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Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels., 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 Ltd. All rights reserved.)

Background: Erythropoietin resistance is present in some patients with chronic kidney disease, especially in those undergoing hemodialysis, and is often treated using roxadustat rather than iron supplements and erythropoiesis-stimulating agents (ESAs). However, some patients cannot afford full doses of roxadustat. This retrospective study investigated the efficacy of low-dose roxadustat combined with recombinant human erythropoietin (rhuEPO) therapy in 39 patients with erythropoietin-resistant renal anemia undergoing maintenance hemodialysis (3-4 sessions/week)., Methods: The ability of the combination of low-dose roxadustat and rhuEPO to increase the hemoglobin concentration over 12 weeks was assessed. Markers of iron metabolism were evaluated. Eligible adults received 50-60% of the recommended dose of roxadustat and higher doses of rhuEPO., Results: The mean hemoglobin level increased from 77.67 ± 11.18 g/dL to 92.0 ± 8.35 g/dL after treatment, and the hemoglobin response rate increased to 72%. The mean hematocrit level significantly increased from 24.26 ± 3.99% to 30.04 ± 3.69%. The soluble transferrin receptor level increased (27.29 ± 13.60 mg/L to 38.09 ± 12.78 mg/L), while the total iron binding capacity (49.22 ± 11.29 mg/L to 43.91 ± 12.88 mg/L) and ferritin level (171.05 ± 54.75 ng/mL to 140.83 ± 42.03 ng/mL) decreased., Conclusion: Therefore, in patients with ESA-resistant anemia who are undergoing hemodialysis, the combination of low-dose roxadustat and rhuEPO effectively improves renal anemia and iron metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Huang, Liu, Wang, Liu, Song, Dou, Lv and Liu.)

Ethnopharmacological Relevance: Jian-Pi-Yi-Shen (JPYS) formula is an effective herbal therapy against renal injury, and JPYS has been clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. JPYS possessed anti-fibrosis effects in experimental CKD. Nevertheless, research on the mechanisms of JPYS in ameliorating renal anemia (RA) through suppressing renal fibrosis remains to be clarified., Aim of the Study: Our study here was carried out to investigate the mechanisms of JPYS in protecting against RA., Materials and Methods: An adenine-induced anemia model in rats with CKD at three different time points was established, and bio-samples taken from each group were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters. Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to evaluate the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating RA. Finally, the expression levels of key targets were analyzed and validated by using Western blot and enzyme-linked immunosorbent assay (ELISA)., Results: JPYS treatment improved kidney function, suppressed renal fibrosis and enhanced hematological parameters in CKD rats. Moreover, JPYS treatment restored the increased expression levels of fibrotic markers and the declined EPO with time dependence. In parallel, data indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus in the renal interstitium and thus promoted the expression of EPO. Transcriptomic profiling disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-β (TGF-β)/Smad pathways were closely associated with RA. Ultimately, experimental validation results presented that the increased expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment., Conclusion: Our findings suggest that JPYS may improve RA by alleviating renal fibrosis, and the mechanisms of which involve in inhibiting the NF-κB and TGF-β/Smad pathways., 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.)

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.

Objective: Anemia is a common condition in end-stage renal disease (ESRD) patients. Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in these patients. However, concerns have been raised regarding their potential effects on blood pressure. This systematic review and meta-analysis aim to investigate the relationship between ESAs and changes in systolic and diastolic blood pressure in hemodialysis patients., Method: This study is a systematic review and meta-analysis based on clinical trial studies published in various databases, including Web of Science, Cochrane Library, Science Direct, PubMed, Embase, Scopus, and Google Scholar, between 1980 and the end of 2022. We evaluated the quality of articles using the Jadad scale checklist and analyzed the data using Stata 15 software., Results: Our meta-analysis included 34 clinical trial studies. The results showed a significant increase in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) after the consumption of ESAs compared to before consumption. The mean difference in SBP was 4.84mmHg (95% CI: 2.74-6.94; p-value<0.001) and in DBP was 4.69mmHg (95% CI: 2.67-6.71; p-value<0.001). No publication bias was observed. Our meta-regression analysis showed that sample size, quality assessment score, and geographical location of the study were significant factors related to observed heterogenicity in to mean difference of SBP (p-value≤0.20). For DBP, the sample size, quality assessment score and follow-up duration were significant variables (p-value≤0.20)., Conclusion: Based on the findings of our study, it appears that receiving ESAs is associated with a significant increase in both SBP and DBP in hemodialysis patients, with an increase of about 5mmHg., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) is highly prevalent in haemodialysis (HD) patients and is associated with an increased risk of death. Roxadustat and recombinant human erythropoietin (rHuEPO, abbreviated as EPO) are the main treatment strategies for renal anaemia in HD patients, but it has not been clear whether there is a difference in their effect on LVH., Methods: In this multi-centre, prospective, randomized trial of 12-month duration, study participants were randomized in a 1:1 ratio to the roxadustat group or the EPO group. The doses of both treatment regimens were adjusted so that the patients had a haemoglobin level of 10.0-12.0 g per dL. The primary study endpoint was the change from baseline to 12 months in the left ventricular mass index (LVMI, g/m 2 ) measured by echocardiography., Results: In total, 114 patients were enrolled. The mean age was 50 years, and the median dialysis duration was 33 months. Sixty-one patients were men, and 24 were diabetic. LVMI decreased from 116.18 ± 27.84 to 110.70 ± 25.74 g/m 2 in the roxadustat group. However, it increased from 109.35 ± 23.41 to 114.99 ± 28.46 g/m 2 in the EPO group, with a significant difference in the change in LVMI between the two groups [-5.48 (-11.60 to 0.65) vs. 5.65 (0.74 to 10.55), p < 0.05]. Changes in left ventricular mass, end-diastolic volume and 6-min walk test seemed superior in the roxadustat group. There were no significant differences in other cardiac geometry, biochemical parameters and major adverse cardiovascular events between the two groups., Conclusions: Compared to EPO, roxadustat is more helpful in the regression of LVH in HD patients., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Anaemia is one of the most common complications of chronic kidney disease (CKD), having a significant impact on quality of life, and is also associated with a number of adverse clinical outcomes. Its pathogenesis is multifactorial, caused largely by an inadequate production of erythropoietin from the diseased kidneys, with iron deficiency, inflammation, shortened red cell lifespan and enhanced blood loss also being contributory factors. The management of this condition was transformed in the late 1980s by the advent of recombinant human erythropoietin (epoetin), and treatment paradigms have developed over the last three decades, largely focusing on a combination of epoetin or its analogues (erythropoiesis-stimulating agents; ESAs) along with iron supplementation, often administered intravenously due to increased hepcidin levels limiting iron absorption from the gut. Indeed, in patients with early CKD and iron deficiency, iron per se may be sufficient to improve the anaemia, delaying the need for ESA therapy. Other causes of anaemia should be excluded and corrected (if possible) before resorting to treatment with ESAs and iron. More recently, the hypoxia-inducible factor-prolyl hydroxylase inhibitors have entered the therapeutic arena; these are orally active agents that upregulate endogenous erythropoietin production as well as a number of iron-regulatory genes which may also enhance erythropoiesis. The latter drugs are highly efficacious, and may have advantages in inflammatory conditions causing resistance to conventional ESA therapy, but concerns exist regarding their safety, particularly in the longer term. This article reviews the current standards of treatment, as well as recent novel developments in the management of anaemia in CKD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: The aim of this study was to assess the efficacy and safety of a third-generation lentivirus-based vector encoding the feline erythropoietin (EPO) (feEPO) gene in vitro and in rodent models in vivo. This vector incorporates a genetic mechanism to facilitate the termination of the therapeutic effect in the event of supraphysiologic polycythemia, the herpes simplex virus thymidine kinase (HSV-TK) "suicide gene.", Animals: CFRK cells and replication-defective lentiviral vectors encoding feEPO were used for in vitro experiments. Eight Fischer rats were enrolled in the pilot in vivo study, 24 EPO-deficient mice were used in the initial mouse study, and 15 EPO-deficient mice were enrolled in the final mouse study., Methods: Efficacy of a third-generation lentivirus encoding feEPO was determined in vitro using western blot assays. Subsequently, in a series of rodent experiments, animals were administered the viral vector in progressively increasing inoculation doses with serial measurements of blood packed cell volume (PCV) over time., Results: We documented production of feEPO protein in transduced CRFK cells with subsequent cessation of production when treated with the HSV-TK substrate ganciclovir. In vivo, we demonstrated variably persistent elevated PCV values in treated rats and mice with eventual return to baseline values over time., Clinical Relevance: These results provide justification for a lentiviral gene therapy approach to the treatment of nonregenerative anemia associated with chronic renal disease in cats.

Chronic anemia is more prevalent in people living with HIV (PLWH) compared to the general population. The mechanisms that drive chronic anemia in HIV are multifaceted and include functional impairment of hematopoietic stem cells, dysregulation of erythropoietin production, and persistent immune activation. Chronic inflammation from HIV infection adversely affects erythropoiesis, erythrocyte lifespan, and erythropoietin response, leading to a heightened risk of co-infections such as tuberculosis, persistent severe anemia, and increased mortality. Additionally, chronic anemia exacerbates the progression of HIV-associated nephrotoxicity and contributes to cardiovascular risk through immune activation and inflammation. This review highlights the cardinal role of chronic inflammation as a link connecting persistent anemia and cardiovascular complications in PLWH, emphasizing the need for a universal understanding of these interconnected pathways for targeted interventions.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was early appearent that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Introduction: Anemia of chronic kidney disease (CKD) has a high incidence and is associated with many disease conditions. Iron dysmetabolism is an important contributor to anemia in CKD patients., Methods: ALTAI, a randomized, active-controlled, phase 4 trial, investigated the efficacy of roxadustat versus recombinant human erythropoietin (rHuEPO) on gastrointestinal iron absorption in patients with anemia of CKD (stage 4/5). The primary endpoint was change from baseline to day 15 in gastrointestinal iron absorption (serum iron area under the concentration-time curve; AUC 0-3h ) following single-dose oral iron., Results: Twenty-five patients with a mean age of 55.1 years were randomized 1:1 to roxadustat (n = 13) or rHuEPO (n = 12). Baseline iron profiles were similar between treatment groups. Change from baseline to day 15 in serum iron AUC 0-3h was not statistically significantly different between the roxadustat and rHuEPO groups. Mean (SD) change from baseline in serum iron AUC 0-3h was 11.3 (28.2) g × 3 h/dl in the roxadustat group and - 0.3 (9.7) g × 3 h/dl in the rHuEPO group. Roxadustat treatment was associated with decreased hepcidin and also increased transferrin, soluble transferrin receptor, and total iron-binding capacity (TIBC), with nominal significance. The proportion of patients experiencing one or more adverse events was 38.5% when treated with roxadustat and 16.7% with rHuEPO., Conclusions: The study showed no significant difference between roxadustat and rHuEPO in iron absorption but was underpowered because of recruitment challenges., Trial Registration: ClinicalTrials.gov Identifier NCT04655027., (© 2024. The Author(s).)

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Recombinant human erythropoietin (rHuEPO) is a prevalent treatment for anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) has the potential to promote the growth of early progenitor cells and correct the depletion. In this study, we investigate the efficacy and the underlying mechanism of the combination therapy of TPO and EPO to EPO resistance. First, the in vivo studies suggested that intensive EPO treatment induced progenitor cell depletion in the bone marrow, where the depletion was corrected by TPO. Then, colony assays showed that EPO and TPO synergistically enhanced the burst-forming unit-erythroid (BFU-E) production but antagonistically boosted the colony-forming units of megakaryocytes (CFU-MK) production. Also, we found TPO promoted hematopoietic stem and progenitor cells (HSPCs) production, while EPO drove HSPCs toward the erythroid lineage. Additionally, EPO induced more megakaryocytic-erythroid progenitors (MEPs) toward the erythroid output. Model-based simulations indicate the efficacy of this combination therapy for treating EPO-resistant anemia in rats. In conclusion, our study demonstrated the efficacy of combination therapy in addressing EPO-resistant anemia by correcting EPO-induced erythroid progenitor depletion., 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 © 2023 Elsevier Inc. All rights reserved.)

Jehovah's Witnesses is a Christian denomination widely recognized for their steadfast refusal of blood transfusions, even when facing severe anemia. We describe a unique case of a 42-year-old Jehovah's Witness woman with severe iron deficiency anemia. She necessitated surgical correction of a malpositioned gastric band within the context of a complex necrotizing aspiration pneumonia secondary to esophageal obstruction. Medical management of this severe anemia has been a challenge as traditional approaches, like a blood transfusion, are not possible. Instead, a multifaceted approach has been described with intravenous iron infusions, recombinant human erythropoietin, vitamin B 12 , folate, and vitamin C administration. We emphasize the lack of consensus on guideline protocols regarding management of severe anemia for Jehovah's Witness patients and the subsequent need for more investigation into that matter. It also underscores the significance of respecting patient autonomy through close collaboration between patients and their health care providers to ensure effective patient-centered care., 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: Inhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) stimulates erythropoiesis in rats, dogs, monkeys, and humans., Hypothesis/objective: Determine if molidustat, a novel HIF-PH inhibitor, stimulates erythropoiesis in healthy cats., Animals: Seventeen healthy adult laboratory cats., Methods: Randomized, placebo-controlled study. Cats were treated PO once daily with suspensions of 0 (Group 1; n = 6), 5 (Group 2; n = 6), or 10 (Group 3; n = 5) mg/kg of molidustat. Effects on red blood cell parameters, reticulocyte indices and plasma erythropoietin (EPO) concentrations were evaluated. Molidustat treatment was stopped when hematocrit (HCT) exceeded 60%., Results: Compared to placebo, a significant increase in mean HCT was evident starting on Day 14 (Group 2:54.4% vs 40.3%, P < .001, 95% confidence interval [CI] for the difference [8.95-19.28]; Group 3:61.2% vs 40.3%, P < .001, 95% CI [15.48-26.43]) and remained significantly higher for the entire treatment period. In molidustat-treated groups, HCT exceeded 60% on Day 21 (Group 2) and Day 14 (Group 3). Mean HCT in molidustat-treated cats returned to within the reference range (29%-45%) after Day 56 and was numerically comparable to placebo from Day 70 onwards. Red blood cell count and hemoglobin concentrations followed a similar pattern as HCT. Mean EPO concentrations significantly increased after molidustat administration on all assessment days. Molidustat treatments were well tolerated., Conclusions and Clinical Importance: Marked erythropoietic effects were identified after daily administration of molidustat to healthy cats and additional studies are warranted to evaluate the effects in anemic cats., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

Background: Erythropoietic effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, were previously demonstrated in healthy cats., Objective: To evaluate the safety and erythropoietic effects of daily PO administration of molidustat in anemic cats with chronic kidney disease (CKD)., Animals: Twenty-one client-owned CKD cats (4-17 years old) with anemia., Methods: Multicenter field study; randomized, masked, and placebo-controlled. Cats were treated PO once daily for 28 days with suspensions of control product (CP; n = 6) or 5 mg/kg of molidustat (n = 15). Hematocrit (HCT) was evaluated at weekly intervals. Individual cat treatment success was defined as a ≥4% point increase in HCT compared to baseline., Results: Control group mean HCT remained low throughout the study (20.1%-23.4%). Mean HCT of molidustat-treated cats increased weekly, and a significant increase compared to baseline (23.6%) was first observed on Day 21 (27.3%; P < .001; 95% confidence interval [CI], 1.69-5.67). Compared to CP group, mean HCT was significantly higher on Day 21 (27.3% vs 20.1%; P < .001; 95% CI, 2.91-10.75) but not significantly higher on Day 28 (27.8% vs 23.4%; P = .06; 95% CI, -0.23 to 9.88). The number of individual treatment successes on Day 28 was higher among remaining molidustat-treated cats (7/14) compared to remaining control cats (1/5), but there was no significant difference between groups., Conclusions and Clinical Importance: Daily PO molidustat administration may stimulate a clinically relevant erythropoietic response in anemic cats with CKD. This HIF-PH inhibitor may be an alternative for managing anemia in cats compared to recombinant EPO treatment., (© 2023 Elanco Animal Health. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Introduction: Hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is important problem in dialysis patients. While proton pump inhibitors (PPIs) may inhibit iron absorption, few studies have examined associations between PPIs and ESA-resistant anemia in hemodialysis patients. This study examined the associations between PPIs and ESA-resistant anemia in hemodialysis patients., Methods: The present study was a cross-sectional study using repeated 4-month observations, up to eight observations/patient, from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). The primary outcome was erythropoietin resistance index (ERI). ESA dose, hemoglobin, proportion of erythropoietin-resistant anemia, transferrin saturation (TSAT), and ferritin were also examined. Linear or risk-difference regression models were used with generalized estimating equations to account for repeated measurements., Results: Of 1,644 patients, 867 patients had PPI prescriptions (52.7%). Patients prescribed PPI had higher ERI, higher ESA dose, and lower TSAT levels. Multivariable analysis for 12,048 four-month observations showed significantly greater ERI in PPI users (adjusted difference 0.95 IU/week/kg/[g/dL] [95% CI: 0.40-1.50]). Significant differences were also found in ESA dose (336 IU/week [95% CI: 70-602]) and the prevalence of erythropoietin-resistant anemia (3.9% [2.0-5.8%]) even after adjusted for TSAT and ferritin. Among possible mediators between the association of PPIs and anemia, TSAT was significantly different between PPI users and non-users (adjusted difference, -0.82% [95% CI: -1.56 to -0.07])., Conclusions: This study showed the associations between PPI and ERI, ESA dose, and TSAT in hemodialysis patients; physicians should consider anemia's associations with PPIs in hemodialysis patients., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Hemolytic disease of the fetus and newborn (HDFN) affects 3/100,000 to 80/100,000 patients yearly and can cause severe anemia and hyperbilirubinemia. Recombinant human erythropoietin has been used as an adjunct therapy in patients with HDFN and hypo-regenerative anemia in the setting of receiving intrauterine blood transfusions. This case describes a patient with HDFN, in which the family were Jehovah Witnesses, and blood transfusions were declined. The patient had symptomatic anemia with a hematocrit nadir of 18.6%. The patient was successfully treated with recombinant human erythropoietin, ferrous sulfate, and folic acid, avoiding the need for transfusion., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6-0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: This cohort study was designed to explore whether roxadustat or erythropoietin could affect thyroid function in patients with renal anemia., Methods: The study involved 110 patients with renal anemia. Thyroid profile and baseline investigations were carried out for each patient. The patients were divided into two groups: 60 patients taking erythropoietin served as the control group (rHuEPO group) and 50 patients using roxadustat served as the experimental group (roxadustat group)., Results: The results indicated that there were no significant differences in serum total thyroxine (TT4), total triiodothyronine (TT3), free triiodothyronine (FT3), free thyroxine (FT4) or thyroid stimulating hormone (TSH) between the two groups at baseline. After treatment, TSH, FT3, and FT4 were significantly lower in the roxadustat group than in the rHuEPO group ( p  < 0.05). After adjusting for age, sex, dialysis modality, thyroid nodules and causes of kidney disease, Cox regression showed that roxadustat was an independent influencing factor on thyroid dysfunction (HR 3.37; 95% CI 1.94-5.87; p  < 0.001). After 12 months of follow-up, the incidence of thyroid dysfunction was higher in the roxadustat group than in the rHuEPO group (log-rank p  < 0.001)., Conclusion: Roxadustat may lead to a higher risk of thyroid dysfunction, including low TSH, FT3 and FT4, than rHuEPO in patients with renal anemia.

Erythropoiesis-stimulating agents (ESAs) have markedly reduced the need for blood transfusion for renal anemia and are included in standard therapies for patients with chronic kidney disease (CKD). Various protective effects of ESAs on the cardiovascular system have been discovered through basic research, and the effects have received much attention because the rates of cardiovascular events and mortality are high in CKD patients. However, randomized clinical trials did not provide strong evidence that ESAs exert cardioprotection in humans, including CKD patients. It is difficult to assess the cardioprotective effects of ESAs in CKD patients through the clinical data that has been reported to date because the relationship between hemoglobin level rather than ESA dose and cardiovascular event rates was examined in most studies. Interestingly, recent studies using a rat model of CKD showed that the infarct size-limiting effect of an ESA was lost when its dose was increased to a level that normalized blood hemoglobin levels, suggesting that the optimal dose of an ESA for myocardial protection is less than the dose required to normalize hemoglobin levels. Furthermore, animal models of traditional coronary risk factors or comorbidities were resistant to the cardioprotective effects of ESAs because of interruptions in signal-mediated mechanisms downstream of erythropoietin receptors. In this review, we briefly discuss basic and clinical data on the impact of anemia on coronary and systemic circulation, the effects of CKD on the cardiovascular system, and the multiple pharmacological actions of ESAs to examine whether the ESAs that are prescribed for renal anemia exert any cardioprotection in patients with CKD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The link between chronic renal failure and anemia has been known for more than 180 years, negatively impacting the quality of life, cardiovascular risk, mortality, and morbidity of patients with chronic kidney disease (CKD). Traditionally, the management of anemia in CKD has been based on the use of replacement martial therapy, vitamin therapy, and the use of erythropoiesis-stimulating agents (ESAs). In recent years, alongside these consolidated therapies, new molecules known as hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF-PHIs) have appeared. The mechanism of action is expressed through an increased transcriptional activity of the HIF gene with increased erythropoietin production. The drugs currently produced are roxadustat, daprodustat, vadadustat, molidustat, desidustat, and enarodustat; among these only roxadustat is currently approved and usable in Italy. The possibility of oral intake, pleiotropic activity on martial and lipidic metabolism, and the non-inferiority compared to erythropoietins make these drugs a valid alternative to the treatment of anemia associated with chronic kidney disease in the nephrologist practice., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

We aimed to estimate the prevalence of anemia in children with nephrotic syndrome (NS), determine its etiology, and correlate severity with disease duration and response to steroids. This was a prospective cohort study carried from 15 th July 2019-14 th July 2021 at the pediatric nephrology clinic, of a teaching hospital in India. We screened children aged 3 months-18 years with NS for eligibility. We excluded those suffering from chronic kidney disease and, on haematinics. All children underwent investigations for evaluation of nephrotic syndrome and anemia. To define the clinical phenotype of nephrotic syndrome, the patients were classified as infrequent relapsers, frequent relapsers, steroid dependent and steroid resistant NS as per ISPN guidelines. Children were followed up at least for a period of one year to define their response to steroids. A total of 125 children were finally analysed for all treatment outcomes. Of 125, 37 (30%) children presented with the first episode of NS. Remaining 88 were follow up cases of NS. Of 125 children, 41 (33%) were found to be anemic as per the WHO criteria. Iron deficiency anemia was found in 21 (51%) children. Steroid resistance was twice more prevalent in the anemic group compared to the non-anemic group, 7.3% vs 4.8% respectively, however this difference was not statistically significant, p = 0.65. Anemic group had a trend of higher no. of children receiving antihypertensives compared to non-anemics (38 (93%) vs. 67 (80%), p = 0.07., Conclusion: Iron deficiency anemia was the commonest cause of anemia and, anemia and need for anti-hypertensives to attain BP control and adequate proteinuria often coexisted in children suffering from nephrotic syndrome., What Is Known: • Anemia is a significant complication in children suffering from nephrotic syndrome. • Cause of anemia in nephrotic syndrome is multifactorial., What Is New: • Iron deficiency anemia was the most common cause of anemia in Indian children with nephrotic syndrome. • Anemia and need for anti-hypertensives to attain adequate BP control and proteinuria often coexisted in children with nephrotic syndrome., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Anemia is a common condition, but its causes are often unclear, especially in elderly adults. Erythropoietin (EPO) levels are known to be elevated in myelodysplastic syndrome and hematologic malignancies, but decreased in chronic benign anemia. This study aimed to investigate whether EPO levels could be used to identify underlying bone marrow diseases including malignancies, among elderly anemic patients with unclear etiology. This single centered retrospective study included patients presented with isolated anemia and had their EPO levels measured at their first visit. Patients were divided into two groups: bone marrow disease and benign etiologic anemia, based on observation and bone marrow test results. Out of 1180 patients reviewed, 81 patients with anemia of unclear etiology were identified, including 67 with benign anemia and 14 with bone marrow disease. Statistically significant difference in EPO levels between these two groups (P < 0.001) were observed. The receiver operating characteristic curve analysis showed that an EPO cut-off value of 36.4 mU/mL had a sensitivity and specificity of 92.8% and 94.0% for detecting underlying bone marrow disease, respectively. We suggest measuring serum EPO levels can aid in the early detection of benign anemia from bone marrow disease, including malignancies, with high sensitivity and specificity., (© 2023. The Author(s).)

Hypoxia-inducible factor (HIFs) is a new class of drug developed for the management of anemia in chronic kidney disease (CKD) patients. HIFs increase the production of erythropoietin in the kidney and liver, enhance the absorption and utilization of iron, and stimulate the maturation and proliferation of erythroid progenitor cells. Besides, HIFs regulate many physiologic processes by orchestrating the transcription of hundreds of genes. Essential hypertension (HT) is an epidemic worldwide. HIFs play a role in many biological processes involved in the regulation of blood pressure (BP). In the current review, we summarize pre-clinical and clinical studies investigating the relationship between HIFs and BP regulation in patients with CKD, conflicting issues, and discuss future potential strategies., (© 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Aim: This study aims to determine if metabolic-dysfunction-associated fatty liver disease (MAFLD) or advanced liver fibrosis is associated with erythropoietin stimulating agent (ESA) hypo-responsiveness in hemodialysis patients., Methods: In a cross-sectional study of 379 hemodialysis patients, FibroTouch transient elastography was performed on all patients. Erythropoeitin resistance index (ERI) was used to measure the responsiveness to ESA. Patients in the highest tertile of ERI were considered as having ESA hypo-responsiveness., Results: The percentage of patients with ESA hypo-responsiveness who had MAFLD was lower than patients without ESA hypo-responsiveness. FIB-4 index was significantly higher in ESA hypo-responsive patients. In multivariate analysis, female gender (aOR = 3.4, 95% CI = 1.9-6.2, p < 0.001), dialysis duration ≥50 months (aOR = 1.8, 95% CI = 1.1-2.9, p < 0.05), elevated waist circumference (aOR = 0.4, 95% CI = 0.2-0.8, p = 0.005), low platelet (aOR = 2.6, 95% CI 1.3-5.1, p < 0.01), elevated total cholesterol (aOR = 0.5, 95% CI 0.3-0.9, p < 0.05) and low serum iron (aOR = 3.8, 95% CI = 2.3-6.5, p < 0.001) were found to be independent factors associated with ESA hypo-responsiveness. Neither MAFLD nor advanced liver fibrosis was independently associated with ESA hypo-responsiveness. However, every 1 kPA increase in LSM increased the chance of ESA-hyporesponsiveness by 13% (aOR = 1.1, 95% CI =  1.0-1.2, p = 0.002) when UAP and LSM were used instead of presence of MAFLD and advanced liver fibrosis, respectively., Conclusion: MAFLD and advanced liver fibrosis were not independently associated with ESA hypo-responsiveness. Nevertheless, higher FIB-4 score in ESA hypo-responsive group and significant association between LSM and ESA hypo-responsiveness suggest that liver fibrosis may be a potential clinical marker of ESA hypo-responsiveness., (© 2023 Asian Pacific Society of Nephrology.)

Introduction: Prenatal alcohol exposure (PAE) impairs offspring growth and cognition, and this is worsened by concurrent iron deficiency. Alcohol disrupts fetal iron metabolism and produces functional iron deficiency, even when maternal iron status is adequate. We used a mouse model of moderate PAE to investigate the mechanisms underlying this dysregulated iron status., Methods: C57BL/6J female mice received 3 g/kg alcohol daily from embryonic day (E) 8.5-17.5 and were assessed at E17.5., Results: Alcohol reduced fetal hemoglobin, hematocrit, and red blood cell counts, despite elevated erythropoietin production. Alcohol suppressed maternal hepcidin expression and the upstream iron-sensing BMP/SMAD pathway, consistent with its effects in the nonpregnant state. In contrast, alcohol elevated fetal hepcidin, although this was not accompanied by an upregulation of the BMP/SMAD or proinflammatory IL-6/STAT3 pathways. Fetal expression of hepatic genes contributing to hemoglobin synthesis and iron metabolism were unaffected by alcohol, whereas those affecting ribosome biogenesis were suppressed, suggesting a novel candidate effector for this fetal anemia., Conclusion: These data confirm and extend prior observations that PAE disrupts maternal and fetal iron metabolism and impairs the fetus's ability to regulate iron status. We propose this dysregulation increases gestational iron needs and represents a conserved response to PAE., Impact: Prenatal alcohol exposure causes a functional iron deficiency in a model that also impairs cognition in later life. Prenatal alcohol exposure causes fetal anemia. This fetal anemia is accompanied by elevated hepcidin and erythropoietin. Findings are consistent with prior observations that prenatal alcohol exposure increases maternal-fetal iron requirements during pregnancy., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Anaemia is common and associated with poor outcomes during and after critical illness. The use of erythropoietin to treat such anaemia is controversial with older studies showing mixed results. In this study, we aimed to evaluate the feasibility of performing a large multicentre randomised controlled trial of erythropoietin in this setting. We randomly allocated patients staying in the ICU for ≥ 72 h with haemoglobin ≤ 120 g.l -1 to either a weekly injection of erythropoietin (40,000 iu, maximum of five injections) or placebo (saline). The primary endpoint was feasibility (as measured by recruitment, randomisation and follow-up rates, and protocol compliance). Secondary endpoints included biological efficacy and clinical outcomes. Forty-two participants were recruited and randomly allocated, all participants received the allocated intervention, but one withdrew their consent and refused the use of their data, leaving 20 in the erythropoietin group and 21 in placebo group. Follow-up was completed for all patients who survived. The overall recruitment rate was 73.7% with 8.4 participants recruited on average per month. The last haemoglobin measured before hospital discharge (or death) was similar between the groups with a mean (SD) haemoglobin of 107 (21) vs. 95 (25) g.l -1 , mean difference (95%CI) 11 (-4-26), g.l -1 , p = 0.154. A large, multicentre randomised controlled trial of erythropoietin to treat anaemia in ICU patients is feasible and necessary to determine effects of erythropoietin on mortality in ICU anaemic patients., (© 2023 Association of Anaesthetists.)

Background: Postoperative anemia is a risk factor for adverse surgical outcomes. Our study aimed to assess the role of intravenous iron and erythropoietin therapy for the rapid correction of anemia following orthopedic surgery., Methods: Patients undergoing elective orthopedic surgery were prospectively enrolled and randomly divided into three groups: Control (placebo), Group 1 (IV iron monotherapy), and Group 2 [combined IV iron and recombinant human erythropoietin (rHuEPO) therapy]. Blood tests were performed preoperative (baseline) and on postoperative days (PODs) 1, 3, and 7., Results: All groups demonstrated significantly lower hemoglobin (Hb) concentrations compared to baseline, with no significant inter-group differences in postoperative Hb concentrations (p > 0.05). Serum erythropoietin, ferritin, and vitamin B 12 levels, and reticulocyte count increased beyond normal ranges in all groups. Significantly lower serum iron levels were observed postoperatively in all groups (p < 0.05). No significant inter-group differences in hepcidin level were observed (p > 0.05)., Conclusion: Postoperative treatment with combined intravenous iron and rHuEPO was ineffective in correcting postoperative anemia among orthopedic surgery patients, besides achieving higher reticulocyte counts in the first week of surgery. No improvement in mobilization of storage iron was achieved with rHuEPO. We further suggest against vitamin B 12 administration during the early postoperative period., (© 2023. The Author(s).)

Anemia of prematurity affects the majority of preterm infants, particularly extremely low birthweight infants. Anemia of prematurity arises from both innate and iatrogenic causes and results in more than 80% of extremely preterm infants receiving red blood cell transfusions during the first month after birth. Multiple randomized controlled trials were conducted to evaluate the effect of using lower versus higher transfusion thresholds based on hemoglobin levels. These trials showed no difference in the primary outcome of neurodevelopmental impairment at 2 years of age between lower and higher thresholds. However, some uncertainties about transfusion thresholds remain. This review elaborates the following: 1) the etiology, prevention, and treatment of anemia of prematurity with a focus on red blood cell transfusions, 2) the history of randomized controlled trials on the treatment of anemia of prematurity, and 3) limitations of the evidence and remaining questions about thresholds for red blood cell transfusions in preterm infants., (Copyright © 2023 by the American Academy of Pediatrics.)

Aging-related anemia contributes to frailty syndrome, cognitive decline and early mortality. The study aim was to evaluate inflammaging in relation to anemia as a prognostic indicator in affected older patients. The participants (73.0 ± 7.2 years) were allocated into anemic ( n = 47) and non-anemic ( n = 66) groups. The hematological variables RBC, MCV, MCH, RDW, iron and ferritin were significantly lower, whereas erythropoietin EPO and transferrin Tf tended toward higher values in the anemic group. Approx. 26% of individuals demonstrated transferrin saturation TfS < 20%, which clearly indicates age-related iron deficiency. The cut-off values for pro-inflammatory cytokine IL-1β, TNFα and hepcidin were 5.3 ng/mL, 97.7 ng/mL and 9.4 ng/mL, respectively. High IL-1β negatively affected Hb concentration (r s = -0.581, p < 0.0001). Relatively high odds ratios were observed for IL-1β (OR = 72.374, 95%Cl 19.688-354.366) and peripheral blood mononuclear cells CD34 (OR = 3.264, 95%Cl 1.263-8.747) and CD38 (OR = 4.398, 95%Cl 1.701-11.906), which together indicates a higher probability of developing anemia. The results endorse the interplay between inflammatory status and iron metabolism and demonstrated a high usefulness of IL-1β in identification of the underlying causes of anemia, while CD34 and CD38 appeared useful in compensatory response assessment and, in the longer term, as part of a comprehensive approach to anemia monitoring in older adults.

The important association of erythropoietin (EPO) serum levels and chronic obstructive pulmonary disease (COPD) with anemia has been inadequately studied and remains a controversial issue. We aimed to shed light on this matter by comparing EPO levels in anemic and non-anemic COPD patients, along with a review of published literature. This cross-sectional study was conducted on COPD patients referred to the pulmonary clinic of Shahid Faghihi Hospital and Motahari clinic, Shiraz, Iran, for one year. We measured complete blood count, red blood cell indices, serum iron, TIBC and ferritin levels, serum EPO levels, and body mass index. Among 35 patients in this study, 28 males and 7 females were enrolled with a mean age of 54.57 ± 8.07 years. The average Forced expiratory volume in first second (FEV1) was 37.26 ± 7.33% and FEV1/FVC was 0.46 ± 0.12. Mean EPO levels were 30.29 ± 2.066 mU/mL. No statistically significant association was observed among erythropoietin levels and Hb, COPD severity, and age. There was no significant difference in EPO levels between anemic and non-anemic patients. EPO level, against the traditional expectation, didn't increase in COPD patients. EPO production also didn't compensate for the anemia of chronic disease which considers as a common comorbid disorder in these patients., (© 2023. The Author(s).)

Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of kidney function. It is associated with high serum levels of uremic toxins (UT), such as Indoxyl Sulfate (IS), which may participate in the genesis of several uremic complications. Anemia is one of the major complications in CKD patients that contribute to cardiovascular disease, increase morbi-mortality, and is associated with a deterioration of kidney failure in these patients. Our study aimed to characterize the impact of IS on CKD-related erythropoiesis. Using cellular and pre-clinical models, we studied cellular and molecular effects of IS on the growth and differentiation of erythroid cells. First, we examined the effect of clinically relevant concentrations of IS (up to 250 μM) in the UT7/EPO cell line. IS at 250 μM increased apoptosis of UT7/EPO cells at 48 h compared to the control condition. We confirmed this apoptotic effect of IS in erythropoiesis in human primary CD34 + cells during the later stages of erythropoiesis. Then, in IS-treated human primary CD34 + cells and in a (5/6 Nx) mice model, a blockage at the burst-forming unit-erythroid (BFU-E) stage of erythropoiesis was also observed. Finally, IS deregulates a number of erythropoietic related genes such as GATA-1, Erythropoietin-Receptor (EPO-R), and β-globin. Our findings suggest that IS could affect cell viability and differentiation of erythroid progenitors by altering erythropoiesis and contributing to the development of anemia in CKD., Competing Interests: Declaration of Competing Interest ZAM reports grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka and the French government, as well as fees and grants to charities from GlaxoSmithKline, Astra Zeneca, Boehringer Ingelheim, and Bayer; these sources of funding are not necessarily related to the content of the present manuscript. GC reports grants from Amgen, Vifor Pharma, GSK and Astellas (honorarium for consultancy and conferences). Other authors had nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Heart failure, renal dysfunction, anemia, and iron deficiency affect each other and form a vicious cycle, a condition referred to as cardiorenal anemia iron deficiency syndrome. The presence of diabetes further accelerates this vicious cycle. Surprisingly, simply inhibiting sodium-glucose co-transporter 2 (SGLT2), which is expressed almost exclusively in the proximal tubular epithelial cells of the kidney, not only increases glucose excretion into the urine and effectively controls blood glucose levels in diabetes but can also correct the vicious cycle of cardiorenal anemia iron deficiency syndrome. This review describes how SGLT2 is involved in energy metabolism regulation, hemodynamics (i.e., circulating blood volume and sympathetic nervous system activity), erythropoiesis, iron bioavailability, and inflammatory set points in diabetes, heart failure, and renal dysfunction.

Iron homeostasis and dyserythropoiesis are poorly investigated in pyruvate kinase deficiency (PKD), the most common glycolytic defect of erythrocytes. Herein, we studied the main regulators of iron balance and erythropoiesis, as soluble transferrin receptor (sTfR), hepcidin, erythroferrone (ERFE), and erythropoietin (EPO), in a cohort of 41 PKD patients, compared with 42 affected by congenital dyserythropoietic anemia type II (CDAII) and 50 with hereditary spherocytosis (HS). PKD patients showed intermediate values of hepcidin and ERFE between CDAII and HS, and clear negative correlations between log-transformed hepcidin and log-EPO (Person's r correlation coefficient =  - 0.34), log-hepcidin and log-ERFE (r =  - 0.47), and log-hepcidin and sTfR (r =  - 0.44). sTfR was significantly higher in PKD; EPO levels were similar in PKD and CDAII, both higher than in HS. Finally, genotype-phenotype correlation in PKD showed that more severe patients, carrying non-missense/non-missense genotypes, had lower hepcidin and increased ERFE, EPO, and sTFR compared with the others (missense/missense and missense/non-missense), suggesting a higher rate of ineffective erythropoiesis. We herein investigated the main regulators of systemic iron homeostasis in the largest cohort of PKD patients described so far, opening new perspectives on the molecular basis and therapeutic approaches of this disease., (© 2023. The Author(s).)

Anemia is associated with increased risk of Acute Kidney Injury (AKI), stroke and mortality in perioperative patients. We sought to understand the mechanism(s) by assessing the integrative physiological responses to anemia (kidney, brain), the degrees of anemia-induced tissue hypoxia, and associated biomarkers and physiological parameters. Experimental measurements demonstrate a linear relationship between blood Oxygen Content (C a O 2 ) and renal microvascular PO 2 (y = 0.30x + 6.9, r 2  = 0.75), demonstrating that renal hypoxia is proportional to the degree of anemia. This defines the kidney as a potential oxygen sensor during anemia. Further evidence of renal oxygen sensing is demonstrated by proportional increase in serum Erythropoietin (EPO) during anemia (y = 93.806*10 -0.02 , r 2  = 0.82). This data implicates systemic EPO levels as a biomarker of anemia-induced renal tissue hypoxia. By contrast, cerebral Oxygen Delivery (DO 2 ) is defended by a profound proportional increase in Cerebral Blood Flow (CBF), minimizing tissue hypoxia in the brain, until more severe levels of anemia occur. We hypothesize that the kidney experiences profound early anemia-induced tissue hypoxia which contributes to adaptive mechanisms to preserve cerebral perfusion. At severe levels of anemia, renal hypoxia intensifies, and cerebral hypoxia occurs, possibly contributing to the mechanism(s) of AKI and stroke when adaptive mechanisms to preserve organ perfusion are overwhelmed. Clinical methods to detect renal tissue hypoxia (an early warning signal) and cerebral hypoxia (a later consequence of severe anemia) may inform clinical practice and support the assessment of clinical biomarkers (i.e., EPO) and physiological parameters (i.e., urinary PO 2 ) of anemia-induced tissue hypoxia. This information may direct targeted treatment strategies to prevent adverse outcomes associated with anemia., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Anemia, which is a manifestation of the deterioration of patients' health and performance, is a common concomitant condition in diseases with signs of inflammation activation. This anemia - anemia of inflammation, is caused by disturbances of iron metabolism that lead to iron retention within macrophages, cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation, and a reduced erytrocyte half-life. Anemia is usually mild to moderate, normocytic and normochromic. It is characterized by low iron circulation, but normal to increased levels of stored ferritin and the hormone hepcidin. The primary therapeutic approach is the treatment of the underlying inflammatory disease. In case of failure, iron supplementation and / or treatment with erythropoietin stimulating agents may be used. Blood transfusions are just an emergency treatment for life-threatening anemia. A new treatment modalities with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors is emerging. However, their therapeutic efficacy needs to be verified and evaluated in clinical trials.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced mainly in osteocytes. In chronic kidney disease (CKD) FGF23 levels increase due to higher production, but also as the result of impaired cleavage and reduced excretion from the body. FGF23 has a significant role in disturbed bone and mineral metabolism in CKD, which leads to a higher cardiovascular risk and mortality in these patients. Current research has emphasized the expression of FGF23 in cardiac myocytes, fibroblasts, and endothelial cells, and in addition to the effects on the kidney, its primary role is in cardiac remodeling in CKD patients. Recent discoveries found a significant link between increased FGF23 levels and anemia development in CKD. This review describes the FGF23 role in cardiac hypertrophy and anemia in the setting of CKD and discusses the best therapeutical approach for lowering FGF23 levels.

Rationale & Objective: Anemia is common in chronic kidney disease (CKD); although anemia is associated with adverse outcomes, the available treatments are not ideal. We characterized the burden, risk factors for, and risks associated with anemia by estimated glomerular filtration rate (eGFR) and hemoglobin level., Study Design: Cross-sectional and prospective cohort study., Setting & Participants: Outpatient data from 5,004,957 individuals across 57 health care centers in the United States from 2016 to 2019, extracted from the Optum Labs Data Warehouse., Exposure: Severity of anemia, presence of low iron test results, eGFR., Outcome: Incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, death., Analytical Approach: The prevalences of anemia, low iron test results, vitamin B 12 deficiency, and erythropoiesis-stimulating agent (ESA) use, stratified by sex and eGFR, were characterized. Polychotomous logistic regression was used to estimate the adjusted odds ratios of different hemoglobin levels across eGFR. Cox proportional hazards regression was used to calculate adjusted hazard ratios for adverse outcomes across hemoglobin level., Results: The mean age was 54 years, and 42% were male. Lower eGFR was very strongly associated with increased prevalence of anemia, even after adjustment. Although iron studies were checked infrequently in patients with anemia, low iron test results were highly prevalent in those tested: 60.4% and 81.3% of men and women, respectively. ESA use was uncommon, with a prevalence of use of<4%. Lower hemoglobin was independently associated with increased risk of incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, and death., Limitations: Reliance on ICD codes for medical diagnoses, death information obtained from claims data, observational study., Conclusions: Severe anemia was common and strongly associated with lower eGFR and multiple adverse outcomes. Low-iron test results were highly prevalent in those tested despite iron studies being checked infrequently. ESA use in nondialysis CKD patients was uncommon., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The improvement of anaemia over time by erythropoiesis stimulating agent (ESA) is associated with better survival in haemodialysis patients. We previously reported that erythrocyte creatine content, a marker of erythropoietic capacity, was a reliable marker to estimate the effectiveness of ESA. The aim of this study was to examine the accuracy and clinical usefulness of erythrocyte creatine content to predict the improvement of anaemia in haemodialysis patients., Methods: ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the study period. Erythrocyte creatine content and haematologic indices were measured at baseline in 92 patients receiving maintenance haemodialysis. Haemoglobin was also measured 3 months after. Improvement of anaemia was defined as ≥ 0.8 g/dL change in haemoglobin from baseline to 3 months., Results: Erythrocyte creatine content was significantly higher in 32 patients with improvement of anaemia compared to 60 patients with no improvement of anaemia (2.47 ± 0.74 vs. 1.57 ± 0.49 μmol/gHb, P = 0.0001). When 9 variables (erythrocyte creatine content, ESA dose, reticulocyte, haptoglobin, haemoglobin at baseline, serum calcium, intact parathyroid hormone, transferrin saturation and serum ferritin) were used in the multivariate logistic regression analysis, erythrocyte creatine emerged as the most important variable associated with the improvement of anaemia (P = 0.0001). The optimal cut-off point of erythrocyte creatine content to detect the improvement of anaemia was 1.78 μmol/gHb (Area under the curve: 0.86). Sensitivity and specificity of erythrocyte creatine content to detect the improvement of anaemia were 90.6% and 83.3%., Conclusion: Erythrocyte creatine content is a reliable marker to predict the improvement of anaemia 3 months ahead in patients receiving maintenance haemodialysis., (© 2023. The Author(s).)

Purpose: Anemia persists as a challenge in chronic kidney disease (CKD) patients. Current therapies are the injectable erythropoietin stimulating agents (ESA). Concerns have been raised regarding ESA cardiovascular safety, therefore search for an alternative, convenient and safe therapy is underway. Hypoxia inducible factors-prolyl hydroxylase inhibitors (HIF-PHI) are oral agents with promising results. Numerous small studies reported favorable effects with lack of large, powered studies., Methods: We conducted a meta-analysis of randomized clinical trials to assess the efficacy and safety of HIF-PHI in non-dialysis-dependent CKD patients. Primary outcome was hemoglobin (Hb) concentration post intervention. Secondary outcomes were all-cause mortality, MACE, and changes in iron metabolism (ferritin, hepcidin). We reported total and serious adverse effects. Data were pooled using a random effect model via RevMan 5.4 software., Results: We identified 7 trials comprising of 8228 patients (mean age 66.5 ± 13.2 years, 42% were females, 53% used iron replacement) with a mean follow-up of 52 weeks. Compared with the standard of care (ESA), HIF-PHI were non-inferior for treatment of anemia, with comparable effect on mortality and major adverse cardiovascular events. HIF-PHI showed no major safety concerns. Main side effect of HIF-PHI was diarrhea., Conclusion: HIF-PHI might represent a safe, and convenient alternative to ESA in non-dialysis dependent CKD patients with anemia., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

To determine whether or not Darbepoetin alpha (DA) was non-inferior to recombinant human erythropoietin (rHuEPO) in the treatment of anemia in children with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis). This was a randomized, open-label, two-arm, parallel group, active-controlled, non-inferiority trial conducted at a tertiary care center in New Delhi, India. Fifty patients of either gender (aged 1-18 years) with CKD stage 3-5 (on or not on dialysis) who had baseline hemoglobin (Hb) between 9 and 12 g/dL and were on stable erythropoietin therapy for at least 8 weeks were randomized (1:1) to either continue rHuEPO or switch to DA therapy for a period of 28 weeks. Doses were titrated in the initial 23 weeks to maintain the Hb between 11 and 12 g/dL, and efficacy was assessed between weeks 24 and 28. The primary efficacy outcome was the mean change in Hb between baseline and the evaluation period. In the intention-to-treat population (n = 50), the adjusted between-group difference in mean Hb change between the baseline and the evaluation period was 0.131 g/dL (95% CI: - 0.439 to 0.719, p = 0.629). The lower limit of the two-sided 95% CI for the difference in the mean change in Hb between the two treatment groups was well above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar pattern of non-inferiority was seen for per protocol population. The safety profile of DA and rHuEPO was also comparable (injection site pain:rHuEPO-3, DA-7; p-0.296).   Conclusion: DA is non-inferior to rHuEPO for the treatment of anemia of CKD (stage 3-5) in pediatric population with a comparable safety profile.   Trial registration: ClinicalTrials.gov Identifier: NCT04959578 (retrospectively registered), Date: July 13, 2021. What is Known: • Limited studies showing darbepoetin alpha is effective in children as an erythropoiesis stimulating agent. • No RCT from Indian subcontinent addressing this topic. What is New: • Darbepoetin alpha is non inferior to recombinant human erythropoietin for treatment of anemia in children with CKD stage 3-5 (on or not on dialysis) with safety comparable to recombinant human erythropoietin. • A cost reduction of approximately 8.6% per patient by shifting to darbepoetin alpha., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Renal anemia is caused by end-stage renal disease (ESRD) but has a complex etiology. The application of dietary fiber (DF) to regulate the gut microbiota has shown effective therapeutic effects in some diseases, but its role in renal anemia is not clear. The aim of this study was to explore the effect of DF on renal anemia by regulating the gut microbiota and its metabolite, short-chain fatty acids (SCFAs)., Methods: A total of 162 ESRD patients were enrolled and randomly distributed into a DF or a control group (received oral DF or potato starch, 10 g/day for 8 weeks). Hemoglobin (Hb), serum iron (Fe 2+ ), serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin and the dosage of recombinant human erythropoietin (rhEPO) before and after intervention in patients were analyzed. The gut microbiota and SCFAs in both groups were analyzed by 16S rDNA sequencing and gas chromatography-mass spectrometry, respectively. Spearman's correlation test was used to analyze the correlation between the gut microbiota, SCFAs and the hematological indicators., Results: Compared with the control group, (1) the patients in the DF group had higher Hb [117.0 (12.5) g/L vs. 94.0 (14.5) g/L, p < 0.001], Fe 2+ [13.23 (4.83) μmol/L vs. 10.26 (5.55) μmol/L, p < 0.001], and SF levels [54.15 (86.66) ng/ml vs. 41.48 (36.60) ng/ml, p = 0.003]. (2) The rhEPO dosage in the DF group was not significantly decreased (p = 0.12). (3) Bifidobacterium adolescentis, Lactobacillus and Lactobacillaceae were increased in the DF group, and Lactobacillus and Lactobacillaceae were positively correlated with Hb (r = 0.44, p < 0.001; r = 0.44, p < 0.001) and Fe 2+ levels (r = 0.26, p = 0.016; r = 0.26, p = 0.016) and negatively correlated with rhEPO dosage (r = - 0.45, p < 0.001; r = - 0.45, p < 0.001). (4) Patients in the DF group had elevated serum butyric acid (BA) levels [0.80 (1.65) vs. 0.05 (0.04), p < 0.001] and BA levels were positively correlated with Hb (r = 0.26, p = 0.019) and Fe 2+ (r = 0.31, p = 0.005) and negatively correlated with rhEPO dosage (r = - 0.36, p = 0.001). Lactobacillus and Lactobacillaceae were positively correlated with BA levels (r = 0.78, p < 0.001; r = 0.78, p < 0.001)., Conclusion: DF may improve renal anemia in ESRD patients by regulating the gut microbiota and SCFAs. Trial registration This study was registered in the China Clinical Trial Registry ( www.chictr.org.cn ) on December 20, 2018 ( ChiCTR1800020232 )., (© 2022. The Author(s).)

Background: Aluminum accumulation is a well-described complication in dialysis patients. Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum overload. Limited evidence suggests that aluminum overload may decline in the era of aluminum removal from dialysis fluids, even with the use of aluminum binders., Methods: We examined the data from January 2014 to June 1, 2020, identified through our electronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The presentation and treatment of aluminum overload were recorded., Results: Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients (47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients had symptoms, including one patient with an unexplained fracture, eight patients with unexplained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with hypercalcemia (serum calcium >11 mg dL -1 ). None of the patients with aluminum overload developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requiring longer treatments (>10 months versus <10 months) had similar basal serum aluminum ( p  = 0.219) but had an increase in serum aluminum after DFO ( p  = 0.041). Furthermore, the treatments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline phosphatase levels <60 U L -1 ( p  = 0.028)., Conclusion: We concluded that aluminum overload existed in the reverse osmosis dialysis era. In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum in dialysis patients should be monitored in countries using aluminum-based phosphate binders, despite reverse osmosis dialysis.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Luspatercept has high clinical activity in patients with transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) and ring sideroblasts (RS) relapsed or refractory to erythropoietin. We report long-term luspatercept safety and efficacy in 108 patients with LR-MDS in the PACE-MDS study, including 44 non-RS and 34 non-transfusion-dependent or previously untreated patients. The primary end point was safety. Secondary end points included rates of hematologic improvement (HI) erythroid (HI-E), HI neutrophil, and HI platelet. Exploratory end points included erythropoiesis biomarker quantitation and mutation data. Median duration of luspatercept exposure was 315 days (range, 21-1,934 days). No new safety signals emerged. HI-E was observed in 53.7% of patients, including 36.4% of non-RS and 70.6% of non-transfusion-dependent patients. HI neutrophil and HI platelet were observed in 33.3% and 9.5% of patients, respectively. An almost three-fold increase in bone marrow late to early progenitor cell ratio accompanied HI-E response, irrespective of RS status. Lower baseline erythropoietin levels in non-RS patients (69.6 v 623.3 IU/L; P = .0077) and higher late to early erythroid progenitor cell ratio (10.44 v 4.48; P = .0106) in RS patients were associated with HI-E. This study highlights luspatercept's effects across LR-MDS subtypes, including untreated MDS-RS, serving as a platform for future trials., Competing Interests: Uwe PlatzbeckerHonoraria: Celgene/Jazz, AbbVie, Curis, Geron, JanssenConsulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co KGResearch Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Chris (Inst)Patents, Royalties, Other Intellectual Property: Part of a patent for a TFR-2 antibodyTravel, Accommodations, Expenses: Celgene Katharina S. GötzeHonoraria: BMSConsulting or Advisory Role: Celgene/BMS, AbbVie, Servier/PfizerResearch Funding: BMS Philipp KieweConsulting or Advisory Role: Roche, Bristol Myers Squibb/Celgene, BeiGene, Amgen, Pfizer, AstraZeneca/MerckSpeakers’ Bureau: Excellence in Oncology Ulrich GermingHonoraria: Celgene/BMS, Jazz Pharmaceuticals, NovartisConsulting or Advisory Role: CelgeneResearch Funding: Celgene (Inst), Novartis (Inst) Karin MayerStock and Other Ownership Interests: Roche Pharma AG, Autolus Therapeutics, Merck Serono, Pfizer, Gilead Sciences, BMSi Markus RadsakHonoraria: CelgeneConsulting or Advisory Role: Takeda, Novartis, CORAT Thomas WolffHonoraria: AstraZeneca, Apogepha, AbbVie, Incyte, SeaganConsulting or Advisory Role: Roche Katja SockelHonoraria: Bristol Myers Squibb/Celgene, Novartis, Alexion Pharmaceuticals, SOBIConsulting or Advisory Role: Takeda, NovartisTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Celgene/Bristol Myers Squibb Detlef HaaseHonoraria: Novartis, Jazz Pharmaceuticals, Takeda, Celgene/Bristol Myers SquibbResearch Funding: Celgene/BMSDTravel, Accommodations, Expenses: Celgene/Bristol Myers Squibb Thomas IllmerConsulting or Advisory Role: Novartis, AstraZeneca, AbbVie Haifa Kathrin Al-AliHonoraria: Novartis, BMSi, Incyte (Inst), Takeda, Pfizer, AbbVieConsulting or Advisory Role: Novartis, BMSi, AbbVieResearch Funding: Novartis (Inst), BMSi (Inst), Incyte (Inst)Travel, Accommodations, Expenses: BMSi, Novartis Gerda SillingTravel, Accommodations, Expenses: AbbVie Joseph G. ReynoldsEmployment: Acceleron Pharma, Inc, C4 TherapeuticsStock and Other Ownership Interests: Acceleron Pharma, Inc Xiaosha ZhangEmployment: Acceleron Pharma, IncStock and Other Ownership Interests: Acceleron Pharma, Inc Kenneth M. AttieEmployment: Acceleron Pharma, Inc, ImaraLeadership: Imara Jeevan K. ShettyEmployment: Bristol Myers Squibb/CelgeneStock and Other Ownership Interests: Bristol Myers Squibb/Celgene Aristoteles GiagounidisStock and Other Ownership Interests: Novartis, RocheHonoraria: Amgen, Novartis, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Bristol Myers Squibb/CelgeneNo other potential conflicts of interest were reported.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis., (© 2022 Wiley Periodicals LLC.)