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Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Treatment with erythropoietin is well established for anemia in chronic kidney disease patients but not well studied in acute kidney injury., Methods: This is a multicenter, randomized, pragmatic controlled clinical trial. It included 134 hospitalized patients with anemia defined as hemoglobin < 11 g/dL and acute kidney injury defined as an increase of serum creatinine of ≥ 0.3 mg/dL within 48 h or 1.5 times baseline. One arm received recombinant human erythropoietin 4000 UI subcutaneously every other day (intervention; n = 67) and the second received standard of care (control; n = 67) during the hospitalization until discharge or death. The primary outcome was the need for transfusion; secondary outcomes were death, renal recovery, need for dialysis., Results: There was no statistically significant difference in transfusion need (RR = 1.05, 95%CI 0.65,1.68; p = 0.855), in renal recovery full or partial (RR = 0.96, 95%CI 0.81,1.15; p = 0.671), in need for dialysis (RR = 11.00, 95%CI 0.62, 195.08; p = 0.102) or in death (RR = 1.43, 95%CI 0.58,3.53; p = 0.440) between the erythropoietin and the control group., Conclusions: Erythropoietin treatment had no impact on transfusions, renal recovery or mortality in acute kidney injury patients with anemia. The trial was registered on ClinicalTrials.gov (NCT03401710, 17/01/2018)., (© 2022. The Author(s).)

Erythropoietin (EPO) is a glycoprotein hormone that has been used to treat anemia in patients with chronic kidney disease and in cancer patients who are receiving chemotherapy. Here, we investigated the accessibility of the glutamine (Gln, Q) residues of recombinant human erythropoietin (rHuEPO) towards a thermoresistant variant microbial transglutaminase (mTGase), TG 16 with the aim of developing novel rHuEPO conjugates that may potentially enhance its biological efficacy. As a model bioconjugation, we studied the reactivity of rHuEPO towards TG 16 with a low molar mass amine group containing substrate, monodansyl cadaverine (MDC). The reactions were carried out at a T m of 54.3 °C, the transition temperature of rHuEPO. Characterization by SDS-PAGE and mass spectrometry confirmed the conjugates formation. Then, we examined the conjugation of rHuEPO with a biodegradable and biocompatible polyester, poly(D-sorbitol adipate) (PDSA). To achieve this, PDSA was enzymatically synthesized using lipase B from Candida antartica (CAL-B), chemically modified with side chains having free primary amine (NH 2 ) groups that can be acyl acceptor substrate of TG 16 , thoroughly characterized by 1 H NMR spectroscopy, and then applied for the TG 16 -mediated conjugation reaction with rHuEPO. rHuEPO conjugates generated by this approach were identified by SDS-PAGE proving that the amine-grafted PDSA is accepted as a substrate for TG 16 . The successful conjugation was further verified by the detection of high molar mass fluorescent bands after labelling of amine-grafted PDSA with rhodamine B-isothiocyanate. Overall, this enzymatic procedure is considered as an effective approach to prepare biodegradable rHuEPO-polymer conjugates even in the presence of N- and O-glycans., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3-5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI., Study Design: Multicenter, single-blind, randomized, placebo-controlled, parallel-group study., Setting & Participants: Anemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37)., Interventions: Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days., Outcomes & Measurements: Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained., Results: Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients., Limitations: Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses., Conclusions: GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Normocytic normochromic anemia is a common complication in chronic kidney disease and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. The introduction of ESAs into clinical practice was a success story, mediating an increase in hemoglobin concentrations without the risk for recurrent blood transfusions and improving quality of life substantially. However, recombinant ESAs are still expensive and require a parenteral route of administration. Moreover, concern has arisen following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm. This, together with changes in ESA reimbursement policy in some countries, has resulted in a significant reduction in ESA prescribing and the hemoglobin level targeted during therapy. Several attempts are being made to develop new drugs with improved characteristics and/or easier manufacturing processes compared with currently available ESAs, including new treatment approaches that may indirectly improve erythropoiesis. We give an update on the new investigational strategies for increasing erythropoiesis, examining in depth their characteristics and possible advantages in the clinical setting and the caveats to be aware of at the present stage of development., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The association between chronic kidney disease (CKD) and cardiovascular disease (CVD) is well established, and there is mounting evidence of interorgan cross talk that may accelerate pathologic processes and the progression of organ dysfunction in both systems. This process, termed cardiorenal syndrome (CRS) by the Acute Dialysis Quality Initiative, is considered a major health problem: patients with CKD and CVD are at much higher risk of mortality than patients with either condition alone. To date, the majority of CRS research has focused on neurohormonal mechanisms and hemodynamic alterations. However, mounting evidence suggests that abnormalities in the normal pathophysiology of the bone-mineral axis, iron, and erythropoietin play a role in accelerating CKD and CVD. The goal of this article is to review the role and interrelated effects of the bone-mineral axis and anemia in the pathogenesis of chronic CRS., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Abstract Background Treatment with erythropoietin is well established for anemia in chronic kidney disease patients but not well studied in acute kidney injury. Methods This is a multicenter, randomized, pragmatic controlled clinical trial. It included 134 hospitalized patients with anemia defined as hemoglobin

Background: Both EPO levels and anemia have shown prognostic value in several cardiac disorders. An observational study with a prospective follow-up was performed to investigate their independent prognostic roles in severe aortic stenosis.Methods: An up to 36-month follow-up of consecutive patients with severe aortic stenosis undergoing TAVR in a high-volume center was performed. Patients with eGRF

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Background & Aims: Anemia is a common adverse event associated with telaprevir-based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management. Methods: This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin <10g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia. Results: Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin <13g/dl subsequently developed anemia. The multivariate analysis revealed older age (>45years), lower BMI (⩽25mg/m2) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment. Conclusions: These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring. [Copyright &y& Elsevier]

Abstract: Red blood cells are rather unique body cells, since they have lost all organelles when mature, which results in lack of potential to replace proteins that have lost their function. They maintain only a few pathways for obtaining energy and reducing power for the key functions they need to fulfill. This makes RBCs highly sensitive to any aberration. If so, these RBCs are quickly removed from circulation, but if the RBC levels reduce extremely fast, this results in hemolytic anemia. Several causes of HA exist, and proteome analysis is the most straightforward way to obtain deeper insight into RBC functioning under the stress of disease. This should result in discovery of biomarkers, typical for each source of anemia. In this review, several challenges to generate in-depth RBC proteomes are described, like to obtain pure RBCs, to overcome the wide dynamic range in protein expression, and to establish which of the identified/quantified proteins are active in RBCs. The final challenge is to acquire and validate suited biomarkers unique for the changes that occur for each of the clinical questions; in red blood cell aging (also important for transfusion medicine), for thalassemias or sickle cell disease. Biomarkers for other hemolytic anemias that are caused by dysfunction of RBC membrane proteins (the RBC membrane defects) or RBC cytosolic proteins (the enzymopathies) are sometimes even harder to discover, in particular for the patients with RBC rare diseases with unknown cause. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. [Copyright &y& Elsevier]

Summary: The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures. [Copyright &y& Elsevier]

Highlights: [•] Human monocytes express EPO receptor mRNA. [•] EPO inhibits IL-6 and TNF producing monocytes in vitro. [•] EPO increases phagocytic ability but does not alter ROS production by monocytes in vitro. [•] EPO administration inhibits cytokine producing monocytes in HCV patients. [Copyright &y& Elsevier]

Introduction. Supplementation of recombinant human erythropoietin (rHuEpo) is one of the methods for the treatment of anemia for patients with colon cancer. However, the results of in vitro studies investigating the influence of rHuEpo on cancer cells are contradictory. Aim. The aim of the present study was an assessment of the effect of rHuEpo on proliferation, as well as Epo and EpoR protein expressions in normoxia and hypoxia conditions on human colon adenocarcinoma cells (DLD-1). Materials and methods. The cells were cultured in medium with rHuEpo in concentrations of 1 and 3 IU without (normoxia) or with (hypoxia) cadmium chloride for 48 hours. Cell viability was counted using a haematocytometer and trypan blue 0.4% (w/v) dye. Expression of Epo and EpoR protein was assessed by western blot. Results and Discussion. We observed a decrease in the number of colon cancer cells in hypoxia. Addition of rHuEpo did not modify cell numbers in normoxia and hypoxia. We found a significant increase of EpoR expression in all cells growing in medium with cobalt chloride in comparison with respective normoxic cells. We also noted that rHuEpo in concentration of 3 IU significantly increased expression of Epo and EpoR protein in colon cancer cells in normoxia and hypoxia conditions. Conclusions. We concluded that Epo and EpoR are constitutively expressed in DLD-1 cells. In hypoxia as well as in the presence of rHuEpo the increase of Epo and EpoR protein was found. However, the expression of Epo and EpoR protein in these cells does not seem essential to their growth. [ABSTRACT FROM AUTHOR]

Until recently the major physiological function of erythropoietin (EPO) was thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO has tissue-protective properties and prevents ischemia induced tissue damage in several organs including the kidney. A pivotal intracellular pathway mediating the beneficial effects of EPO is the activation of Akt, i.e. serine/threonine protein kinase B. As a result, Akt phosphorylates the proapoptotic factor Bad, which in turn causes inhibition of programmed cell death (apoptosis). In the present article we review data on the non-hematological effects of recombinant human EPO (rHuEPO) in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogues substances that are not related to anemia correction. [ABSTRACT FROM AUTHOR]

Background: We previously showed that the content reticulocyte hemoglobin (CHr) is a reliable measure of iron status in chronic dialysis patients with erythrocytopoiesis. The CHr was significantly correlated with conventional parameters of iron deficiency in dialysis patients. We attempted utilize the measurement of CHr levels to monitor iron status and clarify the changes in iron levels that occur as renal anemia progresses in patients with chronic renal failure (CRF). Methods: We measured CHr, iron parameters, and the intrinsic erythropoietin (EPO) concentration in nondialysis CRF patients who visited our outpatient clinic (n=211). Iron deficiency was defined according to the transferrin saturation (TSAT) and ferritin levels. Conventional red blood cell parameters and CHr levels were measured using an ADVIA120 autoanalyzer (Bayer Medical, USA). Results: The mean CHr value of the nondialysis CRF patients (creatinine clearance less than 70 mL/min) was 32.3 pg, which was not significantly different from that of the dialysis patients. Significant correlations were found between CHr and ferritin levels (r=0.042, p < 0.0403) and CHr and TSAT levels (r=0.040, p< 0.0157). A positive correlation was observed between the CHr and serum creatinine levels. Nondialysis CRF patients treated with recombinant human EPO (rHuEPO) at a dose of 24,000 U/month exhibited lower CHr levels, compared with those of other patients who received less than 24,000 U/month. Conclusion: CHr is an easily measurable and trustworthy marker of iron status in nondialysis CRF patients. Moreover, the CHr level was also sensitive to iron alterations in nondialysis CRF patients receiving rHuEPO treatment, and thus, the CHr value could likely provide useful information regarding the need for iron supplementation. [ABSTRACT FROM AUTHOR]

Background. The available literature is still controversial and shows that surgical (parathyroidectomy, PTX) or medical (calcitriol) treatment actually improved or even corrected the rhEPO-resistant anemia of ESRD patients with severe SHP. The aims of this study were to 1) assess the influence of SHP on hematological parameters in ESRD patients, 2) evaluate whether or not calcitriol could improve anemia and reduce the need of erythropoietin in dialysis patients, and 3) investigate the longitudinal effect of a parathyroidectomy for 6 months on regarding any improvements in calcitriol-refractory ESRD patients. METHODS: 37 chronic hemodialysis patients in Chang Gung Memorial Hospital Dialysis Unit were divided into two groups: patients with SHP (iPTH > 300 pg/mL) and patients without SHP (ipTH < 300 pg/mL) before calcitriol therapy was applied. Sixteen patients remain with a status of hyperparathyroidism and were considered candidates for calcitriol therapy. Furthermore, we divided the patients according to the response of HPT to calcitriol into responding patients and nonresponding patients. Among nonresponder groups, three patients agreed to accept surgical intervention to treat their hyperparathyroidism status. RESULTS: The phosphate levels and serum alkaline phosphatase levels in patients with SHP were significantly higher when compared with those without SHP (P < 0.05). As for the hematological data, hematocrit for patients with SHP was significantly higher than those without SHP (10.5 ± 0.6 vs. 8.9 ± 0.8, p < 0.05). Other hematological parameters such as transferrin saturation and serum ferritin were not significantly different. We found a significant difference in alkaline phosphate levels in responding and nonresponding patients at 6 months on calcitriol therapy. Concomitantly, the hematocrit level is significantly higher in responding group when compared responding group (10.63 ± 0.72 vs. 8.96 ± 1.21, p < 0.01). As for the dose of EPO requirement, significant difference between groups was also found after 6-month treatment (3617 ± 2011 vs. 5416 ± 1947, p < 0.05). As for rhEPO dose requirement, positive effects of PTX were significantly found. The rhEPO doses needed to maintain patients in the hematocrit target range of 30–33% decreased gradually by 29% from 5323 ± 1326 µ to 3774 ± 2145 µ per week. The hematocrit level showed a significant increase at 3 months after PTX (p < 0.05). This effect lasted until 6 months after PTX. The serum ferritin level was constantly around 350 to 400 pg/mL. While the transferrin saturation decreased 3 months after PTX (p < 0.05) and recovered at 6 months. CONCLUSION: ESRD patients with SHP, usually associated with more severe anemia show resistance to rhEPO. In this case, investigation of SHP is strongly recommended with measurement of serum PTH, phosphate and alkaline phosphatase level. Treatment of calcitriol has a beneficial effect on renal anemia in ESRD patients with SHP. In addition, PTX could also provide another choosing therapy in improving renal anemia when medical treatment fails. [ABSTRACT FROM AUTHOR]

Background: Erythropoietin (EPO) is a glycoprotein hormone produced by specialized cells in the kidney that acts as the primary regulator of erythropoiesis. Serum EPO measurements are useful for diagnostic evaluations of anemia and polycythemia. Methods: The IMMULITE 2000 is an automated random access immunoassay analyzer for the central laboratory. The limit of detection (LOD), linearity, imprecision, comparison to another commercially available assay, and reference interval of a new EPO assay for this analyzer were assessed. Results: The LOD was 0.2 U/l. The assay was linear within an allowable systematic error of 10% over the range tested (2–178 U/l). The total imprecision of the new assay was <7% for concentrations from 15.8 to 68.4 U/l. Comparison with the Advantage EPO assay method showed comparable results. Deming regression analysis gave a slope of 1.13±0.02, an intercept of −1.09±0.97, and a Sy/x of 7.1 (r=0.99) over the range tested (2–200 U/l). Conclusions: The IMMULITE 2000 EPO assay shows acceptable performance and is suitable for routine clinical use. [Copyright &y& Elsevier]

Background: In a previous report, 31 patients with neuropsychiatric porphyria were studied and nine of these patients were anaemic in association with inappropriately low serum erythropoietin levels. We were also able to demonstrate that treatment with erythropoietin in non-porphyric patients (mainly diabetic patients with autonomic neuropathy) significantly reduced urinary δ-aminolaevulinic acid levels. Methods: We treated six porphyric patients, five of whom were anaemic, with recombinant human erythropoietin (1000–2000 IU thrice weekly). They were all in clinical but not biochemical remission. Full blood count, including reticulocytes and platelets, urinary δ-aminolaevulinic acid, porphobilinogen and total porphyrins were measured monthly. Baseline serum ferritin, vitamin B12, folate and C-reactive protein levels were all within the normal range and serum creatinine did not exceed 126 μmol/l. Results: After 3 months of treatment, the average baseline haemoglobin increased significantly (p=0.01). When treatment was stopped, the haemoglobin decreased and after 3 months pre-treatment, haemoglobin levels were reached. Urinary δ-aminolaevulinic acid, porphobilinogen and porphyrin levels all tended to decrease during treatment with erythropoietin, but the difference between baseline and 3 months of erythropoietin was statistically significant only for porphobilinogen (p=0.03). The severity of porphyria attacks was reduced and the quality of life increased during treatment with erythropoietin. Conclusion: We conclude that in some porphyric patients treatment with erythropoietin reduces urinary δ-aminolaevulinic acid, porphobilinogen and porphyrin levels with an increase in well-being and a reduction in the severity of porphyria attacks. [Copyright &y& Elsevier]

Rare cases of unexplained sudden severe anemia or red cell aplasia and resistance to recombinant human erythropoietin (rHuEPO) in patients with chronic renal failure (CRF) have been attributed to the development of anti-EPO antibodies. The development and validation of a radioimmunoprecipitation (RIP) assay to detect human anti-EPO antibodies in serum or plasma has been hampered by the lack of purified antibody to fully characterize and validate the assay. We have prepared an affinity-purified human antibody to EPO and used the antibody to characterize and validate a sensitive and reproducible RIP assay that can qualitatively measure anti-EPO antibody in serum or plasma samples. The lower limit of detection of the assay is 8 ng/ml of purified antibody. The threshold for detecting antibody is ≥0.9% cpm bound. The precision of the assay using purified antibody standards ranges from 5.8% to 15.3% and the precision of the assay using dilutions of the positive control ranges from 15.9% to 18.7%. EPO in the samples did not interfere with detection of the anti-EPO antibody except at high concentrations. [Copyright &y& Elsevier]

About one third to one half of patients with heart failure are anemic, in that they have a hemoglobin level of less than 12 g/dL. Anemia is more common and more severe as the clinical status of CHF worsens. In addition, anemia is associated with a higher mortality and higher rate of hospitalization, as well as with signs of malnutrition. In anemic CHF patients who are resistant to maximally tolerated CHF medications and who remain very symptomatic, both uncontrolled studies of a combination of subcutaneous erythropoietin (EPO) and IV ferric sucrose have reported a correction of the anemia. This correction has been associated with an improvement in NYHA functional status, left ventricular ejection fraction, and a marked reduction in the doses of diuretic needed and in the frequency and duration of hospitalizations. Renal function, which had been steadily falling before the correction of the anemia, was also stabilized. Other controlled studies have also found that anemia correction with EPO increased oxygen utilization during maximal exercise, exercise endurance and quality to life. The anemia is probably due mainly to a combination of renal failure and excessive cytokines, both of which interfere with EPO production and utilization. If confirmed by larger studies, correction of anemia with the EPO-IV iron combination may become a useful adjuvant to the treatment of CHF. [Copyright &y& Elsevier]

In patients with chronic kidney disease (CKD), adverse outcomes such as systemic inflammation and anemia are contributing pathologies which increase the risks for cardiovascular mortality. Amongst these complications, abnormalities in mineral metabolism and the metabolic milieu are associated with chronic inflammation and iron dysregulation, and fibroblast growth factor 23 (FGF23) is a risk factor in this context. FGF23 is a bone-derived hormone that is essential for regulating vitamin D and phosphate homeostasis. In the early stages of CKD, serum FGF23 levels rise 1000-fold above normal values in an attempt to maintain normal phosphate levels. Despite this compensatory action, clinical CKD studies have demonstrated powerful and dose-dependent associations between FGF23 levels and higher risks for mortality. A prospective pathomechanism coupling elevated serum FGF23 levels with CKD-associated anemia and cardiovascular injury is its strong association with chronic inflammation. In this review, we will examine the current experimental and clinical evidence regarding the role of FGF23 in renal physiology as well as in the pathophysiology of CKD with an emphasis on chronic inflammation and anemia. [ABSTRACT FROM AUTHOR]

In patients with primary as well as secondary chronic kidney disease (CKD), anemia has been identified as an independent risk factor for progression. In these patients anemia is thought to be a surrogate parameter for tissue hypoxia that perpetuates preexisting renal tissue injury, and treatment of anemia with recombinant human erythropoietin (rHuEPO) was therefore expected to retard progression. However, results of recently published large trials in patients with CKD did not fulfill these expectations. The reason for the discrepant findings may be distinct molecular pathways and/or EPO tissue receptor affinities that mediate the effect of EPO on erythropoiesis and tissue protection by EPO. A pivotal intracellular pathway is the activation of Akt (i.e., serine/threonine protein kinase B), but further potential pathways have been identified that may play an important role in tissue protection. In this study, we review data on the non-hematological effects of rHuEPO in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogue substances that are not related to anemia correction.Kidney International (2007) 72, S21–S25; doi:10.1038/sj.ki.5002484 [ABSTRACT FROM AUTHOR]

Lead (Pb) poisoning has numerous effects on the erythropoietic system, but the precise mechanism whereby high dose exposure causes anemiais not entirely clear. We previously reported that Pb exposure is associated with depressed serum erythropoietin (EPO) in pregnant women residing in a Pb mining town and in a nonexposed town in Kosovo, Yugoslavia. In a prospective study, we tested the hypothesis that blood Pb concentration (BPb) may be associated with depressed EPO in children. BPb, hemoglobin (Hgb), and serum EPO were measured at ages 4.5, 6.5, and 9.5 years in 211, 178, and 234 children, respectively. At 4.5 years of age, mean BPbs were 38.9 and 9.0 5g/dl in the exposed and nonexposed towns, respectively; BPbs gradually declined to 28.2 and 6.55g/dl, respectively, by age 9.5 years. No differences were found in Hgb at any age. At age 4.5 years, a positive association between BPb and EPO (beta = 0.21; p = 0.0001), controlled for Hgb, was found. The magnitude of this association declined to 0.11 at age 6.5 years (p = 0.0103) and 0.03 at age 9.5 years (p = 0.39). These results were confirmed using repeated measures analyses. We concluded that in Pb-exposed children, the maintenance of normal Hgb requires hyperproductionof EPO. With advancing age (and continuing exposure), this compensatory mechanism appears to be failing, suggesting a gradual loss of renal endocrine function due to Pb exposure. [ABSTRACT FROM AUTHOR]