losartan-potassium and Cardiovascular-Diseases

Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker

Topics: Adult; Cardiovascular Diseases; Dietary Supplements; Erythropoietin; Humans; Kidney Failure, Chronic; Minerals; Randomized Controlled Trials as Topic; Renal Dialysis; Vitamin D; Vitamin D Deficiency; Vitamins

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular Diseases; Enzyme Inhibitors; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Renal Insufficiency, Chronic

In this review paper, we examine the latest evidence regarding the use of iron supplementation, erythropoiesis-stimulating agents (ESAs), and blood transfusions as therapeutic targets for anemia to mitigate morbidity and mortality in patients with cardiovascular disease.. Intravenous ferric carboxymaltose (FC) injections in heart failure (HF) have resulted in improved self-reported patient symptoms; higher exercise capacity, as measured by 6-min walk test distance in anemic patients; and lower re-hospitalization rates in iron deficient patients. Darbepoetin alfa has shown evidence of improved Kansas City Cardiomyopathy Questionnaire scores. No mortality benefits have been noted thus far with FC injections or darbepoetin in HF, with an increase in adverse events with darbepoetin. Aggressive transfusions (Hg < 10 g/dL) are not associated with improved outcomes in cardiovascular disease. Quality of life metrics, rather than mortality, appear to improve with IV FC and ESA use in HF. More studies are required to see if these treatments have a role in coronary artery disease. Current evidence suggests that anemia is a marker of underlying disease severity, with a limited role in disease modification. Further studies are required to solidify our understanding of this topic.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Quality of Life; Severity of Illness Index

The findings of recent clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors produce effects beyond glucose lowering and have demonstrated beneficial cardiovascular effects that have been observed across a broad range of patients with type 2 diabetes mellitus. In particular, the cardiovascular benefit results largely from substantial and early effects of SGLT2 inhibition on cardiovascular death and hospitalization for heart failure. Recent cardiovascular outcomes trials (CVOTs) have also shown that relative risk reductions in cardiovascular outcomes were observed with SGLT2 inhibition both in patients with current and prior heart failure. Since the observed reductions of cardiovascular outcomes with SGLT2 inhibitor therapy were observed much earlier than would be expected by an anti-atherosclerotic effect, these results have led to speculation about the potential underlying pathways. Suggested mechanisms include natriuresis and osmotic diuresis; reductions in inflammation, oxidative stress, and arterial stiffness; reductions in blood pressure and body weight; and possible renoprotective effects. These effects could produce cardiovascular benefits through a range of cardiac effects, including reduction in left ventricular load, attenuation of cardiac fibrosis and inflammation, and improved myocardial energy production. Other possible mechanisms include inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury. It is likely that a range of mechanisms underlie the observed cardiovascular benefits of SGLT2 inhibitors; further elucidation of these mechanisms will be answered by ongoing research.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Cardiovascular System; Diuresis; Erythropoietin; Heart; Humans; Inflammation; Kidney; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Natriuresis; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchangers; Vascular Stiffness

Doping is the use of a substance that artificially increases an individual's physical ability for competition purpose. Products and methods used in doping are not without risk, especially at cardiovascular level. Here we review the most common doping substances in sport and their cardiovascular consequences.

Topics: Adrenergic beta-2 Receptor Antagonists; Anabolic Agents; Blood Transfusion, Autologous; Cannabinoids; Cardiovascular Diseases; Central Nervous System Stimulants; Diuretics; Doping in Sports; Erythropoietin; Glucocorticoids; Hormone Antagonists; Humans

Protein carbamoylation is a non-enzymatic post-translational modification that binds isocyanic acid, which can be derived from the dissociation of urea or from the myeloperoxidase-mediated catabolism of thiocyanate, to the free amino groups of a multitude of proteins. Although the term 'carbamoylation' is usually replaced by the term "carbamylation" in the literature, carbamylation refers to a different chemical reaction (the reversible interaction of CO

Topics: Biomarkers; Cardiovascular Diseases; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Protein Processing, Post-Translational; Urea

Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).. To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.. Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.. We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life.. There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Cause of Death; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Middle Aged; Polyethylene Glycols; Publication Bias; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Thrombosis

Erythropoietin (EPO) is the main regulator of red blood cell production. Since the 1990s, EPO has been used for the treatment of anemia associated with end-stage renal failure and chemotherapy. The erythropoietin receptors were found on other organs such as the brain, spinal cord, heart and skin. In addition, it has been shown that many tissues produce and locally release EPO in response to hypoxic, biochemical and physical stress. In cellular, animal and clinical studies, EPO protects tissues from ischemia and reperfusion injury, has antiapoptotic effects and improves regeneration after injury. In this article, we mainly review the nonhematopoietic effects and new possible clinical indications for EPO.

Topics: Animals; Cardiovascular Diseases; Cognition; Diabetes Mellitus; Erythropoietin; Humans; Kidney; Memory; Neovascularization, Physiologic; Neurodegenerative Diseases; Neuroprotective Agents; Obesity; Retina

Chronic kidney disease (CKD) is an important health problem, because of unsuccessful outcomes such as CKD progression to end stage renal disease and high risk of cardiovascular disease (CVD). Anemia, associated with CKD, is considered a non-traditional risk factor for CVD which may contribute to faster CKD progression. Anemia treatment with erythropoiesis-stimulating agents (ESAs) seems to exert non-hematopoietic effects on different tissues and organs, including cardiovascular system and kidneys. On the other hand, clinical use of high doses of short-acting ESAs and higher target hemoglobin level were associated with higher risk of CVD. Literature data indicate the usefulness of long-acting ESAs in treatment of anemia in non-dialysis CKD patients. In particular, continuous erythropoietin receptor activator seems to be a good choice in these patients because of its efficiency, safety and monthly administration. Continuous but slower erythropoietin receptor activation, using methoxy polyethylene glycol-epoetin beta (MPG-EPO), administered once a month, slowly corrects anemia without exceeding the recommended hemoglobin level. An overview of the available literature may suggest nephroprotective and cardiovascular protective effects of MPG-EPO. It seems possible that anemia treatment with a novel ESAs, MPG-EPO in early stages of CKD may reduce CVD risk in these patients and delay CKD progression. This review of available literature evaluates the correlation between continuous erythropoietin receptor activation using MPG-EPO and CKD progression and CVD risk in non-dialysis CKD patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematinics; Humans; Kidney; Polyethylene Glycols; Renal Insufficiency, Chronic; Risk Factors

In the TREAT and RED-HF trials, patients who received a high darbepoetin dose had an increased risk of adverse events. To find an explanation, the published literature was analyzed on the pharmacokinetics and pharmacodynamics of darbepoetin.. Based on the sigmoid Emax model, the concentration producing 50% of the maximum erythropoietin effect is reported as CE50 = 0.41 ng/ml and the Hill coefficient as H = 3.0 for darbepoetin. Accordingly, a pharmacodynamics-based threshold concentration can be estimated with CE05 = 0.153 ng/ml producing 5% of Emax and a ceiling concentration with CE95 = 1.098 ng/ml producing 95% of Emax, respectively.. Darbepoetin trough levels should not be less than the threshold concentration but peak levels above the ceiling concentration could be associated with an increased risk of adverse events. The time span associated with the concentration fluctuation between the ceiling and the threshold concentration is estimated with 236 h (= 2.84 times elimination half-life of 83 h) and shorter than the 336 h when dosing every other week. According to such time-dependent pharmacodynamics, a weekly dosing regimen might be more effective and associated with less adverse events than higher doses every other week in patients with suboptimal response to a normal darbepoetin dose.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Humans; Treatment Outcome

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.

Topics: Anemia; Bone and Bones; Calcifediol; Calcitriol; Calcium; Cardio-Renal Syndrome; Cardiovascular Diseases; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Iron; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic

The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation.

Topics: Animals; Cardiovascular Diseases; Cytoprotection; Erythropoietin; Hematinics; Humans; Kidney; Kidney Transplantation; Nitric Oxide Synthase Type III; Oligopeptides; Receptors, Erythropoietin; Recombinant Proteins; Reperfusion Injury; Risk Factors; Translational Research, Biomedical

Topics: Aged; Algorithms; Anemia; Anemia, Iron-Deficiency; Cardiovascular Diseases; Cohort Studies; Comorbidity; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Peptides; Renal Dialysis

Anemia in chronic kidney disease (CKD) may affect up to 90% of the patients. It is one of the non typical risk factors of cardiovascular disease, specific for this population. The main reasons of the anemia in CKD are iron and erythropoietin deficiency. It is recognized in women with hemoglobin concentration < 11 g/dl and in men and postmenopausal women with hemoglobin concentration < 12 g/dl. Other potentially reversible reasons of anemia should be excluded in differential diagnosis. Iron and erythropoiesis stimulating agents (ESA) constitute the main treatment of anemia of CKD.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Causality; Comorbidity; Erythropoietin; Female; Hematinics; Humans; Male; Renal Insufficiency, Chronic; Risk Factors

Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.. Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level.. Patients with anemia of CKD irrespective of dialysis status.. We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.. ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.. All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement.. 31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events.. Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders.. In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.

Topics: Aged; Anemia; Cardiovascular Diseases; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Renal Insufficiency, Chronic; Risk Factors; Treatment Outcome

From the trials published till now, it is clear that the most important and frequent adverse reactions related to the treatment with recombinant human erythropoietin (rHuEpo) are thrombovascular accidents and systemic hypertension. Only on very rare occasions cephalea and epileptic fits may occur. Even if these adverse reactions are so precisely defined, there is no evident interpretation of the biological and pathophysiological mechanisms that sustain these events. This work intends to describe the state of the art in the international literature in order to enable the reader to understand the real risks of rHuEpo administration.

Topics: Cardiovascular Diseases; Erythropoietin; Humans; Hypertension; Recombinant Proteins

Anemia is a very common complication of chronic kidney disease (CKD). Anemia confers significant risk of cardiovascular disease and contributes to decreased quality of life. Anemia in CKD patients can be multi-factorial, including but not invariably due to the underlying renal insufficiency. Identifying the type of anemia is important in this group of patients and can often be challenging. Diagnosing anemia of renal disease due to erythropoietin (EPO) deficiency is a diagnosis of exclusion. Erythropoiesis stimulating agents (ESA) are the mainstay for the treatment of anemia secondary to CKD. However, over the last four years the use of ESA in the treatment of anemia in CKD patients has undergone a severe interrogation as several trials have reported adverse outcomes with targeting higher hemoglobin (Hb) levels with these agents. Thereby, this review describes the pathophysiology of anemia in CKD patients, diagnosis and the current role of ESA's as it relates to anemia of CKD as well as safety and efficacy of ESA's.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematinics; Humans; Incidence; Kidney Failure, Chronic; Risk Factors; United States

Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Cardiovascular System; Erythropoietin; Humans; Molecular Targeted Therapy; Receptors, Erythropoietin

Interpretation of the results of earlier meta-analyses in chronic kidney disease (CKD) patients on the impact of anaemia treatment with erythropoiesis-stimulating agents (ESAs) on clinical outcomes has been hampered by the inclusion of small trials and trials of short duration. We re-evaluated the benefits and harms of treating anaemia, including only relevant clinical trials.. We conducted a systematic review and meta-analysis of randomised controlled trials performed in adults with CKD which allocated patients to different doses of ESAs, and we compared the effect of these interventions on vascular access thrombosis, stroke, risk of end-stage renal disease (ESRD) and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants.. Five trials (7,902 participants) met the inclusion criteria and were included in the meta-analysis. The number of patients enrolled in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. A higher haemoglobin target was associated with increased risk of vascular access thrombosis (RR 1.343; 95% CI 1.162-1.554; p = 0.0005) and stroke (RR 1.735; 95% CI 1.323-2.275; p = 0.0005), and no effect on risk of ESRD (RR 1.089; 95% CI 0.986-1.203; p = 0.094) or all-cause mortality (RR 1.148; 95% CI 0.977-1.350; p = 0.093).. In CKD patients, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk.

Topics: Adult; Anemia; Cardiovascular Diseases; Comorbidity; Erythropoietin; Hematinics; Humans; Incidence; Renal Insufficiency, Chronic; Risk Factors; Survival Analysis; Survival Rate; Treatment Outcome

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio-renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases.

Topics: Biomarkers; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Prognosis; Signal Transduction

Topics: Animals; Cardiovascular Diseases; Erythropoietin; Humans

Despite the advances in the cardiovascular field, cardiovascular diseases remain an important health problem with a high mortality rate. Novel therapeutic attempts that target myocardial ischemia and heart failure offer attractive adjuncts and/or alternatives to commonly employed regimens. The development of novel laboratory technologies over the last decade has led to substantial progress in bringing new therapies to the bedside.. Current experimental and clinical trials in the use of erythropoietin (EPO) in cardiovascular diseases are reviewed.. This review will widen knowledge of the therapeutic potential of EPO's non-erythropoietic beneficial effects in a clinical cardiovascular setting.. Results from preclinical trials regarding the non-erythropoietic effects of erythropoietin are really encouraging. Further clinical studies are warranted to define the beneficial role of EPO in the clinical setting of coronary artery disease, heart failure and peripheral artery disease.

Topics: Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Receptors, Erythropoietin; Recombinant Proteins

Premature cardiovascular disease (CVD) is a frequent complication in patients with chronic kidney disease (CKD). The traditional (Framingham) risk factors only partly explain the high prevalence of CVD in these patients and nontraditional risk factors/markers such as oxidative stress, persistent inflammation, cardiovascular ossification, endothelial dysfunction and anaemia are prevalent and seem to play an important role in the pathogenesis of CVD in CKD patients. In addition, the so-called reverse epidemiology phenomenon, which occurs in advanced kidney disease, complicates the search for causative mechanisms. Here we review a few recently developed concepts regarding the high incidence of CVD in CKD patients.

Topics: Anemia; Cardiovascular Diseases; Chronobiology Disorders; Endothelium, Vascular; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Netherlands; Ossification, Heterotopic; Oxidative Stress; Prevalence; Risk Assessment; Risk Factors

The European Renal Best Practice (ERBP), which are issued by ERA-EDTA, are suggestions for clinical practice in areas in which evidence is lacking or weak, together with position statements on recently published randomized controlled trials, or on existing guidelines and recommendations. In 2009, the Anaemia Working Group of ERBP published its first position statement about the haemoglobin target to aim for with erythropoietin-stimulating agents (ESA) and on issues that were not covered by K-DOQI in 2006-07. This second position paper of the group follows the publication of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Study. This multi-centre, placebo-controlled trial compared cardiovascular and renal outcomes in 4038 patients with type 2 diabetes, chronic kidney disease not on dialysis, and anaemia who were randomized to complete anaemia correction (haemoglobin target of 13 g/dL using darbepoetin alpha) or placebo (with a haemoglobin rescue value of 9 g/dL). Following the findings of the TREAT study, the Anaemia Working Group of ERBP maintains its view that 'Hb values of 11-12 g/dL should be generally sought in the CKD population without intentionally exceeding 13 g/dL' and that the doses of ESA therapy to achieve the target haemoglobin should also be considered. More caution is suggested when treating anaemia with ESA therapy in patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages). In those with ischaemic heart disease or with a previous history of stroke, possible benefits should be weighed up against an increased risk of stroke recurrence, when deciding which Hb level to aim for. These recommendations are not intended to represent a new guideline as they are not the result of a systematic review of the evidence.

Topics: Anemia; Cardiovascular Diseases; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Treatment Outcome

Publication of the first large randomized placebo-controlled study of erythropoiesis-stimulating agent (ESA) treatment of anemia in patients with chronic kidney disease (CKD) not on dialysis, the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) along with recent changes in the regulatory environment and reimbursement policies related to ESA treatment have prompted reexamination of clinical ESA use in patients with CKD, including those on dialysis. This review addresses this and other recent studies of ESA treatment for renal anemia to higher hemoglobin (Hgb) targets above the range of 10-12 g/dl.. TREAT and other recent large randomized, controlled trials of ESA treatment in patients with CKD have not demonstrated a clinical benefit in terms of mortality, morbidity, or quality of life improvement of targeting Hgb levels greater than 12-13 g/dl. Some of these studies have demonstrated increased risk of stroke, vascular access thrombosis, hypertension, and other events. These findings are generally consistent with those of an earlier study of patients with end-stage renal disease (ESRD) on hemodialysis.. ESA treatment for renal anemia should be aimed at reducing transfusion risk, with a treatment target in most patients of 10-12 g/dl; therapy should be individualized, rapid increases in Hgb level should probably be avoided, and lowest appropriate ESA doses should be used. Temptation to increase ESA doses to very high levels in an attempt to overcome ESA hypo responsiveness should be resisted.

Topics: Anemia; Blood Transfusion; Cardiovascular Diseases; Darbepoetin alfa; Erythropoietin; Evidence-Based Medicine; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome

Anemia resulting from iron and erythropoietin deficiencies is a common complication of advanced chronic kidney disease (CKD). This article covers major advances in our understanding of anemia in patients with CKD, including newly discovered regulatory molecules, such as hepcidin, to innovative intravenous iron therapies. The use of erythropoiesis-stimulating agents (ESA) in the treatment of anemia has undergone seismic shift in the past 3 years as a result of adverse outcomes associated with targeting higher hemoglobin levels with these agents. Potential mechanisms for adverse outcomes, such as higher mortality, are discussed. Despite the disappointing experience with ESAs, there is a tremendous interest in other novel agents to treat anemia in CKD. Lastly, while awaiting updated guidelines, the authors outline their recommendations on how to best manage patients who are anemic and have CKD.

Topics: Anemia, Iron-Deficiency; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cardiovascular Diseases; Erythropoietin; Ferrosoferric Oxide; Heart Failure; Hematinics; Hepcidins; Humans; Indicators and Reagents; Iron, Dietary; Kidney Failure, Chronic

The erythropoietin is produced by the kidney and other organs. EPO does not only affect erythroid cells, but also other blood cell lines, such as myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytes function of the polymorph nuclear cells and reduces the activation of macrophages, thus modulating the inflammatory process. Hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors also on mesangial and myocardial cells and smooth muscle fibro-cells has prompted the study of the pleiotropic actions of this hormone. Through its receptors, spread out over the body, it carries out many actions which range from the erythrogenesis after hypoxic stimuli to the tissue protection of the heart and the brain after ischemia. Erythropoietin also acts in the endothelial proliferation of new vessels involving the tumor genesis, but it opens new frontiers to the employment of rHuEPO in the Regenerative Medicine.

Topics: Anemia; Animals; Brain; Cardiovascular Diseases; Endothelium, Vascular; Erythroid Cells; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia; Ischemia; Kidney; Mice; Models, Biological; Myeloid Cells; Myocardium; Neovascularization, Pathologic; Neovascularization, Physiologic; Organ Specificity; Oxygen; Receptors, Erythropoietin

Erythropoietin (EPO) is a therapeutic product of recombinant DNA technology and it has been in clinical use as stimulator of erythropoiesis over the last two decades. Identification of EPO and its receptor (EPOR) in the cardiovascular system expanded understanding of physiological and pathophysiological role of EPO. In experimental models of cardiovascular and cerebrovascular disorders, EPO exerts protection either by preventing apoptosis of cardiac myocytes, smooth muscle cells, and endothelial cells, or by increasing endothelial production of nitric oxide. In addition, EPO stimulates mobilization of progenitor cells from bone marrow thereby accelerating repair of injured endothelium and neovascularization. A novel signal transduction pathway involving EPOR--β-common heteroreceptor is postulated to enhance EPO-mediated tissue protection. A better understanding of the role of β-common receptor signaling as well as development of novel analogs of EPO with enhanced nonhematopoietic protective effects may expand clinical application of EPO in prevention and treatment of cardiovascular and cerebrovascular disorders.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Erythropoietin; Humans

Endothelial progenitor cells (EPCs) reside in the bone marrow and are mobilized into the circulation by specific stimuli such as certain drugs, ischemia, and exercise training. Once in the circulation EPCs are thought to participate in the maintenance of the endothelial cell layer. Recently it was clearly demonstrated that the amount and function of EPCs is significantly impaired in different cardiovascular diseases. Furthermore, the level of circulating EPCs predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients at increased cardiovascular risk. After demonstrating the beneficial effect of applied EPCs in several animal experiments, these cells were also used to treat humans with different cardiovascular diseases. This review will focus on the characterization and liberation of EPCs from the bone marrow, as well as on the most important clinical cardiovascular diseases for which EPCs were used therapeutically.

Topics: Animals; Bone Marrow Cells; Cardiovascular Diseases; Chemokine CXCL12; Endothelial Cells; Erythropoietin; Exercise; Humans; Insulin-Like Growth Factor I; Regeneration; Stem Cell Transplantation; Stem Cells; Vascular Endothelial Growth Factor A

Recent studies, in which the cardiovascular risk and mortality associated with high and low hemoglobin target values, respectively, have been investigated, challenged the concept that hemoglobin normalization improves prognosis.. The results of these studies are reviewed with respect to differences in study populations, study design and methodological limitations to provide guidance for their interpretation and relevance for clinical practice.. There are important differences with respect to enrolled populations, design and conduct of the studies. Each study has its specific, inherent methodological limitations. Importantly, there is no statistically significant and consistent pattern of negative results for cardiovascular and mortality outcomes, although in general outcomes are not in favor of hemoglobin normalization. On the other hand, the reported data on quality of life are consistently and significantly better with higher hemoglobin values.. Recent evidence from large outcome studies suggested an increased risk associated with hemoglobin normalization. On the other side, several study-inherent and methodological limitations must be considered before simply extrapolating the negative findings of these studies into clinical practice. However, until new evidence becomes available from ongoing and future clinical studies, an upper Hb limit of 12 g/dl should not be exceeded.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

Anaemia is common in patients with heart failure and is associated with poorer prognosis. The aetiology of anaemia in heart failure is diverse and includes renal failure, iron and vitamin deficiency, the use of medication, and insensitivity of the bone marrow to erythropoietin. Recently, small-scale clinical trials investigating the effect of erythropoietin on anaemia showed an improvement in the surrogate cardiovascular endpoints exercise tolerance, haemodynamics and number of hospitalisations. Erythropoietin also has non-haematopoietic (pleiotropic) effects, such as inhibition of apoptosis and neovascularisation. In preclinical studies, erythropoietin had a beneficial effect on heart function following acute myocardial infarction and in heart failure. Currently, these pleiotropic effects are being studied in patients with acute myocardial infarction.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Myocardial Revascularization; Prognosis

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Charcoal; Chronic Disease; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Life Style; Mineralocorticoid Receptor Antagonists

Chronic kidney disease (CKD) is now recognized as a risk factor of both end-stage renal disease (ESRD) and independently cardiovascular disease (CVD). Therefore, a specific renoprotective intervention is strongly recommended, including blood pressure control as well as anemia improvement with erythropoietin stimulating agents (ESAs). Treatment of renal anemia with ESAs has been proved to improve quality of life (QOL) and finally reduce patient mortality. Recently, Silverberg, et al. created a novel clinical entity of Cardio-Renal Anemia (CRA) syndrome, in which anemia plays a key role for worsening both CKD and cardiac performance in a vicious circle. An appropriate and vigorous treatment of anemia has now been accepted to terminate or weaken the circle. Recently, two large-scaled randomized controlled trials were reported, being the CREATE (cardiovascular risk reduction by early anemia treatment with epoetin beta) study and the CHOIR (correction of hemoglobin and outcomes in renal insufficiency) study. They demonstrated that early initiation of ESA treatment and targeting at higher hemoglobin level (near normal level) failed to show the lowering effects for cardiovascular events as compared to a group in which Hb targeting was lower (sub-normal level) in pre-dialysis CKD patients. While there has been many argues in these reports especially about baseline patients characteristics, being a quite high incidence of severe cardiovascular co-morbidity. Thus, further evidences should be accumulated to resolve a proper target level of Hb in ESA treatment.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Disease Progression; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Syndrome

Endothelial injury is thought to play a pivotal role in the development and progression of vascular diseases, such as atherosclerosis, hypertension or restenosis, as well as their complications, including myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. Coronary artery disease and its risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, are associated with a reduced number and impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC levels are associated with endothelial dysfunction and an increased risk of cardiovascular events, compatible with the concept that impaired EPC-mediated vascular repair promotes progression of vascular disease. In this review we summarize recent data on the effects of pharmacological agents on mobilization and functional activity of EPCs. In particular, several experimental and clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, PPAR-gamma agonists and erythropoietin increase the number and functional activity of EPCs. The underlying mechanisms remain largely to be defined; however, they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of NAD(P)H oxidase activity of progenitor cells.

Topics: AC133 Antigen; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antigens, CD; Antigens, CD34; Atherosclerosis; Benzopyrans; Carbazoles; Cardiovascular Diseases; Carvedilol; Cell Differentiation; Coronary Disease; Endothelium, Vascular; Erythropoietin; Ethanolamines; Glycoproteins; Hematopoietic Stem Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin; Nebivolol; Neovascularization, Physiologic; Oxidative Stress; Peptides; PPAR gamma; Propanolamines; Receptors, Angiotensin; Regeneration; Risk Factors; Rosiglitazone; Stem Cells; Thiazolidinediones; Vasodilator Agents

Patients with chronic kidney disease (CKD) are exposed to extremely higher risks of atherothrombotic complications of the cardio- and cerebrovascular systems. In pertinent meta-analyses, overviews, editorials and comments, it has been considered unproven, on the basis of current data from randomized controlled trials, that a higher hemoglobin (Hb) value provides overall-survival benefits for CKD. At present, there is a "gray zone" between the intervention threshold of Hb < 9 g/dl and an Hb level > 13 g/dl, at which CKD is associated with a higher risk of cardiovascular events. This paper discusses in depth the hemostaseological hypothesis of increased mortality as a result of higher Hb levels during treatment of renal anemia with erythropoiesis-stimulating agents (ESA). It seems to be clearly evident that ESA activate platelets directly and indirectly, and that pathologically extended bleeding time is normalized when an Hb level of 10 g/dl is reached; from the hemostaseological perspective, a threshold level for treatment of renal anemia with ESA is thus defined. According to the present state of knowledge, an Hb target range of 10-11 g/dl seems reasonable for renal anemia; this is also compatible with current recommendations by ESA producers and the Food and Drug Administration (FDA). This target range avoids the upper and lower risk levels for Hb, and probably ensures a positive ESA effect on quality of life; it is much more cost-efficient than the target range of 11-12 g/dl recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2007.

Topics: Age Factors; Aged; Anemia; Bleeding Time; Blood Transfusion; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Follow-Up Studies; Hematinics; Hemoglobinometry; Hemoglobins; Hemolysis; Humans; Kidney Diseases; Meta-Analysis as Topic; Platelet Activation; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Survival Analysis; Time Factors

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Evidence-Based Medicine; Hemoglobins; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Communicable Diseases; Erythropoietin; Evidence-Based Medicine; Hematocrit; Hemoglobinometry; Hemoglobins; Hospitalization; Humans; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Risk Factors; Treatment Outcome

Erythropoietin is a hormone produced by the kidney, which regulates proliferation, differentiation and maturation of red cells. Recombinant human EPO (rH-EPO) is well known to correct anaemia in patients with chronic renal failure in terminal stage. However, recent studies showed the existence of several not haematopoietic effects of erythropoietin. EPO receptors have been found to be expressed in several tissues, included the cardiovascular system. An increase in cardiac systolic function has been observed in patients with chronic heart failure treated with EPO. Other beneficial effects appear to be related to the pro-angiogenic properties on endothelial cells and could be useful for treatment of ischemic heart disease. These findings suggest that EPO could provide potential therapeutic benefits in the management of cardiovascular diseases beyond anaemia correction. This review focuses its attention on the pleiotropic effects of EPO and its future promising applications in cardiovascular pathology.

Topics: Anemia; Apoptosis; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Heart Failure; Humans; Myocardial Ischemia; Receptors, Erythropoietin; Recombinant Proteins

The mortality rate in diabetics with chronic kidney disease (CKD) is seven times higher than end-stage renal disease mainly because of cardiac causes. Anaemia may have a relevant role in the pathogenesis of cardiovascular (CV) disease in CKD. Anaemia occurs at an earlier stage of CKD in diabetic individuals than in those with other causes of CKD. Observational findings support the unfavourable influence of anaemia on mortality in CKD patients, and the combination of anaemia and CKD in diabetics identifies a group with a particularly high mortality risk. While the effect of erythropoietin on these patients' quality of life is known, its impact on mortality and CV risk is uncertain. The recent Anaemia Correction in Diabetes (ACORD) trial in diabetic CKD patients, which targeted haemoglobin levels of 13-15 mg/dl, disclosed no statistically significant favourable or adverse effects on mortality or morbidity over the 2-year follow-up, while other studies endeavouring to nearly normalize haemoglobin have reportedly proved risky. Even if anaemia is causally involved, the pathogenesis of CV disease in diabetics with CKD is so complex that addressing just one factor (anaemia) may not suffice to prevent CV risk, and normalizing haemoglobin levels may even be harmful.

Topics: Anemia; Cardiovascular Diseases; Diabetic Nephropathies; Erythropoietin; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Risk

Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim was to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease.. We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trial registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks.. We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01-1.35; p=0.031) and arteriovenous access thrombosis (1.34, 1.16-1.54; p=0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08-1.50; p=0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1.31, 0.97-1.78; p=0.075). The incidence of myocardial infarction was much the same in the two groups.. To target higher haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

Topics: Aged; Anemia; Blood Pressure; Cardiovascular Diseases; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

The well-established physiological function of erythropoietin (EPO) is the induction of erythropoiesis. A growing body of evidence indicates that EPO has tissue-protective effects and prevents tissue damage during ischemia and inflammation. Tissue protection after ischemia and injury has been found in the brain, heart, and kidney. It has been speculated that EPO has anti-apoptotic effects in cardiovascular cells. These novel effects of EPO seem to be independent of its erythropoietic activity. Unclear is the role of the known EPO receptor or whether other signaling pathways are involved; a novel EPO receptor might be involved in tissue protection by this hormone. This review article summarizes present knowledge of cardiovascular and renal protective effects of EPO and discusses possible underlying mechanisms.

Topics: Acute Kidney Injury; Anemia; Animals; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Vascular Diseases

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Female; Gene Expression; Glomerular Filtration Rate; Hemoglobins; Humans; Iron; Kidney Diseases; Kidney Failure, Chronic; Male; Prognosis; Quality of Life; Recombinant Proteins; Renal Dialysis; Risk Factors

Erythropoietin (EPO) is a glycoprotein hormone implicated in the regulation of red blood cell production. Anemia is common in chronic heart failure (CHF) patients and associated with an inappropriately low EPO-production, suggesting a role for its recombinant human form (rhEPO) in treatment. Although safety concerns have been raised regarding treatment with rhEPO in patients with chronic kidney disease, treatment with rhEPO in patients with CHF has so far been safe and well tolerated. The effect of rhEPO on outcome in anemic CHF patients is under investigation in a phase III clinical trial. In addition to its erythropoietic effects, EPO has been detected in the cardiovascular system, fueling intense research into possible non-hematopoietic effects. EPO has been shown to exert protective effects on the heart during acute myocardial ischemia and improve cardiac function in experimental CHF. Acute protection is mediated through reduction of apoptotic cell death. Improvement of cardiac function in CHF is related to myocardial neovascularization. EPO exhibits a vast array of beneficial effects in cardiovascular disease. In addition to the correction of anemia in CHF, rhEPO might benefit patients with cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Treatment Outcome

Erythropoietin (EPO) is a 30,400 daltons glycoprotein, consisting of 165 amino acids produced mainly in the kidney and in the liver and regulating erythrocyitosis. It primarily acts on erythroid precursor cell at colony-forming units-erythroid stage inhibiting the apoptosis. EPO binds on a specific membrane receptor thereby activating at least three specific intracellular signaling pathways, such as phosphatidylinositol 3-kinase/ protein kinase B, Ras-mitogen-activated protein kinase and some members of the signal transducers and activators of transcription family. In addition to kidney and liver, EPO mRNA has been detected in other tissues; accordingly EPO receptor has been identified in several type of cells and recent reports have suggested new roles for EPO in non-haematopoietic tissues with a robust evidence for neuroprotective and cardioprotective activity. In different animal models, in vitro, in isolated perfused heart and in vivo, recombinant human erythropoietin protects heart from ischemia reperfusion injury and reduces myocardial damage. EPO tissue protective activity can be separated from erythropoietic activity. Molecules owing the first property but not the second one have been described. In patients with acute myocardial infarction serum EPO level correlates inversely with infarct size. Acute coronary syndrome, extracorporeal circulation and percutaneous coronary intervention are potential fields of application for tissue protective EPO activity to reduce myocardial damage, increase cardiac function ad improve outcome.

Topics: Animals; Cardiovascular Diseases; Erythropoietin; Humans; Receptors, Erythropoietin; Recombinant Proteins

Anemia is a frequently encountered problem of chronic kidney disease (CKD) and deteriorates as renal function declines. Anemia increases the risk of death in CKD patients with diabetes and hypertension, which are the 2 leading causes of CKD. Recent studies suggest that correction of anemia improves patient quality of life and may delay the progression to end-stage renal disease. Anemia is often only treated in the late stages of CKD or after the initiation of renal replacement therapy. Thus, anemia of CKD is often unnoticed and lacks appropriate treatment. To practically manage high-risk patients with CKD and its associated cardiovascular diseases, it is mandatory to diagnose and appropriately treat anemia of CKD earlier. The optimal level of hemoglobin for greatest clinical benefit is unclear, but at present, it is recommended to remain > or = 11 g/dL. This paper provides recommendations for the diagnosis and management of anemia associated with CKD based on international practice guidelines.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases

The glycoprotein erythropoietin was originally discovered as a principal regulator that promotes the survival, proliferation and differentiation of erythroid progenitor cells. Despite potentially detrimental effects, such as increased blood pressure and hyperviscosity, recombinant human erythropoietin has been demonstrated to be a safe drug, as millions of anemia sufferers have received it over the last decade as a form of treatment. Recently, erythropoietin receptors have been discovered in a variety of tissues, including the cardiovascular system, and erythropoietin has been demonstrated to have a beneficial effect in congestive heart failure patients with anemia. The purpose of this review is to summarize the pleiotropic cardioprotective effects of erythropoietin in the cardiovascular system and to evaluate its potential role as a biomarker in these disorders.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Erythropoietin; Humans; Myocardium; Receptors, Erythropoietin

Allogeneic red blood cell (RBC) transfusions are associated with multiple disadvantages, such as limited availability, high costs, multiple risks and side effects. In addition, large outcome studies comparing liberal (hemoglobin transfusion trigger range 9-10 g/dL) and restrictive (hemoglobin transfusion trigger range 7-9 g/dL) transfusion regimens still need to be performed for surgical patients. Different transfusion alternatives are known for the pre-, intra- and postoperative period. Autologous blood donation and erythropoietin are efficacious in the preoperative period. Intraoperatively, acute normovolemic hemodilution (ANH), cell salvage, antifibrinolytics, specific anesthetic and surgical techniques, coagulation monitoring, acceptance of minimal hemoglobin values and hopefully soon artificial oxygen carriers can reduce allogeneic RBC transfusions. In the postoperative period cell salvage, antifibrinolytics, and accepting minimal hemoglobin values represent alternatives to RBC transfusions. When treating a bleeding patient, the initial administration of crystalloids and colloids to restore and maintain normovolemia is important. RBC transfusions are recommended under the following circumstances: for hemoglobin levels <6 g/dL and for physiologic signs of inadequate oxygenation such as hemodynamic instability, oxygen extraction rate >50% and myocardial ischemia, detectable by new ST-segment depressions >0.1 mV, new ST-segment elevations >0.2 mV or new wall motion abnormalities by transesophageal echocardiography. The aim of this article is to review the efficacy, risk and side effects of RBC transfusions, to discuss transfusion alternatives and to summarize current indications for RBC transfusions. This information will help the physician to judiciously use RBC transfusions when they are indeed indicated.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Blood Loss, Surgical; Blood Transfusion; Blood Transfusion, Autologous; Cardiovascular Diseases; Child; Critical Care; Erythropoietin; Hemoglobins; Hemorheology; Humans; Immune System; Infant, Newborn; Oxygen; Oxyhemoglobins; Postoperative Period; Risk; Sepsis; Transfusion Reaction

Intravenous (i.v.) iron and recombinant human erythropoietin (EPO), like all other medications, are associated with the risk of adverse events. Historically, the primary concern with iron therapy has been the possibility of iron overload, which exposes the individual to the effects associated with nontransferrin-bound iron. Experience with EPO use has demonstrated an association with hypertension and with the upregulation of a number of markers of inflammation. The impact of these potential adverse effects merits careful analysis, given that both i.v. iron and EPO are designed for long-term use in a patient population at high risk for infection and cardiovascular disease. However, the incidence of iron overload and the risks associated with nontransferrin-bound iron have dramatically been reduced since the introduction of EPO therapy, and no data exist that demonstrate a definitive association between i.v. iron and an increased risk of morbidity related to infection or cardiovascular disease. On the other hand, EPO use is associated with hypertension, endothelial dysfunction, and prothrombotic and inflammatory states in hemodialysis patients. Risks associated with hypertension can be minimized by using the lowest effective EPO dose, which may be achieved through the regular use of i.v. iron. Judicious use of both i.v. iron and EPO may optimize cardiovascular outcomes.

Topics: Anemia, Iron-Deficiency; Blood Pressure; Cardiovascular Diseases; Comorbidity; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Ferritins; Hemoglobins; Hemosiderosis; Humans; Hypertension; Inflammation; Injections, Intravenous; Iron; Patient Care Planning; Recombinant Proteins; Renal Dialysis; Risk Assessment

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in people with diabetes and in those with chronic kidney disease (CKD). Diabetes, occurring in epidemic proportions in the United States and worldwide, is also the leading cause of CKD and kidney failure. Identification of modifiable risk factors for CVD in patients with diabetes and CKD is thus of paramount importance. Anemia is increasingly recognized as a potential CVD risk factor in patients with diabetic nephropathy, in whom it is generally more severe and occurs at an earlier stage of CKD. In this review, we discuss the epidemiologic evidence, pathophysiologic mechanisms, and the current research findings, highlighting the role of anemia as a potential modifiable risk factor for CVD in patients with diabetic nephropathy, a particularly vulnerable population for CVD.

Topics: Anemia; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Risk Factors

Anemia is prevalent in renal transplant recipients (RTRs), as it is in all chronic kidney disease (CKD) populations. Mild anemia occurs in up to 40% of RTRs, and more severe anemia (110 g/L) occurs in about 9% to 22% of patients. As in CKD, impaired graft (renal) function is a major predictor of anemia identified in nearly all studies, suggesting a major role for erythropoietin deficiency. Chronic inflammation, malnutrition, iron deficiency, and medications (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mycophenolate, azathioprine, and sirolimus) are contributory factors seen in some, but not all, studies. Although pathophysiologic and observational data strongly support a causal association between low hemoglobin levels and cardiovascular outcomes in RTRs, no randomized controlled trial to date has been able to show a clear benefit of anemia treatment on cardiovascular outcomes or mortality in either RTR or other CKD populations. This important paradox has led some investigators to question the causal nature of the association between anemia and heart disease. Resolution of this paradox, at least for patients with stage 2/3 CKD, will depend on the outcome of randomized controlled trials currently in progress. Similar trials sorely are needed in renal transplant populations. In the interim, current opinion favors treating persistent anemia in RTRs to achieve targets similar to those recommended for dialysis and CKD patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Oxidative Stress; Randomized Controlled Trials as Topic; Risk Factors

Anemia in the setting of chronic kidney disease is a well-recognized phenomenon that is associated with decreasing renal function and deficiency of or resistance to erythropoietin. However, anemia in the post-renal transplantation setting has received comparatively less attention in the literature. In this review, we aim critically to appraise the available literature regarding posttransplantation anemia, concentrating in particular on the prevalence of posttransplantation anemia, its etiopathogenesis, potential effects on morbidity and mortality, and the rationale for intervention and treatment. Despite deficiencies in the literature, we conclude that posttransplantation anemia is a common phenomenon that can occur either early or late posttransplantation, and its causation is usually multifactorial and includes contributions notably from poor or decreasing renal function, immunosuppression, and iron deficiency. Conversely, there is a shortage of well-conducted prospective studies looking at the morbidity attributable to posttransplantation anemia and a lack of trial evidence to determine whether intervention improves patient morbidity and outcome.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Prevalence; Recombinant Proteins; Risk Factors

Topics: Cardiovascular Diseases; Endocrine System Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Natriuretic Agents; Renin-Angiotensin System; Risk; Vitamin D

Topics: Anemia; Bias; Cardiovascular Diseases; Confounding Factors, Epidemiologic; Drug Monitoring; Erythropoietin; Evidence-Based Medicine; Hemoglobins; Humans; Kidney Failure, Chronic; Morbidity; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Recently there has been considerable interest in the associations between blood hemoglobin (Hb) level, renal function, and cardiovascular disease. Anemia is a common feature of end-stage renal disease, but it also accompanies lesser degrees of chronic kidney disease (CKD). The degree of anemia roughly approximates the severity of CKD. Anemia seen in diabetes has been linked to diabetic nephropathy; however, diabetes itself affects the hematologic system in several ways. Anemia is associated with left ventricular hypertrophy, cardiovascular morbidity, progressive loss of kidney function, and poor quality of life. Anemia seems to act as a mortality multiplier; that is, at every decrease in Hb below 12 g/dL, mortality increases in patients with CKD, cardiovascular disease, and those with both. Unlike blood transfusion, treatment of anemia with exogenous erythropoietin in patients with cardiorenal disease has shown promise in reducing morbidity and in improving survival and quality of life. Increasing the Hb level from less than 10 g/dL to 12 g/dL has resulted in favorable changes in left ventricular remodeling, improved ejection fraction, improved functional classification, and higher levels of peak oxygen consumption with exercise testing. Clinical trials are underway to test the role of erythropoietin in patients with CKD and in patients with heart failure.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Comorbidity; Diabetes Complications; Erythropoietin; Humans; Prevalence; Prognosis; Renal Insufficiency; Risk Factors

The combination of diabetes and chronic kidney disease is associated with increased mortality and reduced quality of life. Recent studies have shown that, in general, late referral of patients to the renal unit increases mortality, and that patients with diabetes who are referred late have a particularly poor prognosis. Several co-morbid conditions have been shown to contribute to poor patient outcomes, including both cardiovascular disease and anaemia. In patients with diabetic nephropathy, anaemia is more severe and is seen earlier than in patients with non-diabetic renal disease. Although the treatment of anaemia with recombinant human erythropoietin (rhEPO; epoetin) is well established, the only data currently available concerning the effects of early intervention in patients with diabetic nephropathy are from small-scale studies. Therefore, two large-scale studies have been designed to provide information on the efficacy of epoetin treatment and on how current management strategies might be improved. The Anaemia CORrection in Diabetes (ACORD) study will provide information on the potential cardiac benefits of early anaemia management in patients with early, type 2 diabetic nephropathy. The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study will provide evidence-based guidance in risk factor management, by assessing the efficacy of individualized interventions.

Topics: Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Referral and Consultation; Survival Rate

Erythropoietin is a hypoxia-induced hormone that is a major regulator of normal erythropoiesis. Over the last decade, the production of recombinant human erythropoietin has revolutionized the treatment of anemia associated with chronic renal failure, and has led to a greater understanding of anemia pathophysiology and to the elucidation of the interactions of erythropoietin, iron, and erythropoiesis. Anemia has been shown to be independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia have expanded considerably the indications of erythropoietin use in various patient populations and are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia. The results of such treatment are promising in a variety of new clinical settings, including anemia associated with congestive heart failure. Furthermore, the erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes and preclinical studies have established erythropoietin to be a pleiotropic cytokine with anti-apoptotic activity and tissue-protective actions in the cardiovascular system, beyond correction of hemoglobin levels. Despite some potential adverse effects, such as hypertension, and the occurrence of erythropoietin resistance, early studies in heart failure patients with anemia suggest that erythropoietin therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Anemia is found in about one-third of all cases of congestive heart failure (CHF). The most likely common cause is chronic renal insufficiency, which is present in about half of all CHF cases. However, anemia can occur in CHF without renal insufficiency and is likely to be due to excessive cytokine production. The anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Long-standing anemia of any cause can cause left ventricular hypertrophy, which can lead to cardiac cell death through apoptosis and worsen CHF. Therefore, a vicious circle, cardio-renal anemia syndrome, is set up wherein CHF causes anemia, and the anemia causes more CHF and both damage the kidneys worsening the anemia and the CHF

Topics: Amino Acid Sequence; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Molecular Sequence Data; Recombinant Proteins

Recombinant human erythropoietin (rHuEPO) is a hormone essential for normal erythropoiesis. The rHuEPO receptor is distributed in the cardiovascular system predominantly in endothelial cells and cardiomyocytes. RHuEPO has potentially beneficial effects on cardiovascular system, including anti-apoptic, mitogenic and angiogenic activity. On the other hand rHuEPO improves anemia observed in some patients with heart failure. Direct cardiac activity of rHuEPO and indirect influence on anemia suggest that rHuEPO therapy is safe and useful in chronic heart failure patients and other cardiovascular settings.

Topics: Cardiology; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Heart Failure; Humans; Recombinant Proteins; Signal Transduction

Several clinical and experimental observations suggest that an intact and activated renin-angiotensin system (RAS) may be an important determinant of erythropoiesis in a variety of clinical conditions, including hypertension, chronic renal insufficiency or failure, chronic obstructive pulmonary disease, and congestive heart failure. Accordingly, RAS inactivation may confer susceptibility to the hematocrit-lowering effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Indeed, a dose-dependent decrease in hematocrit is observed within the first month of such therapy. In the majority of patients with hypertension decreases in hematocrit values after RAS inactivation are small and not clinically important. In extreme conditions, however, such as erythrocytosis after successful renal transplantation, secondary polycythemia of chronically hypoxemic COPD patients, erythrocytosis associated with renovascular hypertension, severe cardiac or renal failure, the hematocrit-lowering effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blocker may be profound and even lead to or worsen anemia. Hematocrit reaches its nadir value within three months, and then it remains stable during long-term observations. After discontinuation of RAS blockade, hematocrit values rise gradually over the next three to four months towards the pretreatment levels. The mechanism(s) related to this phenomenon is not yet fully understood, but angiotensin II seems to be responsible for inappropriately sustaining secretion of erythropoietin despite hematocrit elevation and capable to directly stimulate the erythroid progenitors in bone marrow to produce erythrocytes.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Renin; Renin-Angiotensin System

Several studies showed that anaemia is commonly observed in patients with Chronic Heart Failure (CHF) and is associated with worsened symptoms and survival. When anaemia in these patients is treated with erythropoietin (EPO), a significant improvement in cardiac function and symptoms was observed. Although it was originally believed that EPO specifically acted on haematopoietical cells, recent evidence demonstrated several non-haematopoietical effects. Ischaemia/reperfusion experiments in rat heart and brain showed large infarct reduction when treated with EPO. Other effects of EPO are related to its pro-angiogenic effects on endothelial cells, which could be of potential value in patients with ischaemic heart disease. These preclinical findings suggest that EPO may have potential effects in cardiovascular disease beyond correction of haemoglobin levels.

Topics: Anemia; Apoptosis; Cardiac Output, Low; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Neovascularization, Pathologic; Recombinant Proteins; Stroke

Preoperative anemia in a surgical patient predisposes to poor outcomes and allogeneic blood transfusions. As an alternative to transfusions, pharmacologic management of preoperative anemia with recombinant human erythropoietin (rHuEPO) has been well studied in many different types of surgery. rHuEPO, when used alone or in combination with preoperative autologous blood donation before elective surgery, stimulates erythropoiesis and helps to avoid or reduce the need for allogeneic blood transfusions. The clinical evidence on preoperative use of rHuEPO in orthopedic, cardiac, and cancer surgery, as well as in bloodless surgery, is reviewed.

Topics: Anemia; Blood Loss, Surgical; Blood Transfusion; Cardiac Surgical Procedures; Cardiovascular Diseases; Erythropoietin; Humans; Monitoring, Intraoperative; Neoplasms; Premedication; Recombinant Proteins; Treatment Outcome

Despite the high prevalence and significant morbidity and mortality rates of chronic kidney disease (CKD) related to cardiovascular disease, it remains vastly understudied. Most of the current practice recommendations come from small under-powered prospective studies, retrospective reviews, and assuming patients with CKD will similarly benefit from medications and treatments as patients with normal renal function. In addition, because of the previous lack of a consistent definition of CKD and how to measure renal function, definitions of the degree of renal dysfunction have varied widely and compounded the confusion of these data. Remarkably, despite patients with CKD representing the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus, there has been a systematic exclusion of patients with CKD from therapeutic trials. This review outlines our current understanding of CKD as a cardiovascular risk factor, treatment options, and the future directions that are needed to treat cardiovascular disease in patients with CKD.

Topics: Cardiovascular Diseases; Chronic Disease; Erythropoietin; Glomerular Filtration Rate; Humans; Hyperhomocysteinemia; Kidney Diseases; Myocardial Revascularization; Oxidative Stress; Recombinant Proteins; Risk Factors; United States

Replacement of injured endothelial cells by bone marrow derived endothelial progenitor cells (EPC's) is a new pathway of vascular repair after ischemia. Endothelial progenitor cells contribute less than 0.01% to the peripheral venous compartment of mononuclear cells. The detection of EPC's requires a demonstration of CD 34 and VEGFR-2 (vascular endothelial growth factor receptor-2) antigenic cell membrane determinants and proof of endothelial characteristics after outgrowth and differentiation in cell culture. The most important stimuli to the mobilization and proliferation of EPC's are VEGF, GM-CSF (granulocyte-macrophage colony stimulating factor), erythropoietin, HMG-CoA-reductase inhibitors and tissue ischemia. In vivo in patients EPC's appear to contribute to endothelialization of vascular grafts, the formation of collaterals of ischemic limbs and the healing of myocardial infarcts. The role of EPC's in uremia is currently under investigation.

Topics: Antigens, CD34; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myeloid Progenitor Cells; Myocardial Ischemia; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The failure to lower systolic blood pressure at night (called non-dipping) and sleep apnea are both associated with adverse cardiovascular outcomes. Sleep apnea is a common cause of non-dipping blood pressure.. Sleep apnea increases night time blood pressure through enhanced cardiac pre-load, sleep disturbance and hypoxia. Hypoxia elicits increased levels of norepinephrine, endothelin and erythropoetin. Patients with sleep apnea tend to be elderly and obese, so they have poor endothelial nitric oxide release and blunted baroreflexes. They thus have several stimuli for high blood pressure and poor compensatory mechanisms to lower blood pressure.. Non-dipping patients without sleep apnea have evidence of volume overload and correct their blood pressure pattern in response to diuretics. Individuals with sleep apnea have evidence of increased cardiac pre-load from episodes of negative intrathoracic pressure. Their daytime blood pressure responds poorly to many drugs, but beta blockers may be effective. Their night time blood pressure responds only slightly to therapy of their sleep apnea with continuous positive airway pressure, even though continuous positive airway pressure decreases their norepinephrine, erythropoetin and endothelin levels.

Topics: Blood Pressure; Blood Volume; Cardiovascular Diseases; Circadian Rhythm; Endothelins; Erythropoietin; Humans; Hypertension; Kidney Diseases; Nitric Oxide; Racial Groups; Respiration, Artificial; Sleep Apnea Syndromes; Sleep Wake Disorders

Anaemia correction with recombinant human erythropoietin (rh-EPO, epoetin) in end-stage renal disease (ESRD) patients has been associated with improved survival and quality of life, as well as lower overall treatment costs. Few studies, however, have evaluated the benefits of epoetin treatment given to chronic kidney disease (CKD) patients during the pre-dialysis period. A retrospective study of 89 193 incident haemodialysis patients in the Medicare system (age > or =67 years) assessed consistency of epoetin treatment before the start of dialysis and the outcome of patients once they reached ESRD. Patients were grouped according to consistency of epoetin treatment based on the available months of treatment in the 2-year period before starting dialysis. Only 15.6% of patients in the study received any epoetin before the initiation of dialysis. Patients who received no or infrequent epoetin (i.e. received epoetin in <50% of possible months) had a significantly higher relative risk of cardiac disease and death than patients treated with epoetin more frequently. Patients who received no or infrequent epoetin also had significantly higher rates of hospitalization and overall treatment costs at the time of initial dialysis. These findings suggest that early epoetin treatment warrants further investigation in prospective, randomized studies. In summary, it is evident that the care of CKD patients can be improved. Evidence suggests that timely initiation of epoetin treatment to correct renal anaemia appears to be associated with improved survival of ESRD patients in the first year after start of dialysis and reduced costs of treatment.

Topics: Anemia; Cardiovascular Diseases; Comorbidity; Cost-Benefit Analysis; Erythropoietin; Hospitalization; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Retrospective Studies

A literature review on fish oil supplementation in the population undergoing chronic hemodialysis therapy suggests that supplementation may be beneficial for various challenges to health and well-being prevalent in this population. One study indicated that pruritus symptoms improved with fish oil supplementation, but not with supplementation with two other oils. In a study designed to determine whether fish oils could prevent vascular access graft thrombosis, graft patency rates were approximately 76% in the fish oil and approximately 15% in the placebo group (P>.03). In a pilot study, subjects given fish oil required 16% less erythropoietin and experienced a 3.6% increase in serum albumin levels. Some studies suggest that fish oil supplementation in hemodialysis patients is cardioprotective, with one study finding that "fish eaters" are half as likely to die as "non-fish eaters." Potential risks of supplementation include gastrointestinal distress, prolonged bleeding, and vitamin A toxicity, although the likelihood of serious side effects is probably low. Dietitians are in a position to advise physicians and/or patients regarding appropriate dosages and ways to minimize risks when supplementation seems warranted. Future research could compare the benefits of fish consumption with those of fish oil supplementation and explore the benefits of other n-3 fatty acid sources, such as flaxseed.

Topics: Cardiovascular Diseases; Catheters, Indwelling; Dietary Supplements; Erythropoietin; Female; Fish Oils; Humans; Kidney Failure, Chronic; Male; Pruritus; Renal Dialysis; Seafood; Serum Albumin; Thrombosis

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Prospective Studies

In renal failure, severe anemia and associated fatigue, cognitive and sexual dysfunction have a significant impact on the patient's quality of life. Anemia has also been identified as an important etiologic factor in the development of left ventricular hypertrophy. The major cause of anemia in presence of a reduction of glomerular filtration rate is an inadequate production of a glycoprotein hormone, the erythropoietin (EPO). EPO is the primary regulator of the growth and survival of erythroid progenitor. The introduction of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of anemia in chronic renal failure. The vast majority of patients respond very well to treatment, but 5-10% of patients show some resistance to EPO, the most common cause of which is iron deficiency. Several studies are recently commenced to investigate the effects of preventing renal anemia ever developing. The target of hemoglobin concentration in pre-dialysis and dialysis patients are object of continuous re-examinations.

Topics: Anemia; Animals; Cardiovascular Diseases; Disease Progression; Dogs; Drug Resistance; Erythropoietin; Hemodynamics; Hemoglobins; Humans; Iron Deficiencies; Kidney Failure, Chronic; Quality of Life; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renal Dialysis; Treatment Outcome

End-stage renal disease (ESRD) is characterized by a high mortality rate, derived largely from cardiovascular disease (CVD). In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features that may contribute to malnutrition, anaemia, recombinant human erythropoietin (rHuEPO) resistance, and atherosclerosis. Inflammation predicts poor outcome in ESRD. It is multifactorial in cause and, while it may reflect the underlying CVD, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. In patients with ESRD, the acute-phase response may be influenced by a number of factors unrelated to dialysis and perhaps by the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels resulting in reduced erythropoiesis, accelerated destruction of erythrocytes, and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, rHuEPO resistance has been linked with inflammation, the latter of which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity to handle oxidative stress. There is recent evidence that a relationship may exist between inflammation and oxidative stress and treatment of anaemia with rHuEPO. However, iron may also generate oxidative stress. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to rHuEPO can be defined.

Topics: Anemia; Cardiovascular Diseases; Cytokines; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins; Treatment Failure

Doping consists in the use of artificial means or substances with the unique aim of improving performance despite adverse effects on health. Amphetamines stimulate the central nervous system by increasing motivation and vigilance. Often consumed in association with analgesics, they increase the fatigue threshold during prolonged or repeated exercise. Addiction and dependency to these substances are extremely rapid. Side-effects include insomnia, exhaustion, violence and can lead to serious heart diseases. By enhancing capacity for intensive training, anabolic steroids improve strength, alertness and speed. This action is often further strengthened by the use of growth hormones DHEA and IGF-1. Extremely high dosage is used and is in no way comparable with natural secretions or those necessary to re-balance an exhausted glandular system. During prolonged endurance exercise, doping aims at improving the circulation of oxygen in the blood and thus its availability to the muscles. Firstly, the blood haemoglobin concentration was increased by blood transfusions. At present the production of red blood cells is stimulated by repeated injections of exogenous erythropoietin. The extreme viscosity of the blood leads to a risk of vascular thromboses and high blood pressure and accentuates greatly and sometimes even fatally the possibility of brachycardia which is common with sportsmen.

Topics: Amphetamines; Anabolic Agents; Bradycardia; Cardiovascular Diseases; Doping in Sports; Erythropoietin; Fatigue; Growth Hormone; Humans; Hypertension; Thrombosis

The beneficial effects of treating the anaemia of dialysis-dependent patients with erythropoietin on the improvement of cardiac status, exercise capacity, cognitive function and quality of life are well established. Equally, if not more important is the reduction in morbidity and mortality that accompanies the treatment of anaemia with epoietin. These documented improvements in outcomes of care notwithstanding, mortality and morbidity due to cardiovascular disease (CVD) remain high in dialysis patients. Recent epidemiological evidence indicates that: (i) the prevalence of CVD is very high in patients at the start of dialysis; (ii) pre-existing CVD is the major risk factor for mortality and morbidity on dialysis; (iii) CVD begins early in the course of kidney disease, shows an inverse relationship to kidney function and increases in prevalence and severity with progression of kidney disease; and (iv) corrective measures, which take 3-5 years to show a favourable effect, must be instituted well before the initiation of dialysis. Hypertension and anaemia, which develop in the course of progressive reduction in kidney function, are the principal risk factors for the prevalence of left ventricular hypertrophy (LVH) in those with chronic kidney disease, and their treatment has been shown to arrest or reverse LVH in these individuals. Whereas the treatment of hypertension early in the course of kidney disease has been incorporated into clinical practice, there has been reluctance in the treatment of anaemia because of the possibility of worsening kidney function with epoietin, as shown in rats. There is now convincing evidence that epoietin has no potential adverse effect on kidney function in humans. While the most compelling reason for the early treatment of the anaemia of kidney disease is its beneficial effect on cardiovascular function, other documented potential benefits are improvements in exercise capacity, cognitive function and quality of life.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Prevalence; Renal Replacement Therapy; Risk Factors; Time Factors

Cardiac diseases account for almost 50% of deaths in long-term dialysis patients. Left ventricular dysfunction is present in approximately 80% of these patients and is highly predictive of future ischemic heart disease, cardiac failure, and death. Anemia has been identified as one of several risk factors responsible for cardiac complications. Cardiovascular consequences of renal anemia begin relatively early in the course of renal failure and progress with the decline of renal function and also during dialysis therapy. In chronic renal failure patients with severe anemia (hemoglobin levels <10 g/dL), increased cardiac output, high left ventricular mass, left ventricular end-diastolic and end-systolic diameters, and cardiac symptoms improve after partial correction of anemia (hemoglobin levels >11 g/dL according to the European Best Practice Guidelines). It is disappointing that normalization of hemoglobin levels has only minor effects with respect to regression of left ventricular hypertrophy and left ventricular dilation. There is no benefit of hemoglobin normalization on all-cause mortality of dialysis patients or on survival of end-stage renal disease patients with congestive heart failure or ischemic heart disease. Therefore, prevention of renal anemia may be more efficient than its treatment. Hypertension is one of the major side effects of recombinant human erythropoietin (rHuEPO) therapy. Multiple factors are involved in rHuEPO-induced hypertension. High blood pressure can usually be controlled readily in the majority of the patients.

Topics: Anemia; Cardiovascular Diseases; Comorbidity; Erythropoietin; Hematocrit; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Cardiovascular disease (CVD) is a major cause of death in patients with chronic renal failure (CRF). It is well recognised that dialysis patients have a high burden of factors that predispose to CVD. What is less clear is the extent of this problem in the pre-dialysis patient. This is the subject of this review.. The role of potentially correctable cardiovascular risk factors in pre-dialysis patients has been examined using published data.. Anaemia is a major cardiovascular risk factor in patients with CRF. Partial correction of renal anaemia with recombinant human erythropoietin leads to improvements in cardiac dysfunction in such patients, such as alleviation of left ventricular hypertrophy. Secondly, malnutrition and inflammation have also been recently identified as potentially correctable cardiovascular risk factors in these patients.. Patients continue to enter dialysis with a considerable cardiovascular burden, many having already suffered a stroke or myocardial infarction. Many risk factors, including malnutrition and inflammation, account for the increased incidence of cardiovascular events. Anaemia is common in pre-dialysis patients, and early corrective treatment may help to reduce the incidence of CVD and hence improve long-term outcome.

Topics: Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Cardiovascular disease is a major cause of mortality and morbidity in patients with end-stage renal disease. Anemia, a result of erythropoietin deficiency, is associated with increased all-cause and cardiovascular mortality in this population, and predisposes patients to the development of symptomatic heart disease. Anemia is also associated with the development and progression of left ventricular echocardiographic disorders, which strongly predict cardiac failure and death. Left ventricular dilatation with compensatory hypertrophy, the major pattern of echocardiographic disease progression in hemodialysis patients, is a particularly strong predictor of late mortality. Partial correction of anemia with recombinant human erythropoietin likely reduces left ventricular mass and volume. Complete correction of anemia may prevent progressive left ventricular dilatation in patients with normal left ventricular volumes. A recent trial, however, reports excess mortality and vascular access loss in patients with preexisting symptomatic heart disease when anemia was completely corrected. Consequently, hematocrit target ranges above 32% to 36% cannot be recommended in this population. In patients without symptomatic heart disease, it is not possible to conclude that potential benefits derived from a normalized hematocrit will outweigh potential risks.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Comorbidity; Echocardiography; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Prognosis; Recombinant Proteins; Renal Dialysis; Risk Factors; Survival Analysis

Cushing's syndrome of glucocorticoid excess is named after the eminent Boston neurosurgeon Harvey W. Cushing (1869-1939). The recognition that glucocorticoid excess produces hypertension led to examination of the role of cortisol in essential hypertension, but it is only over the last decade that evidence has emerged to support the concept. Despite the widespread assumption that cortisol raises blood pressure as a consequence of renal sodium retention, there are few data consistent with the notion. Although it has a plethora of actions on brain, heart and blood vessels, kidney, and body fluid compartments, precisely how cortisol elevates blood pressure is unclear. Candidate mechanisms currently being examined include inhibition of the vasodilator nitric oxide system and increases in vasoconstrictor erythropoietin concentration.

Topics: Cardiovascular Diseases; Cushing Syndrome; Disease Models, Animal; Erythropoietin; Glucocorticoids; Humans; Hydrocortisone; Hypertension; Infant, Newborn; Nitric Oxide; Vasoconstriction; Vasodilation

Estimates of the prevalence of anemia during chronic renal insufficiency (CRI) vary depending on how anemia is defined. An analysis of patients beginning dialysis in the United States found that 67% had a hematocrit of less than 30% and 51% had a hematocrit of less than 28%. The anemia of CRI, therefore, appears to be prevalent even as it is underrecognized and undertreated-despite the widespread realization that there is much to be gained by treatment with recombinant human erythropoietin, with little risk of accelerating the progression of kidney disease. It is difficult to separate the effects of anemia in CRI from those of other comorbid conditions, but it is clear that anemia is a strong predictor of mortality and cardiac morbidity. Correction of anemia would be expected to negate the contribution of anemia to the mortality and cardiac morbidity associated with CRI. While this hypothesis is well-validated in hemodialysis patients, data in the population with CRI are preliminary but encouraging. Recent small prospective studies have established that treatment of anemia with recombinant human erythropoietin can reverse some degree of the cardiac morphological changes seen in CRI. While awaiting the results of large long-term clinical trials, the concept of the renal anemia management period (RAMP) draws attention and focus to the need for proactive and aggressive treatment of anemia among patients with CRI. The RAMP is defined as the period of time after the onset of CRI during which anemia develops, requiring diagnosis and treatment. Treatment of anemia during the RAMP has the potential to ameliorate, or even prevent, significant future morbidity in patients with CRI.

Topics: Anemia; Canada; Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Replacement Therapy

The introduction of recombinant human erythropoietin (rHuEPO) more than a decade ago provided the first effective treatment for the anemia of chronic renal insufficiency (CRI). The use of rHuEPO in the treatment of anemia has been associated with partial regression of left ventricular hypertrophy among both dialysis and nondialysis patients, and has been shown to reduce the frequency of cardiac complications such as congestive heart failure and number of days of hospitalization among dialysis patients. Despite this evidence, the anemia of CRI remains highly prevalent, underrecognized, and undertreated. A number of considerations arise regarding the management of anemia among patients with CRI. In this article, we review the rationale for treatment of anemia, current management practices, proposed treatment strategies, and the economic implications of improved anemia treatment.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Intensive iron therapy is now a generally accepted adjunct for the treatment of renal anemia with recombinant human erythropoietin. However, with the emerging role of iron in cardiovascular disease, carcinogenesis, infectious diseases, and other disorders, it is no longer appropriate to assume that any amount of stored iron is safe until proven otherwise. In this article, the history and current status of the "iron hypothesis" on ischemic heart disease are briefly reviewed, followed by comments on iron management practices for renal patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Female; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Recombinant Proteins

Cardiovascular disease is the leading cause of increased mortality in patients with renal failure and vigorous attention to cardiovascular risk factors is therefore required to improve patient outcome. The availability of recombinant human Epo has focused the interest on the role of chronic anaemia in the pathogenesis of cardiovascular disease. Severalfold evidence indicates that anaemia can contribute to cardiac volume overload and together with overhydration, fistula flow and the pressure overload secondary to arterial hypertension, it may play a significant role in the development of cardiac hypertrophy. As in the general population left ventricular hypertrophy is a severe adverse risk factor in renal patients. In addition, in the presence of ischaemic heart disease anaemia may further worsen cardiac oxygen supply. This dual effect of anaemia probably explains why epidemiological studies have shown that a 1 g/dl decrease in haemoglobin levels is an independent, statistically significant risk factor for the development of cardiac morbidity and mortality. Follow-up examinations have demonstrated that partial correction of anaemia with recombinant Epo can improve cardiac oxygen supply and partially reverse pathological changes in left ventricular geometry. However, although partial anaemia correction regularly reduces left ventricular volume, the effects on wall thickness are far less significant. Moreover, in patients with advanced cardiac disease it has recently not been possible to demonstrate that a normalization of haemoglobin levels provides further benefit. It is not unlikely therefore that the development of severe anaemia has to be prevented by early implementation of Epo therapy in order to achieve the maximum benefit with respect to the cardiovascular system.

Topics: Adaptation, Physiological; Adult; Aged; Anemia; Cardiovascular Diseases; Cardiovascular System; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins

The target hematocrit to be achieved when treating anemia in hemodialysis patients with erythropoietin is controversial. Current evidence-based recommendations suggest a target hematocrit range of 33% to 36%. Small studies suggest that normalization of hematocrit with erythropoietin may benefit hemodialysis patients in terms of brain function, physical performance, quality of life, and prevention of progressive left ventricular dilatation. However a recent study of the effects of erythropoietin-induced normalization of hematocrit in hemodialysis patients with symptomatic heart disease has shown an increase in both mortality and the rate of vascular access thrombosis. Currently, normalization of hematocrit in patients with symptomatic heart disease is not recommended, nor is it possible to conclude that possible benefits of normalization of hematocrit will outweigh risks in hemodialysis patients without symptomatic heart disease.

Topics: Anemia; Cardiomyopathies; Cardiovascular Diseases; Clinical Trials as Topic; Cognition; Erythropoietin; Exercise; Hematocrit; Humans; Iron; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Anemia, Hypochromic; Antihypertensive Agents; Blood Transfusion; Cardiovascular Diseases; Combined Modality Therapy; Erythropoietin; Hemoglobins; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Iron; Iron Deficiencies; Kidney Failure, Chronic; Nutrition Disorders; Recombinant Proteins; Renal Dialysis

Erythropoietin has been shown to be effective both in the reversal of anaemia in patients with end-stage renal failure and to increase the volume of autologous red blood cells donated preoperatively as well as to decrease the units of homologous blood transfused. This review analyzes the side effects of erythropoietin reported in the literature for long-term administration (mainly in patients with end-stage renal failure) as well as for acute/short-term administration (in patients participating in an autologous predeposit programme). The most important adverse events reported for long-term administration are as follows: (a) arterial hypertension; (b) cerebral convulsion/hypertensive encephalopathy; (c) thrombo-embolism; (d) iron deficiency; (e) influenza-like syndrome. The numbers given for these side effects are mainly taken from the first and dose-finding studies in patients with renal failure. These figures differ very much from the data given in controlled studies analyzing adverse events as well. Summarizing the results from controlled, multi-center trials in patients with end-stage renal failure or in AIDS patients, no significant differences have been observed between the control group and the patients treated with erythropoietin. The overall-incidence of side effects occurring in either group of these two studies was of approximately 83% and 95%, respectively. In contrast to these results the data published for the dose finding/treatment studies is approximately 30% for development of arterial hypertension, approximately 5% for occurrence of cerebral convulsion/hypertensive encephalopathy, approximately 10% for thrombo-embolic complications/clotting of vascular access, approximately 50% for development of iron deficiency, and approximately 10% for symptoms summarized as influenza-like syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Transfusion, Autologous; Cardiovascular Diseases; Erythropoietin; Humans; Seizures; Thromboembolism; Time Factors

Topics: Anemia; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Erythropoiesis; Erythropoietin; Glutathione; Hemolysis; Humans; Kidney Failure, Chronic; Nutrition Disorders; Oxidation-Reduction

The analysis of the hemodynamic parameters involved in the regulation of blood pressure during correction of anemia shows - although peripheral resistance and cardiac output behave qualitatively as in the nonuremic patient - that the extent of change may be inadequate resulting in an increased blood pressure. The underlying mechanisms are not yet fully understood but to a greater part may be related to preexisting pathology due to a history of long-lasting hypertension. To avoid cardiovascular complications under rhEPO therapy the following should be considered: patients with a history of hypertension, even if they are normotensive in the anemic state, are at a higher risk for developing hypertension under rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. Further studies will demonstrate whether in addition to the benefit of a very low maintenance dose of rhEPO subcutaneous administration will also contribute to the reduction of the incidence of hypertension.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Recombinant human erythropoietin is a major advance in the management of patients with chronic renal failure. The sustained dose-dependent rise in haematocrit which it produces effectively abolishes symptoms of anaemia, but at the cost of an increase in blood viscosity. This in turn predisposes to increased vascular resistance and the development of hypertension. Over half of all deaths of patients with end-stage renal failure are from cardiovascular disease, notably myocardial infarction, heart failure, and stroke, for which hypertension is a known risk factor. Erythropoietin-related increases in blood pressure are therefore of particular concern, and seem to be most severe in previously hypertensive patients. There is now a need to establish the optimum rate and extent of rise of haematocrit required to alleviate symptoms without incurring undue risk.

Topics: Blood Viscosity; Cardiovascular Diseases; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Topics: Animals; Blood Viscosity; Cardiovascular Diseases; Central Nervous System Diseases; Erythrocyte Deformability; Erythropoietin; Female; Fetal Hypoxia; Fetofetal Transfusion; Fetomaternal Transfusion; Fetus; Follow-Up Studies; Gastrointestinal Diseases; Genital Diseases, Male; Global Health; Growth Disorders; Hematocrit; Humans; Hyperbilirubinemia; Hypocalcemia; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Kidney Diseases; Male; Mental Disorders; Polycythemia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy in Diabetics; Prognosis; Respiration Disorders; Sheep; Thrombocytopenia

To investigate the impact of alpha-lipoic acid (ALA) on inflammation, oxidative stress, anemia, and glycemic parameters and their association with cardiovascular risk in diabetic patients on hemodialysis.. In this multi-center, randomized, controlled study, 60 diabetic patients on hemodialysis were randomized into control group (n=30) which received Epoetin-alpha plus insulin therapy, and alpha-lipoic acid group (n=30) which received the same treatment plus alpha-lipoic acid (ALA) 600 mg once daily. Serum levels of high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), 8-hydroxy-2'-deoxyguanosine (8-OHdG), creatinine, urea, blood urea nitrogen (BUN), hemoglobin (Hb), iron parameters, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and fructosamine were measured at baseline and six months after intervention. The ankle-brachial index (ABI) was used to evaluate the clinical outcome. Erythropoietin resistance index (ERI), the weekly cost of Epoetin-alpha doses, and the total cost were calculated.. The two groups were statistically similar at baseline. After the intervention, as compared to the control group, ALA group showed significant reductions in serum levels of hs-CRP, TNF-α, 8-OHdG (p<0.001), urea, and BUN (p=0.029) with significant elevations in Hb concentration (p<0.001), serum iron (p=0.037) and transferrin saturation (p<0.001). ALA group showed a significant decline in FBG (p=0.004), HbA1c (p<0.001), fructosamine (p=0.005), ERI (p<0.001), weekly doses, and the weekly cost of Epoetin-alpha, and the total cost (p<0.001). ALA provided a cardio-protective effect, whereas the percentage of patients with acceptable ABI (0.9-1) was significantly higher in ALA group than in the control group (p=0.024), and those with abnormally low ABI (<0.9) were lower in the ALA group.. Due to its efficacy and safety, alpha-lipoic acid represents a pharmaco-economic supplement for diabetic patients on hemodialysis. Further trials are needed for complete evaluation of ALA effects.

Topics: Anemia; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus; Erythropoietin; Fructosamine; Glycated Hemoglobin; Glycemic Control; Heart Disease Risk Factors; Humans; Iron; Prospective Studies; Renal Dialysis; Risk Factors; Thioctic Acid; Tumor Necrosis Factor-alpha; Urea

There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.. This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m. Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.. In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.

Topics: Aged; Aged, 80 and over; Anemia; Cardiovascular Diseases; Drug Resistance; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Polyethylene Glycols; Prognosis; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD.. We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513.. In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15,. In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

Topics: Aged; Anemia; Cardiovascular Diseases; Cause of Death; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic

Background. Cardiovascular morbidity and mortality are very high in patients with chronic kidney disease (CKD). The purpose of this study is to evaluate the impact of continuous erythropoietin receptor activator (CERA) on selected biomarkers of cardiovascular disease, left ventricle structure, and function in CKD. Material and Methods. Peripheral blood was collected from 25 CKD patients before and after CERA treatment and 20 healthy subjects. In serum samples, we assessed inflammatory markers (IL-1β, TNF-RI, TNF-RII, sFas, sFasL, MMP-9, TIMP-1, and TGF-β1), endothelial dysfunction markers (sE-selectin, sICAM-1, and sVCAM-1), and volume-related marker (NT-proBNP). All subjects underwent echocardiography and were evaluated for selected biochemical parameters (Hb, creatinine, and CRP). Results. Evaluated biomarkers and echocardiographic parameters of left ventricle structure were significantly increased but left ventricle EF was significantly decreased in CKD patients compared to controls. After CERA treatment, we observed a significant increase of Hb and left ventricle EF and a significant decrease of NT-proBNP and MMP-9. There was a significant negative correlation between Hb and TNF-RI, sICAM-1, and IL-1β. Conclusions. Our results indicate that selected biomarkers related to cardiovascular risk are significantly increased in CKD patients compared to controls. CERA treatment has anti-inflammatory action, diminishes endothelial dysfunction, and improves left ventricle function in these patients.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Female; Heart Ventricles; Humans; Inflammation Mediators; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Ventricular Function, Left

The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified.. Retrospective analysis of prospective randomized clinical trial.. We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo.. Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR).. Cause of death as adjudicated by a blinded committee.. Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles.. Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available.. In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Topics: Aged; Cardiovascular Diseases; Cause of Death; Cholesterol, HDL; Cholesterol, LDL; Darbepoetin alfa; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Multivariate Analysis; Renal Insufficiency, Chronic; Retrospective Studies; Triglycerides

The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD.. TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level ≤11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes.. Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics.. Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.

Topics: Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Ethnicity; Follow-Up Studies; Global Health; Glomerular Filtration Rate; Hematinics; Humans; Incidence; Kidney Failure, Chronic; Prognosis; Prospective Studies; Racial Groups; Survival Rate; Time Factors

Randomized trials found that use of erythropoiesis-stimulating agents to target normal hematocrit (Hct) levels (>39%) compared with 27%-34.5% increases cardiovascular risk and mortality among chronic kidney disease patients. However, the effects of the most widely used Hct target in the past 2 decades, 34.5%-39%, have never been examined.. To compare the effects of 2 Hct target strategies-30.0%-34.5% (low) and 34.5%-39.0% (mid) in a high-risk population: elderly dialysis patients with significant comorbidities.. Observational data from the US Renal Data System were used to emulate a randomized trial in which patients were assigned to either Hct strategy. Follow-up started after completing 3 months of hemodialysis and ended 6 months later. We conducted the observational analogs of intention-to-treat and per-protocol analyses. Inverse-probability weighting was used to adjust for measured time-dependent confounding by indication.. A total of 22,474 elderly patients with both diabetes and cardiovascular disease who initiated hemodialysis in 2006-2008.. Hazard ratios (HRs) and survival probabilities for all-cause mortality and a composite cardiovascular and mortality endpoint.. The intention-to-treat HR (95% confidence interval) for mid versus low Hct strategy was 1.05 (0.99-1.11) for all-cause mortality and 1.03 (0.98-1.08) for the composite endpoint. The per-protocol HR (95% confidence interval) for mid versus low Hct strategy was 0.98 (0.78-1.24) for all-cause mortality and 1.00 (0.81-1.24) for the composite outcome.. Among hemodialysis patients, we did not find differences in 6-month survival or cardiovascular risk between clinical strategies that target Hct at 30.0%-34.5% versus 34.5%-39.0%.

Topics: Aged; Anemia, Iron-Deficiency; Cardiovascular Diseases; Comorbidity; Dose-Response Relationship, Drug; Drug Dosage Calculations; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Risk Factors; Survival Analysis; Treatment Outcome; United States

Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis.. In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 μg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point.. In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide.. The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).

Topics: Aged; Anemia; Antibodies; Cardiovascular Diseases; Darbepoetin alfa; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Peptides; Renal Insufficiency, Chronic

Correcting anemia in patients with chronic kidney disease (CKD) to higher hemoglobin (Hb) levels may be associated with increased risk. No optimal target for Hb has been established. This controlled study examined 321 patients with CKD who were not on dialysis, had a Hb level of <10g/dL, and a serum creatinine of 2.0 to 6.0mg/dL. They were randomized into two target Hb groups: 161 to high Hb (11.0-13.0g/dL) to receive darbepoetin alfa and low Hb to 160 (9.0-11.0g/dL) to receive recombinant erythropoietin. The study lasted 48weeks. Of 154 and 153 patients with adverse events, cardiovascular adverse events developed in 42 and 51 patients in the high and low Hb groups, respectively, with no significant difference in the incidence. All quality of life scores improved in the high Hb group and vitality improved significantly more with high Hb (P=0.025). The left ventricular mass index (LVMI) remained stable in the low Hb group, but there was a significant decrease in LVMI in the high group (P<0.001). There were no safety concerns with targeting a higher Hb level during the 48weeks of this study. Patients with a higher Hb target had comparatively better outcomes with respect to quality of life and LVMI.

Topics: Aged; Anemia; Cardiovascular Diseases; Creatinine; Darbepoetin alfa; Erythropoietin; Female; Heart Ventricles; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Quality of Life; Treatment Outcome

This study aims to examine predictors of cardiovascular mortality and morbidity in patients with chronic kidney disease (CKD). Individuals with the triad of diabetes, CKD, and anemia represent a significant proportion of patients with cardiovascular disease and are at particularly high risk for adverse outcomes.. Using Cox proportional hazards models, we identified independent predictors of the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for myocardial ischemia, or heart failure (HF) in 3,847 patients in the TREAT, 961 (25%) of whom experienced this outcome. The predictors (ranked by χ(2) value) were prior HF (hazard ratio [HR] 1.74, 95% CI 1.51-2.01), age (HR 1.03, 95% CI 1.02-1.04 per year), log urine protein/creatinine ratio (HR 1.19, 95% CI 1.13-1.26 per log unit ), C-reactive protein ≥6.6 mg/L (HR 1.44, 95% CI 1.23-1.69, compared with C-reactive protein ≤3.0 mg/L), and abnormal electrocardiogram (HR 1.42, 95% CI 1.21-1.66 ), all P < .0001. Addition of cardiac-derived biomarkers (subset of first 1,000 patients enrolled) significantly enhanced risk estimation, with N-terminal pro B-type natriuretic peptide becoming the highest ranked predictor of outcome (HR 1.30, 95% CI 1.15-1.46 per log unit, P < .001) and troponin T providing additional predictive information. These biomarkers improved risk classification in 17.8% (9.4%-26.2%) of patients.. In patients with diabetes, CKD, and anemia, cardiovascular risk is most strongly predicted by age, history of HF, C-reactive protein, urinary protein/creatinine ratio, abnormal electrocardiogram, and 2 specific cardiac biomarkers, serum N-terminal pro B-type natriuretic peptide and troponin T, which are elevated in many. These findings suggest ways to improve cardiovascular risk stratification of patients with predialysis CKD, support the concept of cardiorenal syndrome, and may help target therapy.

Topics: Aged; Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Prognosis

Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targeting higher hemoglobin levels with ESA causes an increased risk of adverse vascular outcomes. It is possible, but has never been formally tested in a randomized trial, that ESA dose rather than targeted hemoglobin concentration itself mediates the increased risk of adverse vascular outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial will assess the benefits and harms of a high versus a low fixed ESA dose for the management of anemia in patients with end stage kidney disease.. This is a randomized, prospective open label blinded end-point (PROBE) trial due to enrol 2204 hemodialysis patients in Italy. Patients will be randomized 1:1 to 4000 IU/week versus 18000 IU/week of intravenous epoietin alfa or beta, or any other ESA in equivalent doses. The dose will be adjusted only if hemoglobin levels fall outside the 9.5-12.5 g/dL range. The primary outcome will be a composite of all-cause mortality, non fatal stroke, non fatal myocardial infarction and hospitalization for cardiovascular causes. Quality of life and costs will also be assessed.. The C.E.DOSE study will help inform the optimal therapeutic strategy for the management of anemia of hemodialysis patients, improving clinical outcomes, quality of life and costs, by ascertaining the potential benefits and harms of different fixed ESA doses.. Clinicaltrials.gov NCT00827021.

Topics: Adult; Anemia; Cardiovascular Diseases; Cost-Benefit Analysis; Epoetin Alfa; Erythropoietin; Female; Health Care Costs; Hematinics; Hemoglobins; Hospitalization; Humans; Kidney Failure, Chronic; Male; Outcome Assessment, Health Care; Quality of Life; Recombinant Proteins; Renal Dialysis

In patients on long-term hemodialysis, high lipoprotein(a) [Lp(a)] levels are difficult to lower with medications, although they remain a risk factor for cardiovascular disease. We investigated whether ultrapure dialysate (UPD) could lower Lp(a).. We randomly assigned patients stabilized on long-term dialysis to either a low-flux synthetic polysulphone membrane (the UPD group; n=14) or to a conventional dialysate (the CD group; n=13). Blood samples were collected 1 week before dialysis and 1 week, 1 month, 6 months and 12 months after dialysis; Lp(a) was measured by the immunoturbidimetry method. Hemoglobin, interleukin-6, hypersensitive C-reactive protein, beta(2) microglobulin and albumin were also measured. The erythropoietin dosage, Kt/V, and normalized protein catabolic rate were recorded monthly.. At 12 months, mean (SD) serum levels of Lp(a) in the CD patients increased from 143.46 (125.11) to 283.89 (145.81) mg/L (p<0.01), whereas levels in the UPD group remained unchanged: 131.38 (201.45) to 120.90 (122.11) mg/L. Endotoxin levels in the 10 CD patients who completed the study ranged from 0.116 to 0.349 EU/mL and were undetectable in the 11 UPD patients who completed the study. The cultures were less than 200 CFU/mL in CD patients and negative all the time for all UPD patients. Changes in Lp(a) from baseline values were lower in the UPD group than in the CD group (p<0.05). However, changes in other variables did not differ between groups.. Ultrapure dialysate can prevent the rise of Lp(a), potentially decreasing the risk of cardiovascular disease in hemodialysis patients.

Topics: Aged; beta 2-Microglobulin; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Down-Regulation; Endotoxins; Erythropoietin; Female; Hematinics; Hemodialysis Solutions; Hemoglobins; Humans; Inflammation Mediators; Interleukin-6; Kidney Failure, Chronic; Lipoprotein(a); Male; Membranes, Artificial; Middle Aged; Nephelometry and Turbidimetry; Polymers; Recombinant Proteins; Renal Dialysis; Serum Albumin; Sulfones; Time Factors; Treatment Outcome

Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response.. We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug.. Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78).. A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Chi-Square Distribution; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Proportional Hazards Models; Risk; Stroke

This study assessed plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP) as a prognostic marker of cardiovascular risk in patients with chronic kidney disease stages 3-4 and anaemia treated with epoetin beta to two haemoglobin target ranges.. Of 603 patients enrolled in the Cardiovascular Risk Reduction by Early Anaemia Treatment with Epoetin Beta (CREATE) trial (baseline creatinine clearance 15-35 mL/min; haemoglobin 11.0-12.5 g/dL), 291 were included in this sub-study. Patients received subcutaneous epoetin beta either immediately after randomisation (target 13.0-15.0 g/dL; Group 1), or after their haemoglobin levels had fallen < 10.5 g/dL (target 10.5-11.5 g/dL; Group 2). Chronic heart failure New York Heart Association class III-IV was an exclusion criterion. (ClinicalTrials.gov Identifier: NCT00321919). Cardiovascular event rates were higher in patients with baseline NT-proBNP > 400 vs. ≤ 400 pg/mL (39 vs. 13 events; p = 0.0002). Dialysis was initiated in 68 vs. 42 patients with NT-proBNP > 400 vs. ≤ 400 pg/mL (p = 0.0003). Amongst patients with NT-proBNP > 400 pg/mL, there was no significant difference between treatment groups in risk of cardiovascular events (HR = 0.57; p = 0.08) or time to dialysis (HR = 0.65; p = 0.08). The overall interpretation of this substudy is, however, limited by its relatively small sample size which, together with low clinical event rates, result in a lack of statistical power for some analyses and should be viewed as being hypothesis-generating in nature.. In chronic kidney disease patients with mild-to-moderate anaemia, elevated baseline plasma NT-proBNP levels are associated with a higher risk of cardiovascular events and an accelerated progression towards end-stage renal disease.

Topics: Aged; Anemia; Biomarkers; Cardiovascular Diseases; Comorbidity; Erythropoietin; Female; Humans; Male; Middle Aged; Natriuretic Agents; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Assessment

Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes.. Randomized trial.. 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries.. Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo.. TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point.. With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia.

Topics: Aged; Anemia; Cardiovascular Diseases; Cohort Studies; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria; Risk Factors; Treatment Outcome

Partial correction of anemia in patients with chronic kidney disease (CKD) reduces left ventricular hypertrophy (LVH), which is a risk factor for cardiovascular (CV) morbidity, but complete correction of anemia does not improve CV outcomes. Whether LV geometry associates with CV events in patients who are treated to different hemoglobin (Hb) targets is unknown. One of the larger trials to study the effects of complete correction of anemia in stages 3 to 4 CKD was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial. Here, we analyzed echocardiographic data from CREATE to determine the prevalence, dynamics, and prognostic implications of abnormal LV geometry in patients who were treated to different Hb targets. The prevalence of LVH at baseline was 47%, with eccentric LVH more frequent than concentric. During the study, LVH prevalence and mean left ventricular mass index did not change significantly, but LV geometry fluctuated considerably within 2 yr in both groups. CV event-free survival was significantly worse in the presence of concentric LVH and eccentric LVH compared with the absence of LVH (P = 0.0009 and P < or = 0.0001, respectively). Treatment to the higher Hb target associated with reduced event-free survival in the subgroup with eccentric LVH at baseline (P = 0.034). In conclusion, LVH is common and associates with poor outcomes among patients with stages 3 to 4 CKD, although both progression and regression of abnormal LV geometry occur. Complete anemia correction may aggravate the adverse prognosis of eccentric LVH.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Disease-Free Survival; Echocardiography; Erythropoietin; Female; Heart Ventricles; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Renal Insufficiency, Chronic; Stroke

Controlled randomised studies to prove improved cardiovascular stability and improved anaemia management during on-line haemodiafiltration (oHDF) are scarce.. 70 patients were treated with both haemodialysis (HD) and oHDF in a cross-over design during 2 x 24 weeks at a dialysis dose of eKt/V> or =1.2. Patients randomised into group A started on HD and switched over to oHDF, whereas patients in group B began with oHDF and were treated with HD afterwards. Intradialytic morbid events (IME), such as symptomatic hypotension or muscle cramps, were noted in case of appearance. Blood parameters reflecting anaemic status, phosphate status, lipid metabolism, oxidative stress, and accumulation of advanced glycation end products were recorded either monthly or at the end of each study phase.. The mean incidence of IME was 0.15 IME per treatment, and there was no statistical difference between oHDF and HD. A higher haematocrit (oHDF 31.5% vs. HD 30.5%, p < 0.01) at a lower erythropoietin dose (oHDF 4,913 vs. HD 5,492 IU/week, p = 0.02) was found during oHDF, when the sequence of HD and oHDF had not been taken into account. For the study groups, the results were less distinct: in group A, a higher haematocrit (HD 30.4% vs. oHDF 32.0%, p < 0.01) at a comparable erythropoietin dose (HD 5,421 vs. oHDF 5,187 IU/week, ns) was observed during oHDF, whereas in group B an identical haematocrit (oHDF 30.8% vs. HD 30.7%, ns) was achieved at a reduced erythropoietin dose (oHDF 4,622 vs. HD 5,568 IU/week, p < 0.01). During oHDF, lower levels of free and protein-bound pentosidine and of serum phosphate were found.. In contrast to other studies, no benefit regarding cardiovascular stability for oHDF was found, but oHDF could well offer a potential benefit regarding anaemia correction, inflammation, oxidative stress, lipid profiles, and calcium-phosphate product.

Topics: Anemia; Cardiovascular Diseases; Cross-Over Studies; Erythropoietin; Female; Hematocrit; Hemodiafiltration; Humans; Male; Middle Aged; Predictive Value of Tests; Renal Dialysis; Reproducibility of Results

Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established.. We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.. During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1.. In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 [ClinicalTrials.gov].).

Topics: Anemia; Cardiovascular Diseases; Disease Progression; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Survival Analysis

Anemia has received increasing attention as an independent cardiovascular risk factor in patients with chronic kidney disease (CKD); a number of studies have highlighted its clear relationship with CKD mortality, because its impact on cardiac function leads to the development of left ventricular hypertrophy. However, despite the association between higher hemoglobin levels and better outcomes, a number of clinical studies have failed to demonstrate that fully correcting anemia has a positive effect on morbidity and mortality in patients with CKD. The Cardiovascular Reduction Early Anemia Treatment Epoetin beta (CREATE) study was designed from the hypothesis that, as anemia develops early in the course of CKD and nearly at the same time as cardiovascular disease, its earlier correction may provide better protection against the development of cardiovascular abnormalities. This randomized, multicenter, open-label, parallel-group trial involved 603 patients who had moderate anemia (hemoglobin 11 to 12.5 g/dl) and stage 3 to 4 CKD (estimated GFR 15 to 35 ml/min) and were randomly assigned to attain complete or partial anemia correction. The final results are due to be published within a few months, but the preliminary analyses do not show that complete anemia correction leads to any cardiovascular advantage, although the cardiovascular event rate was half that expected, possibly as a result of patient selection, trial effect, and improved medical care. The baseline findings also indicated that the burden of cardiovascular disease already is very high even in relatively early stages of CKD.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Risk Factors; Treatment Outcome

Hemodialysis patients have uremic dyslipidemia, represented by elevated serum intermediate-density lipoprotein cholesterol (IDL-C) levels, and an increased cardiovascular mortality rate. This study was performed to determine the low-dose effects of the angiotensin II receptor blocker losartan and the angiotensin-converting enzyme inhibitor trandolapril on pulse wave velocity (PWV), which predicts cardiovascular morbidity and mortality in hemodialysis patients.. Serum lipid levels and PWV were monitored for 12 months in 64 hemodialysis patients who were administered low doses of losartan or trandolapril or a placebo.. At the start of the study, there were no differences in patient characteristics among the 3 groups. PWV tended to increase in the placebo group during the 12-month study period, but decreased significantly in the losartan and trandolapril groups, and decreases in PWV were similar in the losartan and trandolapril groups. There were no changes in blood pressure, hematocrit, erythropoietin dose, ankle-brachial index, serum lipid levels, serum 8-isoprostane levels, or serum C-reactive protein levels during the 12-month study period, but there was an increase in serum triglyceride levels in the losartan group and a decrease in serum IDL-C levels in the losartan and trandolapril groups.. In hemodialysis patients, trandolapril is as effective as losartan in decreasing PWV independent of its depressor effect and in suppressing elevated IDL-C levels. Long-term blockade of the renin-angiotensin system may have a beneficial effect on the acceleration of atherosclerosis and uremic dyslipidemia.

Topics: Aged; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Comorbidity; Dinoprost; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Hyperlipidemias; Indoles; Kidney Failure, Chronic; Lipids; Lipoproteins; Lipoproteins, LDL; Losartan; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome; Vascular Resistance

The ongoing Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta (CREATE) trial is investigating the effect of early anaemia correction in around 600 patients with moderate anaemia [haemoglobin (Hb) 11.0-12.5 g/dl] and chronic kidney disease (CKD) not yet requiring renal replacement therapy (creatinine clearance 15-35 ml/min). Patients are being randomized to early treatment or late treatment with epoetin beta (NeoRecormon) administered subcutaneously. The early treatment group starts epoetin beta therapy immediately, aiming for a target Hb level of 13-15 g/dl. The late treatment group only starts epoetin beta therapy once the Hb level has declined to below 10.5 g/dl (target Hb level 10.5-11.5 g/dl). The objective of the study is to examine the impact of an early anaemia treatment strategy on cardiovascular risk in this patient population. Preliminary baseline data from patients recruited so far indicate there are no clinically relevant differences between treatment groups in terms of their baseline characteristics. The baseline data also confirm the heavy burden in terms of cardiovascular disease present in these patients. The CREATE trial is anticipated to provide important new data that could have an impact on new strategies for management of patients with moderate anaemia and CKD not yet requiring renal replacement therapy.

Topics: Aged; Anemia; Cardiovascular Diseases; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Risk Factors

Renal anaemia is an independent risk factor for the development of left ventricular hypertrophy (LVH), heart failure and mortality. Studies show that partial correction of anaemia leads to partial regression of LVH. However, early initiation of anaemia therapy may be the optimal way to reduce cardiac morbidity and mortality. The Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial will investigate the effect of early anaemia correction on cardiovascular risk reduction in patients not yet on renal replacement therapy. The primary objectives of this open, randomized, multicentre trial are to investigate the effect of early anaemia correction on the change in left ventricular mass index after 1 year, and the time to first cardiovascular event. The trial comprises two treatment arms: early intervention where patients will receive epoetin beta when their haemoglobin (Hb) level is 11-12.5 g/dl and their target Hb will be 13-15 g/dl, and late intervention, where patients will receive epoetin beta once their Hb level is <10.5 g/dl and their target Hb will be 10.5-11.5 g/dl. The study will be event-driven with a continuous evaluation and an interim analysis once every year. The inclusion of 600 patients is based on assumption of a 15-20% event rate in the control group and that 200 events are needed to detect a reduction of about one-third. In conclusion, the CREATE trial will examine whether early anaemia treatment will prevent development of LVH, reduce cardiovascular morbidity and provide other benefits.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Topics: Adult; Aged; Anemia; Biocompatible Materials; Biological Factors; Cardiovascular Diseases; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Hypoxia; Informed Consent; Male; Membranes, Artificial; Middle Aged; Permeability; Polymethyl Methacrylate; Recombinant Proteins; Renal Dialysis; Uremia

In a controlled European multicenter study, clinical tolerance of subcutaneously administered recombinant human erythropoietin (rh-EPO) therapy and its influence on the course of illness in 362 hemodialyzed patients (162 males, 200 females) from 16 European dialysis centers was studied. Of these, 181 patients served as a control group in the first year and received rh-EPO therapy in the second year. Of the 837 adverse events that occurred, 277 were classified as serious and 560 as nonserious. Thirty-two deaths have been reported for the study population: 18 in the control group and 14 in the therapy group. The individual analysis of the serious adverse events including death demonstrates a protective effect of rh-EPO on the high-risk cardiovascular situation of dialysis patients. Hypertension was no problem, and under rh-EPO therapy an increase in resistance to infection was observed. Subcutaneous rh-EPO treatment might have an even better safety profile than intravenous application.

Topics: Adult; Anemia; Cardiovascular Diseases; Erythropoietin; Female; Humans; Hypertension; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Responsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown.. This multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF).. The median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03-2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14-2.23), MACE (HR: 1.60, 95% CI: 1.19-2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40-2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23-3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI.. Baseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.

Topics: Anemia; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Hematinics; Humans; Iron; Kidney Failure, Chronic; Prospective Studies; Renal Dialysis

We examined the combined effect of erythropoietin (EPO) hyporesponsiveness and low handgrip strength (HGS) on the prognosis of patients undergoing hemodialysis (HD).. EPO hyporesponsiveness combined with low HGS were found to be significant predictors of a poor outcome, and the synergistic effects of the two factors had stronger predictive ability than either single factor.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Female; Hand Strength; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prognosis; Prospective Studies; Renal Dialysis

Anaemia is one of the hallmarks of advanced chronic kidney disease (CKD); it correlates with a lower quality of life and increased cardiovascular risk. Currently its management is based on iron and erythropoiesis-stimulating agents (ESAs) therapy. Given safety issues on ESA therapy and excessive iron use, anaemia management is still suboptimal. Areas covered: The inhibitors of the prolyl-hydroxylases domain (PHD) are oral drugs which activate the hypoxia-inducible factors (HIF) and stimulate the production of endogenous erythropoietin. Roxadustat (FG-4592) is a second-generation PHD inhibitor; it is undergoing now phase-III clinical development. Expert opinion: Phase-II clinical trials have shown that roxadustat is effective and save in the short term in either non-dialysis or dialysis CKD patients. Roxadustat is a chemical drug and thus has the potential of being cheaper than traditional ESAs. Given that the peaks of endogenous EPO are much lower than those observed with traditional ESA, it is possible to speculate the roxadustat (and more in general PHD inhibitors) will be safer than ESA on cardiovascular safety end-points. Considering that HIFs are involved in different pathways, with possible promotion of relevant side effects, their safety must be proven in long-term studies.

Topics: Anemia; Animals; Cardiovascular Diseases; Erythropoietin; Glycine; Hematinics; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoietin-stimulating agent hyporesponsiveness (ESAH) is associated with increased cardiovascular mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Dynamic treatment regimes (DTR), a clinical decision support (CDS) tool that guides the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic illnesses that require frequent monitoring and therapy changes. Our objective is to explore the role of utilizing a DTR to reduce ESAH in pediatric hemodialysis patients.. Retrospective analysis of ESRD patients on hemodialysis who received ESAs. Dosing was adjusted using a locally developed protocol designed to target a hemoglobin between 10 and 12 g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hyporesponse index (ESA dose/hemoglobin value) changed due to varying levels of adherence.. Eighteen patients met study criteria. Median hemoglobin was 11.4 g/dl (range 6.1-15.4), and median weekly ESA dose (darbepoetin-equivalent) was 0.4 mcg/kg/dose (range 0-2.1). Full adherence to the DTR was identified in 266 (71%) of the 4-week periods, with a median average adherence score of 0.80 (range 0.63-0.91). As adherence to the DTR improved, ESAH decreased. During the last 12 weeks, 13 out of 18 patients had lower average ESA/hemoglobin ratio than the first 12 weeks.. A DTR appears to be well-suited to the treatment of anemia in ESRD and reduces ESAH. Our work shows the potential of DTRs to drive the development and evaluation of clinical practice guidelines.

Topics: Adolescent; Adult; Anemia; Cardiovascular Diseases; Child; Child, Preschool; Clinical Protocols; Darbepoetin alfa; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Erythropoietin; Female; Guideline Adherence; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Longitudinal Studies; Male; Practice Guidelines as Topic; Renal Dialysis; Retrospective Studies; Treatment Outcome; Young Adult

To show the levels of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) in patients with end-stage renal disease (ESRD) and to show the associations with clinical findings such as demographic features, laboratory findings, comorbidities, and medications.. A total of 73 people, consisting of patients with ESRD (n=38) and healthy subjects (n=35) in Gulhane Education and Research Hospital, Ankara, Turkey, were included in this cross-sectional study between the years 2011 and 2013. Blood samples were obtained and plasma VEGF, sVEGFR-1 analyzes were performed. Results: The VEGF level of ESRD group was not significantly higher (0.280±0.264) than the control group (0.321±0.210) (p=0.475). The sVEGFR-1 level of ESRD group was significantly higher (0.217±0.135) than the control group (0.068±0.047) (p less than 0.001). The correlation between VEGF and sVEGFR-1 was significant and negative (r=-0.246, p=0.036). Average VEGF level of ESRD patients using recombinant human erythropoietin (rhEPO) was significantly higher (0.567±0.28) than the ESRD patients not using rhEPO (0.246±0.24) (p=0.025).. Our study is the first showing the significance of sVEGFR-1 in ESRD patients, and associations with comorbidities, medications. Especially our finding of rhEPO and VEGF may illuminate a reasonable positive effect of rhEPO on angiogenesis. Soluble vascular endothelial growth factor receptor-1 and VEGF may be important markers in the pathophysiology of ESRD.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Aspirin; Calcium Channel Blockers; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Enoxaparin; Erythropoietin; Female; Fibrinolytic Agents; Humans; Insulin; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Physical inactivity and a low maximal aerobic capacity (VO

Topics: Blood Volume; Cardiac Output; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Erythrocytes; Erythropoietin; Exercise; Hematocrit; Hemoglobins; Humans; Hypoxia; Muscle, Skeletal; Oxygen; Oxygen Consumption

In patients with heart failure (HF), serum erythropoietin (EPO) levels are elevated and associated with disease severity and outcome. Whether endogenous EPO levels are prospectively associated with the development of HF or cardiovascular events in the general population is unknown.. Serum EPO levels were measured at baseline in 6686 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Mean age (±SD) was 53 ± 12 years, 49.8% were male, and the median (interquartile range) EPO level was 7.7 (5.9-10.2) IU/L. During a median follow-up of 8.3 (7.7-8.8) years, 209 (3.1%) subjects were newly diagnosed with HF, 97 (1.5%) died of a cardiovascular cause, and 386 (6.0%) subjects had a non-fatal cardiovascular event (277 cardiac events and 93 strokes). Each doubling of EPO level was multivariably associated with new-onset HF [hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.03-1.69, P = 0.031]. EPO levels showed interaction with urinary albumin excretion (P = 0.006) and were only associated with HF in subjects with albuminuria (HR 1.51, 95% CI 1.13-2.03, P = 0.005). There was an independent association of EPO levels with stroke in women (HR 1.82, 95% CI 1.24-2.65, P = 0.002), but not in men. No association was observed for EPO levels with other cardiovascular events or cardiovascular mortality.. High serum EPO levels are independently associated with an increased risk of new-onset HF in subjects with albuminuria. More research into the pathophysiological mechanisms linking EPO levels to HF is needed to understand this association.

Topics: Adult; Aged; Albuminuria; Cardiovascular Diseases; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Ischemia; Myocardial Revascularization; Netherlands; Prognosis; Proportional Hazards Models; Sex Factors; Stroke

Mechanisms of accelerated atherothrombosis in patients with chronic kidney disease (CKD) are only partly characterized. The aims of this study were to evaluate the extent of thromboxane (TX)-dependent platelet activation in patients with CKD, and to characterize the determinants of altered TX biosynthesis in this setting, with particular reference to enhanced lipid peroxidation, low grade inflammation and CKD-related anemia.. A cross sectional comparison between urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, was performed in 115 patients with stage 1-4 CKD.. Levels of both urinary 11-dehydro-TXB2 and 8-iso-PGF2α increased sequentially across the four CKD stages (P<0.0001, Kruskal-Wallis test). Both urinary prostanoids were inversely associated with either estimated glomerular filtration rate (eGFR, P<0.0001) or hemoglobin levels (P<0.0001). A significant direct correlation was also observed between urinary 11-dehydro-TXB2 and 8-iso-PGF2α (Rho=0.620, P<0.0001). On multivariate analysis, urinary 8-iso-PGF2α (β=0.459, P<0.0001), hemoglobin levels (β=- 0.261, P=0.002) and eGFR (β=-0.172, P=0.032) were independent predictors of urinary 11-dehydro-TXB2 (adjusted R(2)=0.488).. This study provides biochemical evidence of persistent platelet activation in patients with CKD. This condition occurs early in the natural history of the disease and is related to kidney function and oxidative stress. Moreover, we found an independent inverse relationship between hemoglobin levels and TX-dependent platelet activation. This finding may provide a mechanistic link between CKD-related anemia and increased cardiovascular risk.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Dinoprost; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Italy; Linear Models; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Platelet Activation; Prostaglandins; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Thromboxane B2

 Patients on dialysis have a high rate of death, mainly of cardiovascular cause. Nephrologists are actively looking for ways to improve patients' outcomes, and alternative dialysis strategies, such as long conventional hemodialysis and hemodiafiltration, are currently being investigated. The aim of this study was to compare anemia, nutrition, inflammation, mineral metabolism, and 3-year survival rates between patients treated with hemodiafiltration and prolonged high-flux hemodialysis (HFH)..  A total of 58 dialysis patients were divided into 2 groups to undergo hemodiafiltration 3 times weekly, 12 hours in total per week, or prolonged duration of HFH (≥ 15 h/w). One-year biochemical parameters were collected retrospectively, together with 36 months patients' survival (prospectively).. Patients in the HFH group had longer dialysis vintage; significantly higher levels of hemoglobin (despite less frequent use of erythropoietin-stimulating agents), serum albumin, serum calcium, and serum bicarbonate; and a lower in-tact parathyroid hormone level. Survival rates were comparable between the two groups. The Cox proportional hazard model showed that patients treated with longer HFH had a 32% relative risk reduction of mortality compared to patients treated with hemodiafiltration, but without statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.21 to 2.20; adjusted for diabetes mellitus).. Longer duration of hemodialysis with high-flux membranes had beneficial effects on anemia indexes, mineral metabolism, nutrition parameters, and acidosis in comparison with hemodiafiltration. However, hemodiafiltration did not offer a 36-months survival benefit over prolonged HFH.

Topics: Aged; Anemia; Bicarbonates; Calcium; Cardiovascular Diseases; Cause of Death; Erythropoietin; Female; Hematinics; Hemodiafiltration; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mortality; Parathyroid Hormone; Prospective Studies; Renal Dialysis; Retrospective Studies; Serum Albumin; Time Factors

Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking.. Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO.. Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure.. DPO versus EPO.. All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.. Unadjusted and adjusted HRs from Cox proportional hazards regression models.. Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25).. Nonrandom treatment assignment, potential residual confounding.. In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO.

Topics: Aged; Ambulatory Care Facilities; Anemia; Cardiovascular Diseases; Cause of Death; Comorbidity; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemodialysis Units, Hospital; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Recombinant Proteins; Registries; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Stroke; Treatment Outcome; United States

The circadian clock and the hypoxic signaling pathway play critical roles in physiological homeostasis as well as in pathogenesis. The bi-directionality of the interaction between both pathways has been shown on physiological and only recently also on molecular level. But the consequences of a disturbed circadian rhythm for the hypoxic response and the cardiovascular system have never been addressed in any organism. Here we show that the hypoxic response of animals subjected to chronodisruption is reduced by approximately 30%, as reflected by decreased expression levels of hypoxia inducible factor 1 and its down-stream target genes erythropoietin, responsible for the generation of red blood cells (RBC) and vascular endothelial growth factor, which is essential for proper vascularization. Beside malformations of their vascular beds, chronodisrupted animals surprisingly revealed elevated numbers of senescent erythrocytes under normoxic conditions, due to a reduced clearance rate via apoptosis. Over-aged erythrocytes in turn are characterized by decreased oxygen transport capacities and an increased tendency for aggregation, explaining the higher mortality of chronodisrupted animals observed in our study. The present study shows for the first time that chronodisruption strongly interferes with the hypoxic signalling cascade, increasing the cardiovascular risk in zebrafish due to elevated proportions of senescent erythrocytes. The results might shed new light on the etiology of the increased cardiovascular risk observed among shiftworkers.

Topics: Animals; Apoptosis; Cardiovascular Diseases; Cellular Senescence; Chronobiology Disorders; Circadian Rhythm; Erythrocytes; Erythropoietin; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Light; Photoperiod; Risk Factors; Time Factors; Vascular Endothelial Growth Factor A; Zebrafish; Zebrafish Proteins

In a landmark study, TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) examined the use of erythropoiesis-stimulating agent (ESA) therapy to treat anemia among patients with chronic kidney disease (CKD) and found no benefit compared to placebo.. A retrospective observational design was used to determine the impact of TREAT on clinical practice.. A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and 4.. ESA prescribing 2 years before and after publication of TREAT.. Rate of ESA prescribing for ESA-naive and -prevalent cohorts.. (1) Monthly ESA prescribing in the 2 years before and after publication of TREAT (ordinary least squares regression), (2) adjusted likelihood of prescribing ESA after TREAT (clustered logistic regression), and (3) probability of receiving ESA therapy based on anemia status (χ(2) test).. For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage 3: change of slope, -0.08 [P<0.001]; stage 4: change of slope, -0.16 [P<0.001]). ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin levels <10g/dL, only 25% of patients with CKD stage 3 and 33% of patients with stage 4 were prescribed ESAs 2 years after TREAT, a notable 50% decline. After adjusting for all covariates, the probability of prescribing ESAs was 35% lower during the 2-year period after versus before publication of TREAT (OR, 0.65; 95% CI, 0.63-0.67).. The cumulative effect of adverse safety concerns in the period before TREAT also influenced physician prescribing of ESA therapy and could not be separated from the influence of TREAT.. TREAT appears to be a watershed study that was followed by a marked decline in ESA prescribing for patients with CKD.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Darbepoetin alfa; Databases, Factual; Erythropoiesis; Erythropoietin; Female; For-Profit Insurance Plans; Humans; Male; Medicare; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome; United States

Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro-inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub-chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in ESRD patients. Optimizing response to EPO therapy is important for both patient outcomes and the cost of treatment, and require consideration of a growing number of factors. Detection of NAFLD by some of non-invasive methods in ESRD patients could identify responsiveness and resistance to EPO therapy. Furthermore, we propose that all the patients who undergo dialysis treatment should be screened for NAFLD in order to identify the patients that will have a poor response to EPO therapy. The work coul

Topics: Anemia; C-Reactive Protein; Cardiovascular Diseases; Dyslipidemias; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Liver; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Prevalence; Quality of Life; Recombinant Proteins; Renal Dialysis; Risk Factors

Many organs suffer from ischaemic injuries that reduce their ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) ameliorates ischaemic injuries by pleiotropic effects. The aim of this study was to investigate the effect and mechanism of a small molecule EH-201, and found it as a potent EPO inducer and its effect in non-haematopoietic cells for therapeutic potential in ischemic disorders.. Mice kidney slices, primary hepatocytes, primary cardiomyocytes and C2C12 myoblasts were treated with EH-201. The effects of this treatment on EPO, Hb expression and mitochondrial biogenesis were analysed. In vivo, doxorubicin-induced cardiomyopathic mice were treated with EH-201. The mice were subjected to an endurance test, electrocardiography and echocardiography, and a histological examination of the isolated hearts was performed. EH-201 was also administered to cisplatin-induced nephropathic mice.. In non-haematopoietic cells, EH-201 was potent at inducing EPO. EH-201 also stimulated mitochondrial biogenesis and enhanced the expression of Hb by a mechanism dependent on EPO-mediated signalling. In mechanistic studies, using EPO and EPO receptor-neutralizing antibodies, we confirmed that EH-201 enhances EPO-EPOR autocrine activity. EH-201 robustly increased the endurance performance activity of healthy and cardiomyopathic mice during hypoxic stress, enhanced myocardial mitochondrial biogenesis and Hb expression, and also improved cardiac function. EH-201 ameliorated anaemia and renal dysfunction in nephropathic mice.. The enhancement and recovery of cellular functions through the stimulation of mitochondrial activity and Hb production in non-haematopoietic cells by an inducer of endogenous EPO has potential as a therapeutic strategy for ischaemic diseases.

Topics: Animals; Cardiovascular Diseases; Cell Line; Cells, Cultured; Cisplatin; Doxorubicin; Erythropoietin; Glucosides; HEK293 Cells; Hemoglobins; Hepatocytes; Humans; Kidney; Male; Mice; Mice, Inbred C57BL; Mitochondria; Myocytes, Cardiac; Receptors, Erythropoietin; Stilbenes

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.

Topics: Animals; Asialoglycoproteins; Brain Diseases; Cardiovascular Diseases; Diabetes Complications; Erythropoietin; Humans; Oligopeptides; Receptors, Erythropoietin

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Erythropoietin; Female; Humans; Male; Pilot Projects; Polyethylene Glycols; Renal Insufficiency, Chronic; Risk Factors

Recently, erythropoietin resistance (ER) has been shown to be related with cardiovascular and overall mortality in hemodialysis (HD) patients. Red blood cell distribution width (RDW) has also shown to be associated with cardiovascular and all cause mortality in general population. Thus in the current study we tested the hypothesis that RDW and erythropoietin resistance as determined by erythropoiesis stimulating agents (ESA) hyporesponsiveness index (EHRI) may be related with each other in iron replete HD patients.. Study participants underwent medical history taking, physical examination, calculation of dialysis adequacy and biochemical analysis. EHRI was calculated as the weekly dose of EPO divided by per kilogram of body weight divided by the hemoglobin level.. Two separate analyses were performed. In the first analysis performed in 94 HD patients; the stepwise linear regression analysis revealed that being female (P=0.031), HD duration (P=0.021), presence of diabetes mellitus (P=0.008), RDW (P=0.023), and predialysis sodium (P=0.05) were independently related with logarithmically converted EHRI. We made second analysis after 4 months. The second analysis revealed that when compared to first EHRI, the EHRI was increased in 40, unchanged in one and decreased in 40 patients The second stepwise regression analysis also showed that the independent relationship with RDW and EHRI was persisted (β=0.050, CI: 0.022-0.078, P=0.001).. Red blood cell distribution width was independently related with EHRI in iron replete HD patients.

Topics: Aged; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Resistance; Erythrocyte Indices; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematinics; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Regression Analysis; Renal Dialysis; Risk Factors; Turkey

Haemoglobin scavenges nitric oxide, and a previous study has shown a negative association between flow-mediated vasodilation (FMD), a measure of nitric oxide (NO)-dependent vasomotor function and haemoglobin concentrations [Hb]. Circulating erythropoietin (EPO) is also negatively associated with [Hb] and could influence availability of NO. The purpose of this study was to examine the association of FMD with [Hb] and EPO concentrations and to determine whether these contribute to the sex difference in FMD. FMD (by high-resolution ultrasound), [Hb], circulating immunoreactive EPO and cardiovascular risk factors were measured in 317 healthy middle-aged men and women (183 women, 33 premenopausal, mean age ± SD, 55 ± 6·8 years) participating in a dietary study.. In the whole mixed-sex group, FMD was negatively correlated with [Hb] (R = -0·23, P < 0·001). However, in a multivariable model, incorporating sex and other confounding factors, FMD was independently negatively correlated only with age, male sex and systolic blood pressure: standardized regression coefficients -0·21 (P < 0·01), -0·17 (P < 0·05) and -0·20 (P < 0·05) respectively and not with [Hb]. Similarly, when the analysis was restricted to men or to postmenopausal women, there was no significant relationship between FMD and Hb. There was no significant correlation between FMD and EPO on either univariate analysis in the whole group, in each sex, or in multivariate analysis.. These results suggest that in healthy middle-aged subjects, FMD is not influenced by [Hb] or EPO and these do not contribute to the gender difference in FMD.

Topics: Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Endothelium, Vascular; Erythropoietin; Female; Hemoglobins; Humans; Male; Menopause; Middle Aged; Nitric Oxide; Postmenopause; Risk Factors; Sex Characteristics; Vasodilation

Cardiovascular disease (CVD) is the main cause of mortality in renal transplant recipients (RTR). Classical factors only partly explain the excess risk. We hypothesized that high EPO--a marker for inflammation, angiogenesis and hypoxia--is associated with CVD in RTR. A total of 568 RTR (51±12 years; 45% female; creatinine clearance (CrCl) 57±20 mL/min/1.73 m(2)) were included at median 6 [IQR 3-11] years after transplantation. Subjects on exogenous EPO and ferritin-depleted subjects were excluded. Median EPO level was 17.3 [IQR 11.9-24.2] IU/L. Gender-stratified tertiles of age-corrected EPO were positively associated with waist circumference (but not BMI), CVD history, time since transplantation, diuretics, azathioprine, CRP, mean corpuscular volume and triglyceride levels, and inversely with CrCl, RAAS-inhibition, cyclosporine, hemoglobin, total- and HDL-cholesterol. During follow-up for 7 [6-7] years, 121 RTR (21%) died, 64 of cardiovascular (CV) causes. Higher EPO (per 10 IU/L) was associated with total (HR1.16 [1.04-1.29], p = 0.01) and CV mortality (HR1.22 [1.06-1.40], p = 0.005), independent of age, gender, hemoglobin, inflammation, renal function and Framingham risk factors. Thus, EPO and mortality are linked in RTR, independent of potential confounders. This suggests that yet other mechanisms are involved. Dissecting determinants of EPO in RTR may improve understanding of mechanisms behind excess CV risk in this population.

Topics: Age Factors; Biomarkers; Cardiovascular Diseases; Cause of Death; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Transplantation; Male; Middle Aged; Netherlands; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Sex Factors; Survival Rate

The aim of this retrospective cohort study was to identify early risk factors of mortality and develop a mortality risk stratification instrument for severely anaemic Jehovah's Witness patients. It has been shown that Jehovah's Witness patients with the Auckland Anaemia Mortality Risk Score (Auckland AMRS) of 0 to 3 had 4% mortality, Auckland AMRS 4 to 5 32%, Auckland AMRS 6 to 7 50% and Auckland AMRS 8 and above 83%. It is concluded that the Auckland AMRS predicts mortality of severely anaemic Jehovah's Witness patients.

Topics: Adolescent; Adult; Aged; Anemia; Cardiovascular Diseases; Erythropoietin; Factor VIIa; Female; Filgrastim; Folic Acid; Granulocyte Colony-Stimulating Factor; Hemorrhage; Hospital Mortality; Hospitals, Public; Humans; Infections; Iron; Jehovah's Witnesses; Kidney Failure, Chronic; Male; Middle Aged; New Zealand; Plasma; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Vitamin B 12; Young Adult

Anemia is common in patients with chronic kidney disease (CKD). Recently, the erythropoiesis-stimulating agent/hemoglobin level (ESA/Hb) index emerged as a new factor associated with increased morbidity and mortality in this population. In this study, we evaluated the factors that influence the ESA/Hb index in a pre-dialysis CKD population.. Ninety-five patients were evaluated for clinical and laboratory parameters, nutritional status and ESA/Hb index. For comparison, we divided our population into 3 groups: G I--no ESA treatment, G II--patients with ESA/index below 50th percentile and G III--patients with ESA/Hb index above 50th percentile. We performed single and multiple regression models and logistic regression analysis.. In a multiple regression model, age (t = -3.456, P = 0.001), SGA (t = 2.059, P = 0.047), ferritin (t = 2.386, P = 0.027), Ca × P (t = 2.066, P = 0.043), TNF-α (t = 2.673, P = 0.009) and IL-6 (t = 2.939, P = 0.004) independently influenced the ESA/Hb index. At logistic regression analysis, gender, cardiovascular disease and TNF-α were independently associated with ESA/Hb higher than 50th percentile compared to the other patients (R(2) = 0.457).. In a pre-dialysis population, female gender, cardiovascular disease, malnutrition and inflammation are associated with a higher ESA/Hb index.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anemia; Cardiovascular Diseases; Chi-Square Distribution; Darbepoetin alfa; Drug Resistance; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Logistic Models; Male; Malnutrition; Middle Aged; Risk Factors; Sex Factors; Tumor Necrosis Factor-alpha

Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

Topics: Animals; Cardiovascular Diseases; Down-Regulation; Enzyme Inhibitors; Erythropoietin; Humans; Male; Mortality; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Physical Conditioning, Animal; Rats; Rats, Wistar; Recombinant Proteins; Risk Factors; Signal Transduction

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Glycated Hemoglobin; Hematinics; Humans; Hyperglycemia; Kidney Failure, Chronic

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Ferritins; Hematinics; Humans; Iron; Kidney Failure, Chronic; Risk

Patients with renal graft dysfunction constitute an increasingly prevalent group of end-stage kidney disease (ESKD) patients that require dialysis therapy. These patients have special characteristics that set them apart from the ESKD general population. The aim of this study was to analyse the clinical condition and evolution of patients entering dialysis with a failed kidney graft at the time of restarting dialysis and over a year of therapy according to the K/DOQI guidelines, and to compare them with incidental patients with end-stage kidney disease. We also investigated whether the modality of kidney replacement therapy may determine the clinical improvement of transplant patients.. This is a retrospective observational study of 106 patients with ESKD followed up in the Ramon y Cajal Hospital. They were classified in two groups. Group one was made up of 50 failed native kidney patients who started dialysis between 2000 and 2009. Group two was comprised of 56 transplant patients with graft dysfunction who returned to dialysis between 1997 and 2009. We studied parameters of kidney function, anaemia, calcium-phosphorus metabolism, cardiovascular risk factors and nutritional status at the time both groups started on dialysis and one year later.. Both groups had a similar clinical status at the time they started on dialysis in most of the parameters analysed with the exception of anaemia. This was more severe in transplant patients, despite the fact that transplant patients received a higher dose of erythropoietin than non-transplant patients. One year later the main difference between both groups was the residual kidney function rate, higher in non-transplant patients. There were no significant differences in the parameters analysed in patients with a failed graft according to the modality of kidney replacement therapy.. Failed transplant patients start dialysis with more severe anaemia than patients entering dialysis for the first time. Twelve months later both groups present a similar clinical condition with the exception of residual kidney function, higher in failed native kidney patients. The method of dialysis treatment after kidney transplant failure did not have a bearing on the clinical improvement of our patients.

Topics: Adult; Aged; Anemia; Calcium; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Phosphorus; Postoperative Complications; Recurrence; Renal Dialysis; Retrospective Studies; Risk Factors; Treatment Outcome

Topics: Anemia; Blood Transfusion; Cardiovascular Diseases; Erythropoietin; Humans

A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time-dependent confounding by indication, estimated separately for diabetic and non-diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000 U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000 U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000 U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients.

Topics: Aged; Cardiovascular Diseases; Databases, Factual; Diabetic Cardiomyopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Humans; Male; Medicare; Recombinant Proteins; Renal Dialysis; Risk Factors; United States

Although hypoxia and ischemia are known to be involved in the pathogenesis of cardiovascular disease, specific therapeutic targets still remain elusive. To address this important issue, we have performed 2 series of experimental studies, aiming at erythropoietin (Epo)/Epo receptor (EpoR) based on the following backgrounds. Epo has long been regarded as a hematopoietic hormone that acts exclusively in the proliferation and differentiation of erythroid progenitors. Although recent studies have demonstrated that EpoR is expressed in the cardiovascular system, the potential protective role of the vascular Epo/EpoR system in vivo remains to be examined. We hypothesized that the vascular Epo/EpoR system plays an important protective role against the development of cardiovascular disease. Using vascular EpoR-deficient mouse, we demonstrated that the vascular Epo/EpoR system plays a crucial role for endothelial function and vascular homeostasis. The vascular Epo/EpoR system is important for the activation of the vascular endothelial growth factor/vascular endothelial growth factor receptor-2 system, inhibits hypoxia-induced pulmonary endothelial damage and promotes ischemia-induced angiogenesis in vivo. These results indicate that the vascular Epo/EpoR system plays an important protective role against hypoxia/ischemia, demonstrating that this system is a novel therapeutic target in cardiovascular medicine.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endothelium, Vascular; Erythropoietin; Homeostasis; Humans; Hypoxia; Mice; Mice, Knockout; Myocardial Ischemia; Receptors, Erythropoietin

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetic Nephropathies; Double-Blind Method; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Placebos; Prospective Studies; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Risk Factors

Topics: Anemia; Cardiovascular Diseases; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Hemoglobins; Humans

To critically examine the cardiovascular and thromboembolic risks associated with erythropoietin stimulating proteins (ESPs) in men with normal hemoglobin levels undergoing open radical retropubic prostatectomy.. Between October 1, 2000, through December 31, 2006, a total of 1308 men underwent open radial retropubic prostatectomy by a single surgeon. Of these men, 1095 received preoperative ESPs. Hematocrit levels measured at baseline, immediately before anesthesia induction and at hospital discharge, were prospectively entered into a database. Thromboembolic and cardiovascular complications were prospectively captured during the hospitalization and after surgery.. The mean Delta preoperative hematocrit level was 5.9 g/dL. The pre-anesthesia induction hematocrit level was 49.2%. Hospital discharge hematocrit level was 33.6 g/dL. The overall risk of cardiovascular and thromboembolic complications in men receiving ESP were 0.55% and 0.45%, respectively. The risk of cardiovascular and thromboembolic complications were independent of the Delta in preoperative hematocrit or the absolute level of the pre-anesthesia induction hematocrit.. ESPs represent a safe and effective preoperative blood management strategy for men undergoing open radical retropubic prostatectomy.

Topics: Aged; Analysis of Variance; Cardiovascular Diseases; Cohort Studies; Erythropoietin; Follow-Up Studies; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Postoperative Complications; Preoperative Care; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Recombinant Proteins; Risk Assessment; Survival Rate; Thromboembolism; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Male; Postoperative Complications; Preoperative Care; Prognosis; Prostatectomy; Prostatic Neoplasms; Recombinant Proteins; Risk Assessment; Survival Analysis; Thromboembolism

Residual kidney function (RKF) is associated with improved survival in peritoneal dialysis patients, but its role in hemodialysis patients is less well known. Urine output may provide an estimate of RKF. The aim of our study is to determine the association of urine output with mortality, quality of life (QOL), and inflammation in incident hemodialysis patients.. Nationally representative prospective cohort study.. 734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998; follow-up until December 2004.. Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained using questionnaires at baseline and year 1.. Primary outcomes were all-cause and cardiovascular mortality, analyzed using Cox regression adjusted for demographic, clinical, and treatment characteristics. Secondary outcomes were QOL, inflammation (C-reactive protein and interleukin 6 levels), and erythropoietin (EPO) requirements.. 617 of 734 (84%) participants reported urine output at baseline, and 163 of 579 (28%), at year 1. Baseline urine output was not associated with survival. Urine output at year 1, indicating preserved RKF, was independently associated with lower all-cause mortality (HR, 0.70; 95% CI, 0.52-0.93; P = 0.02) and a trend toward lower cardiovascular mortality (HR, 0.69; 95% CI, 0.45-1.05; P = 0.09). Participants with urine output at baseline reported better QOL and had lower C-reactive protein (P = 0.02) and interleukin 6 (P = 0.03) levels. Importantly, EPO dose was 12,000 U/wk lower in those with urine output at year 1 compared with those without (P = 0.001).. Urine volume was measured in only a subset of patients (42%), but agreed with self-report (P < 0.001).. RKF in hemodialysis patients is associated with better survival and QOL, lower inflammation, and significantly less EPO use. RKF should be monitored routinely in hemodialysis patients. The development of methods to assess and preserve RKF is important and may improve dialysis care.

Topics: Aged; Cardiovascular Diseases; Erythropoietin; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Quality of Life; Renal Dialysis; Urine

Anemia, a common multifactorial problem in kidney transplant recipients, represents an important cardiovascular risk factor. The purpose of this study was to assess anemia prevalence after kidney transplantation, the main factors involved in its occurrence, its cardiovascular consequences, and its impact on patient survival and graft function.. This retrospective study evaluated 69 patients undergoing renal transplantation between January 1998 and September 2008 with ≥1 year of follow-up. For all of the patients, we recorded hemoglobin concentrations before and at 1, 3, 6, 12, 36, and 60 months after transplantation. Anemia was defined as recommended by the American Society of Transplantation: hemoglobin level <12 g/dL in women and <13 g/dL in men. To determine the factors involved in anemia occurrence, we compared 2 groups of patients, with versus without anemia, at various times after renal transplantation.. This study showed a high prevalence of anemia in the early posttransplantation period of 82.7% and 42% of kidney transplantation patients at 1 month and 6 months, respectively. It was mainly related to a low pretransplant hemoglobin level. The prevalence declined to 37.7% at 1 year. Renal graft dysfunction was the most important factor in the occurrence of late post-renal transplantation anemia. The presence of anemia increased the risk of renal graft functional deterioration by a factor of 2.9. The decreased prevalence at 1 year after transplantation was significantly associated with a reduction in left ventricular hypertrophy.. The management of anemia is essential to improve renal graft survival, reduce cardiovascular morbidity, and ensure a better quality of life for renal transplant recipients.

Topics: Adolescent; Adult; Aged; Anemia; Biomarkers; Cardiovascular Diseases; Erythropoietin; Female; Graft Survival; Hematinics; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Morocco; Prevalence; Recombinant Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Young Adult

The production of erythropoietin is triggered by impaired oxygen delivery to the kidney, either because of anemia or hypoxemia. High erythropoietin levels have been shown to predict the risk of death among patients with chronic heart failure. We investigated the prognostic value of elevated erythropoietin levels on mortality among very elderly people in the general population.. The Leiden 85-plus Study is a population-based prospective follow-up study involving 599 people aged 85 years in Leiden, the Netherlands, enrolled between September 1997 and September 1999. Erythropoietin levels were determined at age 86. For this analysis, we included 428 participants with a creatinine clearance of at least 30 mL/min. Mortality data, recorded until Feb. 1, 2008, were obtained from the municipal registry.. During follow-up, 324 (75.7%) participants died. Compared with participants whose erythropoietin levels were in the lowest tertile (reference group), those whose levels were in the middle tertile had a 25% increased risk of death (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.95-1.64), and those whose levels were in the highest tertile had a 73% increased risk (HR 1.73, 95% CI 1.32-2.26) (p value for trend < 0.01). The association between erythropoietin levels and mortality remained largely unchanged after we adjusted for sex, creatinine clearance, hemoglobin level, comorbidity, smoking status and C-reactive protein level, and was similar for deaths from cardiovascular and noncardiovascular causes.. Among people aged 85 years and older, elevated erythropoietin levels were associated with an increased risk of death, independent of hemoglobin levels.

Topics: Age Factors; Aged, 80 and over; Aging; Anemia; Biomarkers; Cardiovascular Diseases; Cause of Death; Erythropoietin; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Male; Netherlands; Prognosis; Prospective Studies; Risk Factors; Survival Rate; Urban Population

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Hematinics; Humans; Kidney Diseases

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Risk Factors

Some time has passed since the torrent of discussion surrounding the cardiovascular risk of pushing up hemoglobin concentrations in dialysis patients with erythropoietin. The debate here reflects a look back on the tension produced by confusing data and outcomes. Is it the target hemoglobin per se or the high doses of erythropoietin in subsets of resistant patients that is the problem? You decide.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Risk Factors

Athletes who abuse recombinant human erythropoietin (rhEPO) consider only the benefit to performance and usually ignore the potential short and long-term liabilities. Elevated haematocrit and dehydratation associated with intense exercise may reveal undetected cardiovascular risk, but the mechanisms underlying it remain to be fully explained. This study aimed to evaluate the cardiovascular effects of rhEPO in rats under chronic aerobic exercise. A ten week protocol was performed in four male Wistar rat groups: control--sedentary; rhEPO--50 IU kg(-1), 3 times/wk; exercised (EX)--swimming for 1 h, 3 times/wk; EX + rhEPO. One rat of the EX + rhEPO group suffered a sudden death episode during the week 8. rhEPO in trained rats promoted erythrocyte count increase, hypertension, heart hypertrophy, sympathetic and serotonergic overactivation. The suddenly died rat's tissues presented brain with vascular congestion; left ventricular hypertrophy, together with a "cardiac-liver", suggesting the hypothesis of heart failure as cause of sudden death. In conclusion, rhEPO doping in rats under chronic exercise promotes not only the expected RBC count increment, suggesting hyperviscosity, but also other serious deleterious cardiovascular and thromboembolic modifications, including mortality risk, which might be known and assumed by all sports authorities, including athletes and their physicians.

Topics: Animals; Cardiovascular Diseases; Doping in Sports; Erythropoietin; Male; Models, Animal; Rats; Rats, Wistar; Recombinant Proteins; Risk Factors

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Treatment Outcome

The CREATE and CHOIR studies showed a higher risk for cardiovascular events associated with hemoglobin (Hb) values >13 g/dL in patients with stage 3-4 chronic kidney disease. In 2007, a stricter policy on the use of erythropoietin (EPO) was adopted at our center, with an Hb target of 11 to 12 g/dL and withdrawal or reduction of EPO when Hb was >12.5 to 13 g/dL. This study was designed to evaluate this new approach.. The study included patients under follow-up at the transplant outpatient clinic on December 31, 2006 (n = 725), and December 31, 2007 (n = 768). Data were compared between the study populations concerning renal function, Hb, use of EPO, and associated costs.. No significant differences in creatinine or Hb values were observed between the 2 groups (1.47 +/- 0.6 vs 1.42 +/- 0.9 mg/dL and 13.7 +/- 1.5 vs 13.7 +/- 1.6 g/dL, respectively). After implementation of the new protocol, the frequency of severe anemia (Hb <11 g/dL) increased (2% vs 4%; P = .10), the use of EPO decreased (22.1% vs 17.2%; P = .017), and the mean Hb of EPO-treated patients decreased (12.5 +/- 1.4 vs 11.9 +/- 1.0; P < .001). The Hb target (11-12 g/dL) was met in fewer than one third of patients, with no significant differences between the 2 study times.. A strict policy on EPO application reduces its use and the rate of patients with "excessive" Hb values (which are associated with increased cardiovascular risks), with an acceptable slight increase in severe anemia cases.

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Creatinine; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors

No tangible benefit, but a risk of cardiovascular adverse effects due to haemogloblin levels that are frequently too high compared with other epoetins.

Topics: Anemia; Cardiovascular Diseases; Clinical Trials as Topic; Drug Approval; Drug Combinations; Erythropoietin; Europe; Humans; Polyethylene Glycols

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Erythropoietin; Female; Glycated Hemoglobin; Humans; Male; Middle Aged

Topics: Anemia; Cardiovascular Diseases; Dose-Response Relationship, Drug; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk

Topics: Anemia; Blood Pressure; Cardiovascular Diseases; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Insufficiency, Chronic; Thromboembolism

Epidemiological studies report that a third of the cases of anaemia in older persons is unexplained. We compared erythropoietin (EPO), inflammatory markers and major comorbidities between older subjects with normal haemoglobin levels and those with different aetiologic forms of anaemia, including unexplained anaemia. Participants were a representative sample of 964 persons aged > or =65 years, with no evidence of bleeding, complete blood tests, and a complete blood count within 6 h of phlebotomy. Anaemia was defined as haemoglobin <130 g/l in men and 120 g/l in women, and classified as a result of chronic kidney disease, iron deficiency, chronic disease and B12/folate deficiency anaemia, or unexplained anaemia based on standard criteria. Of the 124 anaemic participants, 42 (36.8%) had unexplained anaemia. Participants with anaemia of chronic diseases had significantly higher interleukin-6 (IL-6) and C-reactive protein (CRP) levels, while those with unexplained anaemia had significantly lower CRP than non-anaemic controls. Iron deficiency anaemia was characterised by significantly higher EPO levels compared with other types of anaemia and normal haemoglobin, B12 and/or folate deficiency. Unexplained anaemia was characterised by unexpectedly low EPO and low lymphocyte count. Unexplained anaemia is associated with reduced kidney EPO response, low levels of pro-inflammatory markers and low lymphocyte counts.

Topics: Aged; Aging; Anemia; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus; Erythropoietin; Female; Health Surveys; Humans; Inflammation Mediators; Interleukin-6; Italy; Kidney Diseases; Lymphocyte Count; Male; Osteoarthritis; Parkinson Disease; Stroke; Tumor Necrosis Factor-alpha

We hypothesized that in growth restricted fetuses, erythropoietin (EPO) secretion is increased in proportion to the severity of cardiovascular compromise.. Thirty-eight growth restricted fetuses underwent Doppler ultrasonography of cardiovascular hemodynamics. An umbilical artery (UA) blood sample was taken at delivery for EPO analysis. Group 1 fetuses (n=9) had normal UA and ductus venosus (DV) velocimetries. Group 2 fetuses (n=18) showed an abnormal UA and a normal DV velocimetry. Group 3 fetuses (n=11) had abnormal UA and DV velocimetries. Normal EPO values were determined in 19 uncomplicated pregnancies (control group).. In group 3, EPO levels were higher (P<.05) than in groups 1 and 2. All fetuses in group 3 had EPO concentrations above the 90th percentile EPO value in the control group. The corresponding incidences were 44% and 50% in groups 1 and 2. Fetuses with retrograde aortic isthmus net blood flow had greater (P<.001) EPO levels than fetuses with antegrade net blood flow. Descending aorta, UA, DV and left hepatic vein pulsatility index values correlated significantly with EPO concentrations.. In fetal growth restriction, serum EPO concentration is increased in proportion to the severity of fetal cardiovascular compromise. Furthermore, in fetuses with retrograde aortic isthmus net blood flow, EPO levels are increased.

Topics: Adult; Cardiovascular Diseases; Erythropoietin; Female; Fetal Diseases; Fetal Growth Retardation; Humans; Pregnancy; Ultrasonography, Prenatal

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Goals; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Thrombophilia

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Drug Industry; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

In medicine a considerable amount of resources are used in research, but very little attention is paid to ensuring that the findings of research are implemented in routine clinical practice. This prospective study has the aim to evaluate the efficiency of some clinical management strategies (feedback, benchmarking and improving plans) on haemodialysis treatment results in 4 different dialysis centres. We collected consensus data related to haemodialysis results every 6-8 months and informed each centre about its own results (feedback) and how these related to the others(benchmarking). We designed improving plans for any bad result detected. By the end of two years of follow up, 294 patients had been included in the study. The results obtained at the end of the study had improved in comparison with those obtained at the beginning (statistically significant) for the following indicators: % of patients with Hb< 11 g/dl, % patients with Kt/v < 1.2, mean Kt/v, mean albumin, % patients with albumin< 3.5 g/dl y % patients with C reactive protein (CRP) > 5 mg/dl. No statistical changes were found in: mean erythropoietin (EPO) doses, blood pressure (BP), phosphorus plasmatic,calcium-phosphorus product, parathormone (PTHi) and vascular access distribution. We explained the absence of any improvement because of adequate start indicators in some areas (BP and vascular access), therapy with limited efficiency (calcitriol, calcium carbonate and others), lack of support resources (dietetic unit) or inadequate design/implementation of improving plans.In conclusion, our intervention illustrates that combined clinical management strategies(feedback, benchmarking and improving plans) are efficiency in improving some areas of haemodialysis treatment (anaemia, dialysis dose, nutrition and inflammation), although it does not improve calcium phosphate metabolism related indicators.

Topics: Aged; Aged, 80 and over; Anemia; Benchmarking; Blood Pressure; C-Reactive Protein; Calcium; Cardiovascular Diseases; Catheters, Indwelling; Comorbidity; Erythropoietin; Feedback; Female; Follow-Up Studies; Hemodialysis Units, Hospital; Humans; Inflammation; Kidney Failure, Chronic; Male; Malnutrition; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Quality Assurance, Health Care; Renal Dialysis; Spain

Topics: Albuminuria; Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Europe; Humans; Practice Guidelines as Topic; Prognosis; Quality of Life

We previously showed that nutritional protein concentrations were predictive of outcome, whereas variables reflecting body composition and dialysis dose were not, in a 30-month prospective follow-up of 1,610 hemodialysis patients. Information on dialysis membrane and erythropoietin use had to be evaluated in an additional follow-up.. A subset of 650 patients from the initial cohort of 1,610 was analyzed for survival in a 2-year extension of follow-up. Detailed data were collected: demographics; cause of renal failure; time on dialysis therapy; type of membrane; erythropoietin treatment; body mass index (BMI); predialysis albumin, prealbumin, and bicarbonate levels; and outcome. Normalized protein catabolic rate (nPCR), dialysis adequacy, and lean body mass were computed from predialysis and postdialysis urea and creatinine values.. Patient characteristics were age of 61 +/- 16 years, 58% men, BMI of 22.7 +/- 4.4 kg/m2 , time on dialysis therapy of 102 +/- 73 months, and 8.8% had diabetes. Dialysis parameters were duration of 247 +/- 31 minutes, Kt/V of 1.4 +/- 0.3, and nPCR of 1.2 +/- 0.3 g/kg/d. Albumin level was 3.73 +/- 0.53 g/dL (37.3 +/- 5.3 g/L), and prealbumin level was 31 +/- 8 mg/dL. The survival rate was 78.7% after 2 years. Survival was influenced by age, presence of diabetes, use of high-flux membrane, and serum albumin level, but not other variables, including Kt/V and prealbumin level. Two-year variations in values for urea, creatinine, and weight were predictive of survival in univariate, but not multivariate, analyses.. In patients on dialysis therapy for a long period, better survival was observed when high-flux dialysis membranes were used.

Topics: Aged; Bicarbonates; Body Composition; Body Mass Index; Cardiovascular Diseases; Cause of Death; Cholesterol; Comorbidity; Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Follow-Up Studies; Humans; Infections; Kidney Failure, Chronic; Life Tables; Male; Membranes, Artificial; Middle Aged; Neoplasms; Permeability; Prealbumin; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Protein-Energy Malnutrition; Renal Dialysis; Serum Albumin; Survival Analysis; Time Factors; Urea

Patients with chronic kidney disease (CKD) stages 2-5 are known to suffer numerous complications and co-morbidities associated with kidney disease. The medication prescription patterns in this population are not well understood. We report on prescription data collected as part of a multicentre longitudinal study in patients with CKD, with a focus on medications with cardiovascular or cardioprotective effects.. Patients were recruited from four academic nephrology centres in the USA, with patient recruitment from June 2000 to March 2002. Medication data were captured at the time of first enrollment into the study. Individual medications were classified into medication groups, and those with predominant cardioprotective effects or for prevention of progression of kidney disease (e.g. medications for treatment of anaemia, lipid-lowering agents, antihypertensives, statins, etc.) were recorded for analysis. Descriptive statistics were used for medication prescription according to baseline demographics and co-morbidities. Predictors of epoetin and iron use were determined by logistic regression adjusting for age, race, sex, diabetes, glomerular filtration rate (GFR), haemoglobin and serum albumin.. Medication data were available for 619 patients with stages 2-5 CKD. Patients were 60.6+/-16.0 years of age, and were prescribed 8+/-4 (range 1-28) medications. Overall, the proportion of patients prescribed different classes of medications included epoetin (20%), intravenous iron (13%), HMG-CoA reductase inhibitors (16%), angiotensin-converting enzyme (ACE) inhibitors (44%), angiotensin receptor blockers (13%), beta-blockers (46%), calcium channel blockers (52%) and aspirin (37%). There was a low use of epoetin (45%) and iron (20%) in patients with anaemia. Only 24% of patients with coronary artery disease were prescribed statins, and ACE inhibitors and angiotensin receptor blockers were used in only 58 and 23% of diabetic patients with proteinuria. Positive predictors of epoetin and iron therapy included white race and diabetes. Higher GFR and higher serum albumin were associated with lower odds of being prescribed epoetin. White race and diabetics were more likely to be prescribed iron.. This study provides an overview of prescription practices in a cohort of CKD patients. Substantial underutilization of certain classes of cardioprotective medications is apparent, and systematic educational efforts in this direction may well prove worthwhile to impact outcomes.

Topics: Aged; Cardiovascular Diseases; Chronic Disease; Drug Utilization; Epoetin Alfa; Erythropoietin; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Logistic Models; Middle Aged; Recombinant Proteins

Health-related quality of life (QOL) is an important measure of how disease affects patients' lives. Dialysis patients have decreased QOL relative to healthy controls. Little is known about QOL in patients with chronic kidney disease (CKD) before renal replacement therapy.. The Medical Outcomes Study Short Form-36 (SF-36), a standard QOL instrument, was used to evaluate 634 patients (mean glomerular filtration rate [GFR], 23.6 +/- 9.6 mL/min/1.73 m2 [0.39 +/- 0.16 mL/s/1.73 m2]) enrolled in a 4-center, prospective, observational study of CKD. SF-36 scores in these patients were compared with those in a prevalent cohort of hemodialysis (HD) patients and healthy controls (both from historical data). QOL data also were analyzed for correlations with GFR and albumin and hemoglobin levels in multivariable analyses.. Patients with CKD had higher SF-36 scores than a large cohort of HD patients (P < 0.0001 for 8 scales and 2 summary scales), but lower scores than those reported for the US adult population (P < 0.0001 for 7 of 8 scales and 1 of 2 summary scales). Patients with CKD stage 4 had lower QOL scores than patients with CKD stage 5, although differences were not significant. Hemoglobin level was associated positively with higher mental and physical QOL scores (P < 0.05) in all individual and component scales except Pain.. SF-36 scores were higher in this CKD cohort compared with HD patients, but lower than in healthy controls. GFR was not significantly associated with QOL. Hemoglobin level predicted both physical and mental domains of the SF-36. Longitudinal studies are needed to define at-risk periods for decreases in QOL during progression of CKD.

Topics: Aged; Anemia; Black or African American; Cardiovascular Diseases; Cohort Studies; Comorbidity; Cross-Sectional Studies; Diabetes Complications; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Obesity; Prospective Studies; Quality of Life; Renal Dialysis; Serum Albumin; Socioeconomic Factors; Surveys and Questionnaires; United States; White People

Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.. The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Humans; Kidney Diseases; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Reduction Behavior

It is unknown whether traditional cardiovascular disease risk factors influence the number of endothelial progenitor cells (EPCs) and whether numbers of EPCs correlate with endothelial function in patients with end-stage renal disease.. In a cross-sectional study of 38 peritoneal dialysis patients, we examined numbers of circulating CD34+/KDR+/CD133+ cells, CD34+ hematopoietic stem cells, and EPCs cultured from peripheral blood. We also assessed conventional cardiovascular disease risk factors, such as history of vascular disease, diabetes, hypercholesterolemia, hypertension, and smoking. We determined endothelial function by measurement of endothelium-dependent and endothelium-independent reactivity of forearm resistance arteries by using strain-gauge plethysmography.. Numbers of EPCs cultured from peripheral blood and forearm blood flow reactivity did not differ between erythropoietin-treated peritoneal dialysis patients and healthy individuals. A history of vascular disease was associated with number of cultured EPCs, but other cardiovascular disease risk factors showed no association. Furthermore, there was no association of endothelial-dependent and endothelial-independent forearm blood flow reactivity with EPCs in peritoneal dialysis patients.. In this first study of EPCs in peritoneal dialysis patients, we found an association between history of vascular disease and EPCs, but no association of EPCs with endothelial function or other cardiovascular disease risk factors.

Topics: Aged; Anemia; Antigens, CD; Blood Cell Count; Blood Flow Velocity; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus; Endothelial Cells; Endothelium, Vascular; Erythropoietin; Female; Forearm; Hematopoietic Stem Cells; Humans; Hypercholesterolemia; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Risk Factors; Smoking; Vascular Resistance

Topics: Adult; Cardiovascular Diseases; Decision Making; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Glomerulosclerosis, Focal Segmental; Hematinics; Humans; Kidney Failure, Chronic; Kidney Transplantation; Morbidity; Neoplasms; Pregnancy; Pregnancy Complications; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy; Risk Assessment; Uremia

Erythropoietin (EPO), a hypoxia-inducible cytokine, is required for survival, proliferation, and differentiation of erythroid progenitor cells. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors (EPORs). In this study we investigated the EPO response of vascular endothelial cells at reduced oxygen tension (5% and 2%), in particular the effect of EPO on nitric oxide (NO) release. Endothelial nitric oxide synthase (eNOS) produces NO, which maintains blood pressure homeostasis and blood flow. We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air. We found a corresponding increase in eNOS expression and NO production in response to EPO during hypoxia. Stimulation of NO production was dose dependent on EPO concentration and was maximal at 5 U/mL. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to EPO by induction of both EPOR and eNOS. This effect of EPO on eNOS may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell mass.

Topics: Cardiovascular Diseases; Cell Differentiation; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Erythropoietin; Hemoglobins; Humans; Hypoxia; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Oligonucleotides; Oxygen; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Time Factors; Ultraviolet Rays

We tested the hypothesis that repetitive severe hypoxemia resulting from obstructive sleep apnea would increase serum erythropoietin, and that this increase would be attenuated by effective treatment of obstructive sleep apnea.. We studied healthy untreated patients with obstructive sleep apnea (18 severe and 10 very mild) before and after acute treatment with continuous positive airway pressure, and 12 healthy control subjects free of obstructive sleep apnea.. Baseline erythropoietin levels before sleep were similar in the obstructive sleep apnea and control groups. However, erythropoietin levels increased (by 20%, P =.037) in patients with severe obstructive sleep apnea after 3.5 hours untreated (lowest O2, 77% +/- 3%), and decreased after 4 hours of continuous positive airway pressure treatment (P =.001). Erythropoietin responses in patients with severe obstructive sleep apnea were different (F = 4.0, P =.03) from controls, in whom erythropoietin levels remained stable throughout the night (P =.94). Erythropoietin responses were similar in very mild obstructive sleep apnea and controls (P =.58).. Our results indicate that untreated severe obstructive sleep apnea results in increased erythropoietin, which decreases after continuous positive airway pressure treatment. Increased erythropoietin may be a potential reversible mechanism to explain the association between obstructive sleep apnea and cardiovascular disease.

Topics: Adult; Cardiovascular Diseases; Continuous Positive Airway Pressure; Erythropoietin; Female; Humans; Hypoxia; Male; Middle Aged; Severity of Illness Index; Sleep Apnea, Obstructive

Topics: Aged; Anemia; Arteriovenous Shunt, Surgical; Cardiovascular Diseases; Catheterization, Central Venous; Comorbidity; Erythropoietin; Female; Hematocrit; Hemoglobins; Hospitalization; Humans; Infections; Kidney Failure, Chronic; Male; Middle Aged; Practice Guidelines as Topic; Renal Dialysis

Topics: Anemia; Biomarkers; Blood Proteins; Cardiovascular Diseases; Comorbidity; Endothelium, Vascular; Erythropoietin; Follow-Up Studies; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Lipoproteins; Recombinant Proteins; Renal Dialysis; Thromboplastin

Adiponectin (ADPN), which is a secretory protein of adipose tissue, attenuates endothelial inflammatory responses in vitro. Among human subjects, plasma ADPN concentrations are reduced among patients with atherosclerotic complications but are substantially increased among patients with advanced renal failure. The clinical and biochemical correlates of plasma ADPN levels were investigated and the predictive power of ADPN levels with respect to survival rates and cardiovascular events was prospectively tested in a cohort of 227 hemodialysis patients, who were monitored for 31 +/- 13 mo. Plasma ADPN levels were 2.5 times higher (P < 0.0001) among dialysis patients (15.0 +/- 7.7 microg/ml) than among healthy subjects (6.3 +/- 2.0 microg/ml), were independent of age, and were higher (P = 0.03) among women (15.2 +/- 7.9 microg/ml) than among men (14.0 +/- 7.4 microg/ml). For both genders, plasma ADPN levels were inversely related to body mass index values, plasma leptin levels, insulin levels, serum triglyceride levels, and homeostatic model assessment index values. Furthermore, plasma ADPN levels were directly related to HDL cholesterol levels and inversely related to von Willebrand factor levels. Plasma ADPN levels were lower (P < 0.05) among patients who experienced new cardiovascular events (13.7 +/- 7.3 microg/ml) than among event-free patients (15.8 +/- 7.8 microg/ml). There was a 3% risk reduction for each 1 microg/ml increase in plasma ADPN levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% confidence interval, 1.12 to 1.99 times) higher among patients in the first ADPN tertile, compared with those in the third tertile. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with end-stage renal disease. Furthermore, ADPN is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.

Topics: Adiponectin; Aged; Cardiovascular Diseases; Erythropoietin; Female; Humans; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Male; Middle Aged; Proteins; Renal Dialysis; Risk Factors; Survival Analysis

Increased serum hepatocyte growth factor (HGF) level is a part of the counter-system against tissue damage and predicts mortality in maintenance haemodialysis (HD) patients. We studied which of the common co-morbid and clinical conditions, and surrogates of metabolic disorders or specific organ damage determine HGF levels in these subjects.. In 86 patients, pre-dialysis serum HGF, soluble endothelial markers--such as thrombomodulin (TM), von Willebrand factor and plasminogen activator inhibitor-1--and hepatitis B and C markers were measured by ELISAs. Inflammatory reactants such as C-reactive protein (CRP), alpha(1)-antitrypsin, alpha(1) acid-glycoprotein, and immunoglobulin M and G were assayed by nephelometry, and lipoprotein(a) was determined by ELISA. Cardiovascular disease (CVD) was identified on a clinical basis.. Serum HGF was directly associated with the presence of viral hepatitis, alanine aminotransferase and TM levels, time on HD, the presence of CVD, CRP and alpha(1)-antitrypsin levels, use of unfractionated heparin (UFH) (vs enoxaparin) during HD, dose of UFH, use of recombinant erythropoietin (rHuEpo) treatment, and Kt/V. In 36 patients not treated with rHuEpo, HGF directly correlated with haemoglobin, but not with endogenous Epo levels. There was no association between HGF and the other endothelial and inflammatory markers, gender, age, smoking, cause of renal failure, body mass index, normalized protein catabolic rate, dialysate buffers, dialysers, blood pressure, antihypertensive treatment, leukocyte and platelet counts, albumin, fibrinogen, lipoprotein(a), markers of iron and calcium-phosphorus metabolism, or metabolic acidosis. Positive viral hepatitis markers, prevalent CVD and rHuEpo treatment (in descending order of significance) were independent predictors of high HGF level. In another 20 HD patients, a 4-week course of rHuEpo treatment resulted in a significant 17% increase in circulating HGF levels.. Serum HGF levels in HD patients are determined by inflammatory conditions such as viral hepatitis and CVD, increase in response to rHuEpo treatment, and may be influenced by type and dose of heparin used during HD procedures.

Topics: Adolescent; Adult; Aged; Anticoagulants; Cardiovascular Diseases; Erythropoietin; Female; Heparin; Hepatitis, Viral, Human; Hepatocyte Growth Factor; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Chronic inflammation, the associated cardiovascular disease, and attendant high mortality remain huge problems in the HD population. Determining the predominant causal factors in the triggering and maintenance of this inflammatory state is of paramount importance in formulating treatment strategies for individuals and for centers. In most cases, causation is multifactorial and several different areas of the HD process need to be considered. In this respect, the water system in HD centers is certainly one parameter that demands careful design, rigorous monitoring and strict adherence to effective disinfection protocols. In this way it may be possible not only to reduce levels of inflammatory markers, but to improve performance in other clinical areas, such as EPO therapy, and perhaps outcomes in the HD population.

Topics: Acute-Phase Reaction; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Quality Control; Quality of Life; Renal Dialysis; Water; Water Purification; Water Supply

The most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span.

Topics: Age Factors; Animals; Blood Vessels; Cardiovascular Diseases; Chronic Disease; Death; Electrocardiography; Erythropoietin; Exercise Tolerance; Female; Hematocrit; Hemodynamics; Humans; Male; Mice; Mice, Transgenic; Microscopy, Electron; Models, Animal; Organ Size; Polycythemia; Sex Factors; Survival Rate

Nitric oxide (NO) induces vasodilatatory, antiaggregatory, and antiproliferative effects in vitro. To delineate potential beneficial effects of NO in preventing vascular disease in vivo, we generated transgenic mice overexpressing human erythropoietin. These animals induce polyglobulia known to be associated with a high incidence of vascular disease. Despite hematocrit levels of 80%, adult transgenic mice did not develop hypertension or thromboembolism. Endothelial NO synthase levels, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels were markedly increased. Administration of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) led to vasoconstriction of peripheral resistance vessels, hypertension, and death of transgenic mice, whereas wild-type siblings developed hypertension but did not show increased mortality. L-NAME-treated polyglobulic mice revealed acute left ventricular dilatation and vascular engorgement associated with pulmonary congestion and hemorrhage. In conclusion, we here unequivocally demonstrate that endothelial NO maintains normotension, prevents cardiovascular dysfunction, and critically determines survival in vivo under conditions of increased hematocrit.

Topics: Animals; Cardiovascular Diseases; Enzyme Inhibitors; Erythropoietin; In Vitro Techniques; Mice; Mice, Transgenic; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Survival Analysis

Topics: Anemia; Cardiovascular Diseases; Catheters, Indwelling; Erythropoietin; Europe; Health Surveys; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Practice Guidelines as Topic; Survival Analysis; Thrombosis

Anaemia is a major risk factor in end-stage renal disease (ESRD) and leads to enhanced cardiac output and left-ventricular hypertrophy (LVH). Recombinant human erythropoietin (rhEPO) partially corrects anaemia and reduces LVH in ESRD. The current study retrospectively analysed mortality data from haemodialysis patients included in the clinical development database for epoetin-beta.. The unselected database, set up to monitor safety from clinical studies of epoetin-beta, comprised 3,111 adult haemodialysis patients included in 17 clinical trials in the clinical development programme (1987-1994). 1,726 and 466 patients were treated for >1 and >2 years, respectively. Untreated control patients (n = 246) were available in two studies. Mortality was measured from fatal adverse event documentation.. The controlled studies showed an approximately 20% reduction in the mortality risk for epoetin-beta versus controls after 1 year. For the overall patient population, all-cause mortality fell from a peak (after about 150 days) of about 10 to about 6 deaths per 100 patient-years in the 3rd year of treatment (p < 0.01). The proportion of deaths due to cardiovascular causes fell from 50 to 20-30% over 3 years. The decline in cardiovascular mortality could not be explained by changes in covariate distribution or by drop-outs.. The cardiovascular mortality risk decreased over time in this population of ESRD patients. The beneficial effects of long-term anaemia correction by epoetin-beta therapy was a likely cause of this favourable development.

Topics: Anemia; Cardiovascular Diseases; Databases, Factual; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Assessment; Time Factors

In 1980, the first Moroccan hemodialysis center was founded in Casablanca. The number of centers has been increasing since then, to reach 61 centers to wards the of 1996. There are 1800 hemodialysed (males 59%, females 41%) with and average age of 51 +/- 4 years. In about one third of the cases, the cause of the end stage renal failure remains unknown. However, chronic glomerulonephritis comes at the head of known causes (25%), followed by interstitial nephritis (19%). A temporary vascular access (catheter) was necessary in 81% of cases when dialysis has started in emergency in 61% of patients. Infections were the most frequent complications (21%) namely septicaemia (8%) and tuberculosis (7%). The vaccination against hepatitis B virus is done systematically in all the centers, and the number of chronic carriers of HBS Ag is about 7%. Further more, serological C virus is positive in 40% of the hemodialysed patients. Cardio-vascular complications were dominated by percarditis (13%) especially at the beginning of the dialysis. Anaemia remains very frequent and often very important requiring multiple blood transfusions (35%) in the absence of erythropoietin treatment. The death rate, which is very difficult to estimate, is of about 18%. Peritoneal dialysis was used in 50 patients but only four patient continued on peritoneal dialysis therapy. 108 patients were transplanted (23 cases in Morocco, 85 in other countries) with a waiting list of 0 to 12 years. Hemodialysed Moroccan's population is characterised by the high number of unknown causes and the gravity of the admission stage. A renal effort in prophylactic should be performed to avoid certain causes of renal failure.

Topics: Adolescent; Adult; Aged; Ambulatory Care Facilities; Anemia; Cardiovascular Diseases; Carrier State; Catheters, Indwelling; Child; Child, Preschool; Comorbidity; Erythropoietin; Female; Glomerulonephritis; Hepatitis, Viral, Human; Humans; Infant; Infections; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Morocco; Nephritis, Interstitial; Peritoneal Dialysis; Renal Dialysis; Transfusion Reaction; Vaccination

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Erythropoietin; Female; Hematocrit; Humans; Italy; Japan; Kidney Failure, Chronic; Male; Middle Aged; Morbidity; Recombinant Proteins; Registries; Renal Replacement Therapy; Risk Factors

Topics: Cardiovascular Diseases; Erythropoietin; Humans; Recombinant Proteins; Risk Factors; Uremia

Topics: Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Renal Dialysis; Risk Factors

Recombinant human erythropoietin is widely used in chronic dialysis patients. However, the long-term effect, especially on the incidence of cardiovascular disease, has not been critically evaluated. We observed the annual incidence of stroke and acute myocardial infarction from April 1988 through March 1993 in Okinawa, Japan. Until April 1990, erythropoietin was not generally used. Therefore, we have two periods: pre-erythropoietin, April 1988 through March 1990, and post-erythropoietin, April 1990 through March 1993. Two thousand one hundred and sixteen patients (1,219 males and 897 females) were on chronic dialysis during the study period by March 31, 1993. Every case of stroke and acute myocardial infarction during the study period was registered. The odds ratio was calculated using the data of the general population in each sex and age class obtained in the same area. A total of 86 cases of stroke and 15 cases of acute myocardial infarction were registered during the study period. The annual incidence, per 1,000 patient-years, of stroke was 12.5 (1988), 10.5 (1989), 12.7 (1990), 14.0 (1991), and 17.5 (1992). The incidence of stroke was increased in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.22 and 95% confidence interval (95% CI 1.06-1.41, p < 0.01). The annual incidence of acute myocardial infarction was 1.0 (1988), 1.8 (1989), 0.8 (1990), 2.9 (1991) and 4.7 (1992). The incidence of acute myocardial infarction was increased significantly in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.87 (95% CI 1.66-2.10, p < 0.01). The odds ratio of stroke to the general population was 4.25 (95% CI 3.10-5.82) in the pre-erythropoietin and 4.58 (95% CI 2.14-9.80) in the post-erythropoietin period. In acute myocardial infarction, it was 2.98 (95% CI 2.84-3.12) and 3.81 (95% CI 3.18-4.56). The odds ratio of acute myocardial infarction was significantly increased (p < 0.01). The introduction of erythropoietin was associated with an increased risk of cardiovascular disease, especially acute myocardial infarction. Erythropoietin may unmask the sclerotic lesion in chronic dialysis patients.

Topics: Cardiovascular Diseases; Cerebrovascular Disorders; Diabetes Mellitus; Erythropoietin; Female; Humans; Japan; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Risk Factors

Patients with chronic renal failure (c.r.f.) are at high risks of death from cardiovascular diseases. It was found that successful treatment of anemia could positively influence not only patients well being but also caused some unfavourable hemodynamic changes. The aim of the study was the estimation of some morphological and functional parameters of left ventricle (lv) in dialyzed and predialyzed patients treated with r-Epo. Two groups of patients with c.r.f. were studied. The I group of 10 dialyzed patients (6 W, 4 M, mean age 34 +/- 11, weight 55 +/- 9 kg), and the II group of 9 pre-dialyzed patients (6 W, 3 M, mean age 50.6 +/- 10, weight 63 +/- 14 kg). r-Epo (Eprex Cilag AG) was administered during 6 months s.c. The I group was given initial dose 3 x 2000 u per week (mean dose 24-46 u/kg b.w./per week, the II was on 3 x 2000 u per week (mean dose 24-46 u/kg b.w./per week) subcutaneously. The doses were adjusted by Hb level in order to keep it within limits (10-12 g/dl). Hematological parameters were monitored once a week by Technicon H1. Morphology and function of the lv were evaluated using echocardiographic measurements performed by Irex IIIA system. According to prescriptions of ASE the following parameters have been assessed: lv dimension, thickness of posterior wall in diastole and systole and thickness of interventricular septum in diastole.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cardiovascular Diseases; Erythropoietin; Female; Heart Ventricles; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Ultrasonography; Ventricular Function, Left

The objective was to evaluate the effect of the treatment of anemia with recombinant human erythropoietin (EPO) on thrombosis of the vascular access used for hemodialysis. The research design was a prospective cohort study comparing EPO-treated hemodialysis patients with a comparison group matched for type of vascular access, clinical center, and age. All patients commencing hemodialysis in the study centers between March 1988 and July 1991 were eligible if either a graft or fistula had been used as a first permanent vascular access. There were 64 matched fistula pairs and 38 matched graft pairs. There were more patients with a history of cardiovascular disease in the EPO group than in the comparison group for both fistulae and grafts, 34 versus 14% for the former and 37 versus 5% for the latter. There was no difference between EPO and comparison groups with respect to time to first thrombosis of fistula, 11.3 versus 10.6%, respectively, by thrombosis of grafts among those treated with EPO--33.6 versus 11.2% (P = 0.02). EPO treatment does not increase the probability of fistula thrombosis, but there is an association with an increased probability of graft thrombosis.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Anemia; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis; Cardiovascular Diseases; Catheters, Indwelling; Cohort Studies; Comorbidity; Diabetes Mellitus; Erythropoietin; Female; Humans; Immunologic Factors; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Thrombosis

Topics: Blood Transfusion, Autologous; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans

Topics: Cardiovascular Diseases; Erythropoietin; Europe; Female; Graft Survival; Humans; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Pregnancy; Renal Dialysis; Renal Insufficiency

Topics: Cardiovascular Diseases; Doping in Sports; Erythropoietin; Humans; Recombinant Proteins; Sports

Reduced oxygen tension is regarded as the primary physiologic signal for the production of erythropoietin (EPO). There is little information available about early changes of EPO production in man due to severe hypoxia. The purpose of the present study was to examine the time course of EPO in serum of patients with acute cardiogenic pulmonary edema (ACPE). In 29 patients (seventy-five +/- six years, mean age +/- SEM) who were hospitalized within two hours after onset of symptoms of ACPE, serum EPO concentrations were monitored for up to seventy-two hours. At the moment of admission all patients showed significantly increased EPO concentrations of 121 +/- 64 mU/mL (mean +/- SEM) compared with a healthy population (15-35 mU/mL). Twenty-three patients who recovered within thirty minutes (group A) exhibited a quick return of their EPO serum levels to normal. The remaining 6 patients (group B) had a protracted clinical course and their EPO concentration showed a further increase up to the end of the observation period. The comparative monitoring of concentrations of alpha-1-proteinase inhibitor, antithrombin III, C-reactive protein, fibronectin, hapotoglobin, and transerrin in serum and plasma revealed no significant changes. Thus a major contribution of fluid shifts into or from the intravascular compartment to the observed changes in EPO concentration seems to be unlikely. The data suggest that the production and release of EPO in the kidneys due to altered oxygen delivery is a fast-responding mechanism.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Proteins; Cardiovascular Diseases; Erythropoietin; Female; Humans; Hypoxia; Kidney; Male; Pulmonary Edema