; HWI: 6.80-11.10mIU/mL; COi + HWI: 6.71-10.91mIU/mL) (P=0.0048) and to the same extent (P=0.3505). On average, females increased EPO while males did not in response to COi (females: 6.17mIU/mL; males: 1.27mIU/mL) (P=0.0010), HWI (females: 6.47mIU/mL; males: 2.14mIU/mL) (P=0.0104), and COi and HWI (females: 6.65mIU/mL; males: 1.76mIU/mL) (P=0.0256). These data emphasize that combining these interventions does not augment EPO secretion and that these interventions may work better in females.

Rheological and Biochemical Properties of Blood in Runners: A Preliminary Report

Purpose: Physical activity induces numerous modifications in the morphological, rheological, and biochemical properties of blood. The purpose of this study was to evaluate changes in blood rheological and biochemical indicators among runners. Also, we assessed how the rheological and biochemical properties of blood in people who practised running characterised the range and direction of exercise modifications and allowed for the diagnosis of transient adaptive effects. Methods: This study included 12 athletes who regularly trained in middle- and long-distance running (6–8 times a week) and presented a high sports level (national and international class). The athletes performed a 30 min warm-up consisting of 15 min of jogging and exercises. After a 10 min rest, they completed a 3 km run with submaximal effort. Blood samples were collected at baseline and after the effort. Results: No statistically significant changes were revealed in erythrocyte, leukocyte, platelet, iron, ferritin, transferrin, erythropoietin, or C-reactive protein concentrations in the examined runners. The same applied to the elongation index at a shear stress within the range of 0.30–60.00 Pa, amplitude and total extent of aggregation, aggregation half-life, and aggregation index. A significant increase (within standard limits) was only observed in fibrinogen concentration after running. Conclusions: The lack of post-exercise changes in blood rheological and biochemical indicators in the investigated runners points at an efficient haemorheological system. This, in turn, reflects well-executed training and remarkably well-trained adaptive systems responsible for regeneration.

56 Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship Confirms Best-in-class Potential of Casdatifan (AB521), a Small Molecule Inhibitor of HIF-2α Being Developed in Renal Cancer

Abstract Background Casdatifan, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. The objective of this analysis was to develop an understanding of the relationship between clinical dose, casdatifan PK, erythropoietin (EPO), a PD biomarker for peripheral (non-tumor) HIF-2α inhibition, and hemoglobin and to use this information to guide dose selection in future clinical trials. Methods Casdatifan plasma concentrations, serum EPO concentration, and hemoglobin data were obtained from 79 healthy participants in two Phase 1 studies, ARC-14 (NCT05117554) and ARC-28 (NCT05999513), and from 71 patients with clear cell renal cell carcinoma (ccRCC) and other solid tumors in an ongoing Phase 1 study, ARC-20 (NCT05536141). The available PK and PD data were collected following single oral doses of casdatifan ranging from 3 mg to 100 mg in healthy participants, and multiple oral doses of casdatifan ranging from 15 mg to 150 mg once daily (QD) in healthy participants and cancer patients. Serial PK, EPO, and Hb data were gathered in all study participants pre-dose till end of treatment. The population PKPD model was developed using mixed effects methodology with NONMEM software to relate dose, PK, and PD (EPO and Hb) data. Results Casdatifan showed dose-proportional increases in plasma exposure over the 3-150 mg dose range after single and multiple doses. Casdatifan PK was also invariant over time in patients with an approximately 2.0-fold accumulation at steady-state compared to first dose. The mean terminal half-life of casdatifan was approximately 24 h. The PK was similar in healthy participants and cancer patients. Dose-dependent reduction in EPO was observed after single and multiple doses in healthy participants and patients. A two-compartment model with first-order absorption adequately described the casdatifan plasma PK across the dose range tested. The effect of casdatifan plasma concentrations on EPO production rate was modeled using an inhibitory function. Analysis of the casdatifan dose-PD (EPO suppression) relationship indicated that casdatifan 20 mg once daily provided a similar level of EPO suppression in patients as belzutifan 120 mg daily (benchmark peripheral PD). Furthermore, due to the dose-proportional PK of casdatifan, the selected dose (100 mg daily) for further development results in plasma levels approximately 5 times higher than those associated with the benchmark peripheral PD. Conclusions Casdatifan exhibits dose-linear and time-invariant PK in the dose range 15-150 mg. Dose-dependent reduction in EPO levels, consistent with the mechanism of action of HIF-2α inhibition, was seen after casdatifan administration. A PKPD analysis of available data indicated that 20 mg daily dose of casdatifan would result in similar EPO effect as the registered dose of belzutifan. Available PKPD data and analyses indicated best-in-class properties of casdatifan.

Ketone monoester plus high-dose glucose supplementation before exercise does not affect immediate post-exercise erythropoietin concentrations versus glucose alone.

The objective of this study was to examine the effect of consuming ketone monoester plus a high dose of carbohydrate from glucose (KE + CHO) on the change in erythropoietin (EPO) concentrations during load carriage exercise compared with carbohydrate (CHO) alone. Using a randomized, crossover design, 12 males consumed KE + CHO (573 mg KE/kg body mass, 110 g glucose) or CHO (110 g glucose) 30 min before 4 miles of self-paced treadmill exercise (KE + CHO:51 ± 13%, CHO: 52 ± 12% V̇O2peak) wearing a weighted vest (30% body mass; 25 ± 3 kg). Blood samples for analysis were obtained under resting fasted conditions before (Baseline) consuming the KE + CHO or CHO supplement and immediately after exercise (Post). βHB increased (p < 0.05) from Baseline to Post in KE + CHO, with no change in CHO. Glucose and glycerol increased (p < 0.05) from Baseline to Post in CHO, with no effect of time in KE + CHO. Insulin and lactate increased (p < 0.05) from Baseline to Post independent of treatment. EPO increased (p < 0.05) from Baseline to Post in KE + CHO and CHO with no difference between treatments. Although KE + CHO altered βHB, glucose, and glycerol concentrations, results from this study suggest that KE + CHO supplementation before load carriage exercise does not enhance immediate post-exercise increases in EPO compared with CHO alone.

The Role of Erythropoietin in Bovine Sperm Physiology.

Erythropoietin (EPO), a hormone secreted mainly by the kidney, exerts its biological function by binding to its cell-surface receptor (EpoR). The presence of EPO and EpoR in the male and female reproductive system has been verified. Therefore, some of the key properties of EPO, such as its antioxidant and antiapoptotic effects, could improve the fertilizing capacity of spermatozoa. In the present study, the effect of two different concentrations of EPO (10 mIU/μL and 100 mIU/μL) on bovine sperm-quality parameters was evaluated during a post-thawing 4-h incubation at 37 °C. EPO had a positive effect on sperm motility, viability, and total antioxidant capacity. Moreover, EPO inhibited apoptosis, as it reduced both BCL2-associated X apoptosis regulator (Bax)/B-cell lymphoma 2 (Bcl-2) ratio and cleaved cysteine-aspartic proteases (caspases) substrate levels in a dose-dependent manner. In addition, EPO induced sperm capacitation and acrosome reaction in spermatozoa incubated in capacitation conditioned medeia. These results establish a foundation for the physiological role of EPO in reproductive processes and hopefully will provide an incentive for further research in order to fully decipher the role of EPO in sperm physiology and reproduction.

Apnoea as a novel method to improve exercise performance: A current state of the literature.

Acute breath-holding (apnoea) induces a spleen contraction leading to a transient increase in haemoglobin concentration. Additionally, the apnoea-induced hypoxia has been shown to lead to an increase in erythropoietin concentration up to 5h after acute breath-holding, suggesting long-term haemoglobin enhancement. Given its potential to improve haemoglobin content, an important determinant for oxygen transport, apnoea has been suggested as a novel training method to improve aerobic performance. This review aims to provide an update on the current state of the literature on this topic. Although the apnoea-induced spleen contraction appears to be effective in improving oxygen uptake kinetics, this does not seem to transfer into immediately improved aerobic performance when apnoea is integrated into a warm-up. Furthermore, only long and intense apnoea protocols in individuals who are experienced in breath-holding show increased erythropoietin and reticulocytes. So far, studies on inexperienced individuals have failed to induce acute changes in erythropoietin concentration following apnoea. As such, apnoea training protocols fail to demonstrate longitudinal changes in haemoglobin mass and aerobic performance. The low hypoxic dose, as evidenced by minor oxygen desaturation, is likely insufficient to elicit a strong erythropoietic response. Apnoea therefore does not seem to be useful for improving aerobic performance. However, variations in apnoea, such as hypoventilation training at low lung volume and repeated-sprint training in hypoxia through short end-expiratory breath-holds, have been shown to induce metabolic adaptations and improve several physical qualities. This shows promise for application of dynamic apnoea in order to improve exercise performance. HIGHLIGHTS: What is the topic of this review? Apnoea is considered as an innovative method to improve performance. This review discusses the effectiveness of apnoea (training) on performance. What advances does it highlight? Although the apnoea-induced spleen contraction and the increase in EPO observed in freedivers seem promising to improve haematological variables both acutely and on the long term, they do not improve exercise performance in an athletic population. However, performing repeated sprints on end-expiratory breath-holds seems promising to improve repeated-sprint capacity.

Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial

The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. Celgene and Acceleron Pharma.

Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Healthy Volunteers and Patients with Chronic Kidney Disease.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in chronic kidney disease (CKD). Single ascending dose (SAD) and multiple ascending dose (MAD) studies assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of vadadustat in healthy volunteers. A single-dose, open-label study was conducted in patients with CKD stages 3 and 4 not on dialysis. In the SAD study, 48 healthy adult men (n = 8/cohort) received single doses of vadadustat (80-1,200 mg) or placebo. In the MAD study, 34 healthy adult men (n = 8-9/cohort) received daily vadadustat (500-900 mg) or placebo for 10 days. In the single-dose CKD study, 22 male and female patients with CKD (stage 3: n = 10; stage 4: n = 12) received single doses of vadadustat (500 mg). PK parameters included plasma vadadustat; PD biomarkers were measured, including erythropoietin (EPO) levels, reticulocytes, and others. Plasma vadadustat peaked 3-4 hours after single or multiple dosing in healthy volunteers, with a mean t 1/2 of approximately 4.5 hours. In patients with CKD, plasma vadadustat peaked at 5-6 hours, with a mean t 1/2 of 7.2 (stage 3) and 8.5 (stage 4) hours. Vadadustat AUC∞ and C max increased dose proportionally in SAD and MAD trials. In all trials, EPO concentrations increased in a dose-related manner and returned approximately to baseline by 24 hours. Adverse events were mild and considered not study drug related. The PK and PD results of these studies were utilized for further clinical development of vadadustat for treatment of anemia in CKD patients.

Linking red blood cell functional phenotypes to environmental tolerance in high-altitude adapted deer mice

Oxygen (O2) is essential for vertebrate life, and complex cardio-respiratory systems have evolved to transport the gas from the environment to each individual cell. Even short disruptions of this O2 flux can have deleterious effects that are linked to numerous disease states. Animals that have adapted to hypoxic environments, such as deer mice ( Peromyscus maniculatus) native to high altitude, can provide valuable insight into naturally evolved solutions to O2 deprivation. Previous work has shown that high-altitude deer mice have evolved a higher hemoglobin O2 affnity and other coordinated changes across the O2 transport cascade that enable higher metabolic rates in hypoxia. Red blood cells (RBC) are the functional unit of O2 and carbon dioxide transport in the blood and play central roles in matching O2 supply and demand in the microcirculation by releasing signaling molecules such as ATP and gasotransmitters; but how these cellular mechanisms respond to hypoxic environments has not been studied. We hypothesized that high-altitude adaptation in deer mice has improved the function of RBCs for cardiovascular gas transport in hypoxia. Lab-raised breeding colonies of deer-mice were established from wild mice caught at low altitude (~400 m in the Great Plains of Nebraska) and at high altitude (~4300 m in the Rocky Mountains of Colorado). Using a common-garden experimental design, third-generation deer mice from high- and low-altitude populations were acclimated to warm normoxia (21°C, 21 kPa O2) or cold hypobaric hypoxia (5°C, 12 kPa O2) for 8 weeks. Blood samples were collected for measurements of hematocrit, hemoglobin concentration, RBC volume, plasma erythropoietin concentration, RBC contents of membrane transport and channel proteins (anion exchanger, aquaporin 1 and rhesus associated glycoprotein) by immunocytochemistry and western blotting, and carbonic anhydrase activity using biochemical techniques. The release of ATP from RBCs was measured in tonometers at decreasing levels of O2 by luminometry, and the vascular sensitivity to ATP was determined by wire myography on second-order mesenteric arteries. Finally, bone marrow samples were collected from the femurs to measure gene expression levels in the erythropoietic tissue. Our experimental design allowed us to examine the interactive effects of cold hypoxic environments on RBC phenotype, by untangling environmentally-induced plasticity from the signatures of adaptation that are unique to high-altitude natives. This work is providing a better understanding of how RBC function participates in matching cardiovascular O2 supply and demand in extreme hypoxia, which has important applications in animal and human health. This work was supported by a NSERC Canada Banting Postdoctoral Fellowship to TSH and a Discovery Grant to GRS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ИССЛЕДОВАНИЕ СЕКРЕЦИИ ЭРИТРОПОЭТИНА У БОЛЬНЫХ ВИЧ-ИНФЕКЦИЕЙ С АНЕМИЕЙ ХРОНИЧЕСКИХ ЗАБОЛЕВАНИЙ, ЖЕЛЕЗОДЕФИЦИТНОЙ АНЕМИЙ И СОЧЕТАНИЕМ ДВУХ ТИПОВ АНЕМИЙ

Aim. To compare the secretion of erythropoietin in patients with infection caused by human immune deficiency virus (HIV infection) with anemia of chronic diseases (ACD), iron deficiency anemia (IDA), and their combination. Material and methods. 125 patients with HIV infection were examined: 101 with anemia (55 males, 46 women, 39.4±9.6 years), 24 - a control group of patients with HIV infection without anemia (13 males, 11 women, average age 37.6± 7.37 years). In all patients, the number of red blood cells, the concentration of hemoglobin, ferritin, C-reactive protein (CRP), transferrin saturation index (TSI) and erythropoietin were examined. All patients with anemia after determining TSI, CRP, ferritin based on Van Santen and Worwood criteria were divided into three groups depending on the type of anemia: group 1 - 36 patients with ACD (19 males, 17 women, average age 41.7 ± 11, 8 years, TSI 16.9[IQR, 10.2-23.1]%, ferritin 638.7[IQR, 326-861] μg/l, CRP 54.5 [IQR, 4.8-103.3] mg/l), group 2 – 30 patients with a combination of ACD/IDA (18 males, 12 women, average age 41.2±10 years, TSI 13.2[IQR, 9.8-14]%, ferritin 156.2 [IQR, 123-235] mcg/l, CRP 5.9 [IQR, 0.5-8.2] mg/l), group 3 – 35 patients with IDA (18 males, 17 women, average age 35.4 ±7.1 years, TSI 11.1[IQR, 4.7-13.7]%, ferritin 29[IQR, 4.2-38.9] µg/l, CRP 2.9[IQR, 0.4 -1.6] mg/l). For quantitative indicators, the median (Me), standard error of the mean (m), and interquartile range (IQR) were calculated. The significance of differences between several unrelated groups was determined using the Kruskal-Wallis test. Results. In the ACD group, a lower number of red blood cells was detected (3.3(2.7-3.8)×1012/l), compared to the group of patients with IDA (3.8(3.7-4.1)×1012/l ). Also, in the group of patients with ACD, the maximum concentration of erythropoietin was detected (28.5[11.2-28.5], U/ml), significantly higher than the concentration of this indicator in the ACD/IDA groups (14[8.1-16.3], U/ml), IDA (15.8[6.2-27.4], U/ml) and patients in the control group (6.3[4.9-7.8], U/ml). Conclusions. In the present study, ACD in isolated form or in combination with IDA was diagnosed in 65.3% of patients with HIV infection and anemic syndrome. In patients with ACD, an increased concentration of erythropoietin is combined with the lowest number of red blood cells in comparison with other groups of patients with anemia (p&lt;0.05). The results obtained indicate a compensatory increase in erythropoietin secretion in response to suppressed erythropoiesis, or to reduced sensitivity of erythropoietin receptors. Further study of the importance of erythropoietin in the pathogenesis of chronic disease in patients with HIV infection is necessary, including to improve its treatment.

Erythropoietin alleviates lung ischemia-reperfusion injury by activating the FGF23/FGFR4/ERK signaling pathway.

The purpose of the present study was to investigate the effect of erythropoietin (EPO) on lung ischemia-reperfusion injury (LIRI). Sprague Dawley rats and BEAS-2B cells were employed to construct an ischemia-reperfusion (I/R)-induced model in vivo and in vitro, respectively. Afterward, I/R rats and tert-butyl hydroperoxide (TBHP)-induced cells were treated with different concentrations of EPO. Furthermore, 40 patients with LIRI and healthy controls were enrolled in the study. It was observed that lung tissue damage, cell apoptosis and the expression of BAX and caspase-3 were higher in the LIRI model in vivo and in vitro than in the control group, nevertheless, the Bcl-2, FGF23 and FGFR4 expression level was lower than in the control group. EPO administration significantly reduced lung tissue damage and cell apoptosis while also up-regulating the expression of FGF23 and FGFR4. Rescue experiments indicated that EPO exerted a protective role associated with the FGF23/FGFR4/p-ERK1/2 signal pathway. Notably, the expression of serum EPO, FGF23, FGFR4 and Bcl-2 was decreased in patients with LIRI, while the expression of caspase-3 and BAX was higher. EPO could effectively improve LIRI, which might be related to the activation of the FGF23/FGFR4/p-ERK1/2 signaling pathway.

Renal dysfunction in adults following cardiopulmonary bypass is linked to declines in S-nitroso hemoglobin: a case series.

Impaired kidney function is frequently observed in patients following cardiopulmonary bypass (CPB). Our group has previously linked blood transfusion to acute declines in S-nitroso haemoglobin (SNO-Hb; the main regulator of tissue oxygen delivery), reductions in intraoperative renal blood flow, and postoperative kidney dysfunction. While not all CPB patients receive blood, kidney injury is still common. We hypothesized that the CPB procedure itself may negatively impact SNO-Hb levels leading to renal dysfunction. After obtaining written informed consent, blood samples were procured immediately before and after CPB, and on postoperative day (POD) 1. SNO-Hb levels, renal function (estimated glomerular filtration rate; eGFR), and plasma erythropoietin (EPO) concentrations were quantified. Additional outcome data were extracted from the patients' medical records. Twenty-seven patients were enroled, three withdrew consent, and one was excluded after developing bacteremia. SNO-Hb levels declined after surgery and were directly correlated with declines in eGFR (R=0.48). Conversely, plasma EPO concentrations were elevated and inversely correlated with SNO-Hb (R=-0.53) and eGFR (R=-0.55). Finally, ICU stay negatively correlated with SNO-Hb concentration (R=-0.32). SNO-Hb levels are reduced following CPB in the absence of allogenic blood transfusion and are predictive of decreased renal function and prolonged ICU stay. Thus, therapies directed at maintaining or increasing SNO-Hb levels may improve outcomes in adult patients undergoing cardiac surgery.

Effect of Leptin and Erythropoietin Concentration Levels on the Productive Traits on a Sample of Awassi Sheep

The most interesting results were obtained when studying the Iraqi Awassi female sheep for leptin and erythropoietin. Leptin hormone concentrations the ewes were divided into three groups according to the levels of leptin and erythropoietin concentrations, low, medium and high, as well as progesterone and estrogen concentrations, increase in ewes with medium leptin concentrations. Leptin concentration had no effect on fertility rate, but twins rates increased in ewes with medium leptin concentration. Dams milk components increased with high level of leptin, while other components remained unchanged. Similarly, erythropoietin concentration and progesterone level were linked to ewes fertility, with the highest progesterone value being 0.29 in medium ewes.

Relationship between Body Condition Score, Reproductive Indicators, and Leptin and Erythropoietin Hormone Levels in Iraqi Awassi Ewes

The experiment was conducted using 35 Awassi ewes with an average body weight 52±2.5 kg. The females were divided into three groups according to the body condition score 3 (overweight, medium, lean) represented by groups 1, 2, and 3 respectively. The medium was the highest percentage, as it reached 71.42% of the total number of animals. This percentage was in accordance with a high pregnancy rate compared to lean and overweight animals, as the pregnancy rate reached ewes from the examination. The first and second examinations were 64% and 24% respectively. The concentration of leptin and erythropoietin were measured in ewes before, during and after applying the vaginal sponges. Barrenness rate had (100%, 24.13% and 100%) in group 1,2 and 3 respectively. The results were high in leptin hormone in the Body Condition Score (BCS) group. 2, especially after withdrawing the vaginal sponges. While there was no significant increase (P>0.05) in erythropoietin hormone before and during applying vaginal sponges. Body Condition Score (BCS 2) ewes had a higher conception rate than Body Condition Score (BCS) 1 and 3 ewes. Leptin and progesterone both play important roles in the regulation of sheep body weight, with higher levels of progesterone resulting in higher levels of leptin.

Recombinant Human Erythropoietin Combined with All-Trans Retinoic Acid and Testosterone Undecanoate in the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes: Updated Results of a Multicenter, Single-Arm, Prospective Trial

[Background] More than 90% of low-risk MDS face refractory anemia and blood transfusion dependence for a long time. At present, recombinant human erythropoietin (EPO) is the main treatment, but the effective rate of single agent is 30%-40%, which seriously affects the quality of life of patients. Previous studies had shown that testosterone undecanoate could promote erythroid hematopoiesis and all-trans retinoic acid (ATRA) had the function of promoting blood cell differentiation in vitro. We previously reported that EPO combined with ATRA and testosterone undecanoate in the treatment of patients with low-risk MDS and demonstrated promising efficacy and safety in a prospective trial (Chen et al, ASH 2022). Here we present an updated analysis of efficacy and safety results in the ongoing study. [Methods] In this multicenter, single-arm trial, patients with newly diagnosed lower-risk MDS based on the 2016 WHO classification and the Revised International Prognostic Scoring System (IPSS-R) from 3 different tertiary medical centers in China were included. Patients were received EPO (10000IU/day) plus ATRA (25mg/m 2/day) and testosterone undecanoate (80mg twice daily) for 3 months. The primary endpoint was overall hemoglobin response rate, defined as an increase in hemoglobin levels of ≥ 1.5g/dL from baseline in 2 or more consecutive assessments (2 weeks apart) and no red blood cell transfusions during this period. Response was assessed after completion of 3months. The data cut-off date was July 25, 2023. [Results] As of July 2023, a total of 43 patients were enrolled, with a median age of 65 years, 24 males and 19 females, with median hemoglobin of 63 g/L, EPO concentration &amp;gt; 500 IU/L in 18 patients, and the overall hemoglobin response rate of 65.1% (28/43). The hemoglobin response rates were 61.1% (11/18) in patients with EPO concentrations greater than &amp;gt; 500 IU/L and 68.0% (17/25) in patients with EPO concentrations ≤ 500, which were not statistically different. Among them, 112 known or putative mutational gene targets in hematologic malignancy were examined for mutations in 32 patients using a custom targeted next-generation sequencing (NGS) gene panel. The most frequent mutations were SF3B1 (15/32, 46.8%) and ASXL1 (8/32, 25.0%). The hemoglobin response rate was 80.0% (12/15) in patients with SF3B1 mutation and 37.5% (3/8) in patients with ASXL1 mutation, respectively. Among 43 patients evaluable for safety analysis, the most common non-hematological adverse events were dry skin (17/43, 39.5%) and fatigue (12/43, 27.9%). No patients had disease progression during the treatment period. [Conclusion]: This study showed that EPO combined with tretinoin and testosterone undecanoate regimen can effectively improve the anemia of lower risk MDS in approximately 65.1% of patients and is not affected by EPO concentration. It has the better efficacy in patients with SF3B1 mutation, but has worse efficacy in patients with ASXL1 mutation. It is worthy of further randomized controlled studies to verify the efficacy.

Daprodustat, a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, Improves Hematological Insufficiency without Progression of Myelodysplastic Syndrome with Chronic Kidney Disease

Introduction Hematological insufficiency is a critical issue in the treatment of myelodysplastic syndrome (MDS). The current standard treatment for cytopenia in MDS involves blood transfusion and the administration of erythropoiesis stimulating agents (ESAs). However, ESAs are only effective in certain patients with low erythropoietin levels; patients who are not suitable candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) require lifelong blood transfusions. As a result, there is a growing demand for new treatments for cytopenia in MDS, and researchers have been exploring various molecular-targeted drugs in recent years. One promising option is the hypoxia-inducible factor -prolyl hydroxylase inhibitor (HIF-PHi). This inhibitor stabilizes HIF1α, which in turn normalizes endogenous erythropoietin production and iron metabolism, leading to improved renal anemia. It is believed that HIF-PHi could potentially enhance MDS-related anemia by increasing erythropoietin levels. However, despite some case reports, there have been no comprehensive clinical studies evaluating the effectiveness and safety of HIF-PH inhibitors for MDS. Moreover, it is essential to address concerns related to HIF1α overexpression, which has been associated with exacerbating various malignant tumors, including MDS. To assess the safety and effectiveness of HIF-PHi for MDS, we conducted a prospective clinical trial evaluating an oral HIF-PHi called daprodustat. Methods The study included MDS patients with chronic kidney disease (CKD) stage ≥ 3, considering daprodustat's approval in Japan, at Ebina General Hospital. Patients with MDS who were treated with deoxyribonucleic acid methylation inhibitors and/or who underwent allo-HSCT were excluded. Participants were administered daprodustat at the approved dose for renal anemia and underwent regular blood sampling and bone marrow examination. The primary and secondary endpoints were the leukemia rate within 1 year after HIF-PHi administration and hematological improvement (HI), respectively. The study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved by the Institutional Review Board of the Ebina General Hospital (approval number: JMA-388). Written informed consent was obtained from all participants. Results Seventeen patients with MDS, with a median age of 81years, were included in the analysis. Revised International Prognostic Scoring System scores (IPSS-R) were very low, low, intermediate, high, and very high in 1, 11, 3, 1, and 1 patients, respectively. Five cases were changed from ESA treatment. Within 1 year after HIF-PHi administration, no patients developed leukemia, and both peripheral blood Wilms tumor 1 protein concentrations and bone marrow myeloblast counts remained unchanged from pre-treatment levels. HI was observed in 8 patients within 6 months, and the median dose was 6 (range, 2-12) mg for HI achievement. On univariate analysis, pretreatment transferrin saturation (TSAT, P = 0.002, Figure 1) and ferritin concentration ( P = 0.016) were inversely associated with HI achievement. However, pretreatment hepcidin concentration, erythropoietin concentration, previous ESA use, and IPSS-R were not associated with HI achievement. Notably, when a TSAT cutoff of &amp;lt; 45% was used, achieving HI showed a sensitivity and specificity of 87.5% and 100.0%. Moreover, patients with TSAT &amp;lt; 45% showed significant improvement in anemia after 3 months and beyond (Figure 2). No significant differences were observed in neutrophil and platelet counts between the two groups. Throughout the study, eleven adverse events occurred, including 6 infections, and 1 case each of myocardial infarction, eosinophilia, erythema multiforme, organizing pneumonia, and spinal fracture. Conclusion HIF-PHi administration did not lead to MDS progression. Notably, in MDS patients with CKD, low TSAT was a predictor for achieving HI by HIF-PHi.