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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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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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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.
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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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Update on mutations in the HIF: EPO pathway and their role in erythrocytosis.
Lappin, TR, Lee, FS
Blood reviews. 2019;:100590
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Abstract
Identification of the underlying defects in congenital erythrocytosis has provided mechanistic insights into the regulation of erythropoiesis and oxygen homeostasis. The Hypoxia Inducible Factor (HIF) pathway plays a key role in this regard. In this pathway, an enzyme, Prolyl Hydroxylase Domain protein 2 (PHD2), constitutively prolyl hydroxylates HIF-2α, thereby targeting HIF-2α for degradation by the von Hippel Lindau (VHL) tumor suppressor protein. Under hypoxia, this modification is attenuated, resulting in the stabilization of HIF-2α and transcriptional activation of the erythropoietin (EPO) gene. Circulating EPO then binds to the EPO receptor (EPOR) on red cell progenitors in the bone marrow, leading to expansion of red cell mass. Loss of function mutations in PHD2 and VHL, as well as gain of function mutations in HIF-2α and EPOR, are well established causes of erythrocytosis. Here, we highlight recent developments that show that the study of this condition is still evolving. Specifically, novel mutations have been identified that either change amino acids in the zinc finger domain of PHD2 or alter splicing of the VHL gene. In addition, continued study of HIF-2α mutations has revealed a distinctive genotype-phenotype correlation. Finally, novel mutations have recently been identified in the EPO gene itself. Thus, the cascade of genes that at a molecular level leads to EPO action, namely PHD2 - > HIF2A - > VHL - > EPO - > EPOR, are all mutational targets in congenital erythrocytosis.
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Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease.
Babitt, JL, Sitara, D
Current opinion in nephrology and hypertension. 2019;(4):304-310
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PURPOSE OF REVIEW Recent research has revealed that regulation of the bone-secreted hormone fibroblast growth factor 23 (FGF23) is not limited to classical mineral factors. Specifically, bidirectional relationships have been described between FGF23 production and anemia, iron status, and inflammation. Here, we will review the latest published articles on the crosstalk between FGF23 and the aforementioned nonclassical factors. RECENT FINDINGS It has been recently reported that erythropoietin, iron deficiency, and inflammation increase FGF23 production and metabolism. Moreover, FGF23 promotes anemia and regulates inflammatory responses. These findings are particularly important in the setting of chronic kidney disease which is characterized by elevated FGF23 levels and several associated comorbidities. SUMMARY Regulation of FGF23 is complex and involves many bone and renal factors. More recently, erythropoietin, iron deficiency, and inflammation have been also shown to affect FGF23 transcription and cleavage. Importantly, FGF23 has emerged as a regulator of erythropoiesis, iron metabolism, and inflammation. These findings provide novel and important insights into the pathophysiologic mechanisms of chronic kidney disease and may present new opportunities for therapeutic clinical interventions.
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Aqueous humour concentrations of PEDF and Erythropoietin are not influenced by subthreshold micropulse laser treatment of diabetic macular edema.
Midena, E, Bini, S, Frizziero, L, Pilotto, E, Esposito, G, Micera, A
Bioscience reports. 2019;(6)
Abstract
Purpose: To determine if aqueous humour (AH) concentrations of Retinal Pigment Epithelium (RPE)'s biomarkers are modified after subthreshold micropulse laser (SMPL) treatment of diabetic macular edema (DME).Methods: Naïve DME and healthy subjects were enrolled. All DME patients received SMPL treatments (577-nm yellow light, 5% duty cycle of 0.2 s, power 250 mW), according to study protocol. AH of DME eyes was sampled at baseline and periodically after first SMPL treatment. Control eyes were sampled before cataract surgery. Pigment Epithelium Derived Factor (PEDF) and Erythropoietin (EPO) were quantified with glass-chip protein array.Results: Eighteen DME patients (central retinal thickness ≤ 400 μm on Spectral Domain Optical Coherence Tomography (SD-OCT)) and ten controls were enrolled. The main exclusion criteria were high refractive error, proliferative diabetic retinopathy, glaucoma and neurodegenerative disorders. PEDF concentration was decreased in DME patients at baseline versus controls (P=0.012), while EPO was increased (P=0.029). Both molecules' concentrations remained stable during follow-up after treatments, compared with DME-baseline.Conclusions: The AH concentrations of RPE biomarkers were significantly different in DME treatment-naïve eyes versus controls. The expression of PEDF and EPO remained unchanged after treatments with SMPL in DME eyes. These data are relevant for future research and applications of SMPL.
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Early erythropoiesis-stimulating agents in preterm or low birth weight infants.
Ohlsson, A, Aher, SM
The Cochrane database of systematic reviews. 2017;(11):CD004863
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BACKGROUND Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions:To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives:Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs:To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance:To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives:To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment.Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low.Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate.Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low.The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darepoetin requires further study.
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Target-based Anemia Management with Erythropoiesis Stimulating Agents (Risks and Benefits Relearned) and Iron (Still More to Learn).
Stivelman, JC
Seminars in dialysis. 2017;(2):142-148
Abstract
The FDA first licensed erythropoiesis stimulating agents (ESA) for use in patients with ESRD in 1989. Hemoglobin targets for treatment with ESAs were established at the outset on the basis of descriptive pre-ESA literature and Phase I-III data in patients with ESRD. Postrelease literature in ESA-treated patients accumulating over time initially supported improvement in indices of both cardiovascular and other organ function as well as quality of life with therapy. Recommended treatment targets for hemoglobin would evolve further in the United States from four iterations of evidence- and opinion-based practice guidelines appearing between 1997 and 2007. Several randomized, controlled trials published from 1998 to 2009 examined normalization and near-normalization of hemoglobin in patients with both ESRD and CKD; they raised fundamental questions as to the safety of robust correction of anemia. These findings, taken together with subsequent actions of the FDA in ESA labeling and CMS's quality expectations for hemoglobin in payment for dialysis treatments, would result in a comprehensive reassessment of the hemoglobin targets in ESA therapy. A marked decrease in both national ESA utilization and hemoglobin attainment has ensued as a result. This discussion addresses the history of the striking changes in enthusiasm for hemoglobin-targeted anemia therapy from 1989 to the present, and similarly examines the evolution of ferritin-targeted iron administration, which has followed different-and markedly slower-historical development.
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Erythropoietin in anemia of unknown etiology: A systematic review and meta-analysis.
Sriram, S, Xenocostas, A, Lazo-Langner, A
Hematology (Amsterdam, Netherlands). 2016;(4):234-40
Abstract
INTRODUCTION We conducted a systematic review and meta-analysis of observational studies in order to explore the relationship between erythropoietin (EPO) and hemoglobin in elderly individuals with anemia of unknown etiology (AUE) and other forms of anemia. METHODS We searched Medline, EMBASE, Web of Science, Biosis Previews, Dissertations, and Theses in addition to meeting abstracts of the European Hematology Association and American Society of Hematology for relevant studies. The meta-analysis was conducted using pooled ratio of means (ROM) through the generic inverse variance method. RESULTS Six studies were included in the meta-analysis, which confirmed that EPO levels were significantly lower in AUE as compared to iron deficiency anemia (ROM 0.7210; random 95% CI 0.7052 to 0.7372; P-value < 0.00001) and anemia of chronic disease (ROM 0.8995; random 95% CI 0.8362 to 0.9677; P = 0.004). EPO levels in AUE were slightly higher than levels in anemia of chronic kidney disease (ROM 1.0940; random 95% CI 1.0557, 1.1337; P < 0.00001). The heterogeneity (I2) of all analyses was 100%. CONCLUSION Our findings suggest that erythropoietin levels in AUE, although elevated, remain inappropriately low, particularly when compared with other forms of anemia. This suggests a relative erythropoietin deficiency or a blunted erythroid cell response.