rHuEPO Group Research Articles

The role of erythropoietin to prevent red blood cell transfusion in a 2018-2020 two-center cohort of preterm infants.

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

Comparison between the influence of roxadustat and recombinant human erythropoietin treatment on blood pressure and cardio-cerebrovascular complications in patients undergoing peritoneal dialysis.

Roxadustat treatment in PD patients is equivalent to ESAs in increasing hemoglobin (Hb). But blood pressure, cardiovascular parameters, cardio-cerebrovascular complications and prognosis in the two groups before and after treatment has not been sufficiently discussed. Sixty PD patients who were treated with roxadustat for renal anemia in our PD center recruited from June 2019 to April 2020 as roxadustat group. PD patients treated with rHuEPO were enrolled at a 1:1 ratio as rHuEPO group using the method of propensity score matching. Hb, blood pressure, cardiovascular parameters, cardio-cerebrovascular complications and prognosis were compared between the two group. All patients were followed up for at least 24 months. There were no significant differences in baseline clinical data or laboratory values between roxadustat group and rHuEPO group. After 24 months of follow-up, there was no significant difference in Hb levels (p > 0.05). There were no significant changes in blood pressure, or the incidence of nocturnal hypertension before and after treatment in roxadustat group (p > 0.05), while blood pressure significantly increased in rHuEPO group after treatment (p < 0.05). Compared with roxadustat group after follow-up, rHuEPO group had a higher incidence of hypertension, the levels of cardiovascular parameters were worse and cardio-cerebrovascular complications had a higher incidence (p < 0.05). Cox regression analysis showed age, systolic blood pressure, fasting blood glucose, and rHuEPO use before baseline were risk factors for cardio-cerebrovascular complications in PD patients, while treatment with roxadustat was a protective factor for cardiovascular and cerebrovascular complications. Compared with rHuEPO, roxadustat had less influence on blood pressure or cardiovascular parameters, and it was associated with a lower risk of cardio-cerebrovascular complications in patients undergoing PD. Roxadustat has a cardio-cerebrovascular protective advantage in PD patients with renal anemia.

Thyroid function analysis after roxadustat or erythropoietin treatment in patients with renal anemia: a cohort study

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.

Comparison of risk of peritoneal dialysis-associated peritonitis between roxadustat and recombinant human erythropoietin in peritoneal dialysis patients: a retrospective comparative cohort study

Roxadustat and recombinant human erythropoietin (rhuEPO) have been approved for the treatment of renal anemia in patients undergoing dialysis. The comparison of risk of peritoneal dialysis (PD)-associated peritonitis between roxadustat and rhuEPO in PD patients remains uncertain. We aimed to compare the risk of PD-associated peritonitis between roxadustat and rhuEPO and examine possible modifiers for the comparison in PD patients. A total of 437 PD patients with renal anemia (defined as hemoglobin ≤10.0 g/dL) from 4 centers were selected. Participants were scheduled for follow-up every 1-3 months at each center. We compared differences in baseline characteristics by medication group and 1:1 matching group based on propensity scores. PD-associated peritonitis was defined according to the International Society for Peritoneal Dialysis guidelines. Univariable and multivariable Cox proportional hazard analyses were performed to compare the risk of PD-associated peritonitis between roxadustat and rhuEPO in PD patients. Propensity score matching method was used to examine the robustness of results. A total of 437 participants, including 291 in roxadustat group and 146 in rhuEPO group, were included in the current study, respectively. During a median follow-up of 13.0 (25th-75th, 10.0-15.0) months, PD-associated peritonitis occurred in 68 patients, including 26 of 291 (0.10 episodes per patient-year) patients in the roxadustat group and 42 of 146 (0.27 episodes per patient-year) patients in the rhuEPO group. Overall, compared to patients in the rhuEPO group, the roxadustat group (hazard ratio, 0.345; 95% confidence interval: 0.202-0.589) was associated with a lower risk of PD-associated peritonitis with adjustment of use of roxadustat medication, age, sex, hypertension status, diabetes status, dialysis vintage, serum potassium, hemoglobin, and albumin. Furthermore, the results were consistent with the propensity score analysis. None of the variables, including age, sex, body mass index, PD vintage, presence of residual renal function, hemoglobin, albumin, serum potassium, and C-reactive protein levels, significantly modified the associations. Our study demonstrated that compared with rhuEPO, roxadustat may reduce the risk of PD-associated peritonitis in PD patients, highlighting the importance of roxadustat for the prevention of PD-associated peritonitis in PD patients.

Micro‐doses of Recombinant Human Erythropoietin Enhance Endurance Performance While Indirect Detection by The Athlete Biological Passport Is Improved by Including The Immature Reticulocyte Fraction

Recombinant human erythropoietin (rHuEPO) is ergogenic but micro-doses remain a challenge for anti-doping authorities. Here, we investigated the hypothesis that frequent micro-doses of rHuEPO enhance maximal oxygen consumption (VO2max) and time trial performance and that the combination of immature reticulocyte fraction (IRF) and the Athlete's Biological Passport (ABP) would enhance detection compared to the ABP alone. In a randomized, double-blinded, placebo-controlled design, 34 trained (VO2max: 52 ± 7 ml×min-1×kg-1, mean ± SD) adults received either rHuEPO (rHuEPO: epoetin-β, 9 IU/kg, n = 16) or placebo (PLA: 0.9% NaCl, n = 18) three times a week for four weeks. Before and after the intervention, VO2max, mean power output during a 400-kcal time trial and total hemoglobin mass (tHb) were measured. Venous blood samples were collected before, each week during rHuEPO administration, and 3, 5 and 10 days after the last injection. Hematological values were evaluated using dedicated ABP software. VO2max increased by 4.7% (p<0.01) and tHb increased by 6.8% (p<0.001) in the rHuEPO group when compared to the PLA group where no changes were evident. Mean power output during the time trial increased by 4.0% (p<0.01) in the rHuEPO group with no changes observed in the PLA group. Inclusion of IRF thresholds improved ABP sensitivity from 47% to 73%, yielding a peak sensitivity during the first two weeks of the rHuEPO treatment and 10 days after cessation of treatment. In conclusion, these findings show that four weeks of rHuEPO micro-doses are sufficient to induce considerable ergogenic effects on both VO2max and time trial performance in trained adults. The inclusion of IRF thresholds into the ABP improved sensitivity during treatment and the viability of including IRF into the ABP should be considered although more studies are needed.

Does subcutaneous administration of recombinant human erythropoietin increase thrombotic events in total hip arthroplasty? A prospective thrombelastography analysis

BackgroundAnemia is one of severe complications in the perioperative period of total hip arthroplasty (THA). Erythropoietin (EPO) has been considered to improve patients’ anemia state, but its efficiency and safety remains controversial.MethodsA total of 152 patients who underwent total hip arthroplasty from January 2017 to March 2019 were randomized to 2 groups. Recombinant human erythropoietin (rHu-EPO) group was treated with rHu-EPO subcutaneous injection 10000 IU after operation and once daily in the next week, while control group was treated with none extra treatment. Routine hematologic examination and thrombelastography (TEG) performed at different time point respectively. Doppler ultrasound for bilateral lower limbs was performed 1 day before surgery and 7 days after surgery. Auxiliary examination outcomes, blood transfusions outcomes, and postoperative complications were recorded as assessment indicators.ResultsThe difference in the relevant indexes of traditional coagulation and TEG values between two groups were not significantly. No significant difference was observed in the incidence of thromboembolism events and other complications between two groups during postoperative period. The amount of intraoperative blood loss was similar between the two groups. However, the postoperative use and dosage of allogeneic blood in the rHu-EPO group were lower than those in the control group. The hemoglobin and hematocrit level in the rHu-EPO group were higher than that in the control group after surgery.ConclusionPostoperative subcutaneous injection of rHu-EPO can improve hematological anemia-related parameters, reduce the use and dosage of allogeneic blood transfusions (ABTs), and has no significant influence on the formation of thrombosis and other complications in patients undergoing total hip arthroplasty in short term.

Additive effect of erythropoietin use on exercise-induced endothelial activation and hypercoagulability in athletes

PurposeRecombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations.MethodsThis double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18–50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-β; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort.ResultsrHuEPO increased P-selectin (+ 7.8% (1.5–14.5), p = 0.02) and E-selectin (+ 8.6% (2.0–15.7), p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0–24.3%), p = 0.0004) higher E-selectin and 32.1% ((4.6–66.8%), p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group.ConclusionIn conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use.

Effect of Zinc Supplementation on Renal Anemia in 5/6-Nephrectomized Rats and a Comparison with Treatment with Recombinant Human Erythropoietin.

Anemia is a severe complication in patients with chronic kidney disease (CKD). Treatment with exogenous erythropoietin (EPO) can correct anemia in many with CKD. We produced 5/6-nephrectomized rats that became uremic and anemic at 25 days post surgery. Injection of the anemic 5/6-nephrectomized rats with 2.8 mg zinc/kg body weight raised their red blood cell (RBC) levels from approximately 85% of the control to 95% in one day and continued for 4 days. We compared the effect of ZnSO4 and recombinant human erythropoietin (rHuEPO) injections on relieving anemia in 5/6-nephrectomized rats. After three consecutive injections, both the ZnSO4 and rHuEPO groups had significantly higher RBC levels (98 ± 6% and 102 ± 6% of the control) than the saline group (90 ± 3% of the control). In vivo, zinc relieved anemia in 5/6-nephrectomized rats similar to rHuEPO. In vitro, we cultured rat bone marrow cells supplemented with ZnCl2, rHuEPO, or saline. In a 4-day suspension culture, we found that zinc induced erythropoiesis similar to rHuEPO. When rat bone marrow cells were supplement-cultured with zinc, we found that zinc stimulated the production of EPO in the culture medium and that the level of EPO produced was dependent on the concentration of zinc supplemented. The production of EPO via zinc supplementation was involved in the process of erythropoiesis.

Effect of preoperative recombinant human erythropoietin administration on inflammatory lung injury due to cardiopulmonary bypass

Objective To discuss the effects of preoperative use of recombinant human erythropoietin (rHuEPO) on inflammatory lung injury patients after cardiopulmonary bypass (CPB) under extracorporeal circulation. Methods A total of 54 patients who were scheduled to receive elective open cardiac operations under CPB were enrolled. They were divided into two groups(n=27). rHuEPO group: patients were titrated intravenously with rHuEPO (100 IU/kg, diluted into 50 ml normal saline) for consecutive three days at the same time period before operation. Control group: equivalent normal saline in place of rHuEPO was given to patients via venous injection. Peak airway pressure (Ppeak), plateau pressure (Pplat), and pulmonary dynamic compliance (Cdyn) were well monitored and recorded before CPB (T1), immediately after chest closure (T2), and 2, 4 h and 6 h after surgery (T3, T4, and T5). At T1, T2, T5, and 12, 24, 48 h, and 72 h after surgery (T6, T7, T8, and T9), arterial oxygenation indices (OI) were also recorded. Furthermore, at pre-rHuEPO treatment (T0), T1, T2, T5, T6, T7, T8, and T9, the plasma levels of the tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-10 were measured. The time of mechanical ventilation and stay in intense care unit (ICU), discharge time and hospitalization stay were also recorded. Results Compared with the control group, Cdyn in the rHuEPO group at T2-T5 were significantly increased (P<0.05), whereas Ppeak and Pplat were decreased (P<0.05). OI values of rHuEPO group at T2 and T5-T9 were significantly higher than that of control group(P<0.05). It was demonstrated that at any time point after closing chest, the plasma concentrations of TNF-α, IL-1β, and IL-10 in both groups were relatively elevated compared with those before, while the concentrations of TNF-α and IL-1β in the rHuEPO group were lower than those in control group (P<0.05). Compared with the control group, patients receiving rHuEPO treatment underwent an apparent reduction in both mechanical ventilation and staying time in ICU (P<0.05). Conclusions Preoperative rHuEPO administration can attenuate the inflammatory lung injury after CPB via the anti-inflammation pathway and ameliorate pulmonary functions. Key words: Recombinant human erythropoietin; Cardiopulmonary bypass; Lung injury; Inflammatory response

Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration

BackgroundRecombinant human erythropoietin (rHuEpo) can improve human performance and is therefore frequently abused by athletes. As a result, the World Anti-Doping Agency (WADA) introduced the Athlete Biological Passport (ABP) as an indirect method to detect blood doping. Despite this progress, challenges remain to detect blood manipulations such as the use of microdoses of rHuEpo.MethodsForty-five whole-blood transcriptional markers of rHuEpo previously derived from a high-dose rHuEpo administration trial were used to assess whether microdoses of rHuEpo could be detected in 14 trained subjects and whether these markers may be confounded by exercise (n = 14 trained subjects) and altitude training (n = 21 elite runners and n = 4 elite rowers, respectively). Differential gene expression analysis was carried out following normalisation and significance declared following application of a 5% false discovery rate (FDR) and a 1.5 fold-change. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo.ResultsALAS2, BCL2L1, DCAF12, EPB42, GMPR, SELENBP1, SLC4A1, TMOD1 and TRIM58 were differentially expressed during and throughout the post phase of microdose rHuEpo administration. The CD247 and TRIM58 genes were significantly up- and down-regulated, respectively, immediately following exercise when compared with the baseline both before and after rHuEpo/placebo. No significant gene expression changes were found 30 min after exercise in either rHuEpo or placebo groups. ALAS2, BCL2L1, DCAF12, SLC4A1, TMOD1 and TRIM58 tended to be significantly expressed in the elite runners ten days after arriving at altitude and one week after returning from altitude (FDR > 0.059, fold-change varying from 1.39 to 1.63). Following application of the adaptive model, 15 genes showed a high sensitivity (≥ 93%) and specificity (≥ 71%), with BCL2L1 and CSDA having the highest sensitivity (93%) and specificity (93%).ConclusionsCurrent results provide further evidence that transcriptional biomarkers can strengthen the ABP approach by significantly prolonging the detection window and improving the sensitivity and specificity of blood doping detection. Further studies are required to confirm, and if necessary, integrate the confounding effects of altitude training on blood doping.

Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial

Substances that potentially enhance performance (eg, recombinant human erythropoietin [rHuEPO]) are considered doping and are therefore forbidden in sports; however, the scientific evidence behind doping is frequently weak. We aimed to determine the effects of rHuEPO treatment in well trained cyclists on maximal, submaximal, and race performance and on safety, and to present a model clinical study for doping research on other substances. We did this double-blind, randomised, placebo-controlled trial at the Centre for Human Drug Research in Leiden (Netherlands). We enrolled healthy, well trained but non-professional male cyclists aged 18-50 years and randomly allocated (1:1) them to receive abdominal subcutaneous injections of rHuEPO (epoetin β; mean dose 6000 IU per week) or placebo (0·9% NaCl) for 8 weeks. Randomisation was stratified by age groups (18-34 years and 35-50 years), with a code generated by a statistician who was not masked to the study. The primary outcome was exercise performance, measured as maximal power output (Pmax), maximal oxygen consumption VO2 max, and gross efficiency in maximal exercise tests with 25 W increments per 5 min, as lactate threshold and ventilatory threshold 1 (VT1) and 2 (VT2) at submaximal levels during the maximal exercise test, and as mean power, VO2, and heart rate in the submaximal exercise tests at the highest mean power output for 45 min in a laboratory setting and in a race to the Mont Ventoux (France) summit, using intention-to-treat analyses. The trial is registered with the Dutch Trial Registry (Nederlands Trial Register), number NTR5643. Between March 7, 2016, and April 13, 2016, we randomly assigned 48 participants to the rHuEPO group (n=24) or the placebo group (n=24). Mean haemoglobin concentration (9·6 mmol/L vs 9·0 mmol/L [estimated difference 0·6, 95% CI 0·4 to 0·8]) and maximal power output (351·55 W vs 341·23 W [10·32, 3·47 to 17·17]), and VO2 max (60·121 mL/min per kg vs 57·415 mL/min per kg [2·707, 0·911 to 4·503]) in a maximal exercise test were higher in the rHuEPO group compared with the placebo group. Submaximal exercise test parameters mean power output (283·18 W vs 277·28 W [5·90, -0·87 to 12·67]) and VO2 (50·288 mL/min per kg vs 49·642 mL/min per kg [0·646, -1·307 to 2·600]) at day 46, and Mont Ventoux race times (1 h 40 min 32 s vs 1 h 40 min 15 s [0·3%, -8·3 to 9·6]) did not differ between groups. All adverse events were grade 1-2 and were similar between both groups. No events of grade 3 or worse were observed. Although rHuEPO treatment improved a laboratory test of maximal exercise, the more clinically relevant submaximal exercise test performance and road race performance were not affected. This study shows that clinical studies with doping substances can be done adequately and safely and are relevant in determining effects of alleged performance-enhancing drugs. Centre for Human Drug Research, Leiden.

Effect of Short-term Erythropoietin Therapy on Insulin Resistance and Serum Levels of Leptin and Neuropeptide Y in Hemodialysis Patients.

Introduction:Insulin resistance (IR) is a known complication of end-stage kidney disease (ESKD). It may be an important therapeutic target in stages of chronic kidney disease.Aim:The study was conducted to evaluate the effect of short-term treatment with recombinant human erythropoietin (rHuEpo) therapy on IR, serum leptin, and neuropeptide Y in ESKD patients on hemodialysis.Materials and Methods:Thirty ESKD patients were enrolled in the study and were randomly assigned into two groups. Erythropoietin (rHuEpo) group consisted of 15 patients (7 females, 8 males, mean age 47.8 ± 9.3 years) treated with rHuEpo therapy after each session of dialysis. No-rHuEpo group consisted of 15 patients (7 females, 8 males, mean age 45.5 ± 8.6 years) not treated with rHuEpo. In addition to, control group consisted of 15 healthy controls (6 females, 9 males, mean age 48.8 ± 11 years).Results:The mean fasting insulin (11 ± 4.2 mU/L) and homeostatic model assessment of IR (HOMA-IR) test (2.6 ± 1.1) were significantly higher in ESKD patients than control group (6.6 ± 1.4 mU/L and 1.5 ± 0.3, respectively). There were significant decreases in glycated hemoglobin (HbA1c) (5.6 ± 1%), fasting insulin level (9.3 ± 3.1 μU/mL), HOMA-IR (2.2 ± 0.7), and serum leptin levels (17.4 ± 8.7 ng/mL) also significant increase in neuropeptide Y levels (113 ± 9.9 pg/mL) after 3 months of rHuEpo therapy, in addition to further significantly decrease fasting insulin levels (7.1 ± 2.1 μU/mL) and HOMA-IR (1.7 ± 6) after 6 months in rHuEpo group. In contrast, there were significantly increases in HbA1c% (5.9 ± 0.5%) and leptin levels (42.3 ± 25.3 ng/mL) in No-rHuEpo group throughout the study.Conclusion:IR and hyperleptinemia are improved by recombinant human erythropoietin therapy.

Effect of Predialysis Recombinant Human Erythropoietin on Early Survival After Hemodialysis Initiation in Patients With Chronic Kidney Disease: Co-JET Study.

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

Effect of recombinant human erythropoietin expressions of apoptosis genes in rats following traumatic brain injury

Purpose: To explore the effect of recombinant human erythropoietin (r-HuEPO) on apoptosis in rats after traumatic brain injury.Methods: A total of 48 traumatic brain-injured Sprague Dawley (SD) rats were obtained by improved Feeney’s traumatic brain injury model, and were randomly divided into four groups: normal salinetreated rats (control) and rats treated with r-HuEPO at doses of 1000 U/kg, 3000 U/kg and 5000 U/kg. Brain tissues were collected on the 7th day after trauma surgery. Apoptotic cells, and NF-kappa B (NFĸB)-, c-myc-, and Fas/Fasl-positive cells were identified in brain tissues by immunohistochemical assay.Results: After treatment with r-HuEPO (3000 and 5000 U/kg), expression of NF-κB and Fas/Fasl were significantly decreased (p &lt; 0.05) compared to control rats, especially at the 5000 U/kg dose (p &lt; 0.01). However, for c-myc, no significant difference was observed between r-HuEPO treatment and control groups (p &gt; 0.05). Compared to the 1000 U/kg r-HuEPO group, Fas/Fasl expression levels were significantly lower in the 3000 and 5000 U/kg r-HuEPO groups (p &lt; 0.05). Additionally, expression of NF-κB and Fasl in the 5000 U/kg r-HuEPO group was significantly lower than that in the 3000 U/kg r- HuEPO group (p &lt; 0.05). Moreover, the number of apoptotic cells in the r-HuEPO group (5000 U/kg) was significantly lower than in the control group (p &lt; 0.05).Conclusion: Thus, r-HuEPO may be beneficial for treating traumatic brain injury via inhibition of NFkappa B and Fas/Fasl expressions.Keywords: Recombinant human erythropoietin, NF-kappa B, Traumatic brain injury, Apoptosis, Neuronal damage, Fas/Fasl expression

Effect of recombinant human erythropoietin on brain injury in patients undergoing cardiac valve replacement with cardiopulmonary bypass

Objective To evaluate the effect of recombinant human erythropoietin (rHuEPO) on brain injury in the patients undergoing cardiac valve replacement with cardiopulmonary bypass (CPB). Methods Forty-five patients with chronic valvular heart disease, aged 36-62 yr, weighing 42-92 kg, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, with New York Heart Association of Ⅱ or Ⅲ, undergoing cardiac valve replacement with CPB, were randomly divided into 3 groups (n=15 each) using a random number table: control group (group C), and different doses of rHuEPO groups (EPO1 group, EPO2 group). In EPO1 and EPO2 groups, rHuEPO 40 and 80 IU/kg were injected intravenously before anesthesia induction, respectively.Before anesthesia induction (T0, baseline value), immediately after endotracheal intubation (T1), immediately after aortic cannulation (T2), immediately after cannulation of superior and inferior vena cava (T3), immediately after the beginning of CPB (T4), when each index was decreased to the minimal value during CPB (T5), after rewarming to 36.5 ℃ (T6), immediately after termination of CPB (T7), and at 1 h after termination of CPB (T8), regional cerebral oxygen saturation (rSO2), tissue hemoglobin index (THI), and changes in concentrations of oxyhemoglobin(△O2Hb), deoxyhemoglobin (△HHb) and total hemoglobin (△cHb) in bilateral frontal lobes were recorded.The patients whose minimal rSO2 ≤50% and decrease in minimal rSO2 ≥20% of the baseline value (△rSO2) were recorded.At T0, T8 and 2 h after termination of CPB (T9), venous blood samples were taken for determination of serum concentrations of S100 protein and neuron-specific enolase (NSE) by ELISA.At 1 day before surgery and 8 days after surgery, the patient's cognitive function was assessed using Mini-Mental State Examination, the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Digit Symbol subtest of the WAIS-R, the Trailing Making Test (Part A) and the Stroop Color Word Interference Test, while depression and anxiety were assessed by Zung Self-Rating Depression Scale and Zung Self-Rating Anxiety Scale, respectively.The occurrence of postoperative cognitive dysfunction was recorded. Results There was no significant difference among the three groups in bilateral rSO2 and △cHb, incidence of bilateral rSO2 ≤50% and postoperative cognitive dysfunction, Zung Self-Rating Depression Scale score, and Zung Self-Rating anxiety Scale score at each time point (P>0.05). Compared with group C, the incidence of left △rSO2≥20% was significantly decreased, the right △O2Hb was increased at T6, 8, the serum NSE concentrations were decreased at T9, the serum S100 protein concentrations were decreased at T8, and the number of the Digit Symbol subtest of the WAIS-R completed was increased in group EPO1, and right THI was significantly decreased at T2, T3, T5, T7 and T8, right △HHb was increased at T2 and T3, and the completion time of Stroop color word interference test B was shortened at 8 days after surgery in group EPO2 (P<0.05 or 0.01). Compared with group EPO1, the incidence of left △rSO2≥20% was significantly increased, the right THI was decreased at T2-4 and T6-8, and the left △O2Hb at T6-7 and right △O2Hb at T8 were decreased in group EPO2 (P<0.05). Conclusion rHuEPO 40 IU/kg injected intravenously before induction of anesthesia can mitigate brain injury in the patients undergoing cardiac valve replacement with CPB. Key words: Erythropoietin, recombinant; Brain injuries; Cardiopulmonary bypass; Heart valve prosthesis implantation

Recombinant human erythropoietin (rHuEPO) reduces transfusion requirements in anaemia of prematurity

Background: During the last two decades with the application of advanced technological supports have improved the survival rate of preterm very low birth weight (PT VLBW) infants. At the same time anemia of prematurity (AOP) one of the most frequent complications of these patients also has been increased in the neonatal units. Packed red blood cell (PRBC) transfusions are the mainstay of treatment of AOP. The frequency of blood transfusion is directly related to the exposure of the tiny preterm infants to various risks of transfusion.Objectives : To evaluate whether recombinant human erythropoietin (rHuEPO) therapy reduces the need of transfusions in AOP.Methods : A randomized controlled trial study was carried out at Neonatal Unit and Intensive Care Unit (ICU) of Dhaka Shishu (children) Hospital, Dhaka, Bangladesh with 60 PTVLBW neonates. Among them 30 in group I (rHuEPO group) and 30 in group II (control) were assigned. Therapy with rHuEPO (200 IU / kg / dose) thrice weekly was initiated on day 7 of life to group I for 2 weeks. From day 14 or after that as soon as enteral feeding was initiated oral iron and folic acid were received by both groups. Hematological assessment (haemoglobin, haematocrit level and reticulocyte count) were done at 6 and 10 weeks of life.Results : At the time of enrollment in the study PTLBW babies of both groups were almost similar in gestetional age, birth weight, hemoglobin, hematocrit values and reticulocyte count (p&gt;0.05). During the 10 weeks observation period, hematological values were increased and the number of blood transfusions as well as the number of infants who received any transfusion were reduced in rHuEPO group compared to control group (p&lt;0.01). No adverse effect of erythropoietin were found.Conclusion : The combination of rHuEPO and Iron, folic acid therapy significantly reduces the number of blood transfusion as well as the percentage of infants who received any transfusion in AOP.Northern International Medical College Journal Vol.6(2) 2015: 53-56

Skin regeneration in deep second-degree scald injuries either by infusion pumping or topical application of recombinant human erythropoietin gel.

Large doses of recombinant growth factors formulated in solution form directly injected into the body is usual clinical practice in treating second-degree scald injuries, with promising results, but this approach creates side effects; furthermore, it may not allow appropriate levels of the factor to be sensed by the target injured tissue/organ in the specific time frame, owing to complications arising from regeneration. In this research, two delivery methods (infusion pumping and local topical application) were applied to deliver recombinant human erythropoietin (rHuEPO) for skin regeneration. First, rHuEPO was given in deep second-degree scald injury sites in mice by infusion pump. Vascularization was remarkably higher in the rHuEPO pumping group than in controls. Second, local topical application of rHuEPO gel was given in deep second-degree scald injury sites in rats. Histological analysis showed that epithelialization rate was significantly higher in the rHuEPO gel-treated group than in controls. Immunohistochemical studies showed that the rHuEPO gel-treated group showed remarkably higher expression of skin regeneration makers than the control group. An accurate method for visualization and quantification of blood vessel networks in target areas has still not been developed up to this point, because of technical difficulties in detecting such thin blood vessels. A method which utilizes a series of steps to enhance the image, removes noise from image background, and tracks the vessels edges for vessel segmentation and quantification has been used in this study. Using image analysis methods, we were able to detect the microvascular networks of newly formed blood vessels (less than 500 μm thickness), which participate in the healing process, providing not only nutrition and oxygen to grow tissues but also necessary growth factors to grow tissue cells for complete skin regeneration. The rHuEPO-treated group showed higher expression of stem cell markers (CD 31, CD 90, CD 71, and nestin), which actively contribute to in-wound-healing processes for new hair follicle generation as well as skin regeneration. Collectively, both rHuEPO group pumping into the systemic circulation system, and injection into the local injury area, prompted mice and rats to form new blood vessel networks in scald injury sites, which significantly participate in the scald healing process. These results may lead to the development of novel treatments for scald wounds.

Perioperative administration of high-dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta-analysis.

Delayed graft function (DGF) due to ischemia-reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta-analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high-dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I(2) = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47-1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25-11.68, P = 0.02). Perioperative, high-dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.

Acetylsalicylic acid mitigates erythropoietin-associated blood pressure increase in nonuremic rats

Background: Approximately 30% of the chronic kidney disease patients using recombinant human erythropoietin (rhuEPO) have an increase in blood pressure (BP). Its mechanism and whether it depends on renal function remain unclear. There is early evidence that acetylsalicylic acid (ASA) prevents the rhuEPO-induced increase in BP. This study aims to verify whether very high doses of rhuEPO can increase BP in nonuremic rats and whether the co-administration of ASA can prevent it. Methods: Forty male Wistar rats were divided into four groups: placebo/placebo; placebo/rhuEPO 200 UI/kg thrice weekly; placebo/ASA 50 mg/kg daily; rhuEPO 200 UI/kg thrice weekly/ASA 50 mg/kg daily. Hematocrit was measured before and after and systolic BP was measured weekly by tail-cuff technique. Direct measurement of the BP was obtained at the end. Results: The rhuEPO groups had higher final hematocrit (rhuEPO/placebo 56.7 ± 7.6, rhuEPO/ASA 56.7 ± 7.7; p < 0.001 versus placebo/placebo, 42.2 ± 4.7 and ASA/placebo 41.2 ± 4.2); and also increase in systolic BP (rhuEPO/placebo 135.1 ± 15.0, p = 0.01 and rhuEPO/ASA 127.2 ± 6.8, p = 0.02), whereas BP in rats from placebo/placebo (120.9 ± 5.0, p = 0.18) and placebo/ASA (124.6 ± 13.3, p = 0.12) groups remained unchanged. By direct measurement, the final BP was higher in rhuEPO/placebo (DBP 123.1 ± 12.0; SBP 157.4 ± 12.5; MBP 139.8 ± 11.9) than placebo/placebo (DBP 105.1 ± 11.5; SBP 141.0 ± 12.6; MBP 122.1 ± 12.1) and placebo/ASA groups (DBP 106.6 ± 8.1; SBP 141.5 ± 8.4, MBP 122.1 ± 7.2) (p < 0.05 by post hoc Bonferroni test ANOVA). The rhuEPO/ASA group (PAD 115.1 ± 11.4, PAS 147.4 ± 9.1, MBP 130.1 ± 10.3) was not different from other groups. Conclusions: The administration of very high doses of rhuEPO is associated with an increase in hematocrit and BP in nonuremic rats. The concomitant use of ASA mitigates the rhuEPO-associated BP increase.

Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery: a randomized, double-blind controlled trial

BackgroundCardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication following coronary bypass graft (CABG) surgery. Multi-factorial causes of CSA-AKI involve oxidative stress and inflammation. Erythropoietin (EPO) has been shown from many studies to have a reno-protective effect. The present study was conducted to examine the role of EPO in preventing CSA-AKI.MethodsThis prospective, randomized, double-blind, placebo-controlled trial was conducted in the Cardiovascular and Thoracic Unit. One hundred patients randomly received either 200 U/kg of rHuEPO (n = 50) or saline (n = 50) intravenously three days before operation, and rHuEPO 100 U/kg or saline at operation time. The serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and urine neutrophil gelatinase-associated lipocaline (NGAL) were measured in order to evaluate renal injury following CABG.ResultsThe incidence of CSA-AKI was significantly lower in rHuEPO group (14%) when compared with the placebo group (38%; p < 0.01). The mean intensive care unit (ICU) and hospital stays of the rHuEPO group were significantly shorter than the placebo group (p < 0.01). Postoperative increases in SCr and decreases in eGFR were significantly lower in the rHuEPO group than the placebo group (p < 0.05). The mean urine NGAL in rHuEPO group was significantly lower than the placebo group at 3 hr, 6 hr, 12 hr and 18 hr after CABG (p < 0.05), respectively.ConclusionsProphylaxis administration with intravenous rHuEPO before cardiac surgery decreased the incidence of CSA-AKI and urine NGAL with reduced days in ICU and hospital in elective CABG patients.Trial registrationClinicalTrials.gov: NCT01066351