Erythropoietin (EPO) is traditionally described as a hematopoietic cytokine or growth hormone regulating proliferation, differentiation, and survival of erythroid progenitors. The use of EPO in patients with chronic kidney disease (CKD) was a milestone achievement in the treatment of anemia. However, EPO involves some degree of risk, which increases with increasing hemoglobin levels. A growing number of studies have assessed the renoprotective effects of EPO in acute kidney injury (AKI) or CKD. Analysis of the biological effects of erythropoietin and pathophysiology of CKD in these studies suggests that treatment with erythropoiesis-stimulating agents (ESAs) may exert renoprotection by pleiotropic actions on several targets and directly or indirectly slow the progression of CKD. By reducing ischemia and oxidative stress or strengthening anti-apoptotic processes, EPO may prevent the development of interstitial fibrosis and the destruction of tubular cells. Furthermore, it could have a direct protective impact on the integrity of the interstitial capillary network through its effects on endothelial cells and promotion of vascular repair, or modulate inflammation response. Thus, it is biologically plausible to suggest that correcting anemia with ESAs could slow the progression of CKD.
The aim of this article is to discuss these possible renoprotection mechanisms and provide a comprehensive overview of erythropoietin and its derivatives.
erythropoietin; erythropoiesis-stimulating agents; nephroprotection; chronic kidney disease; anemia
Multi-tissue erythropoietin receptor (EPO-R) expression provides for erythropoietin (EPO) activity beyond its known regulation of red blood cell production. This review highlights the role of EPO and EPO-R in brain development and neuroprotection. EPO-R brain expression includes neural progenitor cells (NPC), neurons, glial cells and endothelial cells. EPO is produced in brain in a hypoxia sensitive manner, stimulates NPC proliferation and differentiation, and neuron survival, and contributes to ischemic preconditioning. Mice lacking EPO or EPO-R exhibit increased neural cell apoptosis during development before embryonic death due to severe anemia. EPO administration provides neural protection in animal models of brain ischemia and trauma, reducing the extent of injury and damage. EPO stimulation of endothelial cells contributes to neuroprotection and is of particular importance since only low levels of EPO appear to cross the blood-brain barrier when administered at high dose intravenously. The therapeutic potential of EPO for brain ischemia/trauma and neurodegenerative diseases has shown promise in early clinical trial and awaits further validation.
Erythropoietin; receptor, neuroprotection; blood-brain barrier; ischemic preconditioning; brain ischemia; neurogenesis, endothelium
Erythropoiesis usually fails during severe illness because of a blunting of the kidney–erythropoietin (EPO)–bone marrow axis. In this setting, clinical studies have shown that recombinant human erythropoietin (rhEPO), administered in pharmacological amounts, significantly reduces the need for blood transfusions. In addition to the kidney, however, EPO is also produced locally by other tissues in a paracrine–autocrine manner. Here, similar to its role in the bone marrow, EPO rescues cells from apoptosis. Additionally, EPO reduces inflammatory responses, restores vascular autoregulation, and promotes healing. The results of many studies (including a phase II clinical trial in ischemic stroke) demonstrate that rhEPO protects the brain, spinal cord, retina, heart, and kidney from ischemic and other types of injury. Although rhEPO is efficacious in the treatment of EPO-deficient anemia during illness, inadequate effort has been devoted to determining whether direct tissue protection might also result from its administration. Here, we speculate on the potential utility of EPO as a protective cytokine in the context of acute critical illness and suggest key parameters required for a proof-of-concept clinical study.
apoptosis; clinical study; critical illness; cytokine; erythropoietin
Erythropoietin (EPO) is known to have numerous biological functions. Its primary function in the body is to increase red blood cell numbers by way of preventing the apoptosis of erythroid progenitor cells via the homodimeric EPO receptor. The discovery that the local production of EPO within the brain in response to hypoxia or ischemia protects neurons against injury via an anti-apoptotic effect formed the basis of the hypothesis that the local generation of EPO limits the extent of injury. Although the hypothesis proved to be true in pre-clinical models of ischemia/reperfusion injury and inflammation, the randomized, controlled clinical trials that followed demonstrated serious adverse events of EPO due to activation of the hematopoietic system. Consequently, derivatives of EPO that lacked erythropoietic activity were discovered to reduce injury in many pre-clinical models associated with ischemia and inflammation. Unfortunately, there are no published clinical trials to determine the efficacy of non-erythropoietic derivatives of EPO in humans.
The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.
Since the isolation and purification of erythropoietin (EPO) in 1977, the essential role of EPO for mature red blood cell production has been well established. The cloning and production of recombinant human EPO led to its widespread use in treating patients with anaemia. However, the biological activity of EPO is not restricted to regulation of erythropoiesis. EPO receptor (EPOR) expression is also found in endothelial, brain, cardiovascular and other tissues, although at levels considerably lower than that of erythroid progenitor cells. This review discusses the survival and proliferative activity of EPO that extends beyond erythroid progenitor cells. Loss of EpoR expression in mouse models provides evidence for the role of endogenous EPO signalling in nonhaematopoietic tissue during development or for tissue maintenance and/or repair. Determining the extent and distribution of receptor expression provides insights into the potential protective activity of erythropoietin in brain, heart and other nonhaematopoietic tissues.
The aim of this study was to assess the efficacy of two dosing schedules of recombinant human erythropoietin (rHuEPO) in increasing haematocrit (Hct) and haemoglobin (Hb) and reducing exposure to allogeneic red blood cell (RBC) transfusion in critically ill patients.
This was a prospective, randomized, multicentre trial. A total of 13 intensive care units participated, and a total of 148 patients who met eligibility criteria were enrolled. Patients were randomly assigned to receive intravenous iron saccharate alone (control group), intravenous iron saccharate and subcutaneous rHuEPO 40,000 units once per week (group A), or intravenous iron saccharate and subcutaneous rHuEPO 40,000 units three times per week (group B). rHuEPO was given for a minimum of 2 weeks or until discharge from the intensive care unit or death. The maximum duration of therapy was 3 weeks.
The cumulative number of RBC units transfused, the average numbers of RBC units transfused per patient and per transfused patient, the average volume of RBCs transfused per day, and the percentage of transfused patients were significantly higher in the control group than in groups A and B. No significant difference was observed between group A and B. The mean increases in Hct and Hb from baseline to final measurement were significantly greater in group B than in the control group. The mean increase in Hct was significantly greater in group B than in group A. The mean increase in Hct in group A was significantly greater than that in control individuals, whereas the mean increase in Hb did not differ significantly between the control group and group A.
Administration of rHuEPO to critically ill patients significantly reduced the need for RBC transfusion. The magnitude of the reduction did not differ between the two dosing schedules, although there was a dose response for Hct and Hb to rHuEPO in these patients.
The establishment of effective treatment of neonatal anemia using recombinant human erythropoietin (r-HuEPO) requires a thorough understanding of the physiology and mechanism of EPO’s pharmacologic effect. The purpose of the present preclinical study in sheep was to elucidate the stimulatory effect of EPO on erythroid progenitors and their differentiation into reticulocytes useful in predicting optimal r-HuEPO dosing.
Five young adult sheep each underwent two phlebotomies spaced 4–6 weeks apart in which their hemoglobin levels were reduced from 12 g/dL to 3–4 g/dL. Endogenous EPO levels and reticulocyte counts produced in response to anemia were sampled throughout the study and analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model.
The phlebotomy-induced drop in hemoglobin resulted in a increase in EPO levels, which reached a maximum of 764 ± 55 mU/mL (mean ± %CV) in 0.5–2.6 days. The reticulocyte counts increased from baseline values of 76.9 × 103 ± 67/μL to 619 × 103 ± 30/μL in 8 days. The PK/PD analysis indicated an increased maturation time for the reticulocytes (4.88 ± 35 days) and demonstrated that the Emax model for EPO’s activation of the progenitors did not show significant effect saturation at the endogenous EPO levels reached.
In extrapolating from the animal pilot experiment, the present study provides a case for the use of higher r-HuEPO doses in human studies to determine if higher doses are more effective in treatment of neonatal anemia to reduce, and in some less severe cases, eliminate, the need for blood transfusions.
anemia of prematurity; erythropoietin; pharmacokinetic/pharmacodynamic analysis; progenitor activation; reticulocyte
Recombinant human erythropoietin (rhEPO) is arguably the most successful therapeutic application of recombinant DNA technology till date. It was isolated in 1977 and the gene decoded in 1985. Since then, it has found varied applications, especially in stimulating erythropoiesis in anemia due to chronic conditions like renal failure, myelodysplasia, infections like HIV, in prematurity, and in reducing peri-operative blood transfusions. The discovery of erythropoietin receptor (EPO-R) and its presence in non-erythroid cells has led to several areas of research. Various types of rhEPO are commercially available today with different dosage schedules and modes of delivery. Their efficacy in stimulating erythropoiesis is dose dependent and differs according to the patient's disease and nutritional status. EPO should be used carefully according to guidelines as unsolicited use can result in serious adverse effects. Because of its capacity to improve oxygenation, it has been abused by athletes participating in endurance sports and detecting this has proved to be a challenge.
Abuse; continuous erythropoietin receptor activator; darbepoetin; erythropoietin
Anemia is a common finding in patients with CKD, with a prevalence that increases gradually as eGFR declines. The prevalence of renal anemia depends on the size of the study and the selection of participants. Diabetic status increases the prevalence of anemia in patients with CKD. Anemia in CKD is due primarily to reduced production of erythropoietin in the kidney and secondarily to shortened red cell survival. Erythropoeitin (EPO) is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. These cells are sensitive to hypoxia that once sensed leads to an increase in EPO production. EPO circulates in the plasma and induces redcell production in the bone marrow after successful binding to erythroid progenitor cells. Apart from EPO, folate, B12 and iron are needed to assure effective erythropoiesis. Factors that can dysregulate this process include inflammation, uremic toxins, hypothyroidism, hypersplenism and ongoing infection.
The investigation of renal anemia requires the assessment of a variety of biological indices. Among them, the complete blood count, the reticulocyte index, B12, folate, ferritin levels and the saturation of transferrin are the most valuable tools in revealing the cause of renal anemia.
chronic kidney disease; anemiaprevalence; erythropoietin receptors; ferritin; transferrin saturation
Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia.
We examined the hypothesis that EPO receptor (EpoR) ligand-binding, which activates endothelial nitric oxide synthase (eNOS), regulates the pro-survival program of mitochondrial biogenesis in the heart.
Methods and Results
We investigated the effects of EPO on mitochondrial biogenesis over 14 days in healthy mice. Mice expressing a mitochondrial GFP-reporter construct demonstrated sharp increases in myocardial mitochondrial density post-EPO by 3 days that peaked at 7 days and surpassed hepatic or renal effects and anteceded significant increases in blood hemoglobin content. Quantitatively, in wild-type (Wt) mice, Complex II activity, State 3 respiration and mtDNA copy number increased significantly; also resting energy expenditure and natural running speed improved with no evidence of an increase in LV mass index. Mechanistically, EPO activated cardiac mitochondrial biogenesis by enhancement of nuclear respiratory factor-1 (NRF-1), PGC-1α and mitochondrial transcription factor-A gene expression in Wt, but not in eNOS-/- or Akt1-/- mice. EpoR was required, as EpoR silencing in cardiomyocytes blocked EPO-mediated nuclear translocation of NRF-1.
These findings support a new physiological and protective role for EPO, acting through its cell surface receptor and eNOS-Akt1 signal transduction, in matching cardiac mitochondrial mass to the convective O2 transport capacity as erythrocyte mass expands.
cardiac metabolism; erythropoietin; nitric oxide; Akt1/PKB; mitochondrial biogenesis
Erythropoietin (Epo) increases and maintains hematocrit using once weekly dosing in adults with anemia due to end stage renal disease. Epo is used in preterm infants to treat the anemia of prematurity, but has not been studied using once weekly dosing, a schedule which might offer neuroprotection in addition to increasing red cell mass. We compared reticulocyte responses of once weekly Epo dosing with thrice weekly dosing in preterm infants.
Infants ≤1,500 grams and ≥7 days of age were randomized to once weekly Epo, 1,200 units/kg/dose, or thrice weekly Epo, 400 units/kg/dose, subcutaneously for 4 weeks, along with iron and vitamin supplementation. Complete blood counts, absolute reticulocyte counts (ARC), transfusions, phlebotomy losses, and adverse events were recorded.
Twenty preterm infants (962±55 grams, 27.9±0.4 weeks, 17±3 days of age) were enrolled. Groups were similar at baseline. Infants in both groups increased ARC (p<0.01, thrice weekly Epo group). ARC were similar between treatment groups at the start and end of 4 weeks. Hematocrit remained stable, and similar numbers of transfusions were administered. No adverse effects of either dosing schedule were noted.
Preterm infants respond to weekly Epo by increasing ARC and maintaining hematocrit. We speculate that once weekly Epo dosing might be beneficial to preterm infants requiring increased erythropoiesis.
erythropoietin; transfusions; dosing schedule; anemia of prematurity; neuroprotection
Despite the prevalence of anemia in cancer, recombinant erythropoietin (Epo) has declined in use because of recent Phase III trials showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Since Epo receptor (EpoR), Jak2, and Hsp70 are well-characterized mediators of Epo signaling in erythroid cells, we hypothesized that Epo might be especially harmful in patients whose tumors express high levels of these effectors. Because of the insensitivity of immunohistochemistry for detecting low level EpoR protein, we developed assays to measure levels of EpoR, Jak2 and Hsp70 mRNA in formalin-fixed paraffin-embedded (FFPE) tumors. We tested 23 archival breast tumors as well as 136 archival head and neck cancers from ENHANCE, a Phase III trial of 351 patients randomized to Epo versus placebo concomitant with radio-therapy following complete resection, partial resection, or no resection of tumor. EpoR, Jak2, and Hsp70 mRNA levels varied >30-fold, >12-fold, and >13-fold across the breast cancers, and >30-fold, >40-fold, and >30-fold across the head and neck cancers, respectively. Locoregional progression-free survival (LPFS) did not differ among patients whose head and neck cancers expressed above- versus below-median levels of EpoR, Jak2 or Hsp70, except in the subgroup of patients with unresected tumors (n = 28), where above-median EpoR, above-median Jak2, and below-median Hsp70 mRNA levels were all associated with significantly poorer LPFS. Our results provide a framework for exploring the relationship between Epo, cancer progression, and survival using archival tumors from other Phase III clinical trials.
Erythropoietin; Erythropoietin receptor; Erythropoiesis stimulating agents; Growth factors; Tumor progression
Erythropoietin is a growth factor commonly used to manage anemia in patients with chronic kidney disease. A significant clinical challenge is relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses, failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. Erythropoietin acts through the erythropoietin receptor (EpoR) present in erythroblasts. Alternative mRNA splicing produces a soluble form of EpoR (sEpoR) found in human blood, however its role in anemia is not known.
Methods and Findings
Using archived serum samples obtained from subjects with end stage kidney disease we show that sEpoR is detectable as a 27kDa protein in the serum of dialysis patients, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat5) phosphorylation in cell lines expressing EpoR. Importantly, we demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. Finally, we show that sEpoR is increased in the supernatant of a human erythroleukaemia cell line when stimulated by inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha implying a link between inflammation and erythropoietin resistance.
These observations suggest that sEpoR levels may contribute to erythropoietin resistance in end stage renal disease, and that sEpoR production may be mediated by pro-inflammatory cytokines.
Because of its stimulating effect on RBC production, erythropoietin (Epo) is used to treat anemia, for example, in patients on dialysis or on chemotherapy. In β-thalassemia, where Epo levels are low relative to the degree of anemia, Epo treatment improves the anemia state. Since RBC and platelets of these patients are under oxidative stress, which may be involved in anemia and thromboembolic complications, we investigated Epo as an antioxidant. Using flow-cytometry technology, we found that in vitro treatment with Epo of blood cells from these patients increased their glutathione content and reduced their reactive oxygen species, membrane lipid peroxides, and external phosphatidylserine. This resulted in reduced susceptibility of RBC to undergo hemolysis and phagocytosis. Injection of Epo into heterozygous (Hbbth3/+) β-thalassemic mice reduced the oxidative markers within 3 hours. Our results suggest that, in addition to stimulating RBC and fetal hemoglobin production, Epo might alleviate symptoms of hemolytic anemias as an antioxidant.
Serpina3g/Spi2A inhibits cathepsins B/L to enhance erythropoietin induced red blood cell formation.
Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for red blood cell production and exert important cytoprotective effects on select vascular, immune, and cancer cells. To discover novel EPO action modes, we profiled the transcriptome of primary erythroid progenitors. We report Serpina3g/Spi2A as a major new EPO/EPOR target for the survival of erythroid progenitors. In knockout mice, loss of Spi2A worsened anemia caused by hemolysis, radiation, or transplantation. EPO-induced erythropoiesis also was compromised. In particular, maturing erythroblasts required Spi2A for cytoprotection, with iron and reactive oxygen species as cytotoxic agents. Spi2A defects were ameliorated by cathepsin-B/L inhibition, and by genetic co-deletion of lysosomal cathepsin B. Pharmacological inhibition of cathepsin B/L enhanced EPO-induced red cell formation in normal mice. Overall, we define an unexpected EPO action mode via an EPOR–Spi2A serpin–cathepsin axis in maturing erythroblasts, with lysosomal cathepsins as novel therapeutic targets.
Regulation of survival, expansion, and differentiation of erythroid progenitors requires the well-controlled activity of signaling pathways induced by erythropoietin (Epo) and stem cell factor (SCF). In addition to qualitative regulation of signaling pathways, quantitative control may be essential to control appropriate cell numbers in peripheral blood. We demonstrate that Bruton's tyrosine kinase (Btk) is able to associate with the Epo receptor (EpoR) and Jak2, and is a substrate of Jak2. Deficiency of Btk results in reduced and delayed phosphorylation of the EpoR, Jak2, and downstream signaling molecules such as Stat5 and PLCγ1 as well as in decreased responsiveness to Epo. As a result, expansion of erythroid progenitors lacking Btk is impaired at limiting concentrations of Epo and SCF. In addition, we show that SCF induces Btk to interact with TNF-related apoptosis-inducing ligand (TRAIL)–receptor 1 and that lack of Btk results in increased sensitivity to TRAIL-induced apoptosis. Together, our results indicate that Btk is a novel, quantitative regulator of Epo/SCF-dependent expansion and survival in erythropoiesis.
Jak2; Stat5; hematopoiesis; signal transduction
Critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units receive at least 1 red blood cell (RBC) unit during their stay, and the average is close to 5 RBC units. RBC transfusion is not risk free. There is little evidence that 'routine' transfusion of stored allogeneic RBCs is beneficial to critically ill patients. The efficacy of perioperative recombinant human erythropoietin (rHuEPO) has been demonstrated in a variety of elective surgical settings. Similarly, in critically ill patients with multiple organ failure, rHuEPO therapy will also stimulate erythropoiesis. In a randomized, placebo-controlled trial, therapy with rHuEPO resulted in a significant reduction in RBC transfusions. Despite receiving fewer RBC transfusions, patients in the rHuEPO group had a significantly greater increase in hematocrit. Strategies to increase the production of RBCs are complementary to other approaches to reduce blood loss in the intensive care unit, and they decrease the transfusion threshold in the management of all critically ill patients.
anemia; blood transfusion; critical illness; erythropoietin
Since the late 1980s recombinant human erythropoietin (r-Epo) has been studied as an alternative to packed red blood cell (RBC) transfusion for the treatment of anemia of prematurity in very low birth weight (VLBW, <1500 grams) infants. Initial trials and reports focused on r-Epo’s ability to prevent or treat anemia of prematurity with the goal of eliminating RBC transfusion, but achieved limited success. Reduced volumes of blood sampling for laboratory tests and improved blood banking techniques have decreased the need for RBC transfusion. New concerns about the safety of r-Epo administration have emerged. Past cost-benefit analyses of r-Epo administration versus transfusion for the treatment of anemia of prematurity have been nearly balanced. Autologous transfusion, blood-sparing technologies, changes in RBC transfusion technique and safety, and further elucidation of the risk-benefit ratio of r-Epo therapy may change the cost-benefit analysis. The jury is still out with regard to the role of r-Epo therapy in the VLBW population.
erythropoietin; transfusion; very low birth weight; infant; premature
Erythropoiesis maintains a stable hematocrit and tissue oxygenation in the basal state, while mounting a stress response that accelerates red cell production in anemia, blood loss or high altitude. Thus, tissue hypoxia increases secretion of the hormone erythropoietin (Epo), stimulating an increase in erythroid progenitors and erythropoietic rate. Several cell divisions must elapse, however, before Epo-responsive progenitors mature into red cells. This inherent delay is expected to reduce the stability of erythropoiesis and to slow its response to stress. Here we identify a mechanism that helps to offset these effects. We recently showed that splenic early erythroblasts, ‘EryA’, negatively regulate their own survival by co-expressing the death receptor Fas, and its ligand, FasL. Here we studied mice mutant for either Fas or FasL, bred onto an immune-deficient background, in order to avoid an autoimmune syndrome associated with Fas deficiency. Mutant mice had a higher hematocrit, lower serum Epo, and an increased number of splenic erythroid progenitors, suggesting that Fas negatively regulates erythropoiesis at the level of the whole animal. In addition, Fas-mediated autoregulation stabilizes the size of the splenic early erythroblast pool, since mutant mice had a significantly more variable EryA pool than matched control mice. Unexpectedly, in spite of the loss of a negative regulator, the expansion of EryA and ProE progenitors in response to high Epo in vivo, as well as the increase in erythropoietic rate in mice injected with Epo or placed in a hypoxic environment, lagged significantly in the mutant mice. This suggests that Fas-mediated autoregulation accelerates the erythropoietic response to stress. Therefore, Fas-mediated negative autoregulation within splenic erythropoietic tissue optimizes key dynamic features in the operation of the erythropoietic network as a whole, helping to maintain erythroid homeostasis in the basal state, while accelerating the stress response.
Erythropoietin (EPO) is a prime regulator of the growth and differentiation of erythroid blood cells. The EPO receptor (EPO-R) is expressed in late erythroid progenitors (mature BFU-E and CFU-E), and EPO induces proliferation and differentiation of these cells. By introducing, with a retroviral vector, a normal EPO-R cDNA into murine adult bone marrow cells, we showed that EPO is also able to induce proliferation in pluripotent progenitor cells. After 7 days of coculture with virus-producing cells, bone marrow cells were plated in methylcellulose culture in the presence of EPO, interleukin-3, or Steel factor alone or in combination. In the presence of EPO alone, EPO-R virus-infected bone marrow cells gave rise to mixed colonies comprising erythrocytes, granulocytes, macrophages and megakaryocytes. The addition of interleukin-3 or Steel factor to methylcellulose cultures containing EPO did not significantly modify the number of mixed colonies. The cells which generate these mixed colonies have a high proliferative potential as shown by the size and the ability of the mixed colonies to give rise to secondary colonies. Thus, it appears that EPO has the same effect on EPO-R-expressing multipotent cell proliferation as would a combination of several growth factors. Finally, our results demonstrate that inducing pluripotent progenitor cells to proliferate via the EPO signaling pathway has no major influence on their commitment.
Discovery that the hormone erythropoietin (EPO) and its receptor play a significant biological role in tissues outside of the hematopoietic system has fueled significant interest in EPO as a novel cytoprotective agent in both neuronal and vascular systems. Erythropoietin is now considered to have applicability in a variety of disorders that include cerebral ischemia, myocardial infarction, and chronic congestive heart failure. Erythropoietin modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. As a result, cellular protection by EPO is robust and EPO inhibits the apoptotic mechanisms of injury, including the preservation of cellular membrane asymmetry to prevent inflammation. As the investigation into clinical applications for EPO that maximize efficacy and minimize toxicity progresses, a deeper appreciation for the novel roles that EPO plays in the brain and heart and throughout the entire body should be acquired.
The purpose of this study was to determine if the number of red blood cell (RBC) transfusions anemic pediatric intensive care unit patients receive could be reduced by the prophylactic administration of recombinant human erythropoietin (rHuEPO).
This was a randomized, double-blind placebo controlled trial. Patients were randomized to receive either intravenous rHuEPO 300 units/kg/day or placebo. Both groups received elemental iron 6 mg/kg/day.
Twenty-seven patients, ages 1 month to 13 years, were enrolled. Baseline hematocrit (Hct), reticulocyte count, and erythropoietin concentration were similar between the two groups. Three patients randomized to rHuEPO received 1 RBC transfusion each, and 4 patients randomized to placebo received 9 transfusions total (P = .68). The end-of-study Hct was not significantly different between the rHuEPO and placebo groups, 30.3 ± 3.6 and 26.8 ± 4.8, respectively (P = .06). Additionally, neither the % Hct change (baseline to final), nor the % reticulocyte change (baseline to final), was statistically different between the two groups.
In this small group of anemic pediatric intensive care unit patients, prophylactic rHuEPO administration did not reduce the number of patients who received RBC transfusions. Furthermore, it did not significantly increase Hct or reticulocyte count when compared to placebo.
anemia; children; critical care; erythropoietin; transfusion
Preterm infants commonly develop anemia requiring red blood cell transfusions (RBcTx). Although an alternative therapy is recombinant human erythropoietin (Epo), it is not widely employed. To provide a rigorous scientific basis supporting the latter approach, a model-based simulation analysis of endogenous erythropoiesis was developed.
The pharmacodynamic/pharmacokinetic (PK/PD) model identified an optimal Epo dosing algorithm in preterm infants that demonstrated maximal efficacy when Epo was dosed frequently during the early weeks of life (when phlebotomy loss is greatest). Model-based simulations employing optimized epo dosing predicted that 13 of the 27 (46%) infants would avoid RBcTx (“good responders”). Importantly, simulation results identified five subject-specific covariate factors predictive of good epo response.
This simulation study provides a basis for possibly eliminating RBcTx in infants who can be selected for optimized epo therapy.
Epo PD hemoglobin production parameters were determined in 27 preterm infants studied intensively during the first 28 d of life. Model-derived Epo PD parameters were combined with PK parameters derived from the literature to simulate an optimized intravenous Epo bolus dosing schedule. The goal of this simulated optimized schedule was to eliminate RBcTx, as prescribed per current guidelines, in as many preterm infants as possible.
Anemia management in hemodialysis patients poses significant challenges. The present study explored the hypothesis that computerized dosing of intravenous erythropoietin (EPO) would increase the percentage of hemoglobin (Hb) values within the target range and reduce staff time spent on anemia management.
Setting and Participants
In-center hemodialysis patients who received EPO at Dialysis Clinic Inc dialysis units for at least 3 months between Oct 1, 2005 and April 30, 2006
Quality Improvement Plan
Computerized decision support (CDS) for EPO dosing is compared with manual physician-directed dosing.
Outcomes and Measurements
Achieved monthly Hb values, quantity of EPO administered, and time spent by dialysis unit personnel
Monthly Hb values and the quantity of EPO administered to 1118 patients from 18 dialysis units treated by CDS and 7823 patients from 125 dialysis units treated by manual dosing.
There was no difference in the likelihood of a monthly Hb of 11–12 g/dl or 10–12 g/dl with CDS as compared with manual dosing. The likelihood of Hb > 12 g/dL decreased and the likelihood of Hb < 10g/dl increased with CDS. EPO use was 4% lower with CDS, although the difference was not statistically significant. CDS was associated with a nearly 50% reduction (p<0.001) in the time spent by dialysis unit staff on anemia management.
The number of monthly Hb values in a 11 (and 10)–12 g/dl target range and EPO use did not differ with EPO dosing by a CDS as compared with manual dosing. The staff resources devoted to anemia management declined significantly with CDS.
Anemia; hemoglobin; hemodialysis; ESRD; erythropoietin; quality improvement; decision support; computer