-
1.
Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?
German, KR, Comstock, BA, Parikh, P, Whittington, D, Mayock, DE, Heagerty, PJ, Bahr, TM, Juul, SE
The Journal of pediatrics. 2022;:62-67.e1
-
-
Free full text
-
Abstract
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.
-
2.
Does the Combined Effect of Resistance Training with EPO and Iron Sulfate Improve Iron Metabolism in Older Individuals with End-Stage Renal Disease?
Corrêa, HL, Alfaro-Magallanes, VM, Moura, SRG, Neves, RVP, Deus, LA, Honorato, FS, Silva, VL, Raab, ATO, Maia, BCH, Padula, IA, et al
Nutrients. 2021;(9)
Abstract
We sought to investigate the effects of resistance training (RT) combined with erythropoietin (EPO) and iron sulfate on the hemoglobin, hepcidin, ferritin, iron status, and inflammatory profile in older individuals with end-stage renal disease (ESRD). ESRD patients (n: 157; age: 66.8 ± 3.6; body mass: 73 ± 15; body mass index: 27 ± 3), were assigned to control (CTL; n: 76) and exercise groups (RT; n: 81). The CTL group was divided according to the iron treatment received: without iron treatment (CTL-none; n = 19), treated only with iron sulfate or EPO (CTL-EPO or IRON; n = 19), and treated with both iron sulfate and EPO (CTL-EPO + IRON; n = 76). The RT group followed the same pattern: (RT-none; n = 20), (RT-EPO or IRON; n = 18), and (RT-EPO + IRON; n = 86). RT consisted of 24 weeks/3 days per week at moderate intensity of full-body resistance exercises prior to the hemodialysis section. The RT group, regardless of the iron treatment, improved iron metabolism in older individuals with ESRD. These results provide some clues on the effects of RT and its combination with EPO and iron sulfate in this population, highlighting RT as an important coadjutant in ESRD-iron deficiency.
-
3.
Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial.
Nangaku, M, Hamano, T, Akizawa, T, Tsubakihara, Y, Nagai, R, Okuda, N, Kurata, K, Nagakubo, T, Jones, NP, Endo, Y, et al
American journal of nephrology. 2021;(1):26-35
-
-
Free full text
-
Abstract
BACKGROUND Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. METHODS Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients and 25-250 μg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40-52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. RESULTS Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9 g/dL for CERA (n = 109; 95% CI 11.7-12.0); the difference between the groups was 0.1 g/dL (95% CI -0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of -1.0 g/dL. The mean hemoglobin level was within the target range (11.0-13.0 g/dL) during weeks 40-52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. CONCLUSIONS Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.
-
4.
Effect of enteral erythropoietin on feeding-related complications in preterm newborns: A pilot randomized controlled study.
Omar, OM, Massoud, MN, Ghazal, H, Hassouna, H, Somaa, MF
Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology. 2020;(1):37-42
Abstract
BACKGROUND AND STUDY AIMS To evaluate the effects of enteral administration of recombinant human erythropoietin (rhEPO) on feeding-related complications in preterm infants. PATIENTS AND METHODS This double-blind, randomized controlled pilot study enrolled 120 preterm infants born ≤ 32 weeks' gestation who were admitted to the neonatal intensive care unit in a tertiary hospital; 60 patients randomly received recombinant human erythropoietin while the other 60 received placebo. Newborns who underwent cardiopulmonary resuscitation, infants with genetic syndromes, infants with inborn errors of metabolism, infants with major congenital or acquired gastrointestinal tract malformations, infants with previous use of parenteral growth factors such as recombinant human erythropoietin and granulocyte-macrophage colony-stimuating factor (GM-CSF) and infants previously treated with intravenous immunoglobulin were excluded. Overall, 48 patients withdrew from the study because of intravenous haematopoietic growth factor intake or death before treatment was completed. A total of 72 preterm infants remained in the study: 36 preterm infants in the erythropoietin (EPO) group, and 36 preterm infants in the placebo group. The day that enteral feeding was successfully started, the time to establishing one-half, two-thirds, and full enteral feedings (reaching at least 150 mL/kg/day), the number of episodes of feeding intolerance, the time to regain birth weight and the incidence of necrotizing enterocolitis (NEC) were recorded. RESULTS Both groups showed no significant difference in the time to achieve one-half, two-thirds, or full enteral feeding, no signs of feeding intolerance, and no cases of NEC were recorded. CONCLUSION Enteral erythropoietin does not appear to affect feeding intolerance or NEC incidence.
-
5.
Clinical effectiveness of 3 days preoperative treatment with recombinant human erythropoietin in total knee arthroplasty surgery: a clinical trial.
Cao, SL, Ren, Y, Li, Z, Lin, J, Weng, XS, Feng, B
QJM : monthly journal of the Association of Physicians. 2020;(4):245-252
Abstract
AIMS: The purpose of study is to evaluate the effect and complication of preoperative short-term daily recombinant human erythropoietin (rhEPO) treatment for blood-saving in patients undergoing unilateral primary total knee arthroplasty (TKA). METHODS This three-arm randomized clinical trial compared three different rhEPO-based treatment protocols for unilateral primary TKA. Group A: application of daily doses of rhEPO combined with iron supplement starting 3 days before surgery; Group B: application of daily doses of rhEPO combined with iron supplement starting the day of surgery; Group C: iron supplement alone. Perioperative hemoglobin (Hb) level gaps, total perioperative blood loss, reticulocyte levels and treatment-related complications were studied. RESULTS A total of 102 patients were included (35, 35 and 32 patients in Groups A, B and C, respectively). Total blood loss (TBL) in Groups A, B and C was 490.84, 806.76 and 924.21 ml, respectively. Patients in Group A had a significant lower TBL than Groups B and C (A vs. B: P = 0.010; A vs. C: P < 0.001). There was no difference as for TBL between Groups B and C (P = 0.377). Group A patients had significant smaller Hb decline than Group C on the third and fifth postoperative day (P = 0.049, P = 0.037), as well as than Group B on the fifth postoperative day (P = 0.048). There was no difference as for Hb decline between Groups B and C. No difference was shown in levels of inflammatory biomarkers or blood-saving protocol-related complications among three groups. CONCLUSIONS Daily dose of rhEPO combined with iron supplement administered 3 days before TKA procedures could significantly decrease perioperative blood loss and improve postoperative Hb levels, without significantly elevating risks of complication, when compared with admission of rhEPO on the day of surgery and iron supplement alone. Preoperative daily rhEPO treatment could be a more effective blood-saving protocol in TKA procedures.
-
6.
Six weeks of oral Echinacea purpurea supplementation does not enhance the production of serum erythropoietin or erythropoietic status in recreationally active males with above-average aerobic fitness.
Martin, TD, Green, MS, Whitehead, MT, Scheett, TP, Webster, MJ, Hudson, GM
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2019;(7):791-795
Abstract
The purpose of this study was to investigate the effect of 6 weeks of oral Echinacea purpurea supplementation on serum erythropoietin (EPO) and erythropoietic status. Twenty-four males (mean ± SE; age = 25.2 ± 1.4 years, height = 178.1 ± 1.4 cm, body mass = 78.1 ± 1.6 kg, body fat = 12.7 ± 0.9%, maximal oxygen uptake = 52.9 ± 0.9 mL·kg-1·min-1) were randomly grouped using a matched-pair, double-blind design and self-administered 8000 mg·day-1 of either E. purpurea (n = 12) or placebo (n = 12) for 42 consecutive days. Blood samples were collected prior to supplementation (day 0) and every 2 weeks during the supplementation period (days 14, 28, and 42) and were analyzed for EPO, red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Separate 2 × 4 (group × time) factorial ANOVA with repeated measures on time were used to determine statistical differences with significance set at p ≤ 0.05. There were no significant interaction, group, or time effects observed for EPO or erythropoietic status markers for any of the measurement points (p ≤ 0.05). The present study indicated that 6 weeks of oral E. purpurea supplementation in recreationally active males with above average aerobic fitness did not enhance EPO or erythropoietic status. These findings are in contrast with previous reports of E. purpurea supplementation in untrained participants with average fitness levels, but consistent with observations in trained endurance athletes.
-
7.
Combination of intravitreal bevacizumab and erythropoietin versus intravitreal bevacizumab alone for refractory diabetic macular edema: a randomized double-blind clinical trial.
Entezari, M, Flavarjani, ZK, Ramezani, A, Nikkhah, H, Karimi, S, Moghadam, HF, Daftarian, N, Yaseri, M
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019;(11):2375-2380
Abstract
PURPOSE To evaluate the effect of three intravitreal bevacizumab (IVB) injections alone or in combination with intravitreal erythropoietin (EPO) in the treatment of refractory diabetic macular edema (DME). METHODS In a randomized double-blind clinical trial, 48 eyes of 34 diabetic patients with refractory DME were enrolled. Eyes were randomly assigned to receive either 3 monthly injections of 0.05 cc (1.25 mg) IVB plus 0.05 cc (1000 unit) EPO or 0.05 cc (1.25 mg) IVB alone. Main outcome was best-corrected visual acuity (BCVA) changes and secondary outcome was central macular thickness (CMT). The patients were followed for 6 months. RESULTS Mean BCVA changes up to 4 and 6 months were insignificant in both groups. It changed from 0.72 ± 0.56 logMAR at baseline to 0.74 ± 0.5 (P = 0.85) and 0.71 ± 0.44 (P = 0.40) in the combination group and from 0.48 ± 0.39 logMAR to 0.47 ± 0.35 (P = 0.48) and 0.52 ± 0.33 (P = 0.69) in the IVB alone group, at 4 and 6 months, respectively. The difference of mean BCVA changes between the groups was insignificant at both 4 and 6 months (P = 0.07 and P = 0.36, respectively). Within the group changes of mean CMT were significant only in the combination group at 4 and 6 months, from 518 ± 134 μ at baseline to 472 ± 151 to 475 ± 167 μ, respectively (P = 0.01 and P = 0.05). Corresponding changes were not significant in the IVB alone group. However, the difference between the groups was not significant at all visits (P = 0.51 and P = 0.71, respectively). CONCLUSIONS This clinical trial demonstrated that intravitreal erythropoietin had no additional effect to IVB in the treatment of refractory DME in the short term. TRIAL REGISTRATION Clinical trials.gov identifier: NCT03821168.
-
8.
Melatonin Improves Erythropoietin Hyporesponsiveness via Suppression of Inflammation.
Hameed, EN, Hadi Al Tukmagi, HF, Allami, HCA
Reviews on recent clinical trials. 2019;(3):203-208
Abstract
BACKGROUND Inadequate response to Erythropoietin Stimulating Agents (ESA) despite using relatively larger doses regimen represents a potential risk factor of Cardiovascular (CV) related mortality in addition to health-care economic problems in anemic patients with Chronic Kidney Disease (CKD). Erythropoietin (EPO) hyporesponsiveness related to inflammation has been increased progressively. Melatonin is well known as a potent anti-inflammatory agent. Therefore, the current study was designed to evaluate whether melatonin could improve anemic patients response to EPO. METHODS This single controlled clinical study was carried out in 41 CKD patients with hemoglobin (Hb) levels less than 11g/dl divided randomly in a 1:1 ratio into 2 groups; treatment group who received 5mg melatonin plus their regular treatments and control group who received their regular treatments only. Hematological and iron status parameters include Hb level, serum iron (S. iron), Transferrin Saturation Ratio (TSAT) and serum ferritin (S. ferritin) in addition to inflammatory parameters that include tissue necrotic factor alfa (TNF-α), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) determined before and after 12 weeks of treatment. RESULTS Melatonin remarkably increases the Hb level with a significant increase in S. iron and TSAT compared to baseline. The elevation of S. iron and TSAT was significantly higher in the melatonin group. Additionally, all inflammatory markers estimated were reduced significantly by melatonin compared to base line and control group. CONCLUSION The results of the current study showed that melatonin has an advantageous effect on improving EPO response in anemic patients with CKD.
-
9.
Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial.
Spahn, DR, Schoenrath, F, Spahn, GH, Seifert, B, Stein, P, Theusinger, OM, Kaserer, A, Hegemann, I, Hofmann, A, Maisano, F, et al
Lancet (London, England). 2019;(10187):2201-2212
Abstract
BACKGROUND Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. METHODS In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. FINDINGS Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0-3) to zero units in the treatment group (0-2, during the first 7 days (odds ratio 0·70 [95% CI 0·50-0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0-2]) versus the placebo group (1 [0-3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. INTERPRETATION An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. FUNDING Vifor Pharma and Swiss Foundation for Anaesthesia Research.
-
10.
Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.
Aachmann-Andersen, NJ, Christensen, SJ, Lisbjerg, K, Oturai, P, Johansson, PI, Holstein-Rathlou, NH, Olsen, NV
Physiological reports. 2018;(5)
Abstract
The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system.