Erythropoietin Dose Research Articles

Hematologic safety of chronic brain-penetrating erythropoietin dosing in APP/PS1 mice

IntroductionLow blood-brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor-mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB-penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb-EPO dosing, in comparison to recombinant human EPO (rhu-EPO), in AD mice. MethodsMale APPswe PSEN1dE9 (APP/PS1) mice (9.5 months) were treated with saline (n = 11), and equimolar doses of cTfRMAb-EPO (3 mg/kg, n = 7), or rhu-EPO (0.6 mg/kg, n = 9) 2 days/week subcutaneously for 6 weeks, compared to saline-treated wild-type mice (n = 10). At 6 weeks, exploration and memory were assessed, and mice were sacrificed at 8 weeks. Spleens were weighed, and brains were evaluated for amyloid beta (Aβ) load and synaptophysin. Blood was collected at 4, 6 and 8 weeks for a complete blood count and white blood cells differential. ResultscTfRMAb-EPO transiently increased reticulocyte counts after 4 weeks, followed by normalization of reticulocytes at 6 and 8 weeks. rhu-EPO transiently increased red blood cell count, hemoglobin and hematocrit, and significantly decreased mean corpuscular volume and reticulocytes at 4 weeks, which remained low at 6 weeks. At 8 weeks, a significant decline in red blood cell indices was observed with rhu-EPO treatment. Exploration and cognitive deficits were significantly worse in APP/PS1-rhu-EPO mice. Both cTfRMAb-EPO and rhu-EPO decreased 6E10-positive brain Aβ load; however, cTfRMAb-EPO and not rhu-EPO selectively reduced brain Aβ1-42 and elevated synaptophysin expression. DiscussionChronic treatment with cTfRMAb-EPO results in better hematologic safety, behavioral, and therapeutic indices compared with rhu-EPO, supporting the development of this BBB-penetrable EPO analog for AD.

The Performance Effects of Microdose Recombinant Human Erythropoietin Administration and Carbon Monoxide Rebreathing.

Frequent, low doses of recombinant human erythropoietin (rHuEpo) have been shown to increase the oxygen carrying capacity of an athlete and enhance endurance performance, although its effect on repeated sprint ability (RSA) remains unknown. If the mechanisms behind improved RSA performance reside within the augmented O2 carrying capacity, then carbon monoxide (CO) inhalation should inhibit RSA. Purpose: The aim of this study was to assess the effects on maximal oxygen uptake (V˙O2max) and RSA of two interventions known to differentially influence blood oxygen carrying capacity. Methods: Fourteen endurance-trained individuals were administered microdoses of rHuEpo (20-40 IUkg) or placebo twice per week for 7 wk using a randomized, crossover design. V˙O2max and RSA were measured at baseline and after rHuEpo administration. Total hemoglobin mass (tHb-mass) was measured twice at baseline (14 and 7 d before the first injection), three times during rHuEpo administration (10, 24, and 38 d after the first rHuEpo injection) and twice after the cessation of rHuEpo administration (7 and 21 d after the final injection) using the optimized CO rebreathing method. V˙O2max and RSA also were assessed in a separate cohort of 11.

Erythropoietin (EPO) Regulates Bone Mass Via EPO Receptors on Myeloid and Lymphocytic Cells

Background and aims: Erythropoietin (EPO) is the key regulator of red blood cell production. In response to hypoxia, EPO levels can increase 1000-fold and remain high for weeks to promote hematopoiesis. Therapeutically, the introduction of EPO and erythropoietic stimulating agents into clinical practice has revolutionized the treatment of anemia despite certain concerns regarding the safety of the therapy. Recent studies demonstrate that EPO has activities in addition to hematopoiesis, and modulates bone remodeling by increasing bone resorption and decreasing bone formation, leading to trabecular bone loss. In vitro, EPO directly inhibits murine osteoblast differentiation and mineralization at doses relatively lower than those shown to stimulate osteoclastogenesis. The aim of this study was to investigate the dose-response relationship between EPO dose, hemoglobin (Hgb) levels, and the extent of bone loss, as well as to examine the role of the monocytic and B cell EPO receptor (EPOR) in bone metabolism.Results: Treating mice for 2 weeks with escalating doses of EPO, ranging from 6-540 IU/week, led to a dose-dependent increase in Hgb accompanied by a more dramatic decrease in trabecular bone mass; regression slopes of Hgb and bone volume/total volume (BV/TV, a measure of bone density) were 0.009 vs -0.09, respectively (p<0.05). These effects were associated with a significant increase in the number of preosteoclasts (CD115+ cells) in the bone marrow (r=0.74, p<0.05). To assess whether the osteoclast lineage contributes to EPO-induced bone loss, we generated mice lacking EPOR in the monocytic lineage (LysM-cre+/+;EPORflox/flox, cKO). At steady state, these mice and their LysM+/+;EPORwt/wt controls exhibited similar levels of Hgb (16.7±0.57 and 16.8 ±0.25 g/dL, respectively) and BV/TV (2.73%± 0.73 and 3.10%±0.76, respectively). Although not completely abolished, the bone loss induced by high EPO doses (540 IU/week) was significantly attenuated in cKO compared to control mice (60%±4.7 reduction versus 40%±13.2 reduction, respectively). At the same time, the levels of osteoclast precursors (CD115+ cells) increased from 3.08%±1.12 to 4.67%±0.92 in EPO-treated control mice, although there was no change in bone marrow preosteoclasts and preosteoblasts (defined as CD11b-/ALP+) in EPO-treated cKO mice. This suggests that osteoclast EPOR is responsible, at least in part, for mediating the effect of EPO on bone mass. Adding to the complexity of EPO's osteoimmunological roles, new findings suggest that EPO also regulates bone resorption via EPOR signaling in B cells. EPO stimulated surface expression of the osteoclastogenic RANKL in B cells (MFI: 2.6%±0.1 to 3.13%±0.09 P<0.05) and we found a higher bone mass in mice with conditional EPOR KO in B cells (MB1-cre+/-;EPORflox/flox) (vBMD, 52.2±15.1 versus 40.8±8.8 mg HA/cm3 in MB1-Cre+/-;EPORwt/wt, p<0.05).Conclusions: Our data demonstrate the complexity of EPO-induced bone loss mediated at least partly by EPOR signaling in both myeloid and B cell lineages. Furthermore, since patients who require treatment with EPO are prone to osteoporosis, our data suggest that using the lowest effective EPO dose would not only decrease the risk of thromboembolic complications but also minimize adverse skeletal outcomes.SHB and AK - Equal contribution; YG and DN - Equal contributionFunded by the German Israel Foundation, Grant # 01021017 to YG, DN, MR and BW and the Israel Science Foundation, Grant # 343/17 to DN. DisclosuresNo relevant conflicts of interest to declare.

Importance of Transcription Factor Nrf2 for Cereblon Expression and Clinical Response to Combination of Lenalidomide and Erythropoietin in Lower-Risk Myelodysplastic Syndromes

INTRODUCTIONNrf2 (nuclear factor, erythroid-derived 2-like 2 or NF-E2-related factor 2) is a transcription factor involved in antioxidant response by reducing oxidative stress. Erythropoietin (EPO) was described as an inducer of Nrf2 in the brain. Nrf2 binds to the promoter of gene coding for cereblon (CRBN) and stimulates CRBN expression (Lee et al. Biochem.Biphys Res Commun 2010; 399: 711-715). We showed that the high level of full length CRBN mRNA and CRBN protein is important for the efficacy of lenalidomide (LEN) in lower-risk MDS patients (Jonasova et al. Eur J Haematol 2015; 95: 27-34; Fuchs et al. Leuk Res 2017; 55 S1: S132, abstr. 227). Addition of EPO to LEN restored transfusion independence of MDS patients when their anemia relapsed during the course of LEN treatment (Jonasova et al. Leuk Res 2018; 69: 12-17). LEN inhibits E3 ubiquitin ligase RNF41 (ring finger protein 41), which polyubiquitinates EPO receptor (EPOR) and marks it for degradation in proteasomes. (Basiorka et al. Cancer Res 2016; 76: 3531-3540).AIMSThe aim of our study was to evaluate the levels of Nrf2 mRNA and CRBN mRNA in mononuclear cells obtained from peripheral blood of lower-risk MDS patients after addition of EPO to lenalidomide in MDS patients who relapsed during LEN monotherapy. The further goal was to study the effect of LEN, EPO and combination of LEN plus EPO in cell lines (SKM-1 leukemic cell line established from a patient with progression of MDS to myelomonocytic leukemia and in MDS-L cells a human myeloblastic cell line, established as a MDS92 subline from the bone marrow of an MDS patient with del(5q) (Matsuoka et al. Leukemia 2010; 24: 748-755).METHODSNrf2 mRNA and full-length CRBN mRNA levels were quantified in 9 lower-risk MDS patients with del(5q) and in 2 MDS patients with normal chromosome 5 [nondel(5q)] who were previously resistant to EPO treatment. All patients with median hemoglobin level 80 g/l were transfusion dependent before starting the therapy with LEN (5 or 10 mg/day). Recombinant human EPO (rHuEPO) in dose of 40,000 IU s.c. per week was combined with LEN in these MDS patients who relapsed during LEN monotherapy or were resistant to LEN [one non(del5q) patient]. Four lower-risk MDS patients responsive to EPO after diagnosis were also used for comparison of Nrf2 mRNA and full-length CRBN mRNA levels. Mononuclear cells were isolated by Ficoll-Paque PLUS gradient separation, then washed by phosphate buffered saline and remaining red cells were lysed. Both SKM-1 and MDS-L cells were incubated without or with LEN, EPO and combination of LEN plus EPO for 19, 24 and 43 hours. The end concentration of added Epo was 2U/ml and LEN 10 µM. The levels of Nrf2 mRNA and full length CRBN mRNA were measured using the reverse transcription-quantitative TaqMan PCR assay.RESULTSThe levels of Nrf2 mRNA and full-length CRBN mRNA in peripheral blood mononuclear cells correspond during rHuEPO monotherapy of four responsive lower-risk MDS patients. In these cases no increase of Nrf2 mRNA and CRBN mRNA levels was found. Increased Nrf2 mRNA and CRBN mRNA levels in peripheral blood mononuclear cells were found after addition of rHuEPO to lenalidomide in six MDS patients with del(5q) and one non(del5q) MDS patient who relapsed during LEN monotherapy. All these patients responded to combination of rHuEPO and lenalidomide by increased hemoglobin levels. Addition of or rHuEPO to lenalidomide was without effect on Nrf2 mRNA and CRBN mRNA levels in one non(del5q) patient who was resistant to LEN. Experiments with SKM-1 and MDS-L cells showed that rHuEPO alone did not increased Nrf2 mRNA and CRBN mRNA levels. However LEN and in a greater extent the combination of rHuEPO and LEN increased Nrf2 mRNA and CRBN mRNA levels.CONCLUSIONSOur findings indicate that transcription factor Nrf2 is involved in CRBN expression in mononuclear cells obtained from peripheral blood of lower-risk MDS patients and in SKM-1 and MDS-L cells in culture. Expression of both Nrf2 and CRBN is stimulated by lenalidomide and in a greater extent by combination of lenalidomide and rHuEPO. Measurement of CRBN mRNA level as an important factor for prediction of the efficacy of not only lenalidomide monotherapy but also of combination of LEN and rHuEPO.This work was supported by the research project for conceptual development of research organization (00023736; Institute of Hematology and Blood Transfusion, Prague) and Grant Agency of Charles University, project number 924616. DisclosuresNo relevant conflicts of interest to declare.

Effects of recombinant human erythropoietin on cognition and neural activity in remitted patients with mood disorders and first-degree relatives of patients with psychiatric disorders: a study protocol for a randomized controlled trial

BackgroundBipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a “cognitive control network.” There is an increased prevalence of cognitive dysfunction in psychiatric patients’ first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement.MethodsThe trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library.DiscussionIf this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment.Trial registrationClinicalTrials.gov, NCT03315897. Registered on 20 October 2017.

Dose-dependent exacerbation of ventilation-induced lung injury by erythropoietin in preterm newborn lambs.

Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO1000; n = 5), or 3,000 (EPO3000; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar-arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.

Effect of Erythropoietin Administration on Myocardial Viability and Coronary Microvascular Dysfunction in Anterior Acute Myocardial Infarction: Randomized Controlled Trial in the Japanese Population.

IntroductionCardioprotective effects of erythropoietin (EPO) on infarcted myocardium in acute myocardial infarction (AMI) patients have been inconclusive. This study aimed to assess the effect of EPO administration on coronary microvascular dysfunction (CMD) and myocardial viability in anterior AMI. We also evaluated the serial changes in CMD and cardiac remodeling in these patients.MethodsPatients with a successful percutaneous coronary intervention (PCI) for the first anterior AMI were randomly assigned to two groups (EPO and control groups), and given single-dose intravenous administration of recombinant human EPO (12,000 IU) or saline after PCI. Delayed-enhanced cardiac magnetic resonance imaging was performed at 1 week after AMI to assess the average of transmural extent of infarction and infarct size. Coronary flow velocity reserve (CFVR) of the left anterior descending coronary artery was measured by Doppler echocardiography at 1 week, 1 month, and 8 months after AMI. All patients underwent clinical follow-up for the assessment of cardiac remodeling.ResultsSixty-one patients (EPO 32, control 29) were eligible for analysis. EPO group (2.4 ± 1.2) had a tendency of smaller transmural extent of infarction than that of control group (2.9 ± 1.1; p = 0.063). CFVR-8 months improved significantly in EPO group (2.9 ± 0.6) compared to control group (2.6 ± 0.5; p = 0.04). Left atrial (LA) volume − 8 months was significantly lower in EPO group (47 ± 11) than those of control group (65 ± 20; p = 0.004).ConclusionsA single medium dose of EPO could have a favorable effect on CMD and LA remodeling in the chronic phase of anterior AMI.Trial RegistrationThe institutional ethics committee of Wakayama Medical University, identifier, 1125.Electronic supplementary materialThe online version of this article (10.1007/s40119-018-0122-1) contains supplementary material, which is available to authorized users.

HCV INFECTION AND ERYTHROPOIETIN IN HAEMODIALYSIS PATIENTS

Background: Renal anemia is associated with increased cardio vascular morbidity and mortality and decreased quality of life. It may worsen the preexisting heart disease and consequently may accelerate the progression of renal dysfunction in a vicious circle.Renal anemia related mainly to decreased production of erythropoietin (EPO) by the kidney, decreased it’s response by bone marrow and disturbed iron status. Aim of the Study: Was to evaluate the relationship between HCV infection and erythrropoietin in patients on regular HD. Patients and Methods: This study included 50 hemodialysis patients (25 patients +ve HCV and 25 -ve HCV), 16 were male and 34 were female, and their ages ranged from 20 to 67 years, with a mean ± SD of 50.5 ± 12.7 years, 15 apparently healthy individuals with normal kidney function and not anemic were included in the study as a control Group. Results: The patients were divided into two groups as the following: Group I consisted of 25 hemodialysis patients were positive for HCV antibody, which was confirmed by PCR, and their ages ranged from 27 to 67 years, with a mean of 47.28 ± 11.91 years. Group II consisted of 25 hemodialysis patients were negative for HCV antibody; their ages ranged from 20 to 65 years, with a mean age of 46.32 ± 11.50 years. In contrast, 15 patients served as age-matched and gender-matched; their ages ranged from 20 to 55 years, with a mean age of 44.13 ± 10.76 years, and were used as controls. Conclusion: Serum levels of erythropoietin correlate with chronic hepatitis C infection, which was associated with an increased number of RBCs and higher values of hemoglobin and hematocrit, which Result in lowering of the necessary erythropoietin dose and iron therapy.

Intradialytic Parenteral Nutrition: A Method of Copper Replacement

Copper is essential trace metal which plays vital role in electron transport reactions, iron hemostasis, pigment formation, neurotransmitter production, connective tissue biosynthesis and antioxidant defense mechanisms. A 58-year-old Caucasian man with ESRD on intermittent hemodialysis, chronic diarrhea and malabsorption after gastric bypass surgery on Intradialytic parenteral nutrition (IDPN) was evaluated for anemia with sub optimal response to high doses of erythropoietin and pancytopenia suspicious of myelodysplastic syndrome. Investigations listed in Figure 1. Bone Marrow biopsy showed refractory cytopenias with multi-lineage dysplasia. Cytogenetics showed no definitive immunophenotypic evidence of high-grade hematopoietic neoplasia, lymphoproliferative disease or plasma cell dyscrasia. He was started on daily oral therapy with copper gluconate with no improvement in the hematological parameters. Copper chloride was added to IDPN with improvement of all hematological parameters and copper levels [figure 2]. On attempting to withdraw therapy, severe drop in copper and cell counts were noted and was corrected with resumption of IDPN with copper supplementation. Copper deficiency can present as anemia and leukopenia, thrombocytopenia. Typical bone marrow findings mimic myelodysplastic syndrome including left shift in granulocytic & erythroid maturation & presence of ringed sideroblasts/hemosiderin containing plasma cells. Neurologic manifestations include ataxia, myeloneuropathy and cognitive deficits. Unlike neurologic deficits, hematologic manifestations can be reversed with copper supplementation. The current adult recommended intake is 0.9mg/day. The American society for metabolic and Bariatric surgery clinical practice recommend treatment of mild to moderate deficiency with oral (3-8mg/dl) and IV copper (2-4mg/dl) for severe deficiency. Oral supplementation may fail in patients with gastric bypass as copper is absorbed in stomach and duodenum. IDPN is relatively safe and efficacious modality of nutritional support which allows the administration of nutrients through extracorporeal circuit during hemodialysis in these patients. Other causes of copper deficiency include Post gastric bypass surgery, Excessive zinc ingestion or overloading during hemodialysis, celiac disease, cystic fibrosis, IBD and Bacterial overgrowth.2453_A Figure 1. Initial Patient Laboratory Values2453_B Figure 2. Hematological changes during treatment with copper. WBC - White blood cell count, HB - Hemoglobin, IDPN - Intradialytic Parenteral Nutrition, Oral - Oral supplementation

Brain Penetrating Bifunctional Erythropoietin-Transferrin Receptor Antibody Fusion Protein for Alzheimer's Disease.

Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has neuroprotective effects in rodent models of Alzheimer's disease (AD). However, high therapeutic doses or invasive routes of administration of EPO are required to achieve effective brain concentrations due to low blood-brain barrier (BBB) penetrability, and high EPO doses result in hematopoietic side effects. These obstacles can be overcome by engineering a BBB-penetrable analog of EPO, which is rapidly cleared from the blood, by fusing EPO to a chimeric monoclonal antibody targeting the transferrin receptor (cTfRMAb), which acts as a molecular Trojan horse to ferry the EPO into the brain via the transvascular route. In the current study, we investigated the effects of the BBB-penetrable analog of EPO on AD pathology in a double transgenic mouse model of AD. Five and a half month old male APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with saline ( n = 10) or the BBB-penetrable EPO ( n = 10) 3 days/week intraperitoneally for 8 weeks, compared to same-aged C57BL/6J wild-type mice treated with saline ( n = 8) with identical regiment. At 9 weeks following treatment initiation, exploration and spatial memory were assessed with the open-field and Y-maze test, mice were sacrificed, and brains were evaluated for Aβ peptide load, synaptic loss, BBB disruption, microglial activation, and microhemorrhages. APP/PS1 mice treated with the BBB-penetrable cTfRMAb-EPO fusion protein had significantly lower cortical and hippocampal Aβ peptide number ( p < 0.05) and immune-positive area ( p < 0.05), a decrease in hippocampal synaptic loss ( p < 0.05) and cortical microglial activation ( p < 0.001), and improved spatial memory ( p < 0.05) compared with APP/PS1 saline controls. BBB-penetrating EPO was not associated with microhemorrhage development. The cTfRMAb-EPO fusion protein offers therapeutic benefits by targeting multiple targets of AD pathogenesis and progression (Aβ load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD.

Potential predictor factors of protein-energy wasting syndrome in hemodialysis patients

Rationale: Protein-energy wasting syndrome (PEW) is a mild-moderate frequent condition associated with adverse outcomes and mortality in hemodialysis (HD) patients. The aim of this study was assess the nutritional-inflammatory status and its relationship with hospital admissions, doses of erythropoietin stimulating agents (ESA) and comorbidities.

Effects of erythropoietin on the clinical outcomes of patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention: Ameta-analysis .

To investigate the effects of erythropoietin (EPO) on the clinical outcomes of patients with acute ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI). We collected randomized controlled studies conducted before April 15, 2017, and performed a meta-analysis using RevMan5.3 software. Compared with the conventional revascularization group, mortality (RR=0.79; 95% Cl, 0.42-1.50; p=0.47), stroke events (RR = 2.63; 95% Cl, 0.70-9.85; p=0.15), recurrent myocardial infarction (RR = 0.99; 95% Cl, 0.44 - 2.20; p=0.98), and other clinical endpoints were not significantly different in the EPO group. However, subgroup analysis showed a marginally significant difference between the high-dose EPO group and the control group (MD=1.29; 95% CI, 0.02-2.56; p=0.05) in ejection fraction. The administration of EPO has no effects on the clinical outcomes of patients with acute STEMI after PCI, whilst a high dose of EPO may increase patients' ejection fraction. .

EPO Dosage Optimization for Anemia Management: Stochastic Control under Uncertainty Using Conditional Value at Risk

Due to insufficient endogenous production of erythropoietin, chronic kidney disease patients with anemia are often treated by the administration of recombinant human erythropoietin (EPO). The target of the treatment is to keep the patient’s hemoglobin level within a normal range. While conventional methods for guiding EPO dosing used by clinicians normally rely on a set of rules based on past experiences or retrospective studies, model predictive control (MPC) based dosage optimization is receiving attention recently. The objective of this paper is to incorporate the hemoglobin response model uncertainty into the dosage optimization decision making. Two methods utilizing Conditional Value at Risk (CVaR) are proposed for hemoglobin control in chronic kidney disease under model uncertainty. The first method includes a set-point tracking controller with the addition of CVaR constraints. The second method involves the use of CVaR directly in the cost function of the optimal control problem. The methods are compared to set-point tracking MPC and Zone-tracking MPC through computer simulations. Simulation results demonstrate the benefits of utilizing CVaR in stochastic predictive control for EPO dosage optimization.

Computational design and experimental characterization of a novel β-common receptor inhibitory peptide

In short-term animal models of ischemia, erythropoietin (EPO) signaling through the heterodimeric EPO receptor (EPOR)/β-common receptor (βCR) is believed to elicit tissue protective effects. However, large, randomized, controlled trials demonstrate that targeting a higher hemoglobin level by administering higher doses of EPO, which are more likely to activate the heterodimeric EPOR/βCR, is associated with an increase in adverse cardiovascular events. Thus, inhibition of long-term activation of the βCR may have therapeutic implications. This study aimed to design and evaluate the efficacy of novel computationally designed βCR inhibitory peptides (βIP). These novel βIPs were designed based on a truncated portion of Helix-A from EPO, specifically residues 11–26 (VLERYLLEAKEAEKIT). Seven novel peptides (P1 to P7) were designed. Peptide 7 (P7), VLERYLHEAKHAEKIT, demonstrated the most robust inhibitory activity. We also report here the ability of P7 to inhibit βCR-induced nitric oxide (NO) production and angiogenesis in human umbilical vein endothelial cells (HUVECs). Specifically, we found that P7 βIP completely abolished EPO-induced NO production. The inhibitory effect could be overcome with super physiological doses of EPO, suggesting a competitive inhibition. βCR-induced angiogenesis in HUVEC’s was also abolished with treatment of P7 βIP, but P7 βIP did not inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis. In addition, we demonstrate that the novel P7 βIP does not inhibit EPO-induced erythropoiesis with use of peripheral blood mononuclear cells (PBMCs). These results, for the first time, describe a novel, potent βCR peptide inhibitor that inhibit the actions of the βCR without affecting erythropoiesis.

Pharmacotherapy in Acutely Anemic Jehovah's Witnesses: An Evidence-Based Review.

To determine the pharmacological treatment methods available to anemic Jehovah's Witnesses (JW). MEDLINE and PubMed were searched from inception through February 2018 using the search terms Jehovah's Witnesses, treatment, erythropoietin, hemoglobin-based oxygen carrier, Sanguinate, Hemopure, bleeding, and anemia. All clinical trials, cohort studies, case-control studies, and observational trials involving pharmacotherapy in anemic JW patients were evaluated. Case reports and bibliographies were also analyzed for inclusion. Two studies involving the use of erythropoietin (EPO) and one study involving recombinant factor VIIa were included. Information was also included from other pharmacotherapeutic modalities that had case report data only. Current published evidence is limited with regard to evidence-based management of JW patients. High-dose EPO, intravenous iron supplementation, and hemostatic agents have demonstrated good clinical outcomes in case reports. EPO doses as high as 40 000 units daily have been advocated by some experts; however, pharmacokinetic studies do not support dose-dependent effects. Hemoglobin-based oxygen carriers (HBOCs) are currently not Food and Drug Administration approved. They are available through expanded access programs and may represent a lifesaving modality in the setting of severe anemia. There are currently not enough data to make definitive recommendations on the use of pharmacological agents to treat severe anemia in the JW population. Further evidence utilizing EPO and HBOCs will be beneficial to guide therapy.

Low Dose Oral Iron as a Safe and Effective Iron Administration for Anemia Treatment in Hemodialysis Patients

Background: Oral Ferric Citrate (FC) is an effective iron therapy in hemodialysis patients. We investigated the effect of oral iron on anemia in hemodialysis patients focusing on different effects between sodium ferrous citrate (SF) and FC and dose effect of SF.Methods: Study 1; FC was administered (1500 mg/day) either as a de novo iron administration (Group D) or after a switch from SF (50 mg/day) (Group S). Dose of erythropoietin stimulating agent (ESA), serum hemoglobin levels, ESA/hemoglobin ratio and iron states were investigated for 64 weeks retrospectively. Study 2; 23 stable hemodialysis patients with long-term 50 mg/day of SF were randomly divided to two groups; dose was increased to 150 mg/day (Group 150) and unchanged in the rest (Group 50). Without changing the dose of ESA, hemoglobin levels and iron states were compared for 40 weeks prospectively. Results: Study 1; data were obtained from 28 patients. FC administration increased ferritin levels in both groups (median; Group D; 0W: 49.3, 56W: 214.0, Group S; 0W: 120.0, 56W: 217.0 ng/mL), but hemoglobin levels increased and ESA dose and ESA/hemoglobin ratio decreased only in Group D (0W vs. 12W: p < 0.05). Study 2; 17 patients completed the study. Although higher dose of SF resulted in increased ferritin and hepcidin-25 levels in Group 150 (p < 0.05 and < 0.01, respectively), hemoglobin levels did not change in either group.Conclusions: Instable hemodialysis patients, 50 mg/day of SF have a comparable effect on anemia to that of 1500 mg/day of FC or 150 mg/day of SF with less increase in serum ferritin levels.

Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis.

BackgroundThis study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease.MethodsParticipants (n = 216) with baseline hemoglobin levels of 9–11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10–11.5 g/dL. The primary outcome was characterization of the dose–response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks.ResultsOver the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from −0.29 (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and −0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were ∼14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population.ConclusionsDaprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks.

No association between hyperhomocysteinemia and vascular access thrombosis in chronic hemodialysis.

PURPOSE. Hyperhomocysteinemia, recognized as a risk factor for cardiovascular diseases, has also been related with controversy to vascular access thrombosis in hemodialysis. Our objective was to determine if such an association could be found in our hemodialysis population. METHODS. The survey was conducted in a cohort of 165 chronic hemodialysis patients. Their vascular access history was considered from hemodialysis initiation until November 1999, including the number of vascular accesses created (either native or synthetic fistulae), focussing on vascular access thrombotic events, and excluding primary vascular access dysfunction. Diabetes, hemoglobin, erythropoietin dose, anticoagulation, and methyltetrahydrofolate reductase (MTHFR) status were considered. Serum total homocysteine (tHcy) measures were sampled for all patients in June 1998 and repeated yearly. Patients had not been supplemented routinely with hydrosoluble vitamins until June 1998, after which all received DiaVite (R&D Laboratories, CA, USA) daily. RESULTS. Median survival of native fistulae was significantly longer (81 months, 95%CI 35-127) than for synthetic fistulae (31 months, 95%CI 27-51). Median vascular access survival was reduced for diabetics vs non diabetics (28 vs 57 months) (p<0.05), whereas sex, age and smoking had no impact. No correlation was found between tHcy concentration and the number of vascular access thrombotic events; homozygotes for MTHFR had higher tHcy but no more vascular access thrombotic events. The 38 patients with a mean vascular access survival of less than 12 months (63 months) were compared to the 127 patients with a mean vascular access survival of >= 12 months (3925 months) (p<0.05): no difference in their respective tHcy concentrations before and after DiaVite introduction was found (3113 and 208 vs 3417 and 226 mol/L), but the first group presented more numerous synthetic fistulae (p<0.0001), lower hemoglobin levels, and higher erythropoietin doses. CONCLUSIONS. No significant association between hyperhomocysteinemia and vascular access thrombosis could be found in our population. DiaVite introduction allowed a significant reduction in tHcy, but had no impact on vascular access survival, except for a slight but not significant reduction in the prevalence of vascular access thrombotic events during the year on DiaVite. Potential benefits of approaches to reduce tHcy for vascular access time-life prolongation remain to be demonstrated.

High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial – Background, Aims, and Study Protocol

Background: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. Results and Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

Differential Effects of Low-Dose Erythropoietin in Rat Model of Diabetic Nephropathy

Background. Previous reports on the renoprotective effect of erythropoietin (EPO) in the setting of chronic kidney disease (CKD) have yielded conflicting results. The aim of this study is to clarify the effect of low, non-hematopoietic dose of EPO on the evolution of diabetic nephropathy (DN) in rat model. Methods. Low dose of recombinant human EPO (150 U/kg, s.c. three times/week) was given to streptozotocin (STZ)-induced diabetic rats in two schedules; in the first one, EPO was given from day 2 after STZ injection till the end of the study (28 weeks) as prophylactic treatment; and in the other schedule EPO was given after development of DN (last 8 weeks) as therapeutic treatment. Albuminuria, blood pressure, creatinine clearance, renal venous oxygen tension (vPO2), plasma EPO, hematocrit and renal histopathology were assessed. Results. Unexpectedly, 28 weeks administration of EPO to diabetic rats led to aggravation of albuminuria and worsening of histopathological damage in spite of partial correction of renal hypoxia. Contrary to this, terminal 8 weeks EPO therapy of DN reduced albuminuria and demonstrated some favorable effects on biochemical changes and histologic picture. Conclusion. Low dose EPO exerted differential effects in rat model of DN according to treatment duration. In addition, findings of the present study warrants further investigations of the exact renoprotective role of EPO in diabetic patients with CKD who receive EPO therapy for long periods.