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Background: Epoetin alfa is a derivative of the erythropoietin hormone. This study aims to investigate the epoetin alfa effect on anxiety-like behaviors., Methods: Adult female Wistar Albino rats were divided into Control (n = 8), 1000 U Epoetien alfa, and 2000 U Epoetien alpha. Epoetin alfa was administered intraperitoneally once a week for 4 weeks. The animals were then subjected to open field test, elevated plus maze, light-dark box, and the behaviors were video recorded., Results: Epoetin alfa significantly reduced anxiety-like behaviors in both low- and high-dose groups in a dose-independent manner. This anxiolytic effect was seen in all three anxiety tests. Further, exploratory behaviors such as unsupported rearing and head-dipping behaviors increased with the application of Epoetin alfa. This protocol did not alter locomotor activity., Conclusion: The present study found beneficial effects of epoetin alfa on behaviors. Further studies on the effect of derivatives of erythropoietin hormone on anxiety-like behaviors are needed., Competing Interests: Declarations. Ethical approval: All experiments were carried out as approved by the Ankara University Experimental Animals Ethics Committee, with the approval reference number 2022-15-144 (committee meeting date 07.09.2022). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objectives: To survey practices of iron and recombinant human erythropoietin (rhEpo) administration to infants born preterm across Europe., Study Design: Over a 3-month period, we conducted an online survey in 597 neonatal intensive care units (NICUs) of 18 European countries treating infants born with a gestational age of <32 weeks., Results: We included 343 NICUs (response rate 56.3%) in the survey. Almost all NICUs (97.7%) routinely supplement enteral iron, and 74.3% of respondents to all infants born <32 weeks of gestation. We found that 65.3% of NICUs routinely evaluate erythropoiesis and iron parameters beyond day 28 after birth. Most NICUs initiate iron supplementation at postnatal age of 2 weeks and stop after 6 months (34.3%) or 12 months (34.3%). Routine use of rhEpo was reported in 22.2% of NICUs, and in individual cases in 6.9%. RhEpo was mostly administered subcutaneously (70.1%) and most frequently at a dose of 250 U/kg 3 times a week (44.3%), but the dose varied greatly between centers., Conclusions: This survey highlights wide heterogeneity in evaluating erythropoietic activity and iron deficiency in infants born preterm. Variation in iron supplementation during infancy likely reflects an inadequate evidence base. Current evidence on the efficacy and safety profile of rhEpo is only poorly translated into clinical practice. This survey demonstrates a need for standards to optimize patient blood management in anemia of prematurity., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Delayed cord clamping (DCC) occurs in most preterm births., Objective: Evaluate the association of DCC with acute kidney injury (AKI) and two-year kidney outcomes., Methods: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates born 24 0/7 to 27 6/7 weeks gestation. AKI and two year kidney outcomes were compared in neonates with DCC ( ≥ 30 s after delivery) to those with early cord clamping (ECC) (<30 s after delivery)., Results: The incidence and severity of AKI did not differ between the DCC and ECC groups (aOR 1.17 [95%CI 0.76-1.80]). At two years corrected age, DCC was associated with a 4.5-fold increased adjusted odds of estimated glomerular filtration rate (eGFR) <90 mL/min/1.73m 2 . No significant associations were noted between DCC and albuminuria or elevated blood pressure., Conclusions: DCC was not associated with decreased neonatal AKI, but was associated with higher adjusted odds of eGFR <90 mL/min/1.73m 2 at two years., Competing Interests: Competing interests: The authors declare no competing interests. Consent: Consent was required for parent study but not for this secondary analysis., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Treatment options for severe, refractory iron deficiency anemia are limited in pregnancy., Objective: To review the available literature on the use of recombinant erythropoietin in the treatment of iron deficiency anemia in pregnancy., Search Strategy: An electronic search of seven databases from inception to March 2022 was performed using a combination of keywords., Selection Criteria: We included all randomized controlled or observational studies of pregnant patients with iron deficiency anemia who received recombinant erythropoietin or control. The primary outcome was a change in hematologic parameters (hemoglobin or hematocrit) after treatment. Studies were appraised using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions., Data Collection and Analysis: Data were summarized using narrative synthesis and descriptive statistics as appropriate. This study was registered with PROSPERO, CRD42022313328., Main Results: Of 234 studies screened, five studies met the inclusion criteria and had sufficient data for analysis (n = 103 recombinant erythropoietin and n = 104 controls). All patients in the intervention group received iron supplementation (intravenous or oral) in addition to recombinant erythropoietin. All patients in the control group received iron supplementation (intravenous or oral) alone. As the result of variance between studies in inclusion criteria, the timing of repeat blood draws, and data reporting, a meta-analysis could not be performed. Three studies found that serial recombinant erythropoietin combined with iron supplementation was more effective at raising hematologic laboratory parameters (hemoglobin or hematocrit) than iron alone. One study reported no difference in hemoglobin or hematocrit levels between groups at day 28. However, patients in this study only received one dose of recombinant erythropoietin, whereas those in the other studies received serial doses. Another study also found no difference in hemoglobin levels by day 28, but patients in the recombinant erythropoietin group had lower hemoglobin levels at baseline and a more rapid rise in hemoglobin than iron alone. This is demonstrated by a more significant rise in hemoglobin at day 11 in the recombinant erythropoietin group than in the control group., Conclusions: Serial recombinant erythropoietin administration and iron supplementation may be more effective at treating refractory iron deficiency anemia in pregnancy than iron supplementation alone., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

The main function of erythropoietin (EPO) is to promote hematopoiesis and improve anemia. In addition, EPO also has many non-hematopoietic effects such as anti-inflammation, anti-apoptosis and anti-oxidation. To achieve the protective effects, large doses of EPO are required, so the probability of side effects increases. Previous studies have revealed that EPO can improve pulmonary fibrosis in mice, but it has not been clarified whether the hematopoiesis of EPO contributes to amelioration of pulmonary fibrosis and whether EPO improves overall mortality. Our results show that EPO decreases hydroxyproline content, α-sma and col-1 protein levels in mice with bleomycin-induced pulmonary fibrosis. However, compared with the control group, the weight loss and mortality rate of the EPO group were not improved, while the number of red blood cells (RBCs), hemoglobin (Hb), red cell width distribution-coefficient of variation (RDW-CV) and hematocrit (HCT) were significantly higher. Furthermore, we observed massive thrombosis in the lung of EPO treated lung fibrosis mice but not in control mice. Therefore, our results show that in the condition of lung fibrosis, the hematopoietic activity of exogenous EPO is not conducive to its tissue protective effect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Postpartum iron deficiency anaemia is caused by antenatal iron deficiency or excessive blood loss at delivery and might affect up to 50% of labouring women in low- and middle-income countries. Effective and safe treatment during early motherhood is important for maternal well-being and newborn care. Treatment options include oral iron supplementation, intravenous iron, erythropoietin, and red blood cell transfusion., Objectives: To assess the benefits and harms of the available treatment modalities for women with postpartum iron deficiency anaemia. These include intravenous iron, oral iron supplementation, red blood cell transfusion, and erythropoietin., Search Methods: A Cochrane Information Specialist searched for all published, unpublished, and ongoing trials, without language or publication status restrictions. We searched databases including CENTRAL, MEDLINE, Embase, CINAHL, LILACS, WHO ICTRP, and ClinicalTrials.gov, together with reference checking, citation searching, and contact with study authors to identify eligible studies. We applied date limits to retrieve new records since the last search on 9 April 2015 until 11 April 2024., Eligibility Criteria: We included published, unpublished, and ongoing randomised controlled trials (RCTs) that compared treatments for postpartum iron deficiency anaemia with placebo, no treatment, or alternative treatments. Cluster-randomised trials were eligible for inclusion. We included RCTs regardless of blinding. Participants were women with postpartum haemoglobin ≤ 12 g/dL, treated within six weeks after childbirth. We excluded non-randomised, quasi-randomised, and cross-over trials., Outcomes: The critical outcomes of this review were maternal mortality and fatigue. The important outcomes included persistent anaemia symptoms, persistent postpartum anaemia, psychological well-being, infections, compliance with treatment, breastfeeding, length of hospital stay, serious adverse events, anaphylaxis or evidence of hypersensitivity, flushing/Fishbane reaction, injection discomfort/reaction, constipation, gastrointestinal pain, number of red blood cell transfusions, and haemoglobin levels., Risk of Bias: We assessed risk of bias in the included studies using the Cochrane RoB 1 tool., Synthesis Methods: Two review authors independently performed study screening, risk of bias assessment, and data extraction. We contacted trial authors for supplementary data when necessary. We screened all trials for trustworthiness and scientific integrity using the Cochrane Trustworthiness Screening Tool. We conducted meta-analyses using a fixed-effect model whenever feasible to synthesise outcomes. In cases where data were not suitable for meta-analysis, we provided a narrative summary of important findings. We evaluated the overall certainty of the evidence using GRADE., Included Studies: We included 33 RCTs with a total of 4558 postpartum women. Most trials were at high risk of bias for several risk of bias domains., Synthesis of Results: Most of the evidence was of low or very low certainty. Imprecision due to few events and risk of bias due to lack of blinding were the most important factors. Intravenous iron versus oral iron supplementation The evidence is very uncertain about the effect of intravenous iron on mortality (risk ratio (RR) 2.95, 95% confidence interval (CI) 0.12 to 71.96; P = 0.51; I² = not applicable; 3 RCTs; 1 event; 572 women; very low-certainty evidence). One woman died of cardiomyopathy, and another developed arrhythmia, both in the groups treated with intravenous iron. Intravenous iron probably results in a slight reduction in fatigue within 8 to 28 days (standardised mean difference -0.25, 95% CI -0.42 to -0.07; P = 0.006; I² = 47%; 2 RCTs; 515 women; moderate-certainty evidence). Breastfeeding was not reported. Oral iron probably increases the risk of constipation compared to intravenous iron (RR 0.12, 95% CI 0.06 to 0.21; P < 0.001; I² = 0%; 10 RCTs; 1798 women; moderate-certainty evidence). The evidence is very uncertain about the effect of intravenous iron on anaphylaxis or hypersensitivity (RR 2.77, 95% CI 0.31 to 24.86; P = 0.36; I² = 0%; 12 RCTs; 2195 women; very low-certainty evidence). Three women treated with intravenous iron experienced anaphylaxis or hypersensitivity. The trials that reported on haemoglobin at 8 to 28 days were too heterogeneous to pool. However, 5 of 6 RCTs favoured intravenous iron, with mean changes in haemoglobin ranging from 0.73 to 2.10 g/dL (low-certainty evidence). Red blood cell transfusion versus intravenous iron No women died in the only trial that reported on mortality (1 RCT; 7 women; very low-certainty evidence). The evidence is very uncertain about the effect of red blood cell transfusion on fatigue at 8 to 28 days (mean difference (MD) 1.20, 95% CI -2.41 to 4.81; P = 0.51; I² = not applicable; 1 RCT; 13 women; very low-certainty evidence) and breastfeeding more than six weeks postpartum (RR 0.43, 95% CI 0.12 to 1.57; P = 0.20; I² = not applicable; 1 RCT; 13 women; very low-certainty evidence). Constipation and anaphylaxis were not reported. Red blood cell transfusion may result in little to no difference in haemoglobin within 8 to 28 days (MD -1.00, 95% CI -2.02 to 0.02; P = 0.05; I² = not applicable; 1 RCT; 12 women; low-certainty evidence). Intravenous iron and oral iron supplementation versus oral iron supplementation Mortality and breastfeeding were not reported. One trial reported a greater improvement in fatigue in the intravenous and oral iron group, but the effect size could not be calculated (1 RCT; 128 women; very low-certainty evidence). Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone (RR 0.21, 95% CI 0.07 to 0.69; P = 0.01; I² = not applicable; 1 RCT; 128 women; low-certainty evidence). There were no anaphylaxis or hypersensitivity events in the trials (2 RCTs; 168 women; very low-certainty evidence). Intravenous iron and oral iron may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days (MD 0.00, 95% CI -0.48 to 0.48; P = 1.00; I² = not applicable; 1 RCT; 60 women; low-certainty evidence). Red blood cell transfusion versus no transfusion Mortality, fatigue at day 8 to 28, constipation, anaphylaxis, and haemoglobin were not reported. Red blood cell transfusion may result in little to no difference in breastfeeding more than six weeks postpartum (RR 0.91, 95% CI 0.78 to 1.07; P = 0.24; I² = not applicable; 1 RCT; 297 women; low-certainty evidence). Oral iron supplementation versus placebo or no treatment Mortality, fatigue, breastfeeding, constipation, anaphylaxis, and haemoglobin were not reported. Two trials reported on gastrointestinal symptoms, but did not report results by study arm., Authors' Conclusions: Intravenous iron probably reduces fatigue slightly in the early postpartum weeks (8 to 28 days) compared to oral iron tablets, but probably results in little to no difference after four weeks. It is very uncertain if intravenous iron has an effect on mortality and anaphylaxis/hypersensitivity. Breastfeeding was not reported. Intravenous iron may increase haemoglobin slightly more than iron tablets, but the data were too heterogeneous to pool. However, changes in haemoglobin levels are a surrogate outcome, and treatment decisions should preferentially be based on patient-relevant outcomes. Iron tablets probably result in a large increase in constipation compared to intravenous iron. The effect of red blood cell transfusion compared to intravenous iron on mortality, fatigue, and breastfeeding is very uncertain. No studies reported on constipation or anaphylaxis/hypersensitivity. Red blood cell transfusion may result in little to no difference in haemoglobin at 8 to 28 days. The effect of intravenous iron and oral iron supplementation on mortality, fatigue, breastfeeding, and anaphylaxis/hypersensitivity is very uncertain or unreported. Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone, and in little to no difference in haemoglobin. The effect of red blood cell transfusion compared to non-transfusion on mortality, fatigue, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported. Red blood cell transfusion may result in little to no difference in breastfeeding. The effect of oral iron supplementation on mortality, fatigue, breastfeeding, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported., Funding: This Cochrane review had no dedicated funding., Registration: Protocol and previous versions are available: Protocol (2013) [DOI: 10.1002/14651858.CD010861] Original review (2004) [DOI: 10.1002/14651858.CD004222.pub2] Review update (2015) [DOI: 10.1002/14651858.CD010861.pub2]., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Anemia is a hallmark of chronic kidney disease (CKD), worsens with disease progression, and profoundly affects a patient's well-being. Major pathogenic factors are inadequate kidney erythropoietin (EPO) production and absolute and functional iron deficiency. The 2 mainstays of current anemia treatment are a) replacement therapy with recombinant EPO or 1 of its glycosylated derivatives, administered subcutaneously or intravenously, and b) intravenous (IV) iron injections. Over the past 5 years, hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in many countries for the management of anemia in both nondialysis and dialysis-dependent patients with CKD. Due to cardiovascular safety concerns, only 2 HIF-PHIs, daprodustat and vadadustat, have been approved for marketing in the United States, and only for patients on maintenance dialysis. HIF-PHIs are oral agents that are effective at improving and maintaining hemoglobin levels by activating HIF signaling in anemic patients with CKD. They stimulate the production of endogenous EPO, increase total iron-binding capacity through their direct effects on transferrin gene transcription, lower plasma hepcidin indirectly, and have beneficial effects on red blood cell parameters. Here, we discuss the mechanisms of action and pharmacologic properties of different HIF-PHIs. We discuss unwanted on-target and off-target effects, review cardiovascular and other safety concerns, and provide a benefit/risk-based perspective on how this new class of oral drugs might impact current anemia management in CKD. A clinical case is presented that highlights the clinical complexities and therapeutic challenges in managing anemia in CKD., (Copyright © 2024 by The American Society of Hematology.)

This study aimed to investigate the correlation between ultrafiltration rate (UFR) and hemoglobin levels and erythropoietin (EPO) response in patients receiving maintenance hemodialysis (MHD). 225 MHD patients were divided into three groups according to the UFR: < 10 ml/h/kg, 10-13 ml/h/kg, and >13 ml/h/kg. Clinical parameters and prognosis were compared among the groups. Multiple linear correlation and regression analyses were conducted. SPSS 26.0 (IBM, Chicago, IL, USA) was used to analyze all statistics. The UFR < 10 ml/h/kg group was older than the other groups ( p  < 0.05). The UFR > 13 ml/h/kg group had the highest SpKt/V ( p  < 0.05), monthly EPO dose/weight ( p  < 0.001), and EPO resistance index ( p  < 0.001), as well as the lowest dry weight ( p  < 0.001), BMI ( p  < 0.001), hemoglobin ( p  < 0.001), hematocrit ( p  < 0.05), and red blood cell count ( p  < 0.05). Multiple linear regression analysis showed that sex, dry weight, UFR, calcium, phosphorus, albumin, and C-reactive protein levels were associated with hemoglobin levels. Multivariate logistic regression analysis revealed that a higher UFR was associated with lower hemoglobin levels, while male sex and higher levels of calcium and albumin were associated with higher hemoglobin levels. High UFR is associated with more severe anemia and EPO resistance in MHD. This study provides new insights into anemia management in patients undergoing hemodialysis.

Anemia is a common complication of chronic kidney disease with major option treatment of erythropoiesis-stimulating agents (ESAs). This study aimed to investigate the influencing factors of erythropoietin resistance index (ERI) and its association with mortality in maintenance hemodialysis (MHD) patients. Patients enrolled from China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5 were included. ERI was calculated as follows: ESA (IU/week)/weight (kg, post-dialysis)/hemoglobin level (g/dL). The Cox regression model was used to analyze the influencing factors on survival outcomes. Stepwise multivariate logistic regression was used to identify the related risk factors, and subgroup analyses were performed. A total of 1270 MHD subjects (687 males and 583 females) were included, with an average age of 60 (49.0, 71.0) years. All subjects were divided into two groups by the median ERI of 14.03. Multivariate logistic regression showed that dialysis vintage (OR 0.957, 95% CI: 0.929-0.986), white blood cells (OR 0.900, 95% CI: 0.844-0.960), high flux dialyzer use (OR 0.866, 95% CI: 0.755-0.993), body mass index (OR 0.860, 95% CI: 0.828-0.892), males (OR 0.708, 95% CI: 0.625-0.801), and albumin (OR 0.512, 95% CI: 0.389-0.673) had a negative association with high ERI baseline (all p  < 0.05). There were 176 (13.9%) deaths in total including 89 cardiac/vascular deaths during follow-up. Cox regression analysis showed that ERI was positively associated with all-cause mortality, especially in some subgroups. ERI was associated with increased all-cause mortality in MHD patients, indicating the possibility of death prediction by ERI. Patients with high ERI warrant more attention.

Objective: Cardiac surgery is known to have high rates of perioperative red blood cell (RBC) transfusions which are associated with increased postoperative mortality and morbidity. Perioperative erythropoietin (EPO) has been suggested to lower perioperative RBC transfusions, and the effect on postoperative morbidity or mortality is unknown., Methods: The registered study protocol is available on PROSPERO (CRD42022314538). We searched the Pubmed, EMbase, and Cochrane CENTRAL databases for randomized controlled trials (RCT) of EPO in cardiac surgery. Outcomes were short-term mortality, acute kidney injury (AKI), re-operation, cerebrovascular accident (CVA), perioperative myocardial infarction (MI), infectious complications, and RBC transfusions. RCT studies of perioperative EPO that reported at least one prespecified outcome of interest were included., Results: A total of 21 RCT's (n = 2,763 patients) were included. Mortality analysis included 17 studies (EPO 1,272 patients, control 1,235) and showed no significant difference (risk difference (RD) 0.0004, 95%CI: -0.016, 0.009). EPO did not reduce the incidence of AKI (RD -0.006, 95% CI: -0.038, 0.026) and reoperation (RD 0.001, 95% CI: -0.013, 0.015). The incidence of CVA (RD -0.004, 95% CI: -0.015, 0.007) and perioperative MI (RD -0.008, 95% CI: -0.021, 0.005) was similar between the groups., Conclusions: Although EPO had been proven to reduce perioperative RBC transfusions, we did not find that it reduces the incidence of postoperative short-term mortality, AKI, and reoperation. The study results support that perioperative EPO is also safe, with no rise in thrombotic events, including CVA and perioperative MI., (Copyright © 2024 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia associated with chronic kidney disease (CKD). EPO-induced Pure Red Cell Aplasia (PRCA) is a rare condition of profound anemia with EPO treatment. Upon finding the development of EPO-induced PRCA, the treatment requires immediate withdrawal of EPO therapy and initiate new treatments with immunosuppression or renal transplantation. Anti-EPO antibody assay is not always positive in EPO-induced PRCA. Here, we report a case on the sudden development of PRCA in a hemodialysis patient receiving EPO and how we treated the condition successfully with cyclosporine and subsequently maintained the hemoglobin with Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Even though the anti-EPO antibody was negative by Enzyme Linked Immunosorbent Assay (ELISA) in our case, the clinical course, the markedly reduced reticulocyte count < 10,000/μL, the bone marrow (BM) biopsy revealing reduced erythroblasts, and its subsequent response to cyclosporine, were similar to EPO-induced PRCA. The clinical picture of EPO-induced PRCA, the limitation of the EPO-neutralizing antibody (Ab) assay, and treatment strategies were discussed., Competing Interests: Declarations. Conflict of interest: The authors declared no conflict of interest. Ethical approval: The Medical Ethics Committee of Hong Kong University-Shenzhen Hospital has approved the publication of this case report (IRB approval number 伦[2023]271) which meets the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent for publication: The patient has given consent to the publication of this case report., (© 2024. The Author(s).)

Background: Burn injuries can cause significant mortality and morbidity. This study aimed to evaluate the efficiency of topical recombinant human erythropoietin (rhEPO) on enhancing burn wound healing., Methods: In this randomized double-blind controlled clinical trial, we enrolled 40 participants aged 18 years and older who were referred to a burn center during the first 24 h of burning. The participants with no concurrent comorbidities had superficial and deep second-degree burns, no respiratory burns, no face and perineum burns, no keloid formation, or a healed, fully epithelialized, hypertrophic burn scar. Topical rhEPO or nitrofurazone/Vitamin A was administered every other day, and the patients were scheduled for follow-up visits to receive wound cleansing, debridement, and dressing changes. Burn wound healing response to treatment was measured as the study main outcome., Results: At the second follow-up visit, all parameters were significantly lower in the rhEPO group compared with the control group except for itchiness. The results of the next two follow-up sessions were also the same. The total value of the modified Vancouver Scar Scale (VSS) at days 5, 7, and 14 was significantly lower in the rhEPO group compared with the routine of care group. Trial Registry Date: 2022-03-02, Trial Registry number: IRCT20190810044500N23 CONCLUSIONS: The results of the present study suggested that topical rhEPO is a potential option in burn wounds and patient satisfaction, without causing intolerable side effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests regarding the publication of this paper., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Purpose: Despite various therapeutic attempts, an approved treatment for Methanol-induced optic neuropathy (MION), a sight-threatening disorder, is still lacking. Erythropoietin known as an erythropoietic cytokine, possesses various non-hematopoietic properties that make it a candidate for MION treatment. This systematic review aims to assess the potential therapeutic role of erythropoietin in MION., Method: We systematically searched English and Persian databases including PubMed, Scopus, Embase, Web of Science, and Scientific Information Database (SID) as of July 2024. Two independent authors screened the articles based on their titles, abstracts, and full texts to finalize the included articles in this study. The selected articles underwent quality assessments via the Joanna Briggs Institute (JBI) checklists., Results: Out of 139 studies identified in the databases, 11 were finally included in the analysis. These studies encompassed 212 participants, with 192 receiving erythropoietin treatment. Visual acuity (VA) improved in 184 patients, with improvements ranging from no light perception to full vision recovery, or minor enhancements such as an improvement from 1.75 ± 0.72 to 1.32 ± 0.79 LogMAR. Only 8 patients showed no change or experienced deterioration. Additionally, 21 cases exhibited a reduction in retinal nerve fiber layer thickness, with one showing a reduction towards the normal range., Conclusion: This review highlights erythropoietin's positive impact on VA in patients with MION. However, simultaneous use of erythropoietin and corticosteroids in studies without control groups complicates evaluating erythropoietin's independent efficacy. Future research should involve large, controlled trials to clarify erythropoietin's role and establish it as a standard treatment., Prospero Registration Number: CRD42023485772., Competing Interests: Declarations. Ethics approval and consent to participate: Not applied. Consent for publication: Not used. Competing interests: There is no conflict of interest, according to the authors., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Background: Post-operative delirium (PD) is a common post-operative complication with significant clinical and financial impacts on patients. Erythropoietin (EPO), a multi-functional glycoprotein hormone, exhibits erythropoietic and non-erythropoietic anti-inflammatory properties. This study aimed to determine the role of perioperative EPO administration in the development of postoperative delirium in older adult patients undergoing total joint arthroplasty., Methods: Seventy-one patients (> 65 years old) scheduled for total joint arthroplasty were randomly assigned to two groups: EPO-treated (EPO, n = 35) and placebo (control, n = 36). All patients completed the Mini Mental State Examination (MMSE) pre-operatively and on post-operative day (POD) 2. The confusion assessment method (CAM) was used to assess the patients until discharge (POD 5). Serum C-reactive protein (CRP) and inflammatory cytokine levels were measured and compared pre- and post-operatively. The development of delirium and cognitive dysfunction was evaluated post-operatively., Results: One patient in the control group developed delirium on POD 2 (3.2%), whereas no patient in the EPO group developed PD (0% vs. 3.2%, p = 0.500). Post-operatively there was no significant difference in MMSE scores between groups. Both groups showed increases in pro- and anti-inflammatory cytokine levels, with no significant differences. Similarly, CRP levels, neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) showed no intergroup differences in post-operative inflammatory responses., Conclusions: Perioperative EPO reduced the incidence of post-operative delirium, although not statistically significant, with no differences in post-operative cognitive function and inflammatory responses., Trial Registration: The trial was registered on December 12, 2023 at http//clinicaltrials.gov, registration number NCT06178835., Competing Interests: Declarations Ethics approval and consent to participate This study protocol was reviewed and approved by the Institutional Review Board and Hospital Research Ethics Committee of Severance Hospital, Yonsei University Health System (#4-2017-0694). The trial was registered on December 12, 2023 at http://clinicaltrials.gov (registration number NCT06178835), adhered to the CONSORT statement, and was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all participants, who were informed of their rights, including the option to withdraw from the study at any stage. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The effects of various risk and associated factors on post-kidney transplant anemia (PTA) have not been fully compared and estimated. This meta-analysis aims to elucidate factors contributing to PTA and determine the influence of erythropoietin-stimulating agents (ESAs) on renal outcomes, thus offering potential pathways for enhanced management strategies post-transplant., Methods: A systematic review was conducted in electronical database. Studies reporting on risk factors (with cause-effect relationships) and associated factors (without definite cause-effect relationships) of PTA, and the effects of ESAs on post-kidney transplant outcomes, were included. Pooled odds ratios (ORs) and weighted mean differences (WMDs) were analyzed using random-effects models., Results: This systematic review encompassed 38,233 patients from 85 studies. Factors increased PTA risk included African American, older donor age, human antigen leukocyte mismatches, and low pre-transplant hemoglobin levels. Poor allograft function, high interleukine-6, Cytomegalovirus, delayed graft function, allograft rejections, immunosuppressive medications, and renin-angiotensin system blockades were associated with PTA. Native autosomal dominant polycystic kidney disease was a protective factor against PTA. Administration of ESAs with the aim of normalizing hemoglobin levels in patients with chronic allograft dysfunction slowed the decline in eGFR and reduce the risk of death, with a pooled OR of 0.36 (95% CI: 0.14 to 0.89; p = 0.040)., Conclusions: The risks and associated factors for PTA have been elucidated, underscoring the need for individualized treatment approaches. Late ESA therapy, aimed at hemoglobin normalization, suggests a renal-protective effect and reduced mortality, which should be considered in the management of PTA., Systematic Review Registration: PROSPERO CRD42024545330., Competing Interests: Declarations Ethics approval and consent to participate The data in this systematic review and meta-analysis were derived from published literature, making it impossible to identify individual subjects. No data were directly obtained from human or animal subjects. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background and Objectives: Preoperative red blood cell (RBC) transfusions increase post-operative venous thromboembolic (VTE) events. Erythropoietin-stimulating agents (ESAs) increase VTE risk in cancer patients; we aimed to assess ESA versus RBC-associated VTE risks in a broad population of surgical patients., Materials and Methods: We queried TriNetX Diamond Network from 2006 to 2023, comparing patients with anaemia within 3 months preoperatively who received preoperative ESAs with or without intravenous (IV) iron to patients who received preoperative RBCs. Sub-analyses included (1) all surgeries and (2) cardiovascular surgeries. We propensity score matched for demographics, comorbidities, medical services, post-treatment haemoglobin (g/dL) and, for all-surgery comparisons, surgery type. Outcomes included 30-day post-operative mortality, VTE, pulmonary embolism (PE), disseminated intravascular coagulation (DIC) and haemoglobin., Results: In our 19,548-patient cohorts, compared with preoperative RBC transfusion, ESAs without IV iron were associated with lower mortality (relative risk [RR] = 0.51 [95% confidence interval (CI), 0.45-0.59]), VTE (RR = 0.57 [0.50-0.65]) and PE (RR = 0.67 [0.54-0.84]). Post-operative haemoglobin was higher in the ESA without IV iron cohort compared with the transfusion cohort (10.0 ± 1.4 vs. 9.4 ± 1.8 g/dL, p = 0.002). Cardiac surgical patients receiving ESAs with or without IV iron had lower risk for post-operative mortality, VTE and PE (p < 0.001) than those receiving RBCs. Post-operative haemoglobin differed between patients receiving ESAs with IV iron versus RBCs (10.1 ± 1.5 vs. 9.4 ± 1.9 g/dL, p = 0.0009)., Conclusion: Compared with surgical patients who were transfused RBCs, ESA recipients had reduced 30-day post-operative risk of mortality, VTE, PE and DIC and increased haemoglobin levels. IV iron given with ESAs improved mortality., (© 2024 International Society of Blood Transfusion.)

Objectives: This randomized, double-blind, placebo-controlled clinical trial aimed to prospectively examine the effect of pentoxifylline (PTX) on hypoxia-inducible factor-2 alpha (HIF-2α) and its role in controlling anemia in hemodialysis (HD) patients., Methods: Eighty patients on HD were randomized to receive 400 mg of PTX or placebo twice daily for 6 months. The hemoglobin (Hb) and other hematologic parameters, the weekly erythropoiesis-stimulating agents (ESAs), and the ESA resistance index (ERI) were assessed monthly during the study. The HIF-2α, transforming growth factor-β1 (TGF-β1), and high-sensitivity C-reactive protein (hs.CRP) were measured before and after the intervention., Results: In the pentoxifylline group, an appreciable increase in Hb from 9.7 (9.3, 10.3) g/dl to 10.5 (9.3, 11.4) g/dl and hematocrit (Hct) from 31.3 (29.6, 32.4)% to 33.2 (29.4, 35.9)% was observed after one month of PTX administration, and this effect was maintained over the study time ( p  < 0.001). This was along with a decrease in the ESA doses required from 8000 (8000, 11500) IU/wk to 4000 (2000, 8000) IU/wk ( p  < 0.001), and an improvement in the ERI from 11.6 (8.07, 16.97) IU/kg/wk/g/dl to 5.79 (2.01, 10.09) IU/kg/wk/g/dl ( p  < 0.001). Additionally, the HIF-2α increased significantly at the end of the intervention in patients who received PTX from 3245.35 (2886.8, 4691.56) pg/ml to 7208.75 (5382, 9182.7) pg/ml, while TGF-β1 and hs.CRP decreased significantly from 657.78 (539.78, 1146.62) pg/ml and 88.08 (39.93, 100.4) mg/l to 329.94 (228.67, 793.18) pg/ml and 48.65 (34.44, 84.61) mg/l, respectively. The percent changes in HIF-2α, TGF-β1, and hs.CRP levels in the pentoxifylline group were also statistically significant in comparison with the placebo group., Conclusions: PTX could be a promising agent for correcting anemia in HD patients via increasing HIF-2α levels., Clinical Trial Registration: Clinicaltrials.gov, February 2023, registry number: NCT05708248.

Background: Sudanese children with End-Stage Kidney Disease (ESKD) often show limited improvement in hemoglobin levels despite treatment with recombinant human erythropoietin (rHuEPO). This study aims to assess the response to rHuEPO therapy by analyzing β-globin mRNA expression and reticulocyte parameters. Additionally, it classifies anemia among Sudanese pediatric patients based on iron status, considering age and gender as biological markers for evaluating treatment response., Methods: A prospective observational cohort study was conducted from January 2019 to February 2020 in Khartoum, Sudan, involving 45 anemic children aged 2 to 15 years diagnosed with ESKD. The treatment protocol included rHuEPO injections and maintenance hemodialysis. Laboratory assessments consisted of complete blood count (CBC), absolute reticulocyte count, ferritin, and transferrin measurements. β-globin mRNA expression was quantified using reverse transcription polymerase chain reaction (RT-PCR), and reticulocyte parameters, including Reticulocyte Hemoglobin Content (CHr), percentage of hypochromic reticulocytes (HYPO%), and Immature Reticulocyte Fraction (IRF), were measured via flow cytometry., Results: Significant variations in hemoglobin levels were observed across different age groups (p = 0.011). Gender analysis revealed a significant association with IRF, showing a lower IRF in male patients (p = 0.017). However, there were no significant differences in hemoglobin levels between genders (p = 0.999). β-globin mRNA expression showed considerable variability, with a strong positive correlation with hemoglobin levels (r = 0.875, p < 0.0001)., Conclusion: Age and gender significantly influence treatment responses in children with ESKD, highlighting the need to consider growth physiology in anemia management. This study underscores the variability in β-globin mRNA expression and its association with Flow Cytometry parameters, demonstrating their effectiveness in evaluating iron status and guiding rHuEPO dosage., (© 2024. The Author(s).)

Objective: To examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE)., Design: Double-blind pilot randomised controlled trial., Setting: Eight neonatal units in South Asia., Patients: Neonates (≥36 weeks) with moderate or severe HIE admitted between 31 December 2022 and 3 May 2023., Interventions: Erythropoietin (500 U/kg daily) or to the placebo (sham injections using a screen) within 6 hours of birth and continued for 9 days. MRI at 2 weeks of age., Main Outcomes and Measures: Feasibility of randomisation, drug administration and assessment of brain injury using MRI., Results: Of the 154 neonates screened, 56 were eligible; 6 declined consent and 50 were recruited; 43 (86%) were inborn. Mean (SD) age at first dose was 4.4 (1.2) hours in erythropoietin and 4.1 (1.0) hours in placebo. Overall mortality at hospital discharge occurred in 5 (19%) vs 11 (46%) (p=0.06), and 3 (13%) vs 9 (40.9%) (p=0.04) among those with moderate encephalopathy in the erythropoietin and placebo groups. Moderate or severe injury to basal ganglia, white matter and cortex occurred in 5 (25%) vs 5 (38.5%); 14 (70%) vs 11 (85%); and 6 (30%) vs 2 (15.4%) in the erythropoietin and placebo group, respectively. Sinus venous thrombosis was seen in two (10%) neonates in the erythropoietin group and none in the control group., Conclusions: Brain injury and mortality after moderate or severe HIE are high in South Asia. Evaluation of erythropoietin monotherapy using MRI to examine treatment effects is feasible in these settings., Trial Registration Number: NCT05395195., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Anaemia is a frequent complication of chronic kidney disease; if severe and untreated, it leads to a worsening of quality of life and an increased risk of resorting to haemotransfusions. Beginning with studies in physio-pathology that began in the late 19th century and continued into the 20th century, the first step was the identification of erythropoietin, then its purification, identification of the gene involved and finally the synthesis of recombinant human erythropoietin and its 'long-acting' analogues. Today, therapy with erythropoiesis-stimulating agents (ESAs), often in combination with martial therapy, is the standard of care for patients with chronic kidney disease and anaemia. Recently, ESAs have been joined by HIF-PHD inhibitors. Unfortunately, both categories of drugs, although effective and well-tolerated in most cases, may be associated with a possible increased cardiovascular and thrombotic risk, especially in particular categories of patients. For this reason, the choice of therapy with ESA and HIF-PHD must be customised in terms of haemoglobin target, molecule type and dosage to be used., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Iron therapy in nephropathic patients can allow optimizing treatment with EPO identifying the minimum effective dose capable of improving the patient's quality of life. The most recent studies on iron metabolism and on the interference of iron deficiency syndrome on the performance of some organs, in particular the myocardium, suggest the need to intervene very early, especially in patients with cardiomyopathy and systolic deficit. Setting up an iron therapy in nephropathic patients requires a correct diagnosis. That is particularly difficult in comorbid and inflamed patients because of the poor diagnostic reliability of the main biomarkers (ferritin and transferrin saturation). We need to spread the use of biomarkers that are not influenced by the inflammatory state, not expensive and easily accessible: reticulocyte hemoglobin could meet these requirements. The Pivotal study has delineated the optimal iron treatment in incident hemodialysis patients, treated with EPO not inflamed with classical biomarkers. It is yet to be determined, however, whether the Pivotal results are reproducible in more comorbid patients, also considering new and different therapeutic scenarios that the use of hypoxia-inducible factor-prolyl hydroxyl inhibitors may determine., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Objective: To evaluate whether treatment with erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia affects progression-free survival (PFS) in patients receiving front-line chemotherapy following surgery for ovarian cancer (OC)., Methods: We retrospectively reviewed all consecutive patients who received front-line chemotherapy after surgery between 2013 and 2019 at six institutions. The patients were divided according to the use of ESAs during front-line chemotherapy. The primary endpoint was PFS. The secondary endpoint was the occurrence of thromboembolism. Propensity score matching (PSM) analysis was used to compare survival between matched cohorts., Results: Overall, 2147 patients (433 receiving ESA and 1714 for no-ESA) were identified, with a median follow-up of 44.0 months. The ESA group showed a significantly higher proportion of stage III/IV disease (81.8% vs 61.1%; P < 0.001) and postoperative gross residual disease (32.3% vs 21.2%; P < 0.001) than the no-ESA group. In the multivariable Cox regression analysis, the use of ESAs did not affect PFS (adjusted hazard ratio, 1.03; 95% confidence interval [CI]: 0.89-1.20; P = 0.661). The incidence of thromboembolism was 10.2% in the ESA group and 4.6% in the no-ESA group (adjusted odds ratio, 6.58; 95% CI: 3.26-13.28; P < 0.001). When comparing the well-matched cohorts after PSM, PFS did not differ between the ESA (median PFS 23.5 months) and no-ESA groups (median PFS 22.2 months) (P = 0.540, log-rank test)., Conclusions: The use of ESAs during front-line chemotherapy did not negatively affect PFS in patients with OC after surgery but increased the risk of thromboembolism., (© 2024 International Federation of Gynecology and Obstetrics.)

Background: Acute kidney injury (AKI) is characterised by a rapid decline in kidney function and is caused by a variety of clinical conditions. The incidence of AKI in hospitalised adults is high. In animal studies, erythropoiesis-stimulating agents (ESA) have been shown to act as a novel nephroprotective agent against ischaemic, toxic, and septic AKI by inhibiting apoptosis, promoting cell proliferation, and inducing antioxidant and anti-inflammatory responses. As a result, ESAs may reduce the incidence of AKI in humans. Randomised controlled trials (RCTs) have been conducted on the efficacy and safety of ESAs, but no prior systematic reviews exist that comprehensively examine ESAs with respect to AKI prevention, although the effectiveness of these agents has been examined for a range of other diseases and clinical situations., Objectives: This review aimed to look at the benefits and harms of ESAs for preventing AKI in the context of any health condition., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 30 August 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: We included RCTs and quasi-RCTs (in which allocation to treatment was based on alternate assignment or order of medical records, admission dates, date of birth or other non-random methods) that compared ESAs with placebo or standard care in people at risk of AKI., Data Collection and Analysis: Three authors independently extracted data and assessed the risk of bias for included studies. We used random-effects model meta-analyses to perform quantitative synthesis of the data. We used the I 2 statistic to measure heterogeneity amongst the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with their 95% confidence interval (CI). We assessed the certainty of the evidence for each main outcome using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach., Main Results: A total of 20 studies (36 records, 5348 participants) were included. The number of participants ranged from 10 to 1302, and most studies were carried out in single centres (13/20). All the included studies compared ESAs to placebo or usual care. Many of the studies were judged to have unclear or high risk of reporting bias, but were at low risk for other types of bias. ESAs, when compared to control interventions, probably makes little or no difference to the risk of AKI (18 studies, 5314 participants: RR 0.97, 95% CI 0.85 to 1.10; I² = 19%; moderate-certainty evidence), or death (18 studies, 5263 participants: RR 0.92, 95% CI 0.80 to 1.06; I² = 0%; moderate-certainty evidence), and may make little or no difference to the initiation of dialysis (14 studies, 2059 participants: RR 1.16, 95% CI 0.90 to 1.51; I² = 0%; low-certainty evidence). Even with standardised measurement of AKI, the studies showed no difference in results between different routes of administration (subcutaneous or intravenous), background diseases (cardiac surgeries, children or neonates, other adults at risk of AKI), or duration or dose of ESA. ESAs may make little or no difference to the risk of thrombosis when compared to control interventions (8 studies, 3484 participants: RR 0.92, 95% CI 0.68 to 1.24; I² = 0%). Similarly, ESAs may have little or no effect on kidney function measures and adverse events such as myocardial infarction, stroke or hypertension. However, this may be due to the low incidence of these adverse events., Authors' Conclusions: In patients at risk of AKI, ESAs probably do not reduce the risk of AKI or death and may not reduce the need for starting dialysis. Similarly, there may be no differences in kidney function measures and adverse events such as thrombosis, myocardial infarction, stroke or hypertension. There are currently two ongoing studies that have either not been completed or published, and it is unclear whether they will change the results. Caution should be exercised when using ESAs to prevent AKI., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Tongue defects have several etiologies and significantly affect the quality of life. This study was conducted to compare the regenerative potential of erythropoietin (EPO)-loaded hydrogel and adipose derived stem cell (ADSC) secretome on tongue dorsum defects focusing on the role of anti-inflammatory M2 macrophage phenotype., Methods: Rats were subjected to induction of mechanical circular defects on the dorsal surface of the tongue, then divided into three groups; Group I (control): received 0.1 ml phosphate buffered saline, Group II (EPO): received 5000 U/kg EPO-hydrogel, and Group III (ADSC-Secretome): received 0.1 ml ADSC-Secretome. Treatments were injected circumferentially around wound margins after induction. Seven and fourteen days after treatment, specimens were obtained and processed for histological and immunohistochemical staining followed by the relevant histomorphometric and statistical analyses., Results: Seven days after treatment, groups II and III presented defects with some epithelial regeneration at the lateral margins, while the center of the defect showed granulation tissue with much inflammatory cells. The base of the defects showed some muscle fibers and new blood vessels, however group III showed more enhanced neovascularization. Fourteen days after therapeutic intervention, group II defects were completely covered with epithelium showing a thin keratin layer with regular rete pegs interdigitating with the underlying connective tissue papillae, but tongue papillae were not restored. Group III expressed much better healing with developing filiform papillae. The connective tissue showed more vascularity and well-arranged muscle bundles. Both treated groups showed a significant decrease in defect depth and significant increase in anti-inflammatory macrophages compared to the control group at both time intervals, however there was no significant difference between the two treated groups., Conclusion: Both treatments showed promising and comparable results in the treatment of tongue defects reducing inflammation and restoring tongue histological architecture with significant upregulation of M2 macrophage., (© 2024. The Author(s).)

Peripheral nerve injury seriously endangers human life and health, but there is no clinical drug for the treatment of peripheral nerve injury, so it is imperative to develop drugs to promote the repair of peripheral nerve injury. Erythropoietin (EPO) not only has the traditional role of promoting erythropoiesis, but also has a tissue-protective effect. Over the past few decades, researchers have confirmed that EPO has neuroprotective effects. However, side effects caused by long-term use of EPO limited its clinical application. Therefore, EPO derivatives with low side effects have been explored. Among them, ARA290 has shown significant protective effects on the nervous system, but the biggest disadvantage of ARA290, its short half-life, limits its application. To address the short half-life issue, the researchers modified ARA290 with thioether cyclization to generate a thioether cyclized helical B peptide (CHBP). ARA290 and CHBP have promising applications as peptide drugs. The neuroprotective effects they exhibit have attracted continuous exploration of their mechanisms of action. This article will review the research on the role of EPO, ARA290 and CHBP in the nervous system around this developmental process, and provide a certain reference for the subsequent research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: YFM has received honoraria or consulting fees from BMS, Kura Oncology, BluePrint Medicines, Geron, OncLive and MD Education, VJHemOnc, and Medscape Live; has participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences, and Novartis; and has received travel reimbursement from Blueprint Medicines, MD Education, and Morphosys. AED has participated in advisory boards or had a consultancy with and received honoraria from Celgene/BMS, Agios, Novartis, Appellis, and Gilead; and has served on clinical trial committees or data safety and monitoring boards for Novartis, AbbVie, Kura, Geron, Servier, Keros, Shuattuck Labs, and Celgene/BMS.

Historically, neonatal neuroscience boasted a robust and successful preclinical pipeline for therapeutic interventions, in particular for the treatment of hypoxic-ischemic encephalopathy (HIE). However, since the successful translation of therapeutic hypothermia (TH), several high-profile failures of promising adjunctive therapies, in addition to the lack of benefit of TH in lower resource settings, have brought to light critical issues in that same pipeline. Using recent data from clinical trials of erythropoietin as an example, the authors highlight several key challenges facing preclinical neonatal neuroscience for HIE therapeutic development and propose key areas where model development and collaboration across the field in general can ensure ongoing success in treatment development for HIE worldwide., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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)., Findings: 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., Interpretation: 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., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests Editorial and medical writing support were funded by Bristol Myers Squibb. MGDP reports receiving honoraria from and advisory or data safety monitoring board fees from Bristol Myers Squibb. GG-M reports receiving consulting fees from Bristol Myers Squibb; research support from AbbVie, Astex, Bristol Myers Squibb, Chordia, Curis, Genentech, Novartis, Rigel Pharmaceuticals, and Zentalis; and honoraria from Astex and Curis. VS reports receiving honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie and Jazz Pharmaceuticals; and advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Curis, Geron, Gilead, Keros, Menarini, Novartis, Servier, and Syros. AMZ reports receiving grant support from AbbVie, Amgen, Astex, Bristol Myers Squibb, Celgene, Geron, Kura, Novartis, Otsuka, Shattuck Labs, and Syros; and consulting fees and honoraria from AbbVie, Agios, Akeso Pharma, ALX Oncology, Amgen, Astellas Pharma, BeiGene, BioCryst, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chiesi, Daiichi Sankyo, Epizyme, Faron, Genentech, Geron, Gilead, Glycomimetics, Hikma, Janssen, Karyopharma, Keros, Kura, Kyowa Kirin, Lava Therapeutics, Medus, Notable, Novartis, Orum, Otsuka, Pfizer, Regeneron, Rigel Pharmaceuticals, Schrodinger, Servier, Sumitomo Pharma, Syndax, Syros, Taiho, Takeda, Treadwell, Vincerx, and Zentalis. RSK reports receiving grant support from Bristol Myers Squibb; consulting fees from Geron, Janssen, and Sumitomo Pharma; speakers bureau fees from AbbVie, Jazz Pharmaceuticals, Pharma Essentia, Rigel Pharmaceuticals, Servio, and Sobi; and advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, DSI, Jazz Pharmaceuticals, Pharma Essentia, Rigel Pharmaceuticals, Servio, Sobi, and Sumitomo Pharma. JS reports receiving grant support from Amgen Australia, Astex Pharmaceuticals, and Bristol Myers Squibb; consulting fees paid to himself from Astellas Pharma, Mundipharma, Novartis, Otsuka, and Pfizer; speakers bureau fees paid to himself and his institution from Mundipharma and Novartis; support for meeting attendance from AstraZeneca (no payment to healthcare provider); being a named investigator on patent PCT/AU2021/050562 assigned to his institution; trial steering committee fees paid to his institution from Bristol Myers Squibb; and serving an unpaid appointment on the Australasia Leukaemia and Lymphoma Group Scientific Advisory Committee. DV reports receiving consulting fees from Amgen, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Sanofi, and Sobi; honoraria from Agios, Amgen, Astellas Pharma, Bristol Myers Squibb, Gebro, Grifols, Janssen, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Sobi; travel support from Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Sanofi, and Sobi; and advisory or data safety monitoring board fees from Amgen, Bristol Myers Squibb, Grifols, Jazz Pharmaceuticals, Novartis, Servier, and Sobi. AJ reports receiving support for study materials from Bristol Myers Squibb; consulting fees from Bristol Myers Squibb; honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie and Novartis; advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, GSK, and Novartis; and a leadership or fiduciary role as the head of the Czech MDS Group. JL, RP, SK, KLK, TP, and YL are employed by and own stock in Bristol Myers Squibb. JZ is employed by Bristol Myers Squibb. VP is employed by and owns stock in Bristol Myers Squibb and owns stock in Merck. SR is employed by, owns stock in, and has received travel support from Bristol Myers Squibb and owns stock in Celgene. AD reports receiving honoraria from Bristol Myers Squibb; travel support from Johnson & Johnson; and advisory or data safety monitoring board fees from Swixx BioPharma. TC reports receiving consulting fees from AbbVie, Agios, BluePrint, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, Novartis, and Servier; honoraria from Astellas, Bristol Myers Squibb/Celgene, Incyte, Jazz Pharmaceuticals, Novartis, Servier, and Takeda; travel support from AbbVie, Bristol Myers Squibb/Celgene, Gilead, Novartis, Pfizer, and Servier; and advisory or data safety monitoring board fees from Astellas, Bristol Myers Squibb/Celgene, Incyte, Jazz Pharmaceuticals, Novartis, Servier, and Takeda. PF reports receiving grant support from AbbVie, Agios, Bristol Myers Squibb, and Novartis; and honoraria from AbbVie, Agios, Bristol Myers Squibb, and Novartis. UP reports receiving grant support paid to GWT-TUD, from Amgen and Janssen; grant support, paid to University of Leipzig, from Bristol Myers Squibb, Merck, and Novartis; consulting fees from AbbVie, Bristol Myers Squibb, Curis, Geron, Janssen, and Novartis; honoraria from Bristol Myers Squibb and Novartis; and fees for serving on a steering committee and travel support from Bristol Myers Squibb. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Chronic kidney disease (CKD) is among the leading causes of morbidity and mortality as it affects more than 10% of the global adult population. Cognitive impairment has a positive correlation with the stage of CKD. It has been recorded in more than half of CKD patients undergoing kidney replacement therapy. The assessment of cognitive function in dialysis patients presents challenges due to various patient limitations. Such a common debilitating comorbidity of CKD has no approved treatment option, highlighting the importance of preventive measures and screening modalities. Erythropoietin therapy, exercise training, cognitive stimulation or behavioral therapies, alterations in dialysis frequency, dialysate cooling and kidney transplantation have been proposed as potential preventive and/or therapeutic options with variable efficiency at a clinical level. Regular screening, such as yearly, for cognitive impairment in maintenance dialysis patients is not only beneficial for timely and accurate diagnosis but also crucial for effective management and improved patient care. However, current practices face challenges, including the absence of validated tools specific for kidney failure and complications arising from patient conditions., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

We aimed to compare the clinical efficacy and safety of roxadustat with erythropoiesis-stimulating agents, particularly erythropoietin (EPO), in the treatment of maintenance hemodialysis patients with renal anemia. A prospective cohort study was carried out at the Nephrology Department of the Nantong First People's Hospital and Nantong University Affiliated Hospital from December 2020 to December 2021. We compared hemoglobin (Hb) levels, serum ferritin (SF) levels, and adverse cardiovascular events between the roxadustat and EPO groups at 1, 3, and 6 months into the treatment. A total of 209 patients participated in the study, with 112 in the roxadustat group and 97 in the EPO group. At baseline, no statistically significant differences were observed between the 2 groups in terms of age, gender, weight, dialysis modality and duration, previous EPO dosage, Hb levels, SF levels, transferrin saturation, heart function classification, and blood pressure levels (P > .05). After 1 month, Hb levels in the roxadustat group were significantly higher than those in the EPO group (P < .05). However, no statistically significant differences were found between the 2 groups at 3 and 6 months (P > .05). Additionally, there were no significant differences in SF levels and the occurrence of adverse cardiovascular events between the 2 groups after treatment (P > .05). Roxadustat was superior to EPO in the initial treatment phase, while its cardiovascular safety was comparable to that of EPO., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Chronic anemia is an independent risk factor for mortality in patients with heart failure (HF). Restoring physiological hemoglobin (Hb) levels is essential to increase oxygen transport capacity to tissues and improve cell metabolism as well as physical and cardiac performance. Nutritional deficits and iron deficiency are the major causes of chronic anemia, but other etiologies include chronic kidney disease, inflammatory processes, and unexplained anemia. Hormonal therapy, including erythropoietin (EPO) and anabolic treatment in chronic anemia HF patients, may contribute to improving Hb levels and clinical outcomes. Although preliminary studies showed a beneficial effect of EPO therapy on cardiac efficiency and in HF, more recent studies have not confirmed this positive impact of EPO, alluding to its side effect profile. Physical exercise significantly increases Hb levels and the response of anemia to treatment. In malnourished patients and chronic inflammatory processes, low levels of anabolic hormones, such as testosterone and insulin-like growth factor-1, contribute to the development of chronic anemia. This paper aims to review the effect of nutrition, EPO, anabolic hormones, standard HF treatments, and exercise as regulatory mechanisms of chronic anemia and their cardiovascular consequences in patients with HF., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: To evaluate the efficacy of topical erythropoietin for chemical burn induced scleral necrosis., Methods: This study included 18 eyes of 16 patients with chemical burn induced scleral necrosis who presented within 6 weeks of the injury. In the prospective arm, 11 eyes received topical erythropoietin, 3000 IU/mL every 6 h, along with standard medical treatment. Retrospectively, we included 7 consecutive eyes of 7 patients who were managed with conventional treatment as historical control group. The main outcome measure was healing of avascular scleral lesions. The secondary outcome measure was complete re-epithelization of cornea., Results: Mean patient age was 39.8 ± 16.2 years in the erythropoietin group, and they presented 16.6 ± 15.2 days after acute chemical injury. Scleral necrosis improved in all eyes after 30.7 ± 23.2 days of treatment with topical erythropoietin. Corneal epithelial defects were completely healed in 10 eyes 61.9 ± 50.7 days after the start of the medication. In comparison, standard medical treatment alone did not improve scleral necrosis in the historical control group, necessitating ocular surface reconstruction including conjunctival advancement (1 eye) and tenonplasty (6 eyes)., Conclusion: The results of our study showed that topical erythropoietin was effective in the management of chemical burn induced scleral necrosis. This treatment could avoid ocular surface reconstruction procedures in inflamed eyes., Competing Interests: Declaration of Competing Interest The authors do not have competing interests to declare., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Background and Objectives: Packed red blood cell transfusions (pRBCT) in preterm infants have been associated with significant morbidity. Although infants <26 weeks' gestational age typically require several pRBCT, preterm infants born between 26 and 34 weeks' gestational age may also require pRBCT during their hospitalization that are potentially preventable. We aimed to reduce pRBCT in this population by 20%., Methods: This quality improvement project was conducted in the Duke University Hospital NICU between July 2018 and February 2023. Interventions included the implementation of evidence-based transfusion thresholds, supporting bone marrow erythropoiesis, and reducing laboratory specimen volumes by increasing capillary test panels. The rates per 1000 patient days for pRBCT (outcome measure), number of new patients initiated on erythropoietin (process measure), number of basic metabolic panels (process measure), and total capillary panels (process measure) were monitored during the project period. Statistical process control charts were used to observe trends over time., Results: Among infants born between 26 0/7 and 34 6/7 weeks' gestational age, the rate of pRBCT decreased from an average of 23.8 to 12.7 transfusions per 1000 patient days, which is a 46.6% decrease. Increases in the use of erythropoietin and capillary panels were observed, along with a decrease in the use of basic metabolic panels. There was no change in mortality or the rate of necrotizing enterocolitis. Improvement was sustained for 24 months after implementation., Conclusions: pRBCT can be decreased in preterm infants born between 26 and 34 completed weeks' gestation through a combination of strategies utilizing quality improvement methodology., (Copyright © 2024 by the American Academy of Pediatrics.)

Purpose: Renal anemia is a common complication of chronic kidney disease. Currently, recombinant human erythropoietin and roxadustat are the main treatments. In China, diabetic kidney disease is the primary cause of chronic kidney disease. However, high-quality evidence on the efficacy of roxadustat in patients with non-dialysis-dependent chronic kidney disease and diabetes mellitus is scarce. This study aimed to assess the clinical effect of roxadustat in such patients., Methods: Patients with non-dialysis-dependent anemia and diabetes mellitus who received roxadustat or recombinant human erythropoietin for ≥ 4 weeks were enrolled. We compared baseline characteristics, including age, gender, hypertension, and hemoglobin level, and then employed a 1:3 ratio propensity score matching. The primary efficacy outcomes were changes in hemoglobin levels. After propensity score matching, 212 patients were analyzed, including the roxadustat (n = 53) and recombinant human erythropoietin (n = 159) groups. Baseline characteristics were comparable, including hemoglobin level, estimated glomerular filtration rate, and glycated hemoglobin A1c (p > 0.05)., Results: After 4, 12, and 24 weeks of treatment, the median hemoglobin levels in the roxadustat group were 97.5 g/L, 104 g/L, and 106.5 g/L, respectively, significantly surpassing the corresponding levels in the recombinant human erythropoietin group at 91 g/L, 94.5 g/L, and 94.5 g/L (p = 0.002, p = 0.025, p = 0.006, respectively). Additionally, subgroup analysis demonstrated better treatment efficacy of roxadustat patients with elevated high-sensitivity C-reactive protein and low albumin levels., Conclusion: In Chinese patients with anemia and diabetes not on dialysis, roxadustat efficiently and rapidly improved and maintained hemoglobin levels unaffected by elevated high-sensitivity C-reactive protein and low albumin levels., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The most popular treatment for end-stage renal illness is hemodialysis (HD). The study aimed to assess serum ferritin levels and their connection to Epoetin alfa resistance, along with exploring the link between hepatitis C virus, iron overload, and the prevalence of hepatitis C and B infections in chronic HD patients. This was a descriptive-analytical study conducted on 50 Patients with chronic kidney disease (CKD) who were on regular HD in the dialysis unit of Ibin Sina Teaching Hospital in Mosul City, Iraq. Out of 50 patients, 26 (52%) tested positive for Hepatitis C Virus (HCV) Antibody, 10 (20%) for Hepatitis B surface Antigen (HBsAg), and 14 (28%) tested negative for both. Higher serum iron and ferritin levels were found in HCV antibody-positive patients (p < 0.05). Despite Epoetin alfa treatment, patients with elevated ferritin levels exhibited lower Hemoglobin (HB) and Packed Cell Volume (p < 0.05). Non-diabetics exhibited significantly higher serum ferritin, Hemoglobin, Blood urea, and serum creatinine than diabetics (p < 0.05). A noteworthy association was seen between the quantity of blood transfusions and elevated levels of serum ferritin and total serum iron (p < 0.05). Most HD patients were anemic, with Hepatitis B and C prevalent. The main CKD causes were diabetes and hypertension. HCV-positive patients often showed mild to moderate iron overload, and high serum ferritin was linked to poor Epoetin alfa response. Dialysis can elevate blood urea, ferritin, and creatinine, worsening anemia. High ferritin levels may hinder response to Epoetin alfa and iron replacement. Excessive blood transfusions can lead to iron overload and inhibit erythropoiesis. Maintaining HB at 110-120 g/l improves quality of life and reduces anemia-related risks.

Introduction: If left untreated, burn injuries can deepen or progress in depth within the first 72 hours after injury as a result of increased wound inflammation, subsequently worsening healing outcomes. This can be especially detrimental to warfighters who are constrained to resource-limited environments with delayed evacuation times to higher roles of care and more effective treatment. Preventing this burn progression at the point of injury has the potential to improve healing outcomes but requires a field-deployable therapy and delivery system. Subcutaneous therapies known to treat inflammation delivered local to the wound site may prove to be one such avenue for success., Materials and Methods: Seven Yorkshire-cross swine received partial-thickness burn injuries using a previously established contact burn model. Each animal received one of the seven therapies: (1) saline, (2) heparin, (3) ibuprofen, (4) erythropoietin, (5) resolvin, (6) rapamycin, and (7) placental extract, all of which are either currently employed or are experimental in field use and indicated to treat inflammation. Treatments were delivered subcutaneously on the day of injury and 24 hours post-injury to simulate a prolonged field care scenario, before potential evacuation. Animals and wound development were observed for 28 days before euthanasia. Throughout the course of the study, wounds were observed macroscopically via non-invasive imaging. Histological analyses provided the critical metric of burn progression. Treatment success criteria were designated as the ability to prevent burn progression past 80% of the dermal depth in two of the three treated wounds, a clinically relevant metric of burn progression., Results: It was determined that the applied model successfully created reproducible partial-thickness burn injuries in this porcine study. No significant differences with regard to lateral wound size or the rate of lateral wound closure were observed in any treatments. Several treatments including resolvin, rapamycin, ibuprofen, and erythropoietin successfully reduced burn progression to less than 80% of the dermal depth in two of the three wounds, 24 hours after injury., Conclusions: This report employs an established model of porcine contact burn injury in order to test the ability of local subcutaneous delivery of therapeutics to prevent burn progression at the point of injury, via what is believed to be the inhibition of inflammation. Several treatments successfully prevented burn progression to a full-thickness injury, potentially improving wound healing outcomes in a simulated battlefield scenario. Subcutaneously administered therapies combating burn-induced inflammation at the point of injury may serve as a field-deployable treatment modality to improve warfighter recovery and return to duty., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Treatment with recombinant human erythropoietin (rHu-EPO) modestly prevented packed red blood cell transfusions (pRBCTs) in preterm infants in studies performed several years ago. In France, some neonatal units stopped using rHu-EPO, while others continued. The aim of this study was to explore the role of rHu-EPO in the prevention of pRBCTs in a recent cohort of preterm infants., Materials and Methods: Preterm infants who met rHu-EPO indications and were hospitalised between 2018 and 2020 in two neonatal units -one that did not use rHu-EPO and another that did- were eligible. Data about the neonatal history, rHu-EPO and iron treatments and pRBCT indications and volumes were collected. Infants exposed and not exposed to rHu-EPO were compared in univariate and multivariate analyses using backward logistic regression and Cox proportional hazards regression., Results: A total of 257 patients exposed to rHu-EPO and 285 patients who were not exposed were included. Three profiles emerged. In the infants with a gestational age <28 weeks, the cumulative pRBCT volume/kg was similar regardless of rHu-EPO exposure (mean difference -2.8 mL, 95% confidence interval -16.1, 10.5, p=0.68). In the infants born between 28 and 30 weeks, a late pRBCT was prevented in the rHu-EPO group (single pRBCT: no rHu-EPO 22.1% vs rHu-EPO 8%, p=0.003). However, rHu-EPO was not independently associated with avoidance of this pRBCT. Finally, the need for pRBCT was low in the infants born after 30 weeks of gestation, making rHu-EPO treatment futile. In contrast, early iron supplementation was revealed to be critical in preventing pRBCT., Discussion: No benefit of rHu-EPO in preventing pRBCT was observed in our cohort. The place of rHu-EPO in future requires careful consideration of the population concerned, adjustment of the therapeutic schedule and evolution of the indications for pRBCT.

β-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for β-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor β pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb th3/+ thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbb th3/+ mice with or without hematopoietic Tfr2 (Tfr2 BMKO /Hbb th3/+ ) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbb th3/+ and Tfr2 BMKO /Hbb th3/+ animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

We report a case series of two patients with chronic kidney disease (CKD) who developed erythropoietin-induced pure red cell aplasia following a change in erythropoietin preparation. Both patients responded well to immunosuppressive treatments, but unfortunately developed severe infections as a result of being immunosuppressed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hemodialysis patients are common to have renal anemia in the nephrology practice. For the renal anemia, the high-dose iron from the intravenous route is an important treatment option. We can understand the treatment effects and cardiovascular events of high-dose intravenous iron reviewing the randomized clinical trials., Methods: We compared the high-dose and low-dose iron treatments to find if the high-dose intravenous iron can influence the hematological parameters more significantly than the low-dose iron. The cardiovascular events were also analyzed for the high-dose iron treatment. Six studies with a total of 2422 renal anemia patients under hemodialysis were enrolled. We focused the outcomes of hemoglobin, transferrin saturation percentage, ferritin, erythropoietin dose, and cardiovascular events., Results: The high-dose intravenous iron might be associated with a greater number of ferritin, transferrin saturation percentage, and hemoglobin. In addition, the erythropoietin dose was less needed to maintain the ideal hemoglobin range in the high-dose intravenous iron group., Conclusions: In current meta-analysis, the high-dose intravenous iron might show the superior effects on the ferritin, transferrin saturation percentage, and hemoglobin levels and needed dose of erythropoietin when compared to low-dose iron treatment., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: To date, there is limited evidence on patients utilizing both voxelotor and darbepoetin alfa and its impact on hemoglobin levels. The objective is to evaluate the effect of voxelotor and darbepoetin alfa on hemoglobin levels in patients with SCD., Research Design and Methods: This was a retrospective chart review study that assessed the primary independent variable as the utilization of either voxelotor alone, darbepoetin alfa alone, or the concurrent administration of voxelotor and darbepoetin alfa. Descriptive statistics were utilized to obtain the mean standard deviation for numerical variables and proportions for categorical variables., Results: A total of 23 participants were included in this study. When comparing baseline to 2 months and 3 months, participants on voxelotor alone experienced a 3% decrease and a 6.6% increase in hemoglobin, darbepoetin alfa alone group a 4.3% decrease and a 0.6% increase in hemoglobin and voxelotor and darbepoetin group a 4.4% decrease and a 0.5% decrease in hemoglobin levels. Fifty percent of the participants in the voxelotor group and 6 (66.7%) participants in the voxelotor plus darbepoetin alfa group experienced adverse drug events., Conclusions: Voxelotor resulted in a clinically significant difference in the percent change of hemoglobin from baseline to 3 months.

Background: Erythropoietin has an angiogenic effect on the retina and might increase the risk of retinopathy of prematurity (ROP)., Methods: This retrospective cohort study included infants born at 22 to 27 weeks' gestation between 2008 and 2018 who were admitted to neonatal intensive care units (NICUs). We compared mortality and morbidities between infants who received erythropoietin and those who did not., Results: Among 18,955 livebirth infants, this study included 16,031 infants, among which 14,373 infants received erythropoietin. The risk of ROP requiring treatment was significantly higher in the erythropoietin group than in the control group (33% vs. 26%; aOR 1.50 [95% CI 1.28-1.76]). On the other hand, the erythropoietin group had lower risks of death and necrotizing enterocolitis., Conclusions: This study with a large sample size found that erythropoietin use was associated with increased risk of ROP requiring treatment, while being associated with reductions in deaths and NEC., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: The breakthrough in erythropoietin-stimulating agents in the 1990s improved the prognosis and treatment of complications in chronic kidney disease patients and renal anemia. Discovery of the novel molecular mechanisms for hypoxia-inducible factor (HIF) transcription factor under hypoxic conditions has led to the development of oral drugs, HIF-Prolyl Hydroxylase inhibitors (HIF-PHIs), that constantly activate erythropoietin by inhibiting prolyl hydroxylase. HIF-PHIs have gained rapid approval in Asian countries, including Japan, with six distinct types entering clinical application., Areas Covered: This article provides a comprehensive review of the latest literature, with a particular focus on the effectiveness and safety of vadadustat., Expert Opinion: A phase 3, randomized, open-label, clinical trial (PRO 2 TECT) demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa in non-dialysis-dependent patients not previously treated with ESA. However, vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients. It may partly because of imbalances of the baseline eGFR level in those countries. In dialysis-dependent patients, a phase 3 clinical trial (INNO 2 VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels. Adverse events including cancer, retinopathy, thrombosis, and vascular calcification should be evaluated in future clinical studies.

Objective: To describe the population to which we administered recombinant erythropoietin and to determine the effectiveness of this treatment as quantified by the change in hematocrit., Study Design: This retrospective chart review study included infants who received erythropoietin for the treatment of anemia of prematurity., Results: There were 132 infants representing 162 unique treatment courses included in the study. The average duration of therapy was 9 days (±7) and 6 doses (±2). The average change in hematocrit (Hct) was 6.2% (SD 3.9%, p < 0.001). Rise in Hct was associated with a higher number of rEPO doses (p < 0.001) and higher postmenstrual age (p < 0.001). In our small cohort we did not find an association between the number of rEPO doses and retinopathy of prematurity (ROP) requiring treatment., Conclusion: Erythropoietin is safe and effective at treating anemia of prematurity as evidenced by a clinically and statistically significant increase in Hct from baseline., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: Erythropoietin (EPO) exerts tissue-protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis., Methods: Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)-β1 and α1(I) collagen; and the protein levels of Kelch-like ECH-associated protein 1 (Keap1) and nuclear NF-E2-related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO., Results: Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF-β1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86-positive cells (M1 macrophages), while significantly increased the number of CD206-positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value., Conclusions: These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages., (© 2024 The Japanese Urological Association.)

Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment., Competing Interests: Declaration of Competing Interest All authors have no potential conflicts of interest to be disclosed or relevant financial interest in this manuscript. Declaration of interest None No competing interest, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aims: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness., Methods: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks., Results: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group., Conclusion: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.