-
1.
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.
-
2.
The effects of enteral artificial amniotic fluid-containing erythropoietin on short term outcomes of preterm infants.
Hosseini, M, Azampour, H, Raeisi, S, Behtari, M, Valizadeh, H, Saboohi, R
The Turkish journal of pediatrics. 2019;(3):392-398
Abstract
Hosseini M, Azampour H, Raeisi S, Behtari M, Valizadeh H, Saboohi R. The effects of enteral artificial amniotic fluid-containing erythropoietin on short term outcomes of preterm infants. Turk J Pediatr 2019; 61: 392-398. Necrotizing Enterocolitis (NEC) is a common devastating gastrointestinal disease, which usually develops in premature infants. Erythropoietin (EPO) as a hematopoietic hormone produced by the kidney can also be naturally found in amniotic fluid and breast milk. There is some evidence that supports the contribution of EPO in the prevention of inflammation and intestinal tissue repair. This study was aimed to determine if oral administration of artificial amniotic fluid with or without EPO would protect preterm infants against NEC and improve the certain neonatal outcomes. In this study, 150 preterm infants with gestational age 28 weeks or less and birth weight 1250 grams or less were enrolled. The infants were divided randomly into 3 groups: 1) Control group (n=50) with routine feeding protocol without any administration; 2) Amniotic fluid group (n=50) with 5mL/kg synthetic amniotic fluid; 3) EPO group (n=50) with RhuEPO dissolved in the synthetic amniotic fluid. The administrations of the study solution were started 3 days after the birth and were continued for 3 weeks (21 days). The infants in the study groups were followed up until discharge and the frequency of NEC, mortality, and other complications of the disease among the groups were compared. The mortality rate in preterm infants of the amniotic fluid and EPO groups were significantly lower than in the control group (p=0.027). We couldn`t find any significant differences in the frequency of NEC and other complications among the three study groups. The administration of synthetic amniotic fluid (with or without EPO) in preterm infants may decrease the mortality rate. Use of EPO in synthetic amniotic fluid did not affect the frequency of NEC.
-
3.
Erythropoietin and ferritin response in native highlanders aged 4-19 years from the Leh-Ladakh region of India.
Yanamandra, U, Senee, H, Yanamadra, S, Das, SK, Bhattachar, SA, Das, R, Kumar, S, Malhotra, P, Varma, S, Varma, N, et al
British journal of haematology. 2019;(2):263-268
-
-
Free full text
-
Abstract
The pivotal role of erythropoietin (EPO) in hypoxic adaptation has led to various studies assessing the EPO and ferritin response in native highlanders from Andes and Tibet. We assessed the relationship between EPO, haemoglobin and ferritin in 335 native highlanders (172 boys and 163 girls, aged 4 to 19 years) from Leh-Ladakh, India, who had no history of travel to lowland areas. Complete blood counts, serum EPO and ferritin levels were measured. We stratified study subjects based on age, gender, pubertal status and analysed the EPO and ferritin levels between the stratified groups respectively. The mean EPO level in boys was lower than girls. The mean ferritin level in boys was significantly higher (P = 0·013) than in girls. There was no significant variation in the EPO and ferritin levels amongst the various age groups in our study. Near normal EPO levels since childhood with a negative correlation with haemoglobin is suggestive of a robust adaptive mechanism to high altitude from the early years of life. Low ferritin levels are indicative of decreased iron stores in these native highlanders.
-
4.
Erythropoietin Does Not Alter Serum Profiles of Neuronal and Axonal Biomarkers After Traumatic Brain Injury: Findings From the Australian EPO-TBI Clinical Trial.
Hellewell, SC, Mondello, S, Conquest, A, Shaw, G, Madorsky, I, Deng, JV, Little, L, Kobeissy, F, Bye, N, Bellomo, R, et al
Critical care medicine. 2018;(4):554-561
Abstract
OBJECTIVE To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups. DESIGN Single-center, prospective observational study. SETTING A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia. PATIENTS Forty-four patients with moderate-to-severe traumatic brain injury. INTERVENTIONS Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury. MEASUREMENTS AND MAIN RESULTS Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain. CONCLUSIONS Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.
-
5.
Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study.
Locatelli, F, Andrulli, S, Viganò, SM, Concetti, M, Urbini, S, Giacchino, F, Broccoli, R, Aucella, F, Cossu, M, Conti, P, et al
Blood purification. 2017;(4):338-345
Abstract
BACKGROUND Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. METHODS This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. RESULTS Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29). CONCLUSIONS The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.
-
6.
Safety of Early High-Dose Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants.
Fauchère, JC, Koller, BM, Tschopp, A, Dame, C, Ruegger, C, Bucher, HU, ,
The Journal of pediatrics. 2015;(1):52-7.e1-3
Abstract
OBJECTIVE To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. STUDY DESIGN Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. RESULTS There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. CONCLUSIONS Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. TRIAL REGISTRATION ClinicalTrials.gov: NCT00413946.
-
7.
Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial.
Miskowiak, KW, Ehrenreich, H, Christensen, EM, Kessing, LV, Vinberg, M
The Journal of clinical psychiatry. 2014;(12):1347-55
Abstract
OBJECTIVE Available drug treatments for bipolar disorder fail to reverse patients' cognitive deficits. Erythropoietin has neurotrophic actions and aids neurocognitive function. The aim of the study was to investigate the potential of erythropoietin to treat cognitive dysfunction in bipolar disorder. METHOD Patients with an ICD-10 diagnosis of bipolar disorder in remission were randomized, with stratification by age and gender, to receive 8 weekly erythropoietin (40,000 IU) or saline (sodium chloride [NaCl], 0.9%) infusions in a double-blind, parallel-group design. The first patient was randomized in September 2009 and last assessment was completed in October 2012. Patients were assessed at baseline and at weeks 9 and 14. The primary outcome was change in verbal memory indexed by the total words recalled across Rey Auditory Verbal Learning Test learning trials (I-V) from baseline to week 9; secondary outcomes were sustained attention and facial expression recognition; and tertiary outcomes were attention, executive function, subjective cognitive function, and mood. Analysis was by intention to treat, using repeated-measures analysis of covariance adjusted for stratification variables and mood. The statistical threshold for which results were considered significant was P ≤ .05 (2-tailed). RESULTS 44 patients were randomized; given 1 dropout after baseline, results were analyzed for 43 patients (erythropoietin: n = 23; saline: n = 20). There was no significant improvement of verbal memory in erythropoietin versus saline groups (P = .10). However, erythropoietin enhanced sustained attention (P = .001), recognition of happy faces (P = .03), and speed of complex information processing across learning, attention, and executive function (P = .01). These effects occurred in absence of changes in simple reaction times or mood (P values ≥ .16) and were maintained after red blood cell normalization. CONCLUSIONS This is the first trial investigating erythropoietin to treat cognitive dysfunction in bipolar disorder. The findings highlight erythropoietin as a candidate treatment for deficits in attention and executive function in bipolar disorder. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00916552.
-
8.
The influence of erythropoietin (EPO T → G) and α-actinin-3 (ACTN3 R577X) polymorphisms on runners' responses to the dietary ingestion of antioxidant supplementation based on pequi oil ( Caryocar brasiliense Camb.): a before-after study.
Ribeiro, IF, Miranda-Vilela, AL, Klautau-Guimarães, Mde N, Grisolia, CK
Journal of nutrigenetics and nutrigenomics. 2013;(6):283-304
Abstract
BACKGROUND/AIMS: As diet can affect an individual's genes and these can affect response to supplementation, we aimed to investigate the influence of erythropoietin (EPO T→G) and α-actinin-3 (ACTN3 R577X) polymorphisms on plasma lipid peroxidation, hemogram and biochemical dosages of creatine kinase, aspartate aminotransferase, alanine aminotransferase and C-reactive protein (including high-sensitivity C-reactive protein) of runners (n = 123) before and after 14 days of 400 mg pequi oil supplementation, a natural carotenoid-rich oil, after races under closely comparable conditions. METHODS/RESULTS Blood samples were taken immediately after racing to perform the tests. Before pequi oil supplementation, EPO polymorphism influenced erythrogram and plateletgram results, suggesting an aerobic advantage for the TG genotype and a disadvantage for the GG genotype as regards possible microvascular complications, while no association was found for ACTN3 polymorphism with endurance performance. Both polymorphisms influenced the runners' response to pequi oil: significant responses were observed for the EPO TT genotype in erythrocyte, hematocrit, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration values, and for the TT and TG genotypes in red blood cell distribution width values. Significant differences were also observed in the plateletgram for the TT and TG genotypes. ACTN3 mainly influenced aspartate aminotransferase and creatine kinase values: heterozygotes had a significant reduction in aspartate aminotransferase values and homozygous individuals (XX) in creatine kinase values after pequi oil supplementation. CONCLUSION These results emphasize the importance of studying nutrigenomic effects on athletes' performance.
-
9.
Haemoglobin variability in Chinese pre-dialysis CKD patients not receiving erythropoietin.
Szeto, CC, Kwan, BC, Chow, KM, Pang, WF, Leung, CB, Li, PK
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2011;(9):2919-24
Abstract
BACKGROUND Although originally described in dialysis patients treated with recombinant human erythropoietin (rHuEPO), haemoglobin variability has recently also been noted to be increased in patients who have chronic kidney disease (CKD) without dialysis. In our country, pre-dialysis CKD patients generally would not receive rHuEPO treatment. We studied the degree of haemoglobin variability and its prognostic implication in this group of patients. METHODS We reviewed 332 patients with Stages 3 through 5 CKD; patients with overt iron deficiency or requiring blood transfusion were excluded. Patients were followed for up to 5 years. End points include all-cause mortality, progression to dialysis-dependent renal failure and hospitalization. RESULTS The average haemoglobin level was 11.4 ± 2.8 g/dL; intra-individual SD of haemoglobin was 0.76 ± 0.61 g/dL. Haemoglobin variability, as represented by intra-individual SD of haemoglobin, was significantly associated with the average haemoglobin level (r = -0.130, P = 0.017), Charlson's comorbidity score (r = 0.113, P = 0.040) and proteinuria (r = 0.151, P = 0.044). Univariate analysis showed that patients with high haemoglobin variability had a significantly higher all-cause mortality (log-rank test, P = 0.030) and risk of progression to end-stage renal disease (log-rank test, P = 0.021) and was associated with the adjusted duration of hospitalization (r = 0.134, P = 0.015). However, all associations become statistically insignificant after multivariate analysis to control for confounding factors. CONCLUSIONS Fluctuation of haemoglobin level is common and substantial in Chinese pre-dialysis CKD patients. Our results suggests that the observed clinical effect of haemoglobin variability in this patient population is an epiphenomenon secondary to the association between haemoglobin variability and other clinical factors.
-
10.
Hemodiafiltration with endogenous reinfusion with and without acetate-free dialysis solutions: effect on ESA requirement.
Bolasco, PG, Ghezzi, PM, Serra, A, Corazza, L, Murtas, S, Mascia, M, Cossu, M, Ferrara, R, Cogoni, G, Cadinu, F, et al
Blood purification. 2011;(4):235-42
Abstract
BACKGROUND Hemofiltrate reinfusion (HFR) is a form of hemodiafiltration (HDF) in which replacement fluid is constituted by ultrafiltrate from the patient 'regenerated' through a cartridge containing hydrophobic styrene resin. Bicarbonate-based dialysis solutions (DS) used in routine hemodialysis and HDF contain small quantities of acetate (3-5 mM) as a stabilizing agent, one of the major causes of intradialytic hypotension. Acetate-free (AF) DS have recently been made available, substituting acetate with hydrochloric acid. The impact of AF DS during HFR on Hb levels and erythropoietic-stimulating agent (ESA) requirement in chronic dialysis patients was assessed. PATIENTS AND METHODS After obtaining informed consent, 30 uremic patients treated by standard bicarbonate dialysis (BHD, DS with acetate) were randomized to treatment in 3-month cycles: first AF HFR, followed by HFR with acetate, and again AF HFR. At the beginning and end of each period, Hb and ESA requirements were evaluated. RESULTS A significant increase in the Hb level was observed throughout all periods of HFR versus BHD (from 11.1 to 11.86 g/dl; p = 0.04), with a significant decrease of ESA requirements from 29,500 to 25,033 IU/month (p = 0.04). CONCLUSION Regardless of the presence or absence of acetate in DS, HFR per se allows a significant lowering of ESA dosage versus BHD, while at the same time increasing Hb levels. Taking for granted the clinical impact produced, HFR seems to provide a relevant decrease in end-stage renal disease patient costs.