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Are prolyl-hydroxylase inhibitors potential alternative treatments for anaemia in patients with chronic kidney disease?
Locatelli, F, Del Vecchio, L
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(6):926-932
Abstract
Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.
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Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes.
Marathias, KP, Lambadiari, VA, Markakis, KP, Vlahakos, VD, Bacharaki, D, Raptis, AE, Dimitriadis, GD, Vlahakos, DV
American journal of nephrology. 2020;(5):349-356
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Abstract
BACKGROUND Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. SUMMARY The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.
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Effect of iron chelation therapy on EPO-STAT5 signalling pathway and EPO resistance in iron-overloaded low-risk myelodysplastic syndrome patients.
Zhang, Y
Hematology (Amsterdam, Netherlands). 2020;(1):1-10
Abstract
Objectives: Background/aims: We aim to explore low-risk MDS patients' ESA response and the difference between iron-overloaded (IO) group and the control group in the expression of SOCS1, STAT5 and BCL2L1 which play a key role to EPO-STAT5 signal pathway.Methods: 56 low-risk MDS patients were divided into experimental group, IO patients; control group, non-IO patients. Among experimental group, 28 IO patients were treated with iron chelation therapy (ICT). SOCS1, phosphorylated STAT5 (p-STAT5) and BCL2L1 protein concentration in bone marrow supernatant have been analyzed by ELISA, STAT5a+b protein concentration in bone marrow mononuclear cells (BMMC) have been analyzed by Western blot, and mRNA expression of them have been detected in BMMC by RQ-PCR. The percentage of CD71+ cells in BMMC, apoptotic rate of CD71+ cells and ROS expression in CD71+ cells were detected by Flow cytometry.Results: Compared with the control group, the sEPO concentration, the efficacy of ESA and the expression of SOCS1, apoptotic rates of CD71+ cells and ROS expression in CD71+ cells in IO group were increased, the expression of STAT5 and BCL2L1 was reduced. Interestingly, after receiving ICT, some patients with EPO resistance have responded again to ESA treatment, with the decrease of the expression of SOCS1, apoptotic rates of CD71+ cells, ROS expression in CD71+ cells and the increase of the expression of STAT5 and BCL2L1.Conclusion: Iron overload can increase EPO resistance and the expression of SOCS1, inhibit the expression of STAT5 and BCL2L1. ICT could allivation of EPO resistance.
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Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery.
Kaufner, L, von Heymann, C, Henkelmann, A, Pace, NL, Weibel, S, Kranke, P, Meerpohl, JJ, Gill, R
The Cochrane database of systematic reviews. 2020;(8):CD012451
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Abstract
BACKGROUND Approximately 30% of adults undergoing non-cardiac surgery suffer from preoperative anaemia. Preoperative anaemia is a risk factor for mortality and adverse outcomes in different surgical specialties and is frequently the reason for blood transfusion. The most common causes are renal, chronic diseases, and iron deficiency. International guidelines recommend that the cause of anaemia guide preoperative anaemia treatment. Recombinant human erythropoietin (rHuEPO) with iron supplementation has frequently been used to increase preoperative haemoglobin concentrations in patients in order to avoid the need for perioperative allogeneic red blood cell (RBC) transfusion. OBJECTIVES To evaluate the efficacy of preoperative rHuEPO therapy (subcutaneous or parenteral) with iron (enteral or parenteral) in reducing the need for allogeneic RBC transfusions in preoperatively anaemic adults undergoing non-cardiac surgery. SEARCH METHODS We searched CENTRAL, Ovid MEDLINE(R), Ovid Embase, ISI Web of Science: SCI-EXPANDED and CPCI-S, and clinical trial registries WHO ICTRP and ClinicalTrials.gov on 29 August 2019. SELECTION CRITERIA We included all randomized controlled trials (RCTs) that compared preoperative rHuEPO + iron therapy to control treatment (placebo, no treatment, or standard of care with or without iron) for preoperatively anaemic adults undergoing non-cardiac surgery. We used the World Health Organization (WHO) definition of anaemia: haemoglobin concentration (g/dL) less than 13 g/dL for males, and 12 g/dL for non-pregnant females (decision of inclusion based on mean haemoglobin concentration). We defined two subgroups of rHuEPO dosage: 'low' for 150 to 300 international units (IU)/kg body weight, and 'high' for 500 to 600 IU/kg body weight. DATA COLLECTION AND ANALYSIS Two review authors collected data from the included studies. Our primary outcome was the need for RBC transfusion (no autologous transfusion, fresh frozen plasma or platelets), measured in transfused participants during surgery (intraoperative) and up to five days after surgery. Secondary outcomes of interest were: haemoglobin concentration (directly before surgery), number of RBC units (where one unit contains 250 to 450 mL) transfused per participant (intraoperative and up to five days after surgery), mortality (within 30 days after surgery), length of hospital stay, and adverse events (e.g. renal dysfunction, thromboembolism, hypertension, allergic reaction, headache, fever, constipation). MAIN RESULTS Most of the included trials were in orthopaedic, gastrointestinal, and gynaecological surgery and included participants with mild and moderate preoperative anaemia (haemoglobin from 10 to 12 g/dL). The duration of preoperative rHuEPO treatment varied across the trials, ranging from once a week to daily or a 5-to-10-day period, and in one trial preoperative rHuEPO was given on the morning of surgery and for five days postoperatively. We included 12 trials (participants = 1880) in the quantitative analysis of the need for RBC transfusion following preoperative treatment with rHuEPO + iron to correct preoperative anaemia in non-cardiac surgery; two studies were multiarmed trials with two different dose regimens. Preoperative rHuEPO + iron given to anaemic adults reduced the need RBC transfusion (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.38 to 0.80; participants = 1880; studies = 12; I2 = 84%; moderate-quality evidence due to inconsistency). This analysis suggests that on average, the combined administration of rHuEPO + iron will mean 231 fewer individuals will need transfusion for every 1000 individuals compared to the control group. Preoperative high-dose rHuEPO + iron given to anaemic adults increased the haemoglobin concentration (mean difference (MD) 1.87 g/dL, 95% CI 1.26 to 2.49; participants = 852; studies = 3; I2 = 89%; low-quality evidence due to inconsistency and risk of bias) but not low-dose rHuEPO + iron (MD 0.11 g/dL, 95% CI -0.46 to 0.69; participants = 334; studies = 4; I2 = 69%; low-quality evidence due to inconsistency and risk of bias). There was probably little or no difference in the number of RBC units when rHuEPO + iron was given preoperatively (MD -0.09, 95% CI -0.23 to 0.05; participants = 1420; studies = 6; I2 = 2%; moderate-quality evidence due to imprecision). There was probably little or no difference in the risk of mortality within 30 days of surgery (RR 1.19, 95% CI 0.39 to 3.63; participants = 230; studies = 2; I2 = 0%; moderate-quality evidence due to imprecision) or of adverse events including local rash, fever, constipation, or transient hypertension (RR 0.93, 95% CI 0.68 to 1.28; participants = 1722; studies = 10; I2 = 0%; moderate-quality evidence due to imprecision). The administration of rHuEPO + iron before non-cardiac surgery did not clearly reduce the length of hospital stay of preoperative anaemic adults (MD -1.07, 95% CI -4.12 to 1.98; participants = 293; studies = 3; I2 = 87%; low-quality evidence due to inconsistency and imprecision). AUTHORS' CONCLUSIONS Moderate-quality evidence suggests that preoperative rHuEPO + iron therapy for anaemic adults prior to non-cardiac surgery reduces the need for RBC transfusion and, when given at higher doses, increases the haemoglobin concentration preoperatively. The administration of rHuEPO + iron treatment did not decrease the mean number of units of RBC transfused per patient. There were no important differences in the risk of adverse events or mortality within 30 days, nor in length of hospital stay. Further, well-designed, adequately powered RCTs are required to estimate the impact of this combined treatment more precisely.
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Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease.
Mazer, CD, Hare, GMT, Connelly, PW, Gilbert, RE, Shehata, N, Quan, A, Teoh, H, Leiter, LA, Zinman, B, Jüni, P, et al
Circulation. 2020;(8):704-707
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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.
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Iron Nutrition, Erythrocytes, and Erythropoietin in the NICU: Erythropoietic and Neuroprotective Effects.
Kling, PJ
NeoReviews. 2020;(2):e80-e88
Abstract
Prematurity, maternal diabetes, maternal smoking, being medically underserved, and small size for gestational age are common characteristics of neonates in the NICU and can predispose them to develop congenital iron deficiency. Iron is critical for organ development. In the fetus and newborn, iron is prioritized for red blood cell production, sometimes at the expense of other tissues, including the brain. It is critical to optimize iron levels in newborns to support erythropoiesis, growth, and brain development. Available studies support improved neurodevelopmental outcomes with either iron supplementation or delayed umbilical cord clamping at birth. Erythropoietic doses of erythropoietin/erythrocyte-stimulating agents may also improve neurocognitive outcomes. However, the literature on the effect of liberal red blood cell transfusions on long-term neurodevelopment is mixed. Understanding age-specific normal values and monitoring of iron indices can help individualize and optimize the iron status of patients in the NICU.
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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.
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The target hemoglobin content values of reticulocytes for efficient anemia improvement are achieved by low ferritin levels and moderate transferrin saturation: a retrospective observational study.
Ogawa, C, Tsuchiya, K, Tomosugi, N, Shimada, K, Kanda, F, Maeda, K
Hematology (Amsterdam, Netherlands). 2020;(1):71-78
Abstract
Objectives: The optimal iron level in hemodialysis (HD) patients remains unclear. The hemoglobin content of reticulocytes (CHr) is a sensitive indicator of iron used for hematopoiesis. To identify the optimal iron content for HD patients, we investigated the relation between CHr levels and iron status, as well as the levels of hepcidin, a main regulator of iron metabolism.Methods: This study enrolled 181 HD outpatients treated with recombinant human erythropoietin (rHuEPO). A sensitivity analysis, using a generalized linear regression model that included the interaction term, was applied to determine the correlations between levels of CHr and those of serum ferritin (s-ft), transferrin saturation (TSAT), and hepcidin.Results: The greatest changes in correlation coefficients for levels of s-ft and TSAT with CHr levels indicated optimal cut-off points of 50 ng/mL (≤50 ng/mL, r = 0.47 vs >50 ng/mL, r = 0.22) and 24% (≤24%, r = 0.58 vs >24%, r = 0.08), respectively. The correlation coefficient for levels of CHr and hepcidin showed that the optimal lower and upper cut-off points were 20 ng/mL (≤20 ng/mL, r = 0.52 vs >20 ng/mL, r = -0.01) and 70 ng/mL (≤70 ng/mL, r = 0.36 vs >70 ng/mL, r = -0.45), respectively.Discussion: This study indicates that the amount of iron in HD patients is sufficient for hematopoiesis under conditions of low s-ft and moderate TSAT levels. High levels of hepcidin could induce negative iron metabolism in hematopoiesis.Conclusion: Therefore, controlling hepcidin levels to within approximately 20-70 ng/mL may prevent iron deficiency and reduced Hb synthesis, and may thus facilitate effective iron utilization in hematopoiesis.
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Combination treatments with therapeutic hypothermia for hypoxic-ischemic neuroprotection.
Zhou, KQ, Davidson, JO, Bennet, L, Gunn, AJ
Developmental medicine and child neurology. 2020;(10):1131-1137
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Abstract
Therapeutic hypothermia is now proven to reduce death or disability in term and near-term born infants with moderate to severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite treatment with hypothermia. Recent preclinical and clinical studies suggest that current protocols for therapeutic hypothermia are near-optimal. The obvious strategy, in addition to improving early initiation of therapeutic hypothermia after birth, is to combine hypothermia with other neuroprotective agents. We review evidence that the mechanisms of action of many promising agents overlap with the anti-excitotoxic, anti-apoptotic, and anti-inflammatory mechanisms of hypothermia, leading to a lack of benefit from combination treatment. Moreover, even apparently beneficial combinations have failed to translate in clinical trials. These considerations highlight the need for preclinical studies to test clinically realistic protocols of timing and duration of treatment, before committing to large randomized controlled trials.