Doses Of Recombinant Human Erythropoietin Research Articles

Pattern of Monthly Percentage of Hemodialysis Children Achieving the KDIGO Recommended Hemoglobin Targets: A Twelve-Month Prospective Study to Assess the Trend of Anemia

Abstract Background Anemia is one of the common problems in children on maintenance hemodialysis (HD). It leads to poor quality of life and when severe, it is associated with cardiovascular dysfunction, cardiomyopathy, and death. Proper treatment of anemia in these patients results in better physical and mental performance. So, our study aimed to assess the trend of anemia among HD children by following the monthly percentage of patients capable of achieving Hb level between 11-12g/dl. Methods For optimum treatment of anemia, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (2012) recommended to measure Hb every month in HD children targeting monthly Hb concentration of 11-12 g/dl. So, we conducted this 12-months prospective study to assess the trend of anemia among HD children at Pediatric Dialysis Unit of Ain Shams University by following the monthly percentage of patients capable of achieving Hb level between 11-12g/dl. Results This study was done over 12 month-period from April 1st, 2020, till March 31st, 2021. A total of 78 patients were included with a mean age at the time of enrollment in the study of 12.16 ± 3.3 years. They were 45 (57.7%) males and 33 (42.3%) females. All patients were receiving 3 hours every other day HD session for 3 sessions a week with a HD duration range of 3.0 - 140.88 months and a median of 16.51 months. All patients were receiving proper doses of recombinant human erythropoietin (rHuEPO) and intravenous iron therapy. Our study showed that the monthly reported percentages of patients achieved Hb level between 11-12g/dl ranged from 14.7% to 40.8% and that of patients with Hb level <11g/dl ranged between 51.4 – 73.5%. It also revealed statistical evidence of significant association between the presence of anemia in our patients at the time of enrollment in the study and HD durations < 6 months (p < 0.05). Conclusion Despite proper HD treatment and proper doses of recombinant human erythropoietin (rHuEPO) and intravenous iron therapy, anemia is still a prevalent problem among our HD children.

The Impact of Intravenous Iron Supplementation on Hematinic Parameters and Erythropoietin Requirements in Hemodialysis Patients.

Anemia is one of the most common complications of chronic kidney disease (CKD). As a result of the side effects of high doses of recombinant human erythropoietin (rhEPO) and the differences in the standard dose of the injectable iron, this study aimed to evaluate the effect of high and low intravenous iron supplementation on hematinic parameters and EPO requirements in patients under hemodialysis. This multicenter, randomized, double-blind clinical trial was conducted on 60 patients with CKD admitted to Sina and 29 Bahman hospitals in Tabriz, Iran in 2019-2020 to undergo hemodialysis. In the two studied groups, low (100mg/week) and high (400mg/week) doses of iron were administered and subjects were followed up for 6months. The incidence of acute myocardial ischemia, stroke, and mortality during 6months was recorded. The required rhEPO dosage (mg/week) to maintain hemoglobin levels between 10 and 12g/dL in the high-dose iron group was significantly decreased during the follow-up period (52,129.03 ± 23,810 vs. 45,760 ± 20,978.71, P ≤ 0.028). Transferrin saturation (TSAT) index had a significant upward trend after iron injection and significant correlations with the serum levels of Fe (r ≥ 0.353, P ≤ 0.007), ferritin (r ≥ 0.315, P ≤ 0.016), and total iron binding capacity (r ≥ 0.219, P < 0.050) during the follow-up period in the studied groups. High-dose intravenous iron (400mg/week) can reduce the mean dose of rhEPO requirements and increase the TSAT index over a period of 6months in hemodialysis patients. High-dose IV iron administration can decrease cardiovascular events in hemodialysis patients with iron deficiency anemia.

The Use of RNA‐based 5’‐Aminolevulinate Synthase 2 Biomarkers in Dried Blood Spots to detect rhEPO Micro Doses and Hypoxic Stimulation

The hematological module of the Athlete Biological Passport (ABP) is used for indirect detection of blood manipulations; however, the use of this method to detect doping e.g. with micro doses of recombinant human erythropoietin (rhEPO) is problematic. For this reason, sensitivity of ABP have to be enhance with the implementation of new biomarkers. Here we demonstrated that RNA-based 5’-Aminolevulinate Synthase 2 (ALAS2) could be a useful biomarker to improve the indirect detection of rhEPO micro dosing. Moreover, satisfying results were obtain also for specificity in order to distinguish rhEPO administrations from a sojourn in hypoxic conditions. Samples from two different clinical studies were used to monitor levels of different RNA markers, linear-circular (LC) and linear (L), of ALAS2 RNA, Carbonate anhydrase 1 (CA1) and Solute Carrier family 4 member 1 (SLC4A1) after rhEPO microdoses administration and under hypoxic condition. Analysis of RNA based biomarkerswere performed using dried blood spots (DBSs), these ones provide many advantages in terms of the samples collection, transport and storage. In order to monitored transcirptomics biomarkers variations, manual extraction of RNA from DBSs were performed follow by a RT-qPCR. Transcriptomics biomarkerswere monitored along 16 days where five micro doses were administrated, ALAS2 markers illustrated an increase up to 300% in comparison with the baseline value and these variations were statistically different from evolution in control group. Additionally, also CA1 variated in a significant way due to micro doses administrations. Moreover, ALAS2 markers variations under hypoxic conditions are not significant when compared with control group, which is the opposite of CA1 or reticulocytes percentage, where significant differences were obtained. Finally, SLC4A1 has no significant variation in both conditions. This study demonstrated that transcriptomic biomarkers, in particular ALAS2 mRNAs, could be used to improve the sensitivity and specificity of the hematological module of the ABP, and are compatible with the use of DBSs for anti-doping analyses. The expression level of SLC4A1 was not increased by micro doses of rhEPO, indicating that it is not a beneficial biomarker to detect micro dosing. CA1 is an interesting candidate, although, unlike ALAS2, its expression level was increased also significantly following exposure to hypoxia.

Proteomic analysis of plasma proteins of high-flux haemodialysis and on-line haemodiafiltration patients reveals differences in transthyretin levels related with anaemia

A large proportion of end-stage renal disease (ESRD) patients under long-term haemodialysis, have persistent anaemia and require high doses of recombinant human erythropoietin (rhEPO). However, the underlying mechanisms of renal anaemia have not been fully elucidated in these patients. In this study, we will be focusing on anaemia and plasma proteins in ESRD patients on high-flux haemodialysis (HF) and on-line haemodiafiltration (HDF), to investigate using two proteomic approaches if patients undergoing these treatments develop differences in their plasma protein composition and how this could be related to their anaemia. The demographic and biochemical data revealed that HDF patients had lower anaemia and much lower rhEPO requirements than HF patients. Regarding their plasma proteomes, HDF patients had increased levels of a protein highly similar to serotransferrin, trypsin-1 and immunoglobulin heavy constant chain alpha-1, and lower levels of alpha-1 antitrypsin, transthyretin, apolipoproteins E and C-III, and haptoglobin-related protein. Lower transthyretin levels in HDF patients were further confirmed by transthyretin-peptide quantification and western blot detection. Since ESRD patients have increased transthyretin, a protein that can aggregate and inhibit transferrin endocytosis and erythropoiesis, our finding that HDF patients have lower transthyretin and lower anaemia suggests that the decrease in transthyretin plasma levels would allow an increase in transferrin endocytosis, contributing to erythropoiesis. Thus, transthyretin could be a critical actor for anaemia in ESRD patients and a novel player for haemodialysis adequacy.

Low doses of recombinant human erythropoietin does not affect C-terminal FGF23 in healthy men.

Recombinant human erythropoietin (rhEpo) can improve human performance, but misuse remains difficult to detect. C-terminal fibroblast growth factor 23 (cFGF23) was recently demonstrated to increase following injection of a single high dose rhEpo, but the effect of more frequent low doses is unknown. Using a randomized double-blind placebo-controlled design, we investigated whether 2 weeks of subcutaneous injections three times a week of 50 IU/kg Eprex (low-dose) or 20 IU/kg Eprex (micro-dose) increase cFGF23 levels compared with saline (placebo) injections in 24 healthy males. Venous blood was sampled at day -3, 0, 1, 3, 11, 14, 18, and 25 of the treatment and analyzed for cFGF23 and erythropoietin concentration ([EPO]). The level of cFGF23 was similar at days -3, 0, 1, 3, 11, 14, 18, and 25 with the low-dose (23 ± 4, 26 ± 5, 23 ± 7, 27 ± 6, 25 ± 8, 24 ± 10, 22 ± 5, and 24 ± 7 RU/mL, respectively), micro-dose (23 ± 6, 25 ± 5, 23 ± 8, 28 ± 9, 27 ± 7, 25 ± 9, 25 ± 5, and 23 ± 6 RU/mL, respectively) and placebo (23 ± 6, 24 ± 6, 26 ± 7, 26 ± 6, 31 ± 6, 31 ± 7, 24 ± 4, and 27 ± 8 RU/mL, respectively) treatment. The correlation coefficient between plasma [EPO] and plasma cFGF23 levels was R2 = 0.01 and insignificant. The results demonstrate that cFGF23 is not sensitive to low doses of subcutaneous rhEpo injections in healthy males.

Application of Reticulocyte-Based Estimation of Red Blood Cell Lifespan in Anemia Management of End-Stage Renal Disease Patients.

Shortened red blood cell (RBC) lifespan is one of the major factors contributing to anemia in end-stage renal disease (ESRD) patients and should be taken into account in anemia management protocols. In this study, we aimed to estimate RBC lifespan and the source of between-subject variability in ESRD patients. The resulting individual parameters (empirical Bayes estimates) were used to predict hemoglobin concentrations 2weeks in advance. The reticulocyte-based estimation of RBC lifespan (REBEL) and the population modeling of RBC count data were used. A total of 120 blood samples collected biweekly over 10weeks in 24 patients receiving maintenance doses of recombinant human erythropoietin (rHuEPO) subcutaneously were included in this analysis. Typical RBC lifespan was estimated to be 63.3days. RBC lifespan was found to increase with erythroferrone, a recently identified hormone participating in iron metabolism. Approximately, a 10% increase in plasma erythroferrone was associated with a 5% increase in RBC lifespan. In addition, RBC lifespan was 18.7% shorter in females compared with males. Out of 24 subjects, 16 had hemoglobin concentrations predicted within 95% prediction intervals. The median absolute prediction error was 15.9% (interquartile range, 9.5 to 24.7%). We demonstrated that REBEL coupled with the population modeling technique can be used effectively to estimate RBC lifespan. Then, individual parameters can be used to predict future hemoglobin concentrations in ESRD patients.

Role of Erythropoietin in Cerebral Glioma: An Innovative Target in Neuro-Oncology

Erythropoietin (EPO) is a cytokine primarily involved in the regulation of erythropoiesis. In response to hypoxia-ischemia, hypoxia-inducible factor 1 induces EPO production, which, in turn, inhibits apoptosis of erythroid progenitor cells. By the same mechanism and acting through other signaling pathways, EPO exerts neuroprotective effects. Increased resistance to hypoxia and decreased apoptosis are thought to be important mechanisms for tumor progression, including malignant glioma. Because recent studies have demonstrated that EPO and its receptor (EPOR) are expressed in several tumors and can promote tumor growth, in the present study, we investigated EPO and EPOR expression in human glioma and the effect of EPO administration in a rat model of glioma implantation. Using Western blotting and immunohistochemical analysis, we examined the expression of EPO, EPOR, platelet endothelial cell adhesion molecule, and Ki-67 in human glioma specimens and experimentally induced glioma in rats. In the experimental setting, a daily dose of recombinant human EPO (rHuEPO) or saline solution were administered for 21 days in Fischer rats subjected to 9L cell line implantation. In both human and animal specimens, we found an increase in EPOR expression as long as the lesion presented with an increasing malignant pattern. A significant direct correlation was found between the expression of EPOR and Ki-67 and EPOR and platelet endothelial cell adhesion molecule in low- and high-grade gliomas. The rats treated with rHuEPO presented with significantly larger tumor spread compared with the saline-treated rats. The results of our study have shown that the EPO/EPOR complex might play a significant role in the aggressive behavior of high-grade gliomas. The larger tumor spread in rHuEPO-treated rats suggests a feasible role for EPO in the aggressiveness and progression of malignant glioma.

Erythropoietin protects the subventricular zone and inhibits reactive astrogliosis in kaolin-induced hydrocephalic rats.

To elucidate the potential role of erythropoietin (EPO) as a neuroprotective agent against reactive astrogliosis and reducing the thinning rate of subventricular zone (SVZ) in kaolin-induced hydrocephalic rats. Thirty-six ten-week-old Sprague-Dawley rats were used in this study. Hydrocephalus was induced with 20% kaolin suspension injected into the cistern of thirty rats and leaving the six rats as normal group. The hydrocephalic rats were randomly divided into hydrocephalic and treatment group. The treatment group received daily dose of recombinant human erythropoietin (rhEPO) from day 7 to day 21 after induction. The animals were sacrificed at 7 (only for hydrocephalic group) and 14 or 21 (for both groups) days after induction. Brain was removed and was prepared for histological analysis by hematoxylin and eosin staining as well as immunohistochemistry for 4-HNE, GFAP, Iba-1, and Ki-67. Histopathological analysis showed that animals treated with rhEPO had a reduced astrocyte reactivity displayed by lower GFAP expression. Hydrocephalic rats received rhEPO also displayed reduced microglial activation shown by lower Iba-1 protein expression. Exogenous rhEPO exerted its protective action in reducing astrogliosis by inhibiting lipid peroxidation that was documented in this study as lower expression of 4-HNE than non-treated group. The SVZ thickness was progressively declining in hydrocephalus group, while the progression rate could be reduced by rhEPO. Erythropoietin has a potential use for inhibiting lipid peroxidation, and reactive astrogliosis in hydrocephalic animal model. The reduced thinning rate of SVZ demonstrated that EPO also had effect in reducing the hydrocephalus progressivity. Further research is warranted to explore its efficacy and safety to use in clinical setting.

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.

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.

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.

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.

Soluble transferrin receptor as a marker of erythropoiesis in patients undergoing high-flux hemodialysis.

Anemia is a common complication in chronic kidney disease (CKD) patients receiving hemodialysis. The effect of high-flux dialysis (HFD) on anemia remains unclear. This prospective study aimed to evaluate the effect of HFD on anemia, and the potential of soluble transferrin receptor (sTfR) as a marker of iron status and erythropoiesis in CKD patients on hemodialysis. Forty patients, who switched from conventional low-flux dialysis to HFD for 12 months, were enrolled in this study. The levels of sTfR, hemoglobin (Hb), iron, and nutritional markers, as well as the dose of recombinant human erythropoietin (rhEPO) and use of chalybeate were determined at 0, 2, 6, and 12 months after starting HFD. HFD significantly increased the hemoglobin level and reduced sTfR level in CKD patients (p < 0.05). In addition, significant decreasing linear trends were observed for rhEPO dosage and chalybeate use (p < 0.05). The level of sTfR was positively correlated with the percentage of reticulocytes (RET%), rhEPO dose, and chalybeate use, while it was negatively correlated with Hb levels and total iron-binding capacity results (all p < 0.05). A univariate generalized estimating equation (GEE) model showed that the Hb level, RET%, rhEPO dose, and chalybeate use were the variables associated with sTfR levels. A multivariate GEE model showed that the time points when hemodialysis was performed were the variables associated significantly with sTfR levels. Overall, our findings suggest that HFD can effectively improve renal anemia in hemodialysis patients, and sTfR could be used as a marker of erythropoiesis in HFD patients.

Low levels of serum ferritin and moderate transferrin saturation lead to adequate hemoglobin levels in hemodialysis patients, retrospective observational study.

BackgroundOptimal iron levels in patients on hemodialysis are currently unknown, and a higher level than that for the healthy population is usually set for such patients considering the use of erythropoiesis-stimulating agents or the occurrence of chronic inflammation. However, excessive iron causes oxidative stress and impairment of its utilization by cells. Therefore we investigated the relationship between hemoglobin (Hb) level and iron status in hemodialysis patients to identify the optimal iron levels for patients undergoing hemodialysis.MethodsA total of 208 outpatients on maintenance hemodialysis were followed up between July 2006 and June 2007. Men accounted for 64.9% cases [mean age, 59.3 ± 13.1 years and median dialysis history, 7.7 (3.6–13.2) years], and diabetic nephropathy accounted for 25.0% cases. Hemoglobin level was measured twice a month and serum ferritin, serum iron, and total iron-binding capacity were measured once a month. The doses of recombinant human erythropoietin and low-dose iron supplement were adjusted to maintain a hemoglobin level of 10–11 g/dL, according to the guidelines of the Japanese Society for Dialysis Therapy. Hepcidin was measured at baseline. Using the mean values for 1-year period, the relationships among hemoglobin, serum ferritin levels, and transferrin saturation levels were investigated based on a receiver operating characteristic curve and a logistic regression model. In addition, the correlations among serum ferritin, transferrin saturation, and hepcidin levels were analyzed by Pearson product—moment correlation coefficient and linear regression model.ResultsBy receiver operating characteristic curve, the cutoff point of serum ferritin and transferrin saturation levels with a hemoglobin ≥10 g/dL showed <90 ng/mL (sensitivity: 69.1%, specificity: 72.1%, p < 0.001) and ≥20% (sensitivity: 77.6%, specificity: 48.8%, p = 0.302).Upon logistic regression model analysis with a hemoglobin ≥10 g/dL as the endpoint, the analysis of odds ratios relative to a group with serum ferritin ≥90 ng/mL and transferrin saturation <20% revealed that the group with serum ferritin <90 ng/mL and transferrin saturation ≥20% had the highest ratio: 46.75 (95% confidence interval: 10.89–200.70, p < 0.001). In Pearson product—moment correlation coefficient, hepcidin showed a strong positive correlation with serum ferritin [r = 0.78 (95% confidence interval: 0.72–0.83, p < 0.001)] and a weak positive correlation with transferrin saturation [r = 0.18 (95% confidence interval: 0.04–0.31, p = 0.010)]. In the multivariable analyses of the linear regression model, a positive relationship was shown between hepcidin and serum ferritin [β-coefficient of 0.30 (95% confidence interval: 0.27–0.34, p < 0.001)]; however, no relationship was shown with transferrin saturation [β-coefficient of 0.09 (95% confidence interval: −0.31–0.49, p = 0.660)].ConclusionsIn this study, the iron status of serum ferritin <90 ng/mL and transferrin saturation ≥20% was optimal in hemodialysis patients receiving recombinant human erythropoietin for anemia therapy. This result indicates that the threshold values for the optimal iron status may be lower than those currently recommended in iron-level management guideline.

Pathophysiological aspects of red blood cells in end-stage renal disease patients resistant to recombinant human erythropoietin therapy.

Modified, bioreactive red blood cells (RBCs) and RBC-derived microvesicles (MVs) likely contribute to the hematological and cardiovascular complications in end-stage renal disease (ESRD). This study assesses the physiological profile of RBCs in patients with ESRD receiving standard or high doses of recombinant human erythropoietin (rhEPO). Blood samples from twenty-eight patients under sustained hemodialysis, responsive, or not to standard rhEPO administration were examined for RBC morphology, fragility, hemolysis, redox status, removal signaling, membrane protein composition, and microvesiculation before and after dialysis. Acute effects of uremic plasma on RBC features were examined in vitro through reconstitution experiments. Overall, the ESRD RBCs were characterized by pathological levels of shape distortions, surface removal signaling, and membrane exovesiculation, but reduced fragility compared to healthy RBCs. Irreversible transformation of RBCs was found to be a function of baseline Hb concentration. The more toxic uremic context in non-responsive patients compared to rhEPO responders was blunted in part by the antioxidant, antihemolytic, and anti-apoptotic effects of high rhEPO doses, and probably, of serum uric acid. A selective lower expression of RBC membrane in complement regulators (CD59, clusterin) and of CD47 "marker-of-self" was detected in non-responders and responders, respectively. Evidence for different short-term dialysis effects and probably for a different erythrocyte vesiculation mechanism in rhEPO responsive compared to non-responsive patients was also revealed. Deregulation of RBC homeostasis might involve diverse molecular pathways driving erythrocyte signaling and removal in rhEPO non-responders compared to responsive patients.

Study of association between interleukin-17 and interferon-gamma and recombinant human erythropoietin dose in patients undergoing peritoneal dialysis

BackgroundA common complication in patients undergoing peritoneal dialysis (PD) is a chronic inflammatory state and anemia that can be treating by recombinant human erythropoietin (rHuEPO). Higher required dose of rHuEPO could be expected in patients with higher cytokine levels. Additionally, it is known that peritoneal inflammation can be correlated with systemic inflammation and this could contribute to the compromised rHuEPO required dose in anemic patients with end stage renal disease (ESRD). Thus, the current study aimed to evaluate the association between levels of systemic and local interferon (IFN)-γ, interleukin (IL)-17 and other cytokines and the dose of rHuEPO used by patients undergoing PD for the correction of anemia. MethodsThirty-one patients under PD using rHuEPO were evaluated in this cross-sectional study. Plasma and dialysate levels of IL-2, IL-4, IL-6, IL-10, IL-17, tumour necrosis factor (TNF)-α and IFN-γ were determined using the Cytometric Bead Array TM kit (CBA; BD Bioscences, San Jose, CA). The relation between the levels of each cytokine levels and the tertiles of rHuEPO were plotted on box-plot graphics and then the medians of interleukins levels were compared by median comparison test. The significance level adopted was 5% and the analysis was performed by the softwares STATA (version 12.0) and GraphPad Prism 3.0. ResultsThe median of IL-17 and IFN-γ plasma levels were significant higher in the group with higher rHuEPO dosage. However, this association was not observed in the dialysate levels, as well as was not observed a relationship between the other plasma and dialysate cytokines evaluated in this study and the dose of rHuEPO. ConclusionsOur study found increased IL-17 and IFN-γ plasma, but no dialysate levels, in patients receiving higher doses of rHuEPO, suggesting may exist a relationship between systemic inflammation of ESRD, and the necessary levels of rHuEPO for the correction of anemia in these patients.

Study of anemia in nondialysis dependent chronic kidney disease with special reference to serum hepcidin.

We studied the role of serum hepcidin in anemia of chronic kidney disease (CKD) in a hospital-based cross-sectional study. Serum hepcidin, ferritin, and high-sensitivity C-reactive protein (hsCRP) levels were evaluated in patients of CKD. Hepcidin levels were increased in patients as compared to healthy adults. Hepcidin levels increased as CKD progressed through stage 3–5 (P trend = 0.015) but did not correlate with estimated glomerular filtration rate. Hepcidin correlated positively with ferritin (P < 0.0001) and transferrin saturation (TSAT) (P = 0.0217) and negatively with erythropoietin (EPO) levels (P = 0.0258) but did not correlate with either hsCRP or estimated glomerular filtration rate. Iron status influenced hepcidin levels of patients. Patients were divided according to iron status on the basis of TSAT and serum ferritin levels. We observed that while absolute iron deficiency (transferrin saturation <20%, ferritin <40 ng/ml) is associated with downregulation of hepcidin, hepcidin is elevated in other two categories of CKD patients (P = 0.0039). Iron status of patients also influenced interaction between hepcidin and hemoglobin (Hb). Hepcidin correlated negatively with Hb in patients with sufficient iron status (r = −0.7452, P < 0.0001) but nearly correlated positively with Hb in patients with absolute iron deficiency (r = 0.9428, P = 0.0572). Almost similar association persisted when cutoff value for serum ferritin was raised to 100 ng/ml as per NKF/KDOQI 2006 clinical practice guidelines except that no association was observed in absolute iron deficiency category. Cutoff value for hepcidin for differentiating absolute iron deficiency from other categories in our study population is ≤ 34 ng/ml (area under curve = 0.836, P < 0.0001). In conclusion, serum hepcidin level is increased in nondialysis CKD patients as compared to healthy adults possibly due to associated inflammation and decreased renal clearance. Furthermore, iron status modifies hepcidin level and its association with Hb. Raised hepcidin can predict the need for parenteral iron therapy and need for higher dose of recombinant human EPO to overcome iron-restricted erythropoiesis.

Recombinant human erythropoietin improves functional recovery in patients with severe traumatic brain injury: A randomized, double blind and controlled clinical trial

ObjectiveTo investigate the short-term effect of recombinant human erythropoietin (EPO) on patients with severe traumatic brain injury. MethodsOne hundred and fifty-nine patients with severe traumatic brain injury were randomly divided into EPO (n=79) and control group (n=80). EPO group was treated with subcutaneous injection of EPO (100 units/kg) on day 1, 3, 6, 9 and 12 following the brain injury. Glasgow outcome scores (GOS) were used to evaluate the outcomes three months after the treatment. Serum neuron specific enolase (NSE) and S-100β protein were measured within the first three months after treatment. ResultsIn the end, 146 patients (75 of the EPO group and 71 of the control group) completed the trial. Three months after the treatment, Good recovery was found in 33.3% of the EPO and 12.6% of the control group patients (p<0.05). Serum NSE and S-100β protein were decreased gradually in both groups after treatment, but their levels in the EPO group were lower than that of control group (p<0.05). There was no statistically significant difference in blood pressure, hemoglobin levels, pneumonia, sepsis or thromboembolic events between the two groups three months after the treatment (p>0.05). ConclusionTreatment with five doses of recombinant human erythropoietin is associated with an improved functional recovery in patients with severe traumatic brain injury. This treatment does not seem to increase the risk of thromboembolic events or severe infections.

Perioperative erythropoietin protects the CNS against ischemic lesions in patients after open heart surgery.

The aim of this study was to establish erythropoietin as aprotective factor against brain ischemia during open heart surgery. A total of 36consecutive patients scheduled for revascularization heart surgery were included in the study. Of the patients 18 received 3intravenous doses of recombinant human erythropoietin (rHuEpo, 24,000IU) and 18patients received aplacebo. Magnetic resonance imaging (MRI) to detect new brain ischemic lesions was performed. Additionally, S100A, S100B, neuron-specific enolaseA andB (NSE-A andB) and the concentration of antibodies against N‑methyl-D-aspartate receptors (NMDAR) to identify new neurological complications were determined. Patients who received rHuEpo showed no postoperative ischemic changes in the brain on MRI images. In the control group 5 (27.8 %) new ischemic lesions were found. The NMDAR antibody concentration, S100A, S100B and NSE showed no significant differences between the groups for new cerebral ischemia. High levels of lactate before and after external aortic compression (p= 0.022 and p= 0.048, respectively) and duration of operation could predict new ischemic lesions (p= 0.009). The addition of rHuEpo reduced the formation of lesions detectable by MRI in the brain and could be used clinically as neuroprotection in cardiac surgery.

Erythropoietin does not have effects on the ventilatory and pulmonary vascular response to acute hypoxia in men and women.

What is the central question of this study? Does a clinically relevant intravenous dose of erythropoeitin affect the hypoxic ventilatory response and/or hypoxic pulmonary vasoconstriction in healthy humans? What is the main finding and its importance? Erythropoeitin does not influence the ventilatory and pulmonary vascular responses to acute hypoxia in men or women. Sustained and chronic hypoxia lead to an increase in pulmonary ventilation (hypoxic ventilatory response, HVR) and to an increase in pulmonary vascular resistance (hypoxic pulmonary vasoconstriction, HPV). In this study, we examined the effect of a clinical i.v. dose of recombinant human erythropoietin (50IUkg-1 ) on the isocapnic HVR and HPV in seven male and seven female subjects by exposing them to hypoxia for 20min (end-tidal ∼50mmHg) while measuring their ventilation and estimating pulmonary arterial pressure from the maximal velocity of the regurgitant jet over the tricuspid valve during systole (ΔPmax ) with echocardiography. In the placebo session, after 5 and 20min men responded with an increase in ventilation by 0.0056 and 0.0023lmin-1 kg-1 , respectively, indicating the presence of hypoxic ventilatory depression. In women, the increase in ventilation was 0.0067 and 0.0047lmin-1 kg-1 , respectively. In both sexes, erythropoietin did not alter these responses significantly. In the placebo session, mean ΔPmax increased by 6.1±0.7mmHg in men (P=0.035) and by 8.4±1.4mmHg in women (P=0.020) during the hypoxic exposure, whereby women had a∼5mmHg lower end-tidal . Erythropoietin did not alter these responses; in men, ΔPmax increased by 7.5±1.1mmHg (n.s. versus placebo) and in women by 9.7±2.2mmHg (n.s. versus placebo). We conclude that women tended to have a greater HPV in placebo conditions and that a clinical dose of erythropoietin has no effect on the HVR and HPV in either sex.