Efficacy of daprodustat for patients on dialysis with anemia: systematic review and network meta-analysis.

Chronic kidney disease (CKD) is commonly complicated by anemia. Treating dialysis-dependent patients with anemia, including daprodustat and other inhibitors of prolyl hydroxylase of hypoxia-inducible factor, recombinant human erythropoietin (rhEPO), and iron supplements. We conducted this study to test our postulation; daprodustat is superior to rhEPO and other conventional treatments respecting efficacy and safety parameters. We made systematic search through PubMed, Web of Science, Scopus, and Cochrane. Seven unique trials were eventually included for systematic review; six of them with a sample size of 759 patients entered our network meta-analysis (NMA). Daprodustat 25-30 mg was associated with the greatest change in serum hemoglobin (MD=1.86, 95%CI= [1.20; 2.52]), ferritin (MD= -180.84, 95%CI= [-264.47; -97.20]), and total iron binding capacity (TIBC) (MD=11.03, 95%CI= [3.15; 18.92]) from baseline values. Dialysis-dependent patients with anemia had a significant increment in serum Hemoglobin and TIBC and a reduction in serum ferritin, in a dose-dependent manner, when administered daprodustat.

Efficacy of recombinant erythropoietin for the late treatment of anemia of prematurity in a level IV neonatal intensive care unit: a retrospective single-center cohort study.

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

Evaluation of recombinant human erythropoietin as a promoter of bone healing in cats with femoral fractures.

Background: The bone regeneration potential of erythropoietin (EPO) is not yet fully investigated, but some previous experimental studies demonstrated that its application activated the differentiation of osteoblasts and promoted bone formation. Aim: The aim of the present study was to evaluate the effects of recombinant human erythropoietin (rhEpo) on bone healing in cats with fragmented long bone fractures. Methods: Twelve cats were divided into two groups-control (n = 6) in which physiological saline was applied at the fracture gap site and EPO (n = 6) with the application of 1,000 IU rhEpo. The effects of EPO on blood erythrocyte counts, hemoglobin content, and hematocrit were monitored by serial complete blood cell tests, whereas bone formation was evaluated by clinical and radiographic examinations on post-operative weeks 1, 2, 3, 4, 6, and 8. Results: All tested blood parameters were within the reference range. A faster fracture healing and full limb weight-bearing were observed in the EPO group, with statistically significant differences with respect to the control group. Conclusion: The obtained results confirmed that the local application of rhEpo promoted bone healing in cats with fragmented femoral fractures and increased bone callus strength without having significant systemic effects.

Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents.

BACKGROUND AND PURPOSE: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. KEY RESULTS: The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. CONCLUSIONS AND IMPLICATIONS: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.

Topical erythropoietin for the management of scleral necrosis after ocular chemical burns.

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

The Association between High-Dose Allopurinol and Erythropoietin Hyporesponsiveness in Advanced Chronic Kidney Disease: JOINT-KD Study.

INTRODUCTION: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5. METHODS: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs. RESULTS: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57). CONCLUSIONS: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents.

Subcutaneous Anti-inflammatory Therapies to Prevent Burn Progression in a Swine Model of Contact Burn Injury.

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

Topical ocular delivery of nanoparticles with epoetin beta in Wistar Hannover rats.

Topical instillation of drugs targeting the posterior ocular segment is an expanding area of research. Chitosan and hyaluronic acid have remarkable mucoadhesive properties and potentially enhance pre-corneal retention time after topical instillation. Bearing this in mind, we explored the possibility of delivering epoetin beta (EPOß) to the posterior segment of the eye in a chitosan-hyaluronic acid (CS/HA-EPOß) nanoparticulate system using the topical route of administration. Complete ophthalmological examinations, electroretinography and microhematocrit evaluations were performed in Wistar Hannover (WH) rats, before and after topical administration of nanoparticles. The right eye received CS/HA-EPOß and the left eye received only empty nanocarriers (control). Animals were split into 6 groups and at designated timepoints, all animals from each group (n = 3) were euthanized and both eyes enucleated. Retinal morphology and EPOß ocular distribution were assessed, respectively, through hematoxylin and eosin (HE) and immunofluorescence staining. After topical administration, no adverse ocular signs were noted and no significant changes either in microhematocrits nor in electroretinographies were detected. During the study, intraocular pressure (IOP) was always kept within physiological range bilaterally. No histological changes were detected in any of the ocular globes. Immunofluorescence enabled the identification of EPOß in the retina 12 h after the administration, its presence still being detectable at day 21. In conclusion, CS/HA nanoparticles could efficiently deliver EPOß to the retina of WH rats after topical instillation, being considered biologically safe. Topical administration of this nanoformulation could be a valuable tool for retinal neuroprotection, decreasing risks associated with more invasive routes of administration, being cost effective and also increasing long-term patients' compliance.

Investigation into the effect of systemic single high-dose erythropoietin on the healing of Achilles tendons in rats.

OBJECTIVE: This study aimed to examine systemic erythropoietin's effect on the Achilles tendon's healing in a rat model. METHODS: Twenty-five adult Wistar rats were randomly assigned to one of two groups. The Achilles tendon of each rat was transected 5 mm proximal to its insertion to the calcaneus. All Achilles tendons were then repaired using modified Kessler methods. A single dose (5000 U/kg) of intraperitoneal erythropoietin (EPO) was administered to group I. Group II was a control group and did not receive an EPO injection. Four rats from each group were sacrificed at 1, 3 and 6 weeks after injection. Histopathological assessments were performed by observers blinded to the treatment. RESULTS: Groups I and II showed a similar increase in fibroblast cytoplasmic content and fibrillar collagen in the extracellular matrix. Collagen deposition, cellular proliferation, number of lipid vacuoles and capillary increases were similar between the groups. CONCLUSION: Evidence from this study has shown no direct effect of a single systemic high dose of EPO on the histological properties of the Achilles tendon in rats.

Protective effect of NeuroEPO on the reproduction of diabetic rats / Efecto protector de la NeuroEPO en la reproducción de ratas diabéticas

Introduction: Pregestational diabetes constitutes a reproductive risk which requires new treatment strategies. NeuroEPO, a variant of the recombinant human erythropoietin produced in Cuba, has neuroprotective and hypoglycemic effects which can be considered for the treatment of this entity. Objective: To evaluate the protective effect of NeuroEPO on the reproduction of diabetic rats. Material and Methods: Four groups of adult female Wistar rats with streptozotocin-induced diabetes were used. During pregnancy, one group received the vehicle and the rest of the groups received different doses of NeuroEPO (0,5 mg/kg, 0,75 mg/kg, and 1 mg/kg) subcutaneously, on alternate days, for a total of six applications. A group of non-diabetic rats was used as a control group. Glycemia and reproductive variables were evaluated. For comparisons, Analysis of Variance and Fisher's Exact Test were used. There were significant differences with p-values less than 0,05. Results: The group with vehicle presented maintained hyperglycemia, fewer implantations, and embryos, and increased gestational losses. In the group receiving 0,5 mg/kg of NeuroEPO, glycemia decreased significantly and the results of the reproductive variables were similar to the group of non-diabetic rats. With higher doses of NeuroEPO, gestational losses were increased. No congenital malformations were identified in either group. Conclusions: The repeated administration of 0,5 mg/kg of NeuroEPO has a beneficial effect on the reproduction of diabetic rats, which may be associated with the reduction of hyperglycemia. Other cytoprotective mechanisms of NeuroEPO should be evaluated in future studies(AU)

Introducción: la diabetes pre-gestacional constituye un riesgo reproductivo, lo que requiere nuevas estrategias de tratamiento. Teniendo en cuenta que la NeuroEPO, una variante de la eritropoyetina recombinante humana producida en Cuba, tiene efectos neuroprotectores e hipoglicemiantes. Objetivo: evaluar el efecto protector de la NeuroEPO en la reproducción de ratas diabéticas. Material y Métodos: se utilizaron cuatro grupos de ratas Wistar hembras adultas, con diabetes inducida por estreptozotocina. Durante la gestación, un grupo recibió el vehículo y el resto diferentes dosis de NeuroEPO (0,5 mg/kg, 0,75 mg/kg y 1 mg/kg), por vía subcutánea, en días alternos, para un total de seis aplicaciones. Se empleó un grupo de ratas no-diabéticas como control. Se evaluó la glicemia y variables reproductivas. Para las comparaciones se empleó el Análisis de Varianza y la Prueba Exacta de Fisher. Las diferencias se consideraron significativas con valores de p menores que 0,05. Resultados: el grupo con vehículo presentó hiperglicemia mantenida, menor número de implantaciones y embriones, e incremento de las pérdidas gestacionales. En el grupo que recibió 0,5 mg/kg de NeuroEPO, la glicemia disminuyó de forma significativa y los resultados de las variables reproductivas fueron similares al grupo de ratas no-diabéticas. Con las dosis superiores de NeuroEPO se incrementaron las pérdidas gestacionales. No se identificaron malformaciones congénitas en ninguno de los grupos. Conclusiones: la administración reiterada de 0,5 mg/kg de NeuroEPO tiene efecto beneficioso en la reproducción de ratas diabéticas, que puede estar asociado a la reducción de la hiperglicemia. Otros mecanismos citoprotectores de la NeuroEPO deben ser evaluados en futuros estudios(AU)

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: The renoprotective effects of erythropoietin (EPO) are well-known; however, the optimal timing of EPO administration remains controversial. Red blood cell (RBC) transfusion is an independent risk factor for cardiac surgery-associated acute kidney injury (CSA-AKI). We aimed to evaluate the efficacy of EPO on CSA-AKI and RBC transfusion according to the timing of administration. METHODS: We searched the Cochrane Library, EMBASE, and MEDLINE databases for randomized controlled trials. The primary outcome was the incidence of CSA-AKI following perioperative EPO administration, and the secondary outcomes were changes in serum creatinine, S-cystatin C, S-neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, length of hospital and intensive care unit (ICU) stay, volume of RBC transfusion, and mortality. The subgroup analysis was stratified according to the timing of EPO administration in relation to surgery. RESULTS: Eight randomized controlled trials with 610 patients were included in the study. EPO administration significantly decreased the incidence of CSA-AKI (odds ratio: 0.60, 95% confidence interval [CI]: 0.43-0.85, P = .004; I2 = 52%; P for heterogeneity = .04), intra-operative RBC transfusion (standardized mean difference: -0.30, 95% CI: -0.55 to -0.05, P = .02; I2 = 15%, P for heterogeneity = .31), and hospital length of stay (mean difference: -1.54 days, 95% CI: -2.70 to -0.39, P = .009; I2 = 75%, P for heterogeneity = .001) compared with control groups. Subgroup analyses revealed that pre-operative EPO treatment significantly reduced the incidence of CSA-AKI, intra-operative RBC transfusion, serum creatinine, and length of hospital and ICU stay. CONCLUSION: Pre-operative administration of EPO may reduce the incidence of CSA-AKI and RBC transfusion, but not in patients administered EPO during the intra-operative or postoperative period. Therefore, pre-operative EPO treatment can be considered to improve postoperative outcomes by decreasing the length of hospital and ICU stay in patients undergoing cardiac surgery.

Chitosan and Hyaluronic Acid Nanoparticles as Vehicles of Epoetin Beta for Subconjunctival Ocular Delivery.

Neuroprotection in glaucoma using epoetin beta (EPOß) has yielded promising results. Our team has developed chitosan-hyaluronic acid nanoparticles (CS/HA) designed to carry EPOß into the ocular globe, improving the drug's mucoadhesion and retention time on the ocular surface to increase its bioavailability. In the present in vivo study, we explored the possibility of delivering EPOß to the eye through subconjunctival administration of chitosan-hyaluronic acid-EPOß (CS/HA-EPOß) nanoparticles. Healthy Wistar Hannover rats (n = 21) were split into 7 groups and underwent complete ophthalmological examinations, including electroretinography and microhematocrit evaluations before and after the subconjunctival administrations. CS/HA-EPOß nanoparticles were administered to the right eye (OD), and the contralateral eye (OS) served as control. At selected timepoints, animals from each group (n = 3) were euthanized, and both eyes were enucleated for histological evaluation (immunofluorescence and HE). No adverse ocular signs, no changes in the microhematocrits (≈45%), and no deviations in the electroretinographies in both photopic and scotopic exams were observed after the administrations (p < 0.05). Intraocular pressure remained in the physiological range during the assays (11-22 mmHg). EPOß was detected in the retina by immunofluorescence 12 h after the subconjunctival administration and remained detectable until day 21. We concluded that CS/HA nanoparticles could efficiently deliver EPOß into the retina, and this alternative was considered biologically safe. This nanoformulation could be a promising tool for treating retinopathies, namely optic nerve degeneration associated with glaucoma.

Erythropoietin and iron for anemia in HIV-infected patients undergoing maintenance hemodialysis in China: a cross-sectional study.

BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD) and HIV infection. The number of people living with HIV on hemodialysis (HD) is increasing. However, there is no data about anemia and related therapies in this kind of patients in China. We aim to assess the difference in hemoglobin (Hgb) and treatments like erythropoietin and iron between HIV-HD patients and HD patients in Chengdu, China. METHODS: This cross-sectional study was conducted with data collection from January 2020 to June 2020. Thirty-four HIV-infected HD patients and thirty-five non-HIV-infected HD patients were included. Age, gender, dialysis vintage, single-pool (sp) Kt/V, Hgb, the dose of erythropoietin, ferritin, use of iron preparations, and serum albumin were collected in all patients. Time since HIV diagnosis, counts of CD4 + T cells, HIV RNA, and antiretroviral therapy for HIV infection were collected in HIV-infected patients. T-test, Mann-Whitney U test, and chi-square statistics were applied in SPSS. RESULTS: The Hgb of HIV-HD and HD groups were 105.70 (95.93-112.08) g/L and 112.00 (93.00-126.00) g/L respectively (P = 0.064). There was a statistically significant higher erythropoietin dosage used in the HIV-HD population (222.55 ± 115.47 U/kg/week) compared to the HIV-negative HD group (161.86 ± 110.31 U/kg/week) (P = 0.029). 16/34 (47.06%) HIV-HD patients and 5/35 (14.29%) HD patients were treated with iron preparations (P = 0.003). The ferritin levels were 316.50 (117.38-589.75) ng/ml and 272.70 (205.00-434.00) ng/ml in HIV-HD and HD groups respectively. CONCLUSIONS: A higher erythropoietin dosage and a higher probability of iron preparations may be required to maintain Hgb in HIV-HD patients compared with HD patients.

Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

OBJECTIVES: To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.

Detection of recombinant erythropoietin biosimilar Jimaixin™ after administration in healthy subjects.

Jimaixin™ (Jintan Ltd, China) is a biosimilar of recombinant erythropoietin (rEPO) now authorized for therapeutic application in China. With a risk of abuse by athletes, a clear evaluation of its detection using the electrophoretic methods in use in antidoping laboratories was necessary. In a previous work, we showed that Jimaixin™ electrophoretic profile presented slight changes compared with the original drug (first generation rEPO) and that a spike of Jimaixin™ in urine and serum was well identified by SDS-PAGE but with less performance by IEF-PAGE unless a neuraminidase treatment was applied first. The aims of this research were to perform an intravenous administration of Jimaixin™ on three healthy subjects (one microdose [10 IU/kg] and three therapeutic doses [50 IU/kg]) and to evaluate the detection in urine and blood up to 7 days post administration. Analysis of the samples showed that Jimaixin™ detection was complicated by IEF-PAGE due to the loss of the most distinctive basic isoforms. In addition, a neuraminidase treatment did not improve detection (contrary to the observations from spike experiments). On the contrary, Jimaixin™ was very efficiently detected in blood and urine by SDS-PAGE: up to 40 h after a microdose and up to 7 days after the therapeutic doses. The effect of Jimaixin™ on hematological parameters was limited to a clear but transitory increase of the reticulocytes. These data give new elements to better survey a potential misuse of Jimaixin™ by athletes.

Use of Erythropoietin and Fibrin Glue Mixture for Peripheral Nerve Repair.

BACKGROUND: Erythropoietin has neuroregenerative effects. Fibrin glue may be used for nerve repair and controlled release of substances. In this study, the authors investigated the effects of erythropoietin-containing fibrin glue on nerve repair, based on the hypothesis that erythropoietin-containing fibrin glue would positively affect nerve regeneration. METHODS: Thirty-six Long-Evans rats were used. The animals were divided into six groups. Their left sciatic nerves were isolated, transected, and repaired with saline-containing fibrin glue in group 1, with erythropoietin-containing fibrin glue in group 2, with saline-containing fibrin glue and two sutures in group 3, with erythropoietin-containing fibrin glue and two sutures in group 4, with two sutures in group 5, and with four sutures in group 6. Sciatic Functional Index calculation, pin-prick test, and toe-spread test were performed on days 21, 42, and 63. All animals were killed on day 63. The nerve sections were analyzed histologically. RESULTS: The Sciatic Functional Index, pin-prick test, and toe-spread test results were the best in group 4 and the worst in group 5. Group 4 showed superior Schwann cell proliferation (p < 0.05). Groups with epineural suture use (groups 3, 4, 5, and 6) had higher endoneurial collagen synthesis scores than the groups without suture use (groups 1 and 2) (p < 0.05). The myelin protein zero immunostaining results were significantly higher in the erythropoietin-treated groups (groups 2 and 4) (p < 0.05). CONCLUSION: The combined use of erythropoietin-containing fibrin glue and two epineural sutures (group 4) showed a statistically significant improvement in many parameters. CLINICAL RELEVANCE STATEMENT: Fibrin glue is already used in nerve repair. Adding erythropoietin to fibrin glue could be a safe and easy option to improve nerve regeneration.

EpoR stimulates rapid cycling and larger red cells during mouse and human erythropoiesis.

The erythroid terminal differentiation program couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is essential for erythroblast survival, but its other functions are not well characterized. Here we use Epor-/- mouse erythroblasts endowed with survival signaling to identify novel non-redundant EpoR functions. We find that, paradoxically, EpoR signaling increases red cell size while also increasing the number and speed of erythroblast cell cycles. EpoR-regulation of cell size is independent of established red cell size regulation by iron. High erythropoietin (Epo) increases red cell size in wild-type mice and in human volunteers. The increase in mean corpuscular volume (MCV) outlasts the duration of Epo treatment and is not the result of increased reticulocyte number. Our work shows that EpoR signaling alters the relationship between cycling and cell size. Further, diagnostic interpretations of increased MCV should now include high Epo levels and hypoxic stress.

Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury.

Due to (i) the uremia-enhanced sepsis severity, (ii) the high prevalence of sepsis with pre-existing renal injury and (iii) the non-erythropoiesis immunomodulation of erythropoietin (EPO), EPO was tested in sepsis with pre-existing renal injury models with the retrospective exploration in patients. Then, EPO was subcutaneously administered in mice with (i) cecal ligation and puncture (CLP) after renal injury including 5/6 nephrectomy (5/6Nx-CLP) and bilateral nephrectomy (BiNx-CLP) or sham surgery (sham-CLP) and (ii) lipopolysaccharide (LPS) injection, along with testing in macrophages. In patients, the data of EPO administration and the disease characteristics in patients with sepsis-induced acute kidney injury (sepsis-AKI) were evaluated. As such, increased endogenous EPO was demonstrated in all sepsis models, including BiNx-CLP despite the reduced liver erythropoietin receptor (EPOR), using Western blot analysis and gene expression, in liver (partly through hepatocyte apoptosis). A high-dose EPO, but not a low-dose, attenuated sepsis in mouse models as determined by mortality and serum inflammatory cytokines. Furthermore, EPO attenuated inflammatory responses in LPS-activated macrophages as determined by supernatant cytokines and the expression of several inflammatory genes (iNOS, IL-1ß, STAT3 and NFκB). In parallel, patients with sepsis-AKI who were treated with the high-dose EPO showed favorable outcomes, particularly the 29-day mortality rate. In conclusion, high-dose EPO attenuated sepsis with preconditioning renal injury in mice possibly through the macrophage anti-inflammatory effect, which might be beneficial in some patients.