losartan-potassium and Hypertension

Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values.. The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Topics: Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Tubules; Renal Reabsorption; Renin-Angiotensin System; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Hypertension among patients on hemodialysis is predominantly systolic (either isolated or combined with diastolic hypertension), whereas the scenario of isolated diastolic hypertension is rare and more common in younger patients. Uncontrolled hypertension that persists despite aggressive antihypertensive drug therapy is a reflection of the volume overload that is a prominent mediator of systolic and diastolic BP elevation. Clinical-trial evidence supports the notion that dry-weight probing is an effective strategy to improve BP control, even when overt clinical signs and symptoms of volume overload are not present. Accelerated arterial stiffness influences the patterns and rhythms of interdialytic ambulatory BP and is a major determinant of isolated systolic hypertension in hemodialysis. Posthoc analyses of the Hypertension in Hemodialysis patients treated with Atenolol or Lisinopril (HDPAL) trial, however, suggest that arterial stiffness does not make hypertension more resistant to therapy and is unable to predict the treatment-induced improvement in left ventricular hypertrophy. A combined strategy of sodium restriction, dry-weight adjustment, and antihypertensive medication use was effective in improving ambulatory BP control regardless of the severity of underlying arteriosclerosis in HDPAL. Other nonvolume-dependent mechanisms, such as erythropoietin use, appear to be also important contributors and should be taken into consideration, particularly in younger hemodialysis patients with diastolic hypertension. In this article, we explore the role of volume overload, arterial stiffness, and erythropoietin use as causes of systolic vs diastolic hypertension in patients on hemodialysis. We conclude with clinical practice recommendations and with a call for a "volume-first" approach when managing hemodialysis hypertension.

Topics: Atenolol; Diastole; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Lisinopril; Male; Renal Dialysis; Risk Assessment; Systole; Vascular Stiffness; Water-Electrolyte Imbalance

Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce hypertension by provoking calcification and augmenting chronic intermittent hypoxia as occurs in sleep apnea. Others show that there may be an antihypertensive effect via kidney repair. Whether these drugs will alter the risk of hypertension compared with EPO remains to be seen.

Topics: Angiotensin II; Animals; Erythropoietin; Hemoglobins; Humans; Hypertension

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

For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria.

Topics: Animals; Erythropoiesis; Erythropoietin; Humans; Hypertension; Renin-Angiotensin System; Vitamin D

There is a well-documented association between erythropoiesis-stimulating agents (ESAs) and hypertension in chronic kidney disease. Studies suggest that the mechanism for this is multifactorial. First, some chronic kidney disease patients may have a limited ability to accommodate a rapid increase in red cell volume because of a decreased glomerular filtration rate, left ventricular hypertrophy, and decreased arterial compliance. Second, there is likely a direct vasoconstrictor effect of ESAs. Although no large randomized controlled trials of ESAs have been designed with blood pressure as an a priori outcome, several meta-analyses have explored this relationship and generally support the existence of ESA-induced hypertension. There are as of yet no data directly linking ESA-induced hypertension with increased cardiovascular morbidity and mortality. Despite this, clinicians should be vigilant for ESA-induced hypertension, use caution when using ESAs in patients with resistant hypertension, and be attentive to the rate of hemoglobin increase in patients with poorly controlled blood pressure.

Topics: Anemia; Blood Pressure; Drug Resistance; Endothelin-1; Erythropoietin; Hematinics; Humans; Hypertension; Nitric Oxide; Recombinant Proteins; Renal Insufficiency, Chronic; Renin-Angiotensin System

Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies.. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD.. We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion.. Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high.. We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses.. In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Polyethylene Glycols; Recombinant Proteins; Renal Insufficiency, Chronic

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Active oncotherapy, combination chemotherapy of lung cancer is accompanied with many side effects which may impair the patient's quality of life and compromise the effectiveness of chemotherapy, the most frequent one of them being chemotherapy-induced anemia. Anemia decreases not only the patient's quality of life, but also worsens the dose-intensity of chemotherapy. One of the potential treatments of chemotherapy-induced anemia is erythropoietin-stimulating agents (ESAs) for the appropriate indications. Several national and international studies have shown that ESA therapy effectively increases hemoglobin level. However, more recently, contradictory results were published on ESA treatment in terms of survival and tumor progression. The reason for this may be that the tumor cells and endothelial cells may as well express erythropoietin receptor, the role of which has not yet been fully elucidated in tumor progression.. Daganatos betegek körében gyakori szövõdmény az anémia, amelyet maga a betegség vagy az onkológiai kezelés okozhat. A tüdõrák kezelése során az aktív kombinált kemoterápia mellett számos, a beteg életminõségét és az onkoterápia sikerességét rontó mellékhatással kell számolni, ezek közül az egyik leggyakoribb a kemoterápia indukálta anémia. A vérszegénység nemcsak a betegek életminõségét rontja, hanem a citotoxikus kezelés dóziscsökkentéséhez, illetve késleltetéséhez vezethet. A kemoterápia indukálta anémia kezelésének egyik lehetséges útja, az eritropoetin-stimuláló szerek (ESA) használata a megfelelõ indikációval. Számos nemzetközi és hazai tanulmány bizonyította, hogy az ESA-kezelés hatékonyan emeli a hemoglobinszintet. Az utóbbi idõben azonban ellentmondásos eredményeket olvashattunk az ESA-kezelésrõl a túlélés és a daganat progressziója tekintetében. Ennek a hátterében az állhat, hogy a tumorsejtek és az endothelsejtek is kifejezhetnek eritropoetinreceptort, amelynek a szerepe még nem teljesen tisztázott a daganatok progressziójában.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Endothelial Cells; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertension; Lung Neoplasms; Quality of Life; Receptors, Erythropoietin; Severity of Illness Index; Venous Thromboembolism

A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

Topics: Adrenal Cortex Hormones; Alcohol Drinking; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Caffeine; Cocaine; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Glycyrrhiza; Gonadal Steroid Hormones; Humans; Hypertension; Immunosuppressive Agents; Vascular Endothelial Growth Factor A

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

Hypoxia of the placenta is integral to complications of pregnancy, including preeclampsia, intrauterine growth restriction, and small-for-gestational age babies. Hypoxia in the placenta is associated with vascular remodeling, hypertension, metabolic changes, oxidative stress, mitochondrial dysfunction, and endoplasmic reticular stress. Hypoxia induces similar outcomes in other organs such as the lungs, kidney, and gut. Comparing and contrasting the effects of hypoxia on placental functions and functions of lung, kidney, and gut can lead to novel hypotheses and investigations, furthering our understanding of the impact of hypoxia on these diverse yet similar organs. In this review, we compare and contrast hypoxic placental responses to those in the other organ and cell systems.

Topics: Adaptation, Physiological; Altitude; Blood Pressure; Erythropoietin; Female; Gastrointestinal Tract; Humans; Hypertension; Hypoxia; Kidney; Lung; Oxidative Stress; Oxygen; Partial Pressure; Placenta; Pregnancy; Pregnancy Complications

Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoiesis stimulating agents (ESAs) and red blood cell transfusions.. To assess the effects of ESAs to either prevent or treat anaemia in cancer patients.. This is an update of a Cochrane review first published in 2004. We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE and other databases. Searches were done for the periods 01/1985 to 12/2001 for the first review, 1/2002 to 04/2005 for the first update and to November 2011 for the current update. We also contacted experts in the field and pharmaceutical companies.. Randomised controlled trials on managing anaemia in cancer patients receiving or not receiving anti-cancer therapy that compared the use of ESAs (plus transfusion if needed).. Several review authors assessed trial quality and extracted data. One review author assessed quality assessment and extracted data, a second review author checked for correctness.. This update of the systematic review includes a total of 91 trials with 20,102 participants. Use of ESAs significantly reduced the relative risk of red blood cell transfusions (risk ratio (RR) 0.65; 95% confidence interval (CI) 0.62 to 0.68, 70 trials, N = 16,093). On average, participants in the ESAs group received one unit of blood less than the control group (mean difference (MD) -0.98; 95% CI -1.17 to -0.78, 19 trials, N = 4,715). Haematological response was observed more often in participants receiving ESAs (RR 3.93; 95% CI 3.10 to 3.71, 31 trials, N = 6,413). There was suggestive evidence that ESAs may improve Quality of Life (QoL). There was strong evidence that ESAs increase mortality during active study period (hazard ratio (HR) 1.17; 95% CI 1.06 to 1.29, 70 trials, N = 15,935) and some evidence that ESAs decrease overall survival (HR 1.05; 95% CI 1.00 to 1.11, 78 trials, N = 19,003). The risk ratio for thromboembolic complications was increased in patients receiving ESAs compared to controls (RR 1.52, 95% CI 1.34 to 1.74; 57 trials, N = 15,498). ESAs may also increase the risk for hypertension (fixed-effect model: RR 1.30; 95% CI 1.08 to 1.56; random-effects model: RR 1.12; 95% CI 0.94 to 1.33, 31 trials, N = 7,228) and thrombocytopenia/haemorrhage (RR 1.21; 95% CI 1.04 to 1.42; 21 trials, N = 4,507). There was insufficient evidence to support an effect of ESA on tumour response (fixed-effect RR 1.02; 95% CI 0.98 to 1.06, 15 trials, N = 5,012).. ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. There is suggestive evidence that ESAs may improve QoL. Whether and how ESAs affects tumour control remains uncertain. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient's clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression. Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth.

Topics: Anemia; Cause of Death; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Thromboembolism

Several drugs can cause hypertension and/or blunt the effect of antihypertensive treatment. They can exacerbate a previously well controlled hypertension and/or render it resistant to therapy. Accordingly, drugs represent a common cause of resistance of hypertension to treatment. Identification of drug-related hypertension can be achieved with a thorough medical history targeted to ascertain concurrent therapies that are prescribed for conditions other than cardiovascular diseases. This can avoid prescribing a more aggressive antihypertensive treatment and may prevent embarking in costly and sometimes invasive diagnostic procedures. Drugs that commonly raise blood pressure include NSAIDs, steroids, oestroprogestinic agents, immunosuppressants, erythropoietin, inhibitors of angiogenesis, anti-HIV agents, and also some high-density lipoprotein-raising agents. As withdrawal of the offending drug is often impracticable, knowledge of the mechanism(s) by which each drug exerts its pressor effects may help selecting the most effective treatment. Purpose of this review is to examine the most common causes of resistant hypertension that are due to drugs or abuse of substances along with their underlying pathophysiological mechanisms. The strategy for selecting the most appropriate treatment and the reasons for 'a call of action' of research in this area are also examined.

Topics: Angiogenesis Inhibitors; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticholesteremic Agents; Antihypertensive Agents; Drug Antagonism; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Glucocorticoids; Humans; Hypertension; Immunosuppressive Agents; Treatment Failure

Erythropoietin (EPO) has shown promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also to promote regeneration after stroke. Here, we report a systematic review and meta-analysis of the efficacy of EPO in animal models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral outcome. Nineteen studies involving 346 animals for infarct size and 425 animals for neurobehavioral outcome met our inclusion criteria. Erythropoietin improved infarct size by 30.0% (95% CI: 21.3 to 38.8) and neurobehavioral outcome by 39.8% (33.7 to 45.9). Studies that randomized to treatment group or that blinded assessment of outcome showed lower efficacy. Erythropoietin was tested in animals with hypertension in no studies reporting infarct size and in 7.5% of the animals reporting neurobehavioral outcome. These findings show efficacy for EPO in experimental stroke, but when the impact of common sources of bias are considered, this efficacy falls, suggesting we may be overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works best would be beneficial.

Topics: Animals; Behavior, Animal; Brain Ischemia; Databases, Factual; Disease Models, Animal; Erythropoietin; Humans; Hypertension; Neuroprotective Agents; Stroke

Topics: Acidosis; Anemia; Bone Diseases, Metabolic; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Diet, Protein-Restricted; Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Kidney Diseases; Male; Nephrology; Renin-Angiotensin System

Anaemia is a frequent complication of cancer. Recently, some concerns have appeared regarding the safety of erythropoiesis-stimulating agents (ESAs) for the treatment of anaemia in cancer patients. The current review will analyse the main arguments in favour of erythropoietin (EPO), as well as those against EPO in chemotherapy-induced anaemia and in cancer-related anaemia. The principal concerns are tumour progression, increased mortality and the risk of venous thromboembolic events (VTEs). Recent meta-analyses have come to divergent conclusions.. Several meta-analyses have reviewed the data regarding VTEs, EPO receptors on tumours and tumour progression as well as mortality.. As of now, ESAs should only be used within the indications as given in the various guidelines.

Topics: Anemia; Disease Progression; Erythropoietin; Hematinics; Humans; Hypertension; Neoplasms; Red-Cell Aplasia, Pure; Risk Assessment; Seizures

This review summarizes the evidence for a hypertensinogenic effect of Erythropoietin (Epo) in normal human subjects and predialysis, hemodialysis, and continuous ambulatory peritoneal dialysis (CAPD) patients. The possible mechanisms of Epo-induced hypertension are examined with in vivo animal and in vitro data, as well as pathophysiological human studies in both normal subjects and CKD patients. The evidence for a hypertensinogenic effect of erythropoiesis-stimulating agents (ESAs) in normal subjects, predialysis CKD, hemodialysis, and CAPD patients is compelling. Epo increases BP directly and notably independently of its erythropoietic effect and its effect on blood rheology. The potential for the development of future agents that might act as specific stimulators of erythropoiesis, devoid of direct hemodynamic side effects is underscored.

Topics: Anemia; Animals; Arteries; Blood Pressure; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Hematinics; Humans; Hypertension; Kidney Diseases; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Risk Assessment

The glycoprotein hormone erythropoietin is an essential viability and frowth factor for the erythrocytic progenitors. EPO signaling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation on intracellular proteins, kinases and transcription factors. Treatment with recombinant human EPO(rHu EPO) is efficient and safe in improving the management of the anemia associated with chronic kidney disease, and allowing avoidance of transfusions with blood products. however, the unanticipated increase in mortality found in recent randomized studies is prompting a reassessment of this view. The present review will show what is known about the physiology of this plasma factor that, it is now clear, is more than just an erythrocyte production factor, and its pleitropic effects influencing the incidence of malignancy, thrombosis, hypertension and retinopathy.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Hypertension

Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.

Topics: Anemia; Animals; Blood Platelets; Blood Pressure; Causality; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Drug Overdose; Endothelin-1; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Morbidity; Nitric Oxide; Oxidative Stress

A variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents either cause sodium retention and extracellular volume expansion or directly or indirectly activate the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, and an increase in pressure may be encountered after their discontinuation. In general, these pressure increases are small and transient; however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and direct to the optimal antihypertensive therapy. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

Topics: Alcohol Drinking; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Antineoplastic Agents; Blood Pressure; Erythropoietin; Ethanol; Gonadal Steroid Hormones; Humans; Hypertension; Immunosuppressive Agents; Metals, Heavy; Nonprescription Drugs; Recombinant Proteins; Risk Factors; Sympathetic Nervous System

Erythropoietin, the primary regulator of erythropoiesis, is produced by the kidney and levels vary inversely with oxygen availability. Hypoxia-inducible factor-1 (HIF-1), a major transcriptional regulator of several hypoxia-sensitive genes, including erythropoietin, is functionally deactivated by oxygen in a reaction catalyzed by prolyl hydroxylase. Erythropoietin acts by binding to a specific trans-membrane dimeric receptor which has been found in erythroid and non-erythroid cell types. The interaction between erythropoietin and its receptor ultimately leads to conformational change and phosphorylation of the receptor and expression of genes coding for proteins that are anti-apoptotic. Development of erythropoietin stimulating agents is an area of active research. To date, research has focused on activating the erythropoietin receptor, prevention of HIF-1 inactivation, and gene therapy. Even with biologically effective therapies, defining appropriate hemoglobin targets remains challenging. For example, despite decades of clinical trials, target hemoglobin levels in chronic kidney disease remain uncertain, as hemoglobin targets above 13 g/dl have been associated with both benefit (quality of life) and harm (cardiovascular events).

Topics: Animals; Erythrocytes; Erythropoietin; Hematinics; Humans; Hypertension; Hypoxia-Inducible Factor 1; Receptors, Erythropoietin

End-stage renal disease is a troublesome health problem worldwide. The most usual renal replacement therapy is conventional haemodialysis (CHD), performed three times a week, 3.5-4 h per session. It has been proposed that this schedule is unphysiologic and that daily haemodialysis would be a more appropriate schedule. One of the variants of daily haemodialysis is the so-called short daily haemodialysis (SDHD), performed five to seven times per week, 1.5-3 h per session. The objective of this paper is to compare, through a systematic review, the clinical effectiveness and safety of SDHD versus CHD.. The following databases were searched: MEDLINE, EMBASE, NHS Centre for Reviews and Dissemination (HTA, DARE and NHS EED), Cochrane, ISI Web of Knowledge, IME and IBECS. Two independent reviewers decided which papers were to be included after applying inclusion and exclusion criteria. Any discrepancy was resolved by consensus. The quality of the included papers was measured using a quality scale developed for the purpose of this report.. Seventeen original articles were included. There were no randomized controlled trials. SDHD seems to be more effective than conventional dialysis. Patients on daily haemodialysis seem to present less vascular access problems, better control of hypertension and in turn a reduction in the antihypertensive treatment, better quality of life, lower incidence of ventricular hypertrophy, lower consumption of rHuEPO due to the better control of anaemia and a reduction in the use of phosphate binders as a consequence of the better control of plasmatic phosphorous.. SDHD might result in a better clinical effectiveness, mainly through a better control of the arterial tension and, therefore, a lower consumption of antihypertensive drugs, and a better quality of life than CHD.

Topics: Anemia; Antihypertensive Agents; Catheters, Indwelling; Erythropoietin; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Nutritional Status; Quality of Life; Recombinant Proteins; Renal Dialysis; Safety; Treatment Outcome

Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks.

Topics: Anemia; Antineoplastic Agents; Bone Marrow Transplantation; Chronic Disease; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Iron; Neoplasms; Practice Guidelines as Topic; Radiotherapy; Thromboembolism

Pregnancy, although rare in the patient with end-stage renal disease, is not uncommon in the transplant recipient. Physicians taking care of transplant recipients must be able to inform patients about the potential risks of pregnancy in this setting. The patient and her partner must know that the risks associated with pregnancy increase with worsening kidney function and hypertension. Current consensus opinion is that pregnancy can be relatively safely undertaken by 1 year after transplant if the patient has had no rejections during the year, allograft function is adequate, there are no infections that could affect the fetus, the patient is not taking teratogenic medications, and immunosuppressive medication dosing is stable. Consideration must be given to immunosuppression during pregnancy both with respect to the specific agents as well as the level of dosing. None of the medications are FDA category A; all are B or higher. Part of planning for pregnancy should include an evaluation of immunosuppression medication and a plan to modify the regimen prior to conception if its use may be risky for the developing fetus. Rejection can occur during a kidney transplant, so maintaining adequate immunosuppression is important. Other issues that need to be managed when caring for a pregnant transplant patient include: potential for infection (urinary tract infections are very common), hypertension, and anemia. The type of delivery, posttransplant contraception, and breast-feeding also need to be addressed.

Topics: Anemia; Counseling; Erythropoietin; Female; Graft Rejection; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Kidney Transplantation; Patient Care Team; Preconception Care; Pregnancy; Pregnancy Complications; Recombinant Proteins; Time Factors

Recent randomized, controlled trials indicate that there is a strong trend for increased risk for death or adverse composite outcomes with erythropoiesis-stimulating agent treatment in kidney disease to hemoglobin targets higher than those currently recommended. The failure of these trials to find a benefit of higher hemoglobin is in stark contrast to findings from large, observational, population-based studies that continue to demonstrate the association of low hemoglobin with adverse outcomes. The mechanisms for the adverse effect of higher hemoglobin targets that are seen in the randomized, controlled trials are poorly understood. This review explores hypotheses involving (1) the effect of achieved hemoglobin itself, (2) the role of erythropoiesis-stimulating agent treatment, (3) the use of iron supplementation, (4) increased blood pressure, and (5) erythropoiesis-stimulating agent hyporesponsiveness. Because the causal pathway has yet to be determined, further research is strongly encouraged. Clinical practice, however, should avoid erythropoiesis-stimulating agent treatment to higher hemoglobin targets, particularly in those with significant cardiovascular morbidity and those who require disproportionately high dosages of erythropoietin-stimulating agents to achieve recommended hemoglobin levels.

Topics: Anemia; Blood Platelets; Erythropoietin; Hemoglobins; Humans; Hypertension; Iron; Renal Dialysis

Anemia is prevalent in patients with chronic kidney disease (CKD) and is a risk factor for poor disease outcome. Anemia acts as a risk multiplier, significantly increasing the risk of death in anemic versus nonanemic CKD patients with similar comorbidities. Erythropoiesis-stimulating agents (ESA) are a mainstay for the treatment of anemia in renal patients on dialysis, but recent data suggests that earlier treatment of anemia in CKD may delay the onset of end-stage renal disease (ESRD) and decrease mortality. Nonetheless, anemia of CKD is under-recognized and undertreated during the period before initiation of dialysis, when anemia correction may have the greatest impact on disease outcome. This report describes anemia in CKD and its association with diabetes, cardiovascular disease, and poor disease outcome, and offers suggestions for the recognition and treatment of anemia of CKD in the primary care setting.

Topics: Algorithms; Anemia; Comorbidity; Diabetic Nephropathies; Disease Progression; Erythropoiesis; Erythropoietin; Ferritins; Humans; Hypertension; Kidney Diseases; Oxidative Stress; Primary Health Care; Quality of Life; Recombinant Proteins; Risk Factors

Hypertension involves the entire cardiovascular system, and hypertensive vascular disease may promote and exacerbate cardiac and renal dysfunction. We discuss the coexistence of cardiorenal disease as a manifestation of vascular involvement in hypertension, and the relationship of biomarkers of renal vascular involvement in hypertension with cardiovascular endpoints.. Markers of renal dysfunction, especially microalbuminuria, have been considered recently as potent predictors of cardiovascular morbidity and mortality in all explored populations, including hypertensive individuals. Microalbuminuria, per se, is related to vascular injury and to the increased glomerular permeability of albumin as a direct manifestation of renal vascular involvement in hypertension, a systemic vascular disease. Left ventricular hypertrophy in hypertension develops even before proteinuria or impairment of renal function. Factors including anemia, inflammation and hyperuricemia are either induced or exacerbated by renal vascular disease, and each of these may exert additional influence in determining the increased incidence of cardiovascular events with progressive renal dysfunction.. The development and progression of vascular disease is the primary determinant in the progressive cardiac and renal dysfunction observed in hypertension and, therefore, is the underlying mechanism of the overall clinical manifestations of cardiorenal disease. Commonly used biomarkers of renal and vascular function are important tools for determination of the progression and, hence, management of hypertensive disease and its complications.

Topics: Albuminuria; Biomarkers; C-Reactive Protein; Disease Progression; Erythropoietin; Glomerular Filtration Rate; Humans; Hypertension; Hyperuricemia; Natriuretic Peptide, Brain; Renal Insufficiency; Uric Acid

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

Topics: Antihypertensive Agents; Blood Volume; Diagnosis, Differential; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Renin-Angiotensin System; Risk Factors; Vascular Resistance

The rising incidence of type 2 diabetes mellitus and of its complications will make it the most important health care challenge in the first quarter of the 21st Century. Diabetic nephropathy left unchecked will overwhelm the renal resources. Simple methods (proper diet and exercise, prevention of obesity) are successful in preventing type 2 diabetes in the great majority of the persons at risk. In patients with established type 2 diabetes, nephropathy can be prevented or greatly delayed by strict metabolic control, strict control of blood pressure using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the first line of drugs, tight control of serum lipids using statins as indicated, low protein diet, avoidance of smoking and other nephrotoxic influences, prevention of abnormalities in calcium/phosphorus metabolism, and prevention of renal anemia by the early use of erythropoietin. Current research offers the promise of definitive prevention of both type 2 diabetes and diabetic nephropathy.

Topics: Albuminuria; Anemia; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Erythropoietin; Glomerular Filtration Rate; Humans; Hypertension; Mitochondria

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Contraceptives, Oral, Hormonal; Cyclosporins; Erythropoietin; Glycyrrhizic Acid; Humans; Hypertension; Immunosuppressive Agents; Mineralocorticoids; Recombinant Proteins

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Circulation; Renal Dialysis; Renin-Angiotensin System; Sleep Apnea Syndromes; Sympathetic Nervous System; Vascular Resistance

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see ). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration

Topics: Anemia; Bone Marrow Transplantation; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Neoplasms; Quality of Life; Survival Analysis; Thromboembolism

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Growth Hormone; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Models, Molecular; Receptor, Angiotensin, Type 1; Tetrazoles; Thiophenes; Thromboxane A2

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

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

Topics: Anemia; Cardiovascular System; Cell Division; Chromogranins; Endothelium, Vascular; Erythropoietin; GTP-Binding Protein alpha Subunits, Gs; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nerve Tissue Proteins; Platelet Activation; Receptors, Erythropoietin; Recombinant Proteins; Thrombosis

Chronic kidney disease (CKD) affects over 6.2 million people in the U.S. and most commonly results from diabetes and/or hypertension. Patients with CKD have an increased risk of anemia and hypertension. Anemia occurs early in CKD and can be effectively treated with epoetin alfa. Hypertension can be managed with lifestyle modifications and medications. Nurses play a vital role in managing these patients by providing early CKD/anemia screening and intervention, education, patient monitoring, and support for patients and caregivers.

Topics: Algorithms; Anemia; Decision Trees; Diabetes Complications; Erythropoietin; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Life Style; Mass Screening; Nurse's Role; Quality Assurance, Health Care; Risk Factors; Severity of Illness Index; United States

Topics: Aged; Anemia; Chronic Kidney Disease-Mineral and Bone Disorder; Clinical Trials as Topic; Disease Progression; Electrolytes; Epidemiologic Methods; Erythropoietin; Hemodialysis Solutions; Humans; Hypertension; Kidney Failure, Chronic; Male; Models, Biological; Nutrition Disorders; Quality of Life; Renal Dialysis; Toxins, Biological; Uremia

Topics: Combined Modality Therapy; Comorbidity; Diet, Protein-Restricted; Diet, Sodium-Restricted; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Kidney Function Tests; Prognosis; Renal Dialysis; Vasculitis; Water-Electrolyte Balance

Topics: Anemia; Appointments and Schedules; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Kinetics; Models, Biological; Molecular Weight; Patient Acceptance of Health Care; Quality of Life; Renal Dialysis; Survival Analysis; Time Factors; Treatment Outcome; Urea

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

Although recombinant erythropoietin has no short-acting pressor effect in vivo, its long-term administration frequently raises arterial pressure in humans and animals, with renal insufficiency. Contrary to the original view, erythropoietin-induced hypertension is not due to amelioration of anemia, because a similar rise in blood pressure occurs, despite persistent anemia, in erythropoietin-treated iron-deficient animals and humans. Moreover, multiple small blood transfusions administered to simulate the action of erythropoietin fail to increase blood pressure. Finally, iron repletion in severely anemic iron-deficient patients maintained on constant erythropoietin dosages does not raise blood pressure, despite a dramatic increase in hematocrit. Thus, chronic erythropoietin administration results in a hematocrit-independent, vasoconstriction-dependent hypertension that is marked by, and largely due to, elevated resting and agonist-stimulated cytoplasmic calcium concentration, leading to resistance to the vasodilatory action of nitric oxide. In addition, increased endothelin production, upregulation of tissue (but not circulating) renin and angiotensinogen expression, and a possible change in vascular tissue prostaglandin production have been variably demonstrated with erythropoietin administration in humans, intact animals and cultured endothelial cells. Erythropoietin has been shown to promote angiogenesis and stimulate endothelial and vascular smooth muscle cell proliferation. Finally, partial correction of anemia with erythropoietin therapy may partly prevent or reverse left ventricular hypertrophy in dialysis-dependent and dialysis-independent patients with chronic renal insufficiency. However, data on the risks and benefits of complete correction of anemia in this population are limited and inconclusive, and await future investigation.

Topics: Anemia; Animals; Cardiovascular System; Erythropoietin; Humans; Hypertension; Recombinant Proteins

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

Erythropoietin (EPO) has revolutionized the treatment of anemia in renal failure patients, both in the pre- and postdialysis phase. Not only does the treatment improve well being, but also it positively influences cardiac function and permits cardiac hypertrophy to regress. EPO can lead to an increase in blood pressure; the mechanisms of this effect are not entirely clear. By optimizing dialysis treatment, paying close attention to volume regulation, giving EPO subcutaneously and in a fashion to increase hematocrit gradually, the occurrence of blood pressure increases can be minimized. Hypertension has not proved to be a serious general problem in the EPO treated patient.

Topics: Anemia; Animals; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

Since its introduction for clinical use a decade ago, recombinant human erythropoietin (rHuEPO) has revolutionized the management of the anemia of end-stage renal disease. Soon after its release, it became evident that the biological targets of rHuEPO were not limited to the erythroid progenitor cells. Instead, numerous clinical and laboratory studies have shown the modulatory action of rHuEPO on a wide array of cell types and organ systems. The present article is intended to provide an overview of the modulatory actions of rHuEPO on the production and action of vasoregulatory factors and its direct and indirect effects on vascular function and structure.

Topics: Anemia, Iron-Deficiency; Animals; Endothelium, Vascular; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Recombinant Proteins; Renin-Angiotensin System; Risk Assessment; Sensitivity and Specificity; Vasoconstriction

Topics: Erythropoietin; Humans; Hypertension; Polycythemia; Polycythemia Vera

Topics: Erythropoietin; Humans; Hypertension

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

Dialysis was first described and used in 1854 to separate substances in aqueous solution based on different rates of diffusion through a semipermeable membrane. In vivo hemodialysis was performed in animals early in the twentieth century. Hemodialysis was first carried out in patients with acute renal failure in The Netherlands during the Second World War and in the United States in 1948. Repetitive hemodialysis for the treatment of chronic renal failure due to end-stage renal disease had to await the development of an acceptable long-lasting vascular access in 1960. The subsequent successful development of a technique to create an adequate arteriovenous fistula in 1972 permitted the rapid growth of dialysis programs, when the cost of this therapy was largely paid for by Medicare. Equipment has been developed to foster home-care hemodialysis and chronic ambulatory peritoneal dialysis. Enhancements in renal replacement therapy included the availability of recombinant human erythropoietin, calcitriol, and effective antihypertensive drugs. Technical advances in hemodialysis followed the use of bicarbonate dialysate, more biocompatible membranes, membranes of higher porosity, and ultrafiltration. Questions remain regarding the evaluation of the adequacy of dialysis which is to be achieved or prescribed. Careful attention to the management of the patient with progressive chronic renal insufficiency is crucial in dealing with the inevitable onset of uremia and the initiation of dialysis and/or renal transplantation. The cost of renal replacement therefore represents a great societal burden. A better understanding of how to prevent onset and progression of specific nephropathies along with the availability of new and more effective equipment for renal replacement therapy has a high priority.

Topics: Calcitriol; Calcium Channel Agonists; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy; United States

Chronic administration of erythropoietin (EPO) is associated with an increase in arterial blood pressure in patients and animals with chronic renal failure (CRF). Several mechanisms have been considered in the pathogenesis of EPO-induced hypertension. These include the possible role of the rise of hematocrit and erythrocyte mass, changes in production or sensitivity to endogenous vasopressors, alterations in vascular smooth-muscle ionic milieu, dysregulation of production or responsiveness to endogenous vasodilatory factors, a direct vasopressor action of EPO, and finally arterial remodeling through stimulation of vascular cell growth.

Topics: Anemia; Animals; Catecholamines; Endothelins; Erythrocyte Volume; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Renin-Angiotensin System; Time Factors; Vasoconstrictor Agents

The heart and the kidney exert a reciprocal control of their function in order to maintain a steady state of haemodynamics, both in physiological and pathological conditions. The functional relationship between the two organs becomes particularly evident during heart failure. The knowledge of such relationship may play an important role in the management of heart failure. We also report here our experience in the treatment of congestive heart failure with depletive techniques vicarious of kidney function.

Topics: Blood Pressure; Erythropoietin; Heart Failure; Humans; Hypertension; Kidney Diseases; Natriuretic Agents

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

Hypertension is one of the adverse effects associated with recombinant human erythropoietin (rHuEPO) therapy for anaemia in hemodialysed patients. The incidence of hypertension is reported to be 10-15%. The exact mechanism of rHuEPO-induced hypertension has not been fully elucidated, although in this paper several theories have been presented.

Topics: Anemia; Erythropoietin; Humans; Hypertension; Recombinant Proteins

Topics: Blood Pressure; Blood Volume; Cell Size; Controlled Clinical Trials as Topic; Erythrocyte Count; Erythrocytes; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Multicenter Studies as Topic; Renin-Angiotensin System; Vascular Resistance

Topics: Anemia; Blood Pressure; Clinical Trials as Topic; Erythropoietin; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Monitoring, Physiologic; Multicenter Studies as Topic; Recombinant Proteins; Renal Dialysis; Risk Factors; Vascular Resistance

Topics: Acquired Immunodeficiency Syndrome; Autoimmune Diseases; Erythropoietin; Humans; Hypertension; Neoplasms

Topics: Erythropoietin; Humans; Hypertension; Recombinant Proteins; Renal Dialysis

Erythropoietin, a glycoprotein, is synthesized mainly in the kidney. With the destruction of renal tissue, erythropoietin production decreases; this is a major factor in the development of anemia in patients with renal failure. For about ten years now, recombinant human erythropoietin has been available for the treatment of renal anemia. All patients with renal insufficiency, independent of their plan for future renal replacement therapy, may benefit from erythropoietin. At what extent of anemia erythropoietin therapy should be started is still discussed and is certainly dependent on the degree of the patient's impairment by his anemia. Before beginning a therapy with erythropoietin, other forms of anemia observed in patients with renal failure, i.e. mainly iron deficiency, have to be excluded. A strict monitoring of hematocrit during treatment with erythropoietin is mandatory. Hypertension, seizures and cardiovascular complications have been observed with overdosing of erythropoietin. Special emphasis of this review is therefore put on the discussion of the dynamics of the erythropoietin-red cell system.

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Systemic hypertension has been reported to develop, or to worsen, in 20-30% of patients treated with recombinant human erythropoietin (r-HuEPO) worldwide. The greatest increases in blood pressure affect day-time systolic and night-time diastolic blood pressure. Hypertension may develop in some patients as early as 2 weeks and in others as late as 4 months after the start of r-HuEPO treatment. In haemodialysis patients with systemic hypotension, r-HuEPO usually induces a 10% increase in blood pressure, with no significant change in the frequency of hypotensive episodes. Several risk factors for the development, or worsening, of hypertension after r-HuEPO therapy have been identified. They include the presence of pre-existing hypertension, rapid increase in haematocrit, a low baseline haematocrit before r-HuEPO administration, high doses and i.v. route of administration, the presence of native kidneys, a genetic predisposition to hypertension, and possibly a younger age. There are several potential mechanisms by which r-HuEPO therapy may increase blood pressure in haemodialysis patients. They include increased blood viscosity; the loss of hypoxic vasodilation; the activation of neurohumoral systems (catecholamines, the renin-angiotensin system); and especially a direct vascular effect. This last mechanism is supported by several data, and many factors may be involved in its pathogenesis (an increased cell calcium uptake; an imbalance in local vasoactive agents, with increased synthesis of ET-1; a mitogenic effect; and a platelet-dependent mechanism).

Topics: Blood Viscosity; Calcium; Erythropoietin; Humans; Hypertension; Recombinant Proteins; Vasodilation

The induction or the aggravation of a hypertension is a side effect of recombinant human erythropoietin therapy in 30% of dialysed patients. Clinical manifestations can be severe. Pathogenesis of erythropoietin-induced hypertension is ill known. Peripheral vascular changes were found in most studies. Recently, it was demonstrated that erythropoietin increased endothelin-1 release by endothelial cells. Ambulatory blood pressure recording seems to be the best method for evaluating the modification of blood pressure profile during the interdialytic period. Erythropoietin-induced hypertension is easily controlled by drugs, but also by low dose of erythropoietin. Subcutaneous administration of erythropoietin is an approach to avoid the induction of hypertension. Furthermore economical advantages of subcutaneous administration are proven.

Topics: Anemia; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

Erythropoietin (Epo) is a glycoprotein hormone responsible for the control of the proliferation and differentiation of cells of erythroid lineage. Recombinant erythropoietin (rHuEpo) is widely used as a pharmacological agent for the treatment of the anaemia of renal failure. Efficacy of rHuEpo and its superiority over blood transfusions have been proven in large multicentre trials. The most important side-effect of the therapy is the increase of BP which is observed in approximately 30-35% of dialysis patients receiving rHuEpo. It appears that the haemodynamic resetting that occurs with partial correction of anaemia may be inappropriate resulting in an altered vascular resistance in relation to the cardiac output. This is in turn due to the combination of increased blood viscosity and loss of hypoxic vasodilatation. Both these factors, however, cannot account completely for the rise in vascular resistance, and therefore the possibility of a direct and/or hormonally-mediated vasopressor effect of rHuEpo has recently been raised. Moreover, scarce information exists on the possible involvement of endogenous erythropoietin in the pathogenesis of arterial hypertension and haematological disturbances observed in primary and some secondary forms of hypertension.

Topics: Blood Viscosity; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Hypertension; Renal Insufficiency

The purpose of this article is to review and summarize the literature regarding the effects of medications and other substances on blood pressure. Many substances are known to cause or exacerbate hypertension, including sodium chloride, substances of abuse, nonprescription sympathomimetics, nonsteroidal anti-inflammatory drugs, sex steroids, immunosuppressive therapies, erythopoietin, antidepressants, ergot alkaloids, anesthetic agents, and other substances. With the population aging, the increasing incidence of polypharmacy, and the growth of over-the-counter pharmacological agents, including those which were previously available only by prescription, drug-induced hypertension is assuming heightened importance. Furthermore, these agents represent an important modifiable cause of secondary hypertension, and it is imperative that clinicians recognize this causal relationship.

Topics: Adrenergic Agents; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Antihypertensive Agents; Ergot Alkaloids; Erythropoietin; Gonadal Steroid Hormones; Humans; Hypertension; Immunosuppressive Agents; Lead; Sodium Chloride; Substance-Related Disorders

Topics: Anemia; Erythropoietin; Hemodynamics; Humans; Hypertension; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Physical Fitness; Quality of Life; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Erythropoietin; Humans; Hypertension; Recombinant Proteins; Uremia

Recombinant human erythropoietin (r-HuEPO) effectively corrects the anemia of end stage renal disease (ESRD). Development or aggravation of hypertension has been the most commonly reported side-effect of r-HuEPO treatment. Placebo controlled trials have shown incidence rates ranging from 16-21%. Renal failure itself obviously is a prerequisite in the pathogenesis of r-HuEPO-induced hypertension, since it was never observed in anemic patients without renal disease. Increased whole blood viscosity and/or reduced hypoxic vasodilatation due to the rise in hematocrit may play a role in the development of hypertension at high concentrations of hematocrit. However, at hematocrit levels around 30% additional hypertensinogenic effects of r-HuEPO treatment seem likely. Endothelin and prostanoids are possible mediators of this effect. Left ventricular hypertrophy (concentric and eccentric), which can be due to hypertension and anemia, is commonly observed in ESRD patients and has been shown to be a predictor of cardiac morbidity and mortality in these patients. Following correction of anemia with r-HuEPO measures of left ventricular hypertrophy decrease by about 18% within a year. Normalization, though, is generally not achieved and in patients with r-HuEPO induced hypertension the increase of blood pressure may oppose the beneficial effects of r-HuEPO treatment on cardiac hypertrophy.

Topics: Anemia; Animals; Erythropoietin; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Knowledge continues to grow on the biology of endogenous erythropoietin (EPO), its effects on red blood cell physiology, and the use of the recombinant form of the hormone. In addition to oxygen delivery, oxygen consumption may be important in stimulating EPO production. This production is likely mediated by an intracellular messenger system other than cAMP. Once released, EPO prevents programmed cell death of BFU-E and CFU-E cells. Recent evidence suggests that lack of EPO, rather than the presence of EPO inhibitors, is the cause of the anemia seen in renal patients. Recombinant EPO has been available clinically since mid 1989. Nearly two thirds of dialysis patients are receiving this agent, although low doses are the rule, with the average hematocrit achieved of only 31%. EPO dosing has been subjected to kinetic modeling that has revealed a wide range in RBC half-life from patient to patient. This accounts in part for the varying maintenance dosing requirements. An additional modulating factor in the response to EPO is severe, secondary hyperparathyroidism with bone marrow fibrosis which may be reversible with medical or surgical parathyroidectomy. Hypertension continues to occur in 20-35% of patients given EPO. This effect may be mediated by endothelin which appears to be stimulated by EPO administration. Treatment of the anemia of renal failure leads to many organ system benefits including improved muscle metabolism, decreased left ventricular hypertrophy, enhanced immune responses to hepatitis vaccine, and improved brain electrophysiology. he optimal target hematocrit to achieve the greatest benefits for the patient at an acceptable cost remains to be determined.

Topics: Adult; Aged; Anemia; Child; Erythropoiesis; Erythropoietin; Female; Hematocrit; HIV Infections; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Pregnancy; Pregnancy Complications; Recombinant Proteins; Renal Dialysis

Anemia is one of the major limitations to rehabilitation in patients with end-stage renal disease (ESRD). The efficacy of recombinant human erythropoietin (rHuEPO) in the treatment of renal anemia is well established. Nevertheless, rHuEPO therapy has been associated with serious untoward effects. There appears to be an increased risk of hypertension, not infrequently accompanied by hypertensive encephalopathy and seizures. The mechanism of hypertension remains uncertain. It is associated with an increase in blood viscosity, a reversal of hypoxic vasodilatation, and possibly, a direct pressor effect of the hormone. Seizures, otherwise, may be the result of cerebral hypoperfusion and, finally, of a focal cerebral edema. The guidelines for rHuEPO treatment and prevention of associated convulsions are outlined. The possible convulsive risk induced by this treatment, even at low doses, particularly in patients with a previous history of seizures, is stressed.

Topics: Anemia; Erythropoietin; Humans; Hypertension; Recombinant Proteins; Renal Dialysis; Seizures

Topics: Anemia; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Quality of Life; Renal Dialysis; Seizures; Thrombosis

Fifty-five hemodialysis patients (pts) received rHuEpo for 3-5 years (51 +/- 11 months, hematocrit 32.5 +/- 3.7). BP medication was required in 42% of pts prior to rHuEpo (Hct 20.8 +/- 3.5) and 69% (38 patients) now require such therapy. BP was controlled with single therapy in 16 pts and only 8 required 3 or more different BP drugs. Vascular access clotting episodes were rare in pts with autologous fistula (17 of 24 pts had no clotting), whereas access clotting episodes were 10 times more common in pts with AV grafts, yet 20% had no clotting after 3-5 years of rHuEpo. Heart size decreased in most who initially had cardiomegaly. Cardiovascular related and other deaths were decreased in this selected group when compared to other dialysis pts matched for age, race and type of renal disease.

Topics: Anemia; Blood Coagulation; Cardiovascular System; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Seizures; Time Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Carbenoxolone; Cyclosporins; Erythropoietin; Glucocorticoids; Glycyrrhiza; Humans; Hypertension; Plants, Medicinal

Increased blood pressure (BP) has been the most commonly reported side effect in trials of treatment of the anemia of chronic renal failure with recombinant human erythropoietin (rHuEPO). An increase in BP develops in one third of patients, in most cases necessitating initiation or increase of antihypertensive therapy. Elevated BP is not related to dose of rHuEPO, nor to the final hematocrit level achieved or the rate of increase of hematocrit. Increases in BP arise particularly during the first 4 months of therapy, and BP usually stabilizes thereafter. rHuEPO therapy does not appear to affect BP in patients with normal renal function. The mechanism of hypertension related to rHuEPO remains uncertain. An increase in systemic vascular resistance occurs in all patients, whether or not BP increases. This is due largely to increased blood viscosity and reversal of hypoxic vasodilatation, but other factors may also contribute. A lack of adequate reduction in cardiac output distinguishes patients in whom BP increases, and this in turn may be due to abnormal cardiovascular autoregulation in these patients. Acute elevation in BP during rHuEPO therapy occasionally results in hypertensive encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit, but is associated with a rapid increase in BP, and may occur in previously normotensive patients. Hypertension developing during rHuEPO therapy should be controlled by conventional antihypertensive therapy. If hypertension persists, the rHuEPO dose should be reduced or therapy temporarily discontinued. Frequent BP monitoring during the first 4 months of treatment is mandatory.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia; Blood Pressure; Brain Diseases; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

The analysis of the hemodynamics accompanying correction of renal anemia by rhEPO shows that--although they behave qualitatively as in nonuremic anemic patients--cardiac output and peripheral resistance may change inadequately and thereby cause a rise of blood pressure. The underlying mechanisms are not yet fully understood but to a great part may be related to preexisting pathology due to a history of longlasting hypertension. In some patients the development of hypertension may only represent a temporary phenomenon of hemodynamic dysregulation. To avoid cardiovascular complications 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 of developing hypertension during therapy with rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. In case of the development or aggravation of hypertension a reduction of the target hematocrit is indicated.

Topics: Anemia; Cardiac Output; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Vascular Resistance

The treatment of renal anaemia by recombinant human erythropoietin (EPO) is now well established. Several studies have examined the pharmacokinetics and efficacy of the drug given intravenously, intraperitoneally and subcutaneously and there is increasing evidence that the subcutaneous route has several advantages including the requirement for a lower dose. It is also important to stress the need for careful determination of baseline iron status of all patients before commencing EPO therapy. In the long term the extremely high iron stores of transfusion dependent patients will disappear. In the short term, however, the majority of the patients whose serum ferritin is less than 100 micrograms/l will require iron supplementation to allow an appropriate haemoglobin response. Alternatively, a fall in transferrin saturation to less than 20% is certainly an indication for iron supplementation and if oral iron therapy is not adequate then intravenous preparations may have to be considered. Although the anaemia of renal failure can be fully corrected by EPO, partial correction may be sufficient to reverse the problems of reduced exercise capacity, myocardial ischaemia and cardiomegaly which are frequently associated with end-stage renal disease. Partial correction will also result in a lesser rise in whole blood viscosity and, in turn, possibly reduce hypertension, thrombosis and increased peripheral resistance and thus lessen the side effects of EPO therapy.

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Thrombosis

Topics: Anemia; Anemia, Hypochromic; Animals; Drug Hypersensitivity; Erythropoietin; Humans; Hyperkalemia; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Phosphates; Recombinant Proteins; Renal Dialysis; Seizures; Thrombosis; Uremia

Topics: Adult; Aged; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Seizures

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Erythropoietin; Humans; Hypertension; Inflammation; Iron; Kidney Failure, Chronic; Recombinant Proteins; Vascular Resistance

Topics: Anemia; Blood Viscosity; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Onset or exacerbation of hypertension has been observed as a possible complication of recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) therapy for the anemia of end-stage renal disease. This effect is attributed to an overly rapid rise in the hematocrit level and the accompanying consequences, which include increased hemoglobin, blood viscosity, and red cell mass, as well as normalization of the cardiac index of anemia. The sluggish response to these changes by compensatory mechanisms, resulting in increased peripheral vascular resistance, may be the means by which BP becomes elevated during therapy. Although more than one third of patients receiving r-HuEPO therapy have developed sustained increases in diastolic pressure of 10 mmHg or more, this potential problem is controllable. Prevention or correction of hypertension is accomplished by initiating therapy with a low-dose regimen that is slowly increased, thereby preventing a rapid rise in the hematocrit level. Drug intervention, together with dialysis prescription modification and restriction of dietary salt and fluid to regulate weight, can effectively control BP. Discontinuation of therapy for severe and uncontrollable hypertension rarely becomes necessary.

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

Topics: Combined Modality Therapy; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Renal Dialysis

The available data from experimental and clinical studies suggest that in the development of hypertension following correction of renal anemia under rhEPO three mechanisms are operative: (1) an increase in whole blood viscosity; (2) possible also a reduction of hypoxic vasodilatation, and (3) at least in some patients an inadequate reduction of cardiac output. To avoid cardiovascular complications under rhEPO therapy, the following should be considered: Patients that were hypertensive before the start of renal replacement therapy, even if they were normotensive in the anemic state - because of morphological alterations of their peripheral vascular bed-may run a higher risk for developing hypertension under rhEPO. As patients with undetected volume contraction may be more endangered by cardiovascular complications, the hematocrit should be monitored before and after dialysis, especially in patients with high weight gain and in children. Patients who are hypertensive under rhEPO therapy should be treated by antihypertensive drugs as appropriate. Drugs of the first choice are beta-blockers and vasodilating agents. Volume removal should not be the sole measure for blood pressure control and should be applied carefully. To avoid hypertensive and rheological complications, the target hematocrit should not exceed 30 vol%.

Topics: Anemia; Blood Viscosity; Cardiac Output; Erythropoietin; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis; Vasodilation

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

Recombinant human erythropoietin (rhEpo) has been demonstrated in several studies to be effective in correcting the anemia of regular dialysis patients. This was accompanied by a significant improvement of the physical work capacity shown by exercise testing. The main side effect of rhEpo treatment has been the development or aggravation of hypertension in approximately 30% of the treated patients. In 2% hypertensive encephalopathy and convulsions occurred. Data obtained by measurements of regional blood flow indicate the peripheral resistance did increase probably due to rise of blood viscosity and reversal of preexisting hypoxic vasodilatation. To avoid hypertensive complications anemia should be corrected slowly over a period of 12-16 weeks. Target hematocrit should not exceed 30-35 vol. %. Blood pressure and volume status should be monitored closely.

Topics: Anemia; Erythropoietin; Humans; Hypertension; Recombinant Proteins; Renal Dialysis

Recombinant human erythropoietin raises serum erythropoietin concentrations to adequate levels and restores the hematocrit to normal values in the vast majority of anemic, end stage renal disease patients undergoing regular hemodialysis. It can eliminate the need for transfusions and thus the risk of immunologic sensitization, infection and iron overload. Erythropoietin not only alters laboratory findings but improves the well being and performance of patients on hemodialysis as well. Side effects are minimal and neither antibodies nor resistance to the recombinant hormone have been observed so far. Along with the rise in hematocrit and blood viscosity some patients developed increased blood pressure and a few hypertensive encephalopathy, but after brief interruption of therapy erythropoietin treatment could be continued in combination with antihypertensive drugs. The pathophysiology of the increase in blood pressure, the risk of encephalopathy and the possibly somewhat higher risk of thrombosis remain to be elucidated. Nevertheless, the first recombinant hematopoietic hormone has passed its first clinical trials with success.

Topics: Anemia; Antihypertensive Agents; Blood Transfusion; Blood Viscosity; Clinical Trials as Topic; Drug Evaluation; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

Topics: Animals; Aspirin; Blood Coagulation; Blood Platelets; Blood Preservation; Blood Transfusion; Chromium Radioisotopes; Cyclic AMP; Dimethyl Sulfoxide; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Hemolysis; Humans; Hypertension; Kidney; Osmotic Fragility; Platelet Adhesiveness; Prostaglandins; Receptors, Cell Surface; Shock

Topics: Aldosterone; Erythropoiesis; Erythropoietin; Humans; Hypertension; Juxtaglomerular Apparatus; Kidney; Renin; Vitamin D

Topics: Adrenal Glands; Aldosterone; Anemia; Biopsy, Needle; Cholinesterases; Erythropoietin; Fibrin; Graft Rejection; Humans; Hyperparathyroidism; Hypertension; Juxtaglomerular Apparatus; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Proteinuria; Radioisotope Renography; Renin; Transplantation, Homologous; Ultrasonography

Topics: Animals; Central Nervous System Diseases; Erythropoiesis; Erythropoietin; Female; Genes, Regulator; Genital Diseases, Female; Hemodynamics; Humans; Hypertension; Hypoxia; Kidney; Kidney Diseases; Liver Diseases; Male; Polycythemia; Polycythemia Vera; Rats

To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo.. We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs.. ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.

Topics: Acute Kidney Injury; Albuminuria; Double-Blind Method; Erythropoietin; Female; Gestational Age; Glomerular Filtration Rate; Humans; Hypertension; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Male; Recombinant Proteins; Renal Insufficiency, Chronic

Im Rahmen der vorliegenden Studie sollte der Einfluss des Weichteilschadens auf das klinische Ergebnis nach offener Ellenbogenluxation untersucht werden.. Von Oktober 2008 bis August 2015 wurden insgesamt 230 Patienten mit Ellenbogenluxation behandelt. Diese retrospektive Studie umfasst 21 Fälle von offenen Ellenbogenluxationen. Das Durchschnittsalter der Patienten betrug 49 Jahre alt (20–83 Jahre), 6 Patienten waren weiblich (29%), 15 männlich (71%). Das Bewegungsausmaß des verletzten und unverletzten Ellenbogens wurde erhoben und das funktionelle Ergebnis u. a. mittels Mayo Elbow Performance Score (MEPS), Mayo Wrist Score (MWS) und dem Disability of Arm, Shoulder and Hand (DASH) Score erfasst. Zusätzlich wurden Komplikationen und Revisionsoperationen aufgezeichnet. Der Einfluss des Weichteilschadens (I°/II° offen vs. III° offen) und des Luxationstyps (einfach vs. komplex) auf das klinische Ergebnis wurde analysiert.. Offene Ellenbogenluxationen können mit einem zufriedenstellenden klinischen Ergebnis einhergehen. Insbesondere komplexe offene Ellenbogenluxationen sind jedoch sehr komplikationsbehaftet, wobei neurovaskuläre Komplikationen am häufigsten auftreten.. The current high rate of multidrug-resistant gram-negative bacteria infections among hospitalised patients with cUTIs in the studied area is alarming. Our predictive model could be useful to avoid inappropriate antibiotic treatment and implement antibiotic stewardship policies that enhance the use of carbapenem-sparing regimens in patients at low risk of multidrug-resistance.. The results indicated differential patterns of Inhibition of Return between the High and Low shape/weight based self-worth groups. The High group displayed increased inhibition of return for the shape/weight stimuli relative to control stimuli, while the Low group displayed reduced inhibition of return for the shape/weight stimuli compared to control stimuli. The ED group displayed a similar pattern of results to the High group, but this did not reach significance.. The current findings indicate that young women without an eating disorder who base their self-worth on shape/weight display a pattern of avoidance of shape/weight stimuli that is in direct contrast to those at low risk of developing eating disorders. The possible implications of these specific patterns of inhibition of return across those at varying levels of risk for an eating disorder are discussed along with their implications for intervention approaches.. These results indicated that Sr. An unusually high HbA

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Vaginal Creams, Foams, and Jellies; Venezuela; Vitamin K 2; Waist Circumference; Waste Disposal, Fluid; Wastewater; Water Microbiology; Water Pollutants, Chemical; Whole Body Imaging; X-Ray Diffraction; Young Adult; Ytterbium; Yttrium; Yttrium Radioisotopes; Zinc Compounds

Blockade of the renin-angiotensin-aldosterone system exhibits a renoprotective effect; however, blockade of this system may also decrease hemoglobin (Hb) and erythropoietin (EPO) levels. We evaluated the correlation between reduced albuminuria and decreased hemoglobin concentrations after treatment with an angiotensin II receptor blocker (ARB). Two hundred forty-five non-diabetic hypertensive participants with established albuminuria and relatively preserved renal function were treated with an ARB (40 mg/day olmesartan) for eight weeks. Subsequent changes in various clinical parameters, including Hb, EPO, and albuminuria, were analyzed following treatment. After the 8-week treatment with an ARB, Hb and EPO levels significantly decreased. Patients with a greater decrease in Hb exhibited a greater reduction in 24-hour urinary albumin excretion compared with patients with less of a decrease or no decrease in Hb, whereas no associations with a decline in renal function and EPO levels were noted. Multivariate logistic regression analysis demonstrated a correlation between the reduction of urine albumin excretion and the decrease in Hb levels (after natural logarithm transformation, adjusted odds ratio 1.76, 95% confidence interval 1.21-2.56, P = 0.003). Linear regression analysis also supported this positive correlation (Pearson correlation analysis; R = 0.24, P < 0.001). Decreased Hb concentrations following ARB treatment were positively correlated with reduced albuminuria in non-diabetic hypertensive patients, regardless of decreased blood pressure and EPO levels or renal function decline.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Case-Control Studies; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Olmesartan Medoxomil; Receptors, Angiotensin; Renin-Angiotensin System; Treatment Outcome

Renin-angiotensin system (RAS) inhibition has proven to be helpful in reducing cardiovascular and kidney disease progression in the general population; whether kidney transplant patients would derive similar benefits is unknown. RAS inhibition also reduces posttransplantation erythrocytosis in kidney transplant recipients, but its effect on hemoglobin (Hb) levels in patients without posttransplantation erythrocytosis is unclear.. The Specific Management of Anemia and Hypertension in Renal Transplant (SMAhRT) recipients study was designed to examine the cardiovascular benefits of RAS blockade with telmisartan 80 mg versus placebo, and Hb management with darbepoetin α in a randomized, double-blind, single-center controlled trial in 2,000 patients over 3 years. The primary efficacy variable was a composite of all-cause mortality, myocardial infarction or stroke.. The SMAhRT study was stopped prematurely due to a lower than expected event rate. At that point, 136 patients were enrolled and were followed for a mean duration of 15 months. The use of RAS blockade was not associated with an increased risk of adverse events such as worsening anemia or hyperkalemia. Likewise, the correction of Hb with darbepoetin was not associated with any increase in thrombotic events.. This study provides insight into the safety of RAS inhibition and Hb correction with an erythrocyte-stimulating agent in kidney transplant recipients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Benzimidazoles; Benzoates; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Renin-Angiotensin System; Stroke; Telmisartan; Treatment Outcome; Young Adult

To compare effects of valsartan and benazepril on erythropoietin (EPO) levels in essential hypertensive patients with normal renal function.. Sixty essential hypertensive patients were randomly divided into valsartan group (n=30, valsartan 80 mg/day) and benazepril group (n=30, benazepril 10 mg/day). Plasma EPO and hemoglobin (Hb) levels were measured at the start of and at 4 and 8 weeks during the treatments.. EPO and Hb levels were all in normal range in the two groups. Valsartan decreased EPO levels from 14.179∓3.214 U/L (baseline) to 12.138∓2.926 U/L (P<0.05) and Hb levels from 144.32∓13.84 g/L (baseline) to 135.16∓14.78 U/L (P<0.05). Benazepril treatment did not resulted in any obvious changes in EPO or Hb levels (P>0.05).. Valsartan may lower EPO and Hb levels in patients with essential hypertension, while benazepril does not have such effects. The safety of valsartan in anemic hypertensive patients should be further investigated.

Topics: Adult; Aged; Aged, 80 and over; Benzazepines; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Tetrazoles; Valine; Valsartan

Although left ventricular hypertrophy (LVH) is a characteristic finding in hemodialysis (HD) populations, few risk factors for progressive LVH have been identified.. As part of a multinational, blinded, randomized, controlled trial that demonstrated no effect of hemoglobin targets on LV size, 596 incident HD patients, without symptomatic cardiac disease or cardiac dilation, had baseline echocardiograms within 18 months of starting dialysis and subsequently at 24, 48, and 96 weeks later. A wide array of baseline risk factors were assessed, as were BP and hemoglobin levels during the trial.. The median age and duration of dialysis were 51.5 years and 9 months, respectively. LV mass index (LVMI) rose substantially during follow-up (114.2 g/m(2) at baseline, 121 at week 48, 123.4 at week 48, and 128.3 at week 96), as did fractional shortening, whereas LV volume (68.7, 70.1, 68.7, and 68.1 ml/m(2)) and E/A ratio remained unchanged. At baseline, the only multivariate associations of LVMI were gender and N terminal pro-B type natriuretic peptide. Comparing first and last echocardiograms in those without LVH at baseline, independent predictors of increase in LVMI were higher time-integrated systolic BP and cause of ESRD. An unadjusted association between baseline LVMI and subsequent cardiovascular events or death was eliminated by adjusting for age, diabetes, systolic BP, and N terminal pro-B type natriuretic peptide.. Progressive concentric LVH and hyperkinesis occur in HD patients, which is partly explained by hypertension but not by a wide array of potential risk factors, including anemia.

Topics: Anemia; Canada; Disease Progression; England; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Linear Models; Logistic Models; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Renal Dialysis; Risk Factors; Time Factors; Ultrasonography

C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.. Open-label, multicenter, randomized, parallel-group, phase 3 study.. Dialysis patients (age >or= 18 years).. Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly.. The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population.. Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated.. Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin.. Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.

Topics: Anemia; Dose-Response Relationship, Drug; Drug Carriers; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Thrombosis; Treatment Outcome

It is becoming increasingly more common to administer intravenous (i.v.) darbepoetin alfa to haemodialysis (HD) patients at less frequent dosing intervals in routine clinical practice. This study investigated extending the dosing interval for i.v. darbepoetin alfa treatment from once a week (QW) to once every 2 weeks (Q2W) at the same dose in order to maintain target haemoglobin (Hb) concentrations (11-13 g/dl).. Stable HD patients in routine clinical practice receiving i.v. darbepoetin alfa QW for a period of 6 months (n = 105) (treatment period 1) were switched to i.v. Q2W darbepoetin alfa for a further 6 months (treatment period 2) (n = 90). The dose of i.v. darbepoetin alfa was titrated to maintain Hb concentrations between 11 and 13 g/dl throughout the full 12-month study period.. The mean change in Hb for treatment period 2 was 0.04 +/- 1.1 g/dl (+/-SD), which was not clinically relevant (11.7 +/- 0.8 g/dl vs 11.7 +/- 1.0 g/dl; P = 0.8). The mean weekly doses of darbepoetin alfa were similar throughout the treatment periods (34.0 +/- 17.1 microg/week vs 32.1 +/- 17.3 microg/week; P = 0.3, respectively for QW and Q2W dosing). Intravenous darbepoetin alfa was well tolerated.. The treatment of renal anaemia in HD patients with i.v. Q2W darbepoetin alfa effectively and safely maintains Hb concentrations at a less frequent dosing regimen than observed with QW administration. Dose requirements for i.v. darbepoetin alfa administered QW or Q2W were not different. The results of this study demonstrate that i.v. darbepoetin alfa administered Q2W is an effective regimen for HD patients requiring anaemia treatment in routine clinical practice.

Topics: Aged; Aged, 80 and over; C-Reactive Protein; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome

This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.. One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.. One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).. This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Topics: Adult; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium; Canada; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Heart Ventricles; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Lipids; Male; Middle Aged; Organ Size; Parathyroid Hormone; Phosphates; Recombinant Proteins; Renal Dialysis; Single-Blind Method; Treatment Failure; Ultrasonography

Anemia is one of the most serious complications in patients on dialysis. Erythropoietin improves the anemia. However, erythropoietin resistance is sometimes encountered from causes such as functional iron deficiency, secondary hyperparathyroidism, blood loss, or interaction with other drugs. To clarify the interaction between erythropoietin and the renin-angiotensin system, we studied the maintenance dose of recombinant human erythropoietin (rHuEPO) in patients on continuous ambulatory peritoneal dialysis (CAPD) with and without angiotensin converting enzyme inhibitor (ACEIs), angiotensin II type I receptor blockers (ARBs), and calcium channel blockers. We divided 36 hypertensive patients on CAPD into three groups--an ACEI group (n = 12), an ARB group (n = 12), and a Ca channel blocker group (n = 12)--and then we compared the doses of rHuEPO required to maintain the patients' hematocrit (Hct) above 30%. In the Ca channel blocker group, the weekly dose of erythropoietin had not changed significantly at the end of the study (74 +/- 7 U/kg at the end vs. 76 +/- 8 U/kg at the start). The (oral) ACEI group needed a significantly higher weekly dose of erythropoietin at the end of the study (89 -/+ 9 U/kg at the end vs. 74 -/+ 8 U/kg at the start, p < 0.01). The (oral) ARB group also needed a significantly higher weekly dose of erythropoietin at the end of the study (82 -/+ 10 U/kg at the end vs. 76 +/- 8 U/kg at the start, p < 0.05). Furthermore, the weekly dose of erythropoietin required in the ACEI group was significantly larger than that required in the ARB group. We conclude that treatment with ACEIs and ARBs induces erythropoietin resistance in patients on CAPD. The inhibitory effect of ARBs on erythropoiesis is less than that of ACEIs.

Topics: Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Interactions; Drug Resistance; Erythropoietin; Hematocrit; Humans; Hypertension; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

In some of the patients undergoing haemodialysis, (HD) resistance might develop against recombinant human erythropoietin (rHuEPO) used for treatment of anaemia. Recently, angiotensin-converting enzyme (ACE) inhibitors that are used to treat hypertension and congestive heart failure in HD patients have been suggested to contribute to anaemia as well by inhibiting erythropoiesis. Our purpose in this study is to investigate whether or not losartan, an angiotensin II (ATII) receptor antagonist, is causing rHuEPO resistance.. In this prospective study of 12 months, we compared the effects of high dose losartan (100 mg/day) and amlodipine (10 mg/day) on rHuEPO requirement in 40 hypertensive patients receiving rHuEPO for more than 12 months on maintenance HD. Twenty normotensive rHuEPO dependent patients served as control group. Iron deficiency, hyperparathyroidism, aluminium intoxication, infections and inflammations were excluded in all patients.. The mean haemoglobin level was found >8 g/dl in all groups. The mean weekly rHuEPO dose increased in the losartan group (p<0.0001 vs before) and remained constant in the other groups. No significant differences were found with PTH, iron status, aetiologies of renal failure in all groups.. High-dose losartan increases rHuEPO requirement and should be reserved for dialysis patients with hypertension uncontrollable with other antihypertensive medications.

Topics: Adult; Amlodipine; Anemia; Angiotensin Receptor Antagonists; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Renal Dialysis; Safety; Thrombosis; Treatment Outcome

Ten normotensive hemodialysis patients with severe anemia participated in the study. Human recombinant erythropoietin (rHuEpo) was administered i.v. 3 times a week in doses of 50 U/kg of body weight. During 12 weeks of observation, the mean hematocrit value increased from 19%, before start of therapy, to 32%. Simultaneous monitoring of serum plasma noradrenaline (NA) concentration showed an elevation from 202 to 281 pg/ml. An increase of NA concentration after a cold pressure stimulating test (CP) was not statistically significant after as compared to before treatment, but became statistically significant after 12 weeks of rHuEpo therapy (281 pg/ml before to 441 pg/ml after CP test, p < 0.01). The mean arterial blood pressure increased from 92 - 109 mmHg after 12 weeks of rHuEpo therapy (p < 0.001). We have demonstrated significantly increased NA blood concentrations after 12 weeks of rHuEPO therapy in normotensive patients, which correlated with increased MAP. This may suggest that the observed increase of noradrenaline concentration as a vasoactive substance after the CP test may contribute to hypertension during rHuEPO therapy.

Topics: Adrenergic Fibers; Adult; Anemia; Blood Pressure; Cold Temperature; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Norepinephrine; Recombinant Proteins; Regression Analysis; Renal Dialysis; Stress, Physiological; Sympathetic Nervous System

The mechanism of cortisol-induced hypertension remains unknown. We investigated a possible role of erythropoietin (EPO) as a mediator of hypertension in healthy male subjects treated with cortisol. In Study 1, blood pressure (BP) and serum EPO concentrations were measured on alternate days in nine subjects treated with 80 mg of cortisol per day for 5 days. In Study 2 the same parameters were measured in eight subjects randomised to cortisol (80 mg/day) or placebo and 10 subjects randomised to cortisol (200 mg/day) or placebo for 5 days. In Study 1, cortisol caused a significant increase in systolic BP (SBP) (115 +/- 2 vs 126 +/- 2 mm Hg, control vs day 5, P < 0.001) and serum EPO concentrations (14.5 +/- 2.7 vs 24.3 +/- 2.7 mU/mL, P < 0.001). In Study 2 both doses of cortisol increased SBP (118 +/- 2 vs 113 +/- 2 mm Hg, 80 mg cortisol vs placebo, P < 0.05 and 129 +/- 3 vs 113 +/- 2 mm Hg, 200 mg cortisol vs placebo, P < 0.001). Serum EPO concentrations were significantly increased at 200 mg cortisol (25.2 +/- 11.9 vs 15.9 +/- 3.5 mU/mL, P < 0.01) but not 80 mg cortisol (21.3 +/- 2.9 vs 14.9 +/- 3.1 mU/mL). In the 200 mg group there was a positive correlation between the change in SBP and the change in serum EPO concentration (r2 = 0.43, P < 0.05). These results point to a possible role for EPO as the mediator of cortisol-induced hypertension. Journal of Human Hypertension (2000) 14, 195-198.

Topics: Blood Pressure; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Humans; Hydrocortisone; Hypertension; Male; Systole

Levels of adrenomedullin (AM) have been shown to be elevated in hypertension and chronic renal failure, suggesting that AM plays a role in the pathogenesis of these diseases. The objective of the present study was to investigate whether circulating AM is involved in erythropoietin (Epo)-induced hypertension in patients with renal anemia due to progressive renal disease. Following treatment with 6,000 IU of Epo once a week, the hematocrit (Ht) rose significantly from 25.9+/-4.0 to 33.4+/-3.3% (n=54, p<0.001) with an overall rate of increase in Ht of 0.43+/-0.04%/week. In response to treatment with Epo, a rise in mean blood pressure of >10 mmHg (Epo-induced hypertension) was found in 22% (12/54 cases) of the patients enrolled. There was no difference in the rate of Ht increase between patients with and without Epo-induced hypertension. There was a significant positive correlation between mature AM and serum creatinine (Cr) concentration before treatment with Epo. However, no correlation was found between the plasma concentration of total AM and serum Cr concentration. Long-term treatment with Epo did not influence plasma concentration of either mature AM or total AM in patients developing hypertension during the study period. These results suggest that circulating AM may play a role in the progression of renal disease. However, the present study does not support the notion that circulating AM is associated with the pathogenesis of Epo-induced hypertension. It is too early yet to claim that there is no AM-mediated mechanism in Epo-induced hypertension.

Topics: Adrenomedullin; Adult; Aged; Anemia; Creatinine; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Peptides

To evaluate safety and efficacy of recombinant human erythropoietin (r-HuEPO)in reducing the need for red cell transfusions in anemia of prematurity.. forty -two preterm infants (gestational age <32 weeks) were randomly assigned to a "treatment" group (r-HuEPO 400 units/kg every alternate day * 10 doses) or "no treatment" (control) group. All infants on enteral feeds received oral iron 3 mg/kg/day, graded up to 6 mg/kg/day.. Higher reticulocyte counts in week 2 and 3 and higher hemoglobin levels in week 4 were noted after treatment with r-HuEPO. Despite stumulated erythropoiesis, the frequency of transfusions could not be reduced with r-HuEPO therapy.Overall, Phlebotomy losses, frequency and volume of redcell transfusions were significantly more in neonates with birthweight <1000 grams compared with those with birthweight >1000 grams (p<0.05). Associated side effects of r-HuEPO such as neutropenia,sepsis, hypertension or increased risk of late death did not occur.. r-HuEPO therapy was safe without any side effects. Inability of r-HuEPO therapy to minimize red cell transfusions for anemia of prematurity may be explained by a relatively strict red-cell transfusion policy and the desired degree of treatment effect.

Topics: Administration, Oral; Anemia; Birth Weight; Enteral Nutrition; Erythrocyte Count; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Hypertension; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Male; Neutropenia; Phlebotomy; Recombinant Proteins; Reticulocytes; Safety; Sepsis; Survival Rate

Pregnancy in hemodialysis (HD) patients tends to be diagnosed late because of its infrequency and the lack of validity of urine pregnancy tests, and because these patients tend to have menstrual irregularities. The outcome is influenced by pregnancy-related anemia. We investigated the characteristics of pregnancy-related anemia and whether it is a useful diagnostic clue to pregnancy in HD patients.. We retrospectively investigated six pregnancies of 5 HD patients (mean age 30 years), including 4 patients treated with recombinant human erythropoietin (rHuEpo) and a transfusion-dependent patient with two pregnancies in the pre-rHuEpo era.. The mean duration of HD was 6 years, the mean duration of the patients' marriages at the time of pregnancy was 6 years, and the mean gestational age at diagnosis was 11 weeks and 4 days. The progression of anemia (an 8% decrease in the hematocrit) was detected by 8 weeks of gestation in all patients. The prepregnancy hematocrit was stable in 5 pregnancies, facilitating the detection of changes, but during one of the pregnancies of the transfusion-dependent patient the hematocrit was low and was influenced by the transfusions. The amount of rHuEpo required to attain a target hematocrit of 30% increased gradually or rapidly until delivery.. The progression of anemia or hyporesponsiveness to rHuEpo was a useful early diagnostic clue to pregnancy in HD patients. However, the prepregnancy hematocrit should be stabilized with rHuEpo, so that decreases can be easily detected. The precise mechanisms of hyporesponsiveness to rHuEpo, which progressed during pregnancy and subsided after delivery, remain to be clarified.

Topics: Adult; Disease Progression; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Pregnancy; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Topics: Aged; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

Topics: Anemia; Antihypertensive Agents; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Losartan; Prospective Studies

Study of the antitumour effects of erythropoietin on metastatic renal cell carcinoma.. After giving their informed consent, 20 patients with histologically proven metastatic renal cell carcinoma received subcutaneous recombinant erythropoietin three times a day at a dose of 150 IU/kg when haemoglobin was less than or equal to 12 g/dL or 75 IU/kg when haemoglobin was higher than 12 g/dL. Treatment was continued for a minimum of 8 weeks before reassessment and was continued thereafter, except in the case of progression or excessive toxicity. A staging assessment was performed every 8 weeks and the response was assessed on the basis of WHO criteria. A clinical and laboratory assessment was performed every two months to evaluate toxicity, graded according to the WHO scale. All but one of the patients had received immunotherapy or chemotherapy prior to inclusion in the study.. One complete response (> 12 months), one partial response (8 months), two minor responses, 10 cases of stabilisation and 6 cases of progression were observed. 15 patients received treatment at full doses. In 5 patients, the duration of treatment was reduced before the 8 weeks initially defined because of tumour progression in one patient and because of haemoglobin persistently greater than 15 g/dL in 4 other patients. Adverse effects consisted of 1 case of moderate headache, 2 cases of transient bone pain, and 1 case of transient hypertension.. Erythropoietin exerts a moderate antitumour effect which needs to be confirmed by a phase II trial of first-line treatment in selected patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Bone and Bones; Carcinoma, Renal Cell; Disease Progression; Erythropoietin; Female; Headache; Hemoglobins; Humans; Hypertension; Injections, Subcutaneous; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Pain; Prospective Studies; Recombinant Proteins; Remission Induction; World Health Organization

The influence of angiotensin-converting enzyme inhibitors (ACEIs) on recombinant human erythropoietin (rhEPO) maintenance doses in hemodialysis patients was studied. One hundred and eight chronic hemodialysis patients (55 males and 53 females, mean age 61.2+/-12.6 years) were investigated. The rhEPO maintenance doses in the ACEI-treated group (n = 49) were 101.7+/-51.7 U/kg/week and in the nontreated group (n = 59) 79.2+/-37.8 U/kg/week (p < 0.05). No difference was observed in hematocrit between the ACEI-treated and nontreated groups. In stepwise regression analysis, the parameters associated with increased rhEPO maintenance doses were female gender, ACEI administration, low total iron binding capacity, and low serum free carnitine levels. In conclusion, ACEI administration might reduce the response to rhEPO. In hemodialysis patients who need high-dose rhEPO to maintain the target hematocrit in the absence of iron deficiency, hyperparathyroidism, infection, malignancy, malnutrition, and aluminum toxicity, ACEI administration should be considered.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Renal Dialysis; Sex Characteristics; Uremia

Two hundred patients who were scheduled for a major elective orthopaedic operation were enrolled in a prospective study and were randomly assigned to one of three treatment groups. Group 1 consisted of sixty patients who received recombinant human erythropoietin, 300 international units per kilogram of body weight per day; Group 2, seventy-one patients who received recombinant human erythropoietin, 100 international units per kilogram of body weight per day; and Group 3, sixty-nine patients who received a placebo. A total of fifteen doses was given subcutaneously, beginning ten days before the operation and extending through the fourth postoperative day. Patients who declined or were unable to donate autologous blood preoperatively were included in the study and were maintained on iron supplementation orally. The decision to transfuse red blood cells depended on the physician, however, physicians were encouraged not to do so if the hematocrit was more than 0.27 (27 per cent), unless the clinical symptoms warranted it. Of the 185 patients who were evaluable with regard to efficacy, significantly fewer patients received homologous red-blood-cell transfusions in Groups 1 and 2 (17 per cent [nine] and 25 per cent [sixteen], respectively) than in Group 3 (54 per cent [thirty-six]) (p < 0.001). When the patients were stratified into two groups on the basis of the pre-treatment hemoglobin level (more than 100 to 130 grams per liter or more than 130 grams per liter), we found that patients who had received a placebo and had a baseline hemoglobin level of more than 100 to 130 grams per liter were at significantly higher risk for transfusion (78 per cent [twenty-one]) than those who had received a placebo and had a baseline level of more than 130 grams per liter (36 per cent [fourteen]). For patients who had a baseline hemoglobin level of more than 100 to 130 grams per liter, the higher dose of recombinant human erythropoietin appeared somewhat more effective than the lower dose, with 14 per cent (three) of the patients in Group 1 and 39 per cent (nine) in Group 2 needing a transfusion; however, the difference was not significant (p = 0.09). For patients who had a baseline hemoglobin level of more than 130 grams per liter, the two doses of recombinant human erythropoietin produced similar results, with 14 per cent (four) of the patients in Group 1 and 11 per cent (four) in Group 2 needing a transfusion; this was in contrast to a rate of transfusion of 36 per cent (

Topics: Aged; Aged, 80 and over; Analysis of Variance; Dose-Response Relationship, Drug; Double-Blind Method; Erythrocyte Transfusion; Erythropoietin; Female; Hematocrit; Hemoglobins; Hip Prosthesis; Humans; Hypertension; Knee Prosthesis; Male; Middle Aged; Orthopedics; Postoperative Complications; Prospective Studies; Recombinant Proteins; Reticulocyte Count

The increased viscosity of blood of hypertensive patients can be assumed to be a risk factor for the development of cardiovascular diseases. The aim of the present study was to elucidate whether anti-hypertensive treatment has any impact on blood rheology. Twenty patients with previously untreated hypertension who consecutively attended our outpatient hypertension clinic were included in this prospective, open, cross-over study. The patients were randomly selected to treatment with amlodipine or metoprolol. The anti-hypertensive therapy was switched after 4 months. Haemorheological and haemodynamic variables were measured with rotational viscometry and impedance cardiography, respectively. Fifteen and 16 patients could be evaluated after amlodipine or metoprolol treatment respectively. The mean blood pressure (BP) decreased from 159 +/- 22/105 +/- 7 to 139 +/- 21/91 +/- 6 mm Hg on amlodipine and from 162 +/- 22/104 +/- 5 to 145 +/- 24/90 +/- 8 mm Hg on metoprolol therapy. After amlodipine treatment, the total peripheral resistance index decreased whereas metoprolol treatment was accompanied by a decrease in the cardiac index. Decreases in whole blood viscosity, haematocrit and serum erythropoietin were found after amlodipine as well as metoprolol treatment. After amlodipine the plasma viscosity decreased and the erythrocyte deformability increased in the majority of patients. Plasma fibrinogen decreased after metoprolol treatment. Despite the differences in haemodynamic mechanisms underlying the decrease in BP, amlodipine and metoprolol exert beneficial effects on blood viscosity. Haemodilution and a decrease in serum erythropoietin may be factors underlying this decrease in blood viscosity.

Topics: Adult; Aged; Amlodipine; Blood Cell Count; Blood Chemical Analysis; Blood Viscosity; Cross-Over Studies; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Male; Metoprolol; Middle Aged

Water immersion (WI) is followed by hypoxemia and haemodilution, and induces alterations in renal haemodynamics (increase of tubular sodium load). These facts justified the performance of studies which aimed to assess the influence of WI on EPO secretion. Serum EPO and atrial natriuretic peptide (ANP) concentration and plasma renin activity (PRA) were estimated in 18 patients with essential hypertension (EH) and in 9 healthy subjects (HS) before, after two hours of WI and two hours after discontinued WI. WI was followed by a significant increase of plasma volume and decrease of PRA which were of similar magnitude in both examined groups. Patients with EH showed significantly higher basal levels of serum EPO (66.7 +/- 11.4 mU/ml in EH vs 20.0 +/- 3.4 mU/ml in HS) and ANP (110.6 +/- 15.4 pg/ml in EH vs 75.6 +/- 8.2 pg/ml in HS). WI was followed by significant increase of both EPO (by 34.0 +/- 8.9 mU/ml in EH and 17.0 +/- 5.4 mU/ml in HS) and ANP (by 106.9 +/- 19.2 pg/ml in EH and 149.4 +/- 16.9 pg/ml in HS). Only in EH a significant correlation was found between serum EPO level and MAP and post-WI natriuresis respectively.. 1. Patients with EH are characterized by elevated basal serum levels of ANP and EPO. 2. Participation of the renin-angiotensin system and ANP in the regulation of EPO secretion could not be proven both in normotensive and hypertensive patients. 3. Involvement of EPO in the pathogenesis of EH seems to be likely.

Topics: Adult; Aged; Atrial Natriuretic Factor; Erythropoietin; Female; Humans; Hypertension; Immersion; Male; Middle Aged; Potassium; Renin; Renin-Angiotensin System; Sodium

The aim of the present study has been to assess whether the administration of recombinant human erythropoietin (rHuEPO) by the subcutaneous (sc) route improves blood pressure control of dialysis patients with erythropoietin-induced hypertension. We have selected 13 hemodialysis patients who have remained hypertensive after more than one year of i.v. rHuEPO treatment (mean 22 +/- 8 months, range 12-35 months). Hematocrit, rHuEPO dose, predialysis mean arterial pressure and antihypertensive drug dosage had remained constant during the last six months. These patients were switched to sc administration of rHuEPO thrice weekly, with reduction of rHuEPO dose by one third (from 149 +/- 56 to 98 +/- 53 IU/kg/week). Concomitantly, predialysis mean arterial pressure significantly decreased (113.1 +/- 7.8 during the last month of i.v. administration vs 107.8 +/- 9.8 during the first month of sc administration, p < 0.05, and 105.5 +/- 5.2 mmHg at six months, p < 0.05), without relevant changes in hematocrit. After six months of sc administration, 5 patients remained normotensive without drugs and 6 out of the remaining 8 patients required antihypertensive drugs at lower doses. Administration of rHuEPO by sc route decreases dose requirements and improves blood pressure control in hypertensive patients when treated by i.v. route.

Topics: Adult; Erythropoietin; Female; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Renal Dialysis

To establish dose requirements (target hemoglobin > 100 g/L) and safety of subcutaneously administered epoetin beta.. Open multicenter study.. Forty-five anemic patients (21 female, 24 male; mean age 55 years; range 20-79 years) who had been on continuous peritoneal dialysis for 1-157 months (mean 24 months). Thirty patients required blood transfusions during the year prior to the study. Mean hemoglobin concentration pretreatment was 75 g/L (range 57-89 g/L).. After a pretreatment period of two weeks, 60 IU kg-1 week-1 divided into three weekly doses of epoetin beta was administered subcutaneously. The dose was increased by 60 IU kg-1 week-1 after ten weeks, and when necessary, every fourth week in patients with hemoglobin levels below 100 g/L.. Hemoglobin concentration. Analysis of factors affecting the response to epoetin beta. Safety of epoetin beta.. Thirty-eight of the 45 patients completed six months and 21 patients completed one year in the study. Twenty-six patients reached hemoglobin 100 g/L within six months and 8 patients did later on. The mean hemoglobin concentration after three months was 93 g/L (range 64-144 g/L) and after six months was 99 g/L (range 59-130 g/L; mean epoetin beta dose 122 IU kg-1 week-1). During the second six-month period of the study, hemoglobin levels were stable in most patients. After one year, the mean hemoglobin was 110 g/L (range 84-153 g/L) and the mean epoetin beta dose was 107 IU kg-1 week-1. Prolonged correction time and impaired response to epoetin were observed in patients with infections or hemorrhages and in patients with low hemoglobin concentration before starting epoetin treatment. Iron deficiency was controlled by iron supplementation, either orally or, in 10 patients, intravenously. Increased blood pressure, requiring intensified antihypertensive treatment, was observed in 13 patients.. Continuous peritoneal dialysis patients with moderate anemia (Hb 75-90 g/L) and without complicating disorders can be managed with subcutaneous doses of epoetin < 120 IU kg-1 week-1. The epoetin beta dose should be adjusted after the first month of treatment since most patients required higher doses than the initial 60 IU kg-1 week-1.

Topics: Anemia; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Time Factors

Treatment of renal anemia with recombinant human erythropoietin (rEPO) frequently raises arterial blood pressure. The objective of this study was to determine whether this is a direct effect of rEPO or a consequence of the expansion of erythrocyte mass. Twenty-three chronic hemodialysis patients receiving maintenance rEPO therapy who had uncontrolled anemia due to iron deficiency were studied. It was anticipated that repletion of iron stores with iv iron dextran would restore rEPO responsiveness, leading to a gradual rise in hematocrit to the target values (0.30 to 0.33). The effect of the increase in hematocrit on arterial blood pressure could then be dissected from the direct effect of rEPO in patients receiving constant doses of rEPO throughout the study period. To this end, arterial blood pressure, iron indices, hematocrit, and measures of fluid balance were monitored at baseline and for a 10-wk period after iron repletion. In eight patients, the hematocrit transiently rose above 0.33, triggering a reduction in rEPO dosage. In the remaining 15 patients, rEPO dosage was held constant during the study period. In this subgroup, repletion of iron stores led to a rise in hematocrit from 0.25 +/- 0.04 to 0.32 +/- 0.04 (P < 0.001) within 4 wk. Despite the significant rise in hematocrit, both systolic and diastolic blood pressure values remained virtually unchanged. Likewise, body weight and interdialytic fluid gain were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia, Iron-Deficiency; Blood Pressure; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Intravenous recombinant human erythropoietin (Eprex Cilag) was used in 28 hemodialyzed children, treated in 3 French paediatric centers, from November 1989 to November 1990. Transfusion dependency disappeared in all cases: the number of transfusions decreased from 7.3 unit/patient/year to 0.6 unit/pt/year. The mean haemoglobin concentration for the whole group increased from 6.6 +/- 0.8 g/dl, to 9.2 +/- 1.2 at 6 months and 9.7 +/- 0.7 g/dl at 1 year. Twenty-two out of 28 children reached the target haemoglobin value of 9.6 g/dl (6 mmol/dL) within a mean time of 16.5 weeks. Poor responses were due to either a premature withdrawal of treatment because of renal transplantation, or too low a dosage for the age. The study showed indeed that the dose requirement was significantly dependent on physical development: the mean dosage required to maintain haemoglobin concentration at the target value was 300 U/kg/week in children weighing less than 20 kg, 222 U/kg/week in 20-30 kg children, and 135 U/kg/week in those weighing more than 30 kg (p = 0.02). The only complication was an increase in blood pressure, observed in 43% of cases. The increase of anti-hypertensive medication was always successful in controlling blood pressure, and hospitalization was required in only one case. The improvement in general condition was obvious, and in several cases, the cognitive abilities seemed to improve. The growth deficit remained unchanged.

Topics: Adolescent; Anemia; Appetite; Blood Transfusion; Body Weight; Child; Child, Preschool; Cognition Disorders; Dose-Response Relationship, Drug; Erythropoietin; Female; France; Growth Disorders; Hemoglobins; Humans; Hypertension; Immunologic Factors; Infant; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Treatment Outcome

The aims of this clinical study were to compare the maintenance doses for intravenous (i.v.) and subcutaneous (SC) administration of recombinant human erythropoietin (rhEPO) and to investigate whether there is any difference in the increase of the packed cellular volume (PCV) per week under i.v. and SC administration of rhEPO from two production sites (Genetics Institute, Cambridge, USA; and Boehringer Mannheim, Penzberg, Germany). A total of 90 patients suffering from end-stage renal disease were included in the study. All patients had already been treated for at least 6 months with chronic hemodialysis. The study was carried out as a randomized, multicenter parallel group comparison study with a 1-week pretreatment phase, a subsequent 8-week double-blind phase, and a final open phase. The final open phase consisted of a correction phase and a maintenance phase. The production site had no influence on the PCV increase per week, and there were no differences with respect to tolerability. The median rhEPO dose required to maintain the target PCV of 30 to 35 vol.% was 33 U/kg body weight three times a week in the i.v. group compared with 22 U/kg in the SC group (i.e., an average of 30% less with SC administration). Development or aggravation of hypertension under rhEPO therapy was observed, especially during the correction phase and more frequently in the SC group than in the i.v. group. During the maintenance phase, there was no essential difference between the two groups.

Topics: Adult; Aged; Analysis of Variance; Anemia; Double-Blind Method; Erythropoietin; Female; Germany; Hematocrit; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Eleven children aged 0.6-17 years with preterminal chronic renal failure and anemia (mean serum creatinine concentration 4.8 mg/dl; mean hemoglobin concentration 7.9 g/dl) were treated with sc injections of recombinant human erythropoietin (EPO, initial dose 150 U/kg/week) over a mean period of 13 months. When a target hemoglobin concentration of 11.5-13.5 g/dl was reached, the dose was adapted. Iron deficiency was corrected. Hemoglobin concentration increased by > 2 g/dl in all patients within 14-119 (mean 45) days. The last maintenance dose ranged between 75 and 300 (mean 133) U/kg/week. No major adverse effects were observed, except for hypertension which occurred in about half of the patients and necessitated interruption of EPO in one child with advanced renal failure. Additional antihypertensive drugs were given to five patients. Body height increased in two patients by 0.6 and 1.3 SDS/year, respectively. In six patients with a mean observation period of 14 months before and 16 months after the start of EPO, the mean slope of the reciprocal serum creatinine concentration curve improved slightly (p = 0.05). The proposed schedule appears to be safe for the treatment of renal anemia in most pre-dialysis patients. Frequent monitoring of hemoglobin, blood pressure, serum creatinine and ferritin is required.

Topics: Adolescent; Anemia; Antihypertensive Agents; Body Height; Body Weight; Child; Creatinine; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Infant; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Recombinant Proteins

The hematologic effects of recombinant human erythropoietin after allogeneic bone marrow transplantation (BMT) were studied. Nineteen patients received 150 U/kg/day of C127 mouse-cell-derived recombinant human erythropoietin (rHu EPO) as a daily continuous intravenous infusion until hematocrit exceeded 35%. These data were compared with a treatment-matched historical control group of 43 patients. RHu EPO-treated patients recovered erythropoiesis more rapidly and became independent from erythrocyte transfusions after a median of 17 days, which was 7 days earlier than the control patients.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Recombinant Proteins

To investigate a possible involvement of endogenous erythropoietin (EPO) in the salt sensitivity of blood pressure in essential hypertensive (EHT) patients, plasma EPO concentrations were measured during different salt intakes in 14 patients with EHT. All patients were given low salt (34 mmol NaCl/day) and high salt (342 mmol NaCl/day) diet of 7 days each. The plasma EPO concentrations were significantly higher on the high salt diet than those of low salt diet (23.5 +/- 1.9 v 18.7 +/- 1.8 mIU/ml, mean +/- SD, P < .05). The percentage change of plasma EPO concentration with salt loading correlated positively with hematocrit (Ht) at high salt diet (r = -0.62, P < .02) and tended to be correlated with plasma hemoglobin at high salt diet (r = 0.52, P < .10). These results suggest that the secretion of EPO is increased in response to hemodilution caused by the salt loading and the increased EPO concentration in plasma which may contribute to the increase in blood pressure through an expansion of total blood volume due to an enhanced red cell generation in combination with salt and water retentions.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Osmolar Concentration; Renin; Sodium Chloride

The correction of anemia in end stage renal disease with recombinant human erythropoietin (rHuEPO) is associated with hypertension in about a third of hemodialysis patients. In the present study, we investigated the role of endothelin (ET-1) on rHuEPO associated hypertension and the effect of the rHuEPO administration route on plasma ET-1 levels. We studied 50 stable chronic hemodialysis patients who were divided into three groups: 26 patients received rHuEPO intravenously (IV) and 21 subcutaneously (SC). The control group was nine patients who were treated with nandrolone decanoate (ND). Prehemodialysis ET-1 plasma levels were correlated with mean arterial pressure (MAP), hematocrit (Hct), time on dialysis, and rHuEPO doses. The antihypertensive therapeutic index (ATI) was used to determine the changes in blood pressure medication intake. We observed that the ET-1 levels were significantly higher in the IV group (19.3 +/- 2) than the SC (5.0 +/- 0.6) or ND groups (3.6 +/- 0.4 pg/mL) (P < 0.001, IV v SC or ND). After IV rHuEPO treatment, there were increases in both MAP (pre- v post-rHuEPO, P < .001) and in ATI (pre- v post-rHuEPO, P < .001). In the SC group, the increases in MAP and ATI were not significant. Only the IV group showed a significant correlation between MAP and ET-1 levels (r = .05, P = .02). To accomplish the same Hct, the IV group received higher rHuEPO doses than those of the SC (180 +/- 15 v 87 +/- 12 U/kg/week) (P < .001). No significant correlations were found between the plasma ET-1 levels and Hct, time on dialysis and rHuEPO doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aging; Anemia; Blood Pressure; Dose-Response Relationship, Drug; Endothelins; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

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

Treatment with recombinant human erythropoietin (rHuEPO) successfully reverses anemia in uremic patients. Of major concern, however, are blood pressure (BP) increases during rHuEPO therapy, observed particularly in persons with a history of hypertension. To determine whether preexisting hypertension enhances BP increases to rHuEPO, BP responses to 2 wk of rHuEPO or placebo were observed in spontaneously hypertensive rats (SHR) and their normotensive genetic controls (Wistar-Kyoto [WKY] rats. In addition, the role of endothelial-released nitric oxide (NO) in BP alterations caused by rHuEPO through i.v. infusions of endothelium-dependent and independent vasoactive agents were indirectly examined. At trial completion, rHuEPO elevated hematocrit, hemoglobin, and mean cell volume more in SHR than in WKY rats (P less than 0.001). Despite the considerable increase in hematocrit, rHuEPO did not alter BP in either strain. An infusion of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO formation, elevated BP more in rHuEPO-treated SHR than in identically treated WKY rats (P less than 0.05). Further, the administration of L-arginine caused a greater decrease in blood pressure in SHR than in WKY rats, independent of treatment condition (P less than 0.01). Because changes in BP with endothelium-independent agents were similar across groups, responses to L-NMMA and L-arginine were specific to the endothelium and probably independent of basal BP. Thus, rHuEPO provoked greater erythropoiesis in SHR than in WKY rats but did not elevate BP. L-NMMA stimulated higher BP in SHR treated with rHuEPO, suggesting a compensatory increase in vasodilatory NO synthesis to protect against a hypertensive effect of the drug in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Erythropoietin; Hematocrit; Hypertension; Iron; Male; Nitric Oxide; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins

This study analyzed blood pressure in hemodialysis patients treated with epoetin beta in multicenter trials. Antihypertensive drugs were prescribed as usual. Placebo-controlled trials compared epoetin (100 to 150 U/kg; N = 151) with placebo (N = 78) for 82 days. Hemoglobin (108 +/- 18 versus 75 +/- 14 g/L) (mean +/- SD) and diastolic blood pressure (84 +/- 14 versus 78 +/- 15 mm Hg) were greater (P less than 0.05) after epoetin. Clinically important increases in blood pressure (increases in diastolic blood pressure greater than or equal to 10 mm Hg and/or drug therapy) were more frequent with epoetin (58 versus 37%; P = 0.005). A dose-response trial compared epoetin, 25 U/kg (N = 42), 100 U/kg (N = 40), and 200 U/kg (N = 39) for 138 days. Increases in hemoglobin were dose dependent, but clinically important increases in blood pressure were not. In analyses of all patients treated with epoetin (N = 272), no baseline or final level of hemoglobin, or rate of hemoglobin rise, was a threshold for a rise in blood pressure. Patients requiring antihypertensive drugs or having uncontrolled hypertension (diastolic blood pressure greater than 90 mm Hg) at baseline had decreases in blood pressure (P less than 0.05) with antihypertensive therapy. Thus, compared with placebo, 21% of patients had clinically important increases in blood pressure during amelioration of anemia. The baseline or final levels of hemoglobin, the extent or rate of hemoglobin rise, or uncontrolled hypertension or antihypertensive drug use at baseline were not confirmed as risks. Antihypertensive drug therapy was important for blood pressure control.

Topics: Adult; Aged; Anemia; Antihypertensive Agents; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Risk Factors

The effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin (rHuEPO) on blood pressure was evaluated in 20 patients with renal failure on continuous ambulatory peritoneal dialysis. The two groups of patients were commenced on a 16-week course of twice weekly rHuEPO by either the subcutaneous (10 patients) or the intraperitoneal route (10 patients). One patient in the latter group was subsequently excluded because of operation and transfusion. The hemoglobulin increased significantly from 6.9 +/- 0.3 g/dl to 9.8 +/- 0.6 g/dl after subcutaneous rHuEPO treatment (p less than 0.01) at an average dose of 84 +/- 9 U/kg body weight/week. For the intraperitoneal group, despite a higher average rHuEPO dosage (133 +/- 7 U/kg body weight/week), the hemoglobin level was not significantly altered (7.0 +/- 0.4 g/dl to 8.0 +/- 0.4 g/dl, p less than 0.05). During the 16-week period of rHuEPO therapy, an increase in antihypertensive therapy was required more frequently in patients in the intraperitoneal group but the difference between groups failed to reach statistical significance. There was no conclusive evidence that the rise in hematocrit was an independent precipitant of hypertension. Patients who were hypertensive prior to rHuEPO therapy appeared most susceptible to the pressor effects in that 8 of 11 treated hypertensive patients required more intensive antihypertensive treatment during EPO administration whereas none of the untreated patients developed hypertension during the study (Fisher's exact test, p = 0.007). Plasma levels of the vasoactive hormones, atrial natriuretic peptide (ANP), plasma renin activity (PRA), and endothelin (ET) remained unchanged during both subcutaneous and intraperitoneal rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Dose-Response Relationship, Drug; Endothelins; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Injections, Intraperitoneal; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renin; Time Factors

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

One hundred seventeen patients with anemia related to chronic renal failure not severe enough to require maintenance dialysis were randomly assigned to receive recombinant human erythropoietin (rHuEPO; 50, 100, or 150 U/kg body weight) or placebo intravenously (IV) three times a week for 8 weeks or until their anemia was corrected. Correction of anemia (hematocrit of 40% for males, 35% for females) occurred in 87% of those given 150 U/kg, 64% of those given 100 U/kg, 46% of those given 50 U/kg rHuEPO and in 3% of the placebo group. Energy levels and work capacity improved significantly in the group with corrected anemia compared with the group with uncorrected anemia. rHuEPO appeared to be well tolerated. There was no evidence that rHuEPO therapy accelerated the deterioration of renal function as measured by serum creatinine and reciprocal of serum creatinine compared with placebo treatment. However, it is essential that blood pressure and hematocrit be carefully monitored, particularly in hypertensive patients, to prevent the development of complications associated with hypertension.

Topics: Adult; Aged; Anemia; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis

To evaluate the acute and long-term haemodynamic response to recombinant human erythropoietin (rHuEpo) correction of chronic anaemia in haemodialysis-supported patients.. Prospective analysis of randomly chosen patients undergoing the multicentre phase III clinical recombinant erythropoietin trial.. Chronic haemodialysis patients supported in one of two dialysis centres of a large urban tertiary referral centre.. Thirteen of the 59 patients who met the criterion for participation in the multicentre clinical phase III trial of recombinant erythropoietin were randomly chosen. Mean age (42.6 years), and time on dialysis (3.4 years) was representative of the study population. Ten patients were receiving antihypertensive therapy, which remained unchanged throughout the study.. Haemodynamic testing was done in a fasting state, in the supine position, utilising radionuclide angiocardiography. Plasma volume was determined by 125I-labelled serum albumin. Echocardiographic and hormonal evaluations were also performed at each haemodynamic evaluation. All testing was done immediately prior to first dose of drug, upon reaching target haematocrit, and at 6 months and 1 year of continued non-anaemia.. Mean arterial pressure did not seem to change at any of the study periods, while total peripheral resistance did drop at target (34 +/- 2.5 vs 27.2 +/- 3.2 microns2, P = 0.05). Cardiac output (5.6 +/- 0.5 vs 7.6 +/- 0.8 l/min, P = 0.005) and stroke volume (77 +/- 9.6 vs 116 +/- 15.4 ml, P = 0.005) also rose at this same period but returned to baseline during later periods. Ejection fraction increased over baseline at both target and 1 year study points (50 +/- 2.7 vs 57.7 +/- 3 vs 63 +/- 4.3, P = 0.05) while the haematocrit was increased at target (21.8 +/- 0.9 vs 35.6 +/- 1.0, P less than 0.0005), and maintained at this new level throughout the study. Total blood volume (118 +/- 6.7 vs 100.4 +/- 8.1 ml/cm, P less than 0.05) and plasma volume (150 +/- 8.2 vs 108.5 +/- 9.4 ml/cm, P less than 0.001) decreased at 1 year.. Recombinant human erythropoietin is effective in correcting the anaemia of chronic renal failure. Any haemodynamic changes which may be induced seem to occur early in the course of therapy, are different from those changes induced by blood transfusions, and tend to return to baseline with continued treatment.

Topics: Adolescent; Adult; Aged; Anemia; Blood Pressure; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renal Dialysis

Blood pressure (BP) may increase in hemodialysis patients during treatment of anemia with recombinant human erythropoietin (r-HuEPO). Since fluid volume is a determinant of BP in dialysis patients, changes in body fluid spaces during r-HuEPO therapy could affect BP. Thus, 51Cr-labeled red blood cell (RBC) volume, inulin extracellular fluid (ECF) volume, and urea total body water (TBW), as well as cardiac output, plasma renin activity (PRA), and plasma aldosterone concentration were determined postdialysis before and after r-HuEPO therapy in patients in whom changes in BP could be managed by ultrafiltration alone. Eleven patients entered the study: one had a renal transplant and two required addition of antihypertensive drug therapy and were excluded; eight, of whom two required antihypertensive drug therapy following the study, were included in the analyses. Results revealed an increase in predialysis hemoglobin from 67 to 113 g/L (6.7 to 11.3 g/dL) (P = 0.001) during 18 +/- 6 weeks of therapy. Predialysis diastolic BP increased from 80 to 85 mm Hg (P = 0.07), while postdialysis diastolic BP was unchanged at 73 mm Hg. 51Cr-RBC volume increased, from 0.7 to 1.3 L (P = 0.004). ECF tended to decrease, from 13.7 to 10.8 L (P = 0.064), while TBW decreased to a similar extent, but not significantly, 34.3 to 31.2 L (P = 0.16). Postdialysis ECF volume was positively correlated with mean arterial BP at baseline (r = 0.89, P = 0.007) and after therapy (r = 0.74, P = 0.035). However, the regression lines for this relationship were different (P = 0.022) before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Antihypertensive Agents; Blood Pressure; Body Fluid Compartments; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

The treatment of severe anemia related to end-stage renal disease with recombinant human erythropoietin (r-HuEPO; EPOGEN, [epoetin alfa] AMGEN Inc, Thousand Oaks, CA) has been investigated in more than 1,500 hemodialysis patients worldwide. The goal of r-HuEPO therapy is to maintain the hematocrit level at 35%, with a recommended starting dose of 150 mg/kg of body weight, administered intravenously after each dialysis three times a week for 6 to 12 weeks. Hematocrit levels should be measured at least once a week and the dose adjusted in increments or decrements of 10 mg/kg to 25 mg/kg to keep the hematocrit level between 33% and 40%. Patients receiving r-HuEPO must be normotensive. A history of seizures has been cause for exclusion from clinical trials. Patients' iron status should also be adequate at the onset of therapy, which is defined as a serum ferritin level of 100 ng/mL or more, and a transferrin saturation of more than 20%. Iron status and BP must be carefully monitored, and abnormalities corrected with iron supplementation, ultrafiltration, or antihypertensive medication. The lack of controlled studies makes determination of the actual incidence of side effects difficult, but it appears to be minimal. Possible side effects of r-HuEPO therapy include hypertension, seizures, myalgia, malaise, headache, gastrointestinal distress, and injected conjunctiva. The major benefits of r-HuEPO therapy are reduced need for transfusion and marked improvement in quality-of-life parameters.

Topics: Anemia; Anemia, Hypochromic; Blood Pressure; Clinical Trials as Topic; Drug Evaluation; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Monitoring, Physiologic; Recombinant Proteins; Renal Dialysis; Seizures

Topics: Acquired Immunodeficiency Syndrome; Anemia; Clinical Trials as Topic; Drug Administration Schedule; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Hypertension; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Renal Dialysis; Seizures; United States

Topics: Anemia; Blood Transfusion; Dose-Response Relationship, Drug; Erythrocyte Count; Erythrocyte Transfusion; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Multicenter Studies as Topic; Renal Dialysis; Reticulocytes; United States

Topics: Adolescent; Adult; Aged; Anemia; Blood Transfusion; Clinical Trials as Topic; Double-Blind Method; Erythropoietin; Female; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Random Allocation

Topics: Anemia; Arteriovenous Shunt, Surgical; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Multicenter Studies as Topic; Neoplasms; Renal Dialysis; Seizures; Thrombocytosis; Thrombosis

Topics: Adult; Aged; Anemia; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Random Allocation; Renal Dialysis; Reticulocytes; Thrombosis

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Erythrocyte Count; Erythropoietin; Female; Ferritins; Growth; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Multicenter Studies as Topic; Reticulocytes; Seizures; Thrombosis

Recombinant human erythropoietin raises serum erythropoietin concentrations to adequate levels and restores the hematocrit to normal values in the vast majority of anemic, end stage renal disease patients undergoing regular hemodialysis. It can eliminate the need for transfusions and thus the risk of immunologic sensitization, infection and iron overload. Erythropoietin not only alters laboratory findings but improves the well being and performance of patients on hemodialysis as well. Side effects are minimal and neither antibodies nor resistance to the recombinant hormone have been observed so far. Along with the rise in hematocrit and blood viscosity some patients developed increased blood pressure and a few hypertensive encephalopathy, but after brief interruption of therapy erythropoietin treatment could be continued in combination with antihypertensive drugs. The pathophysiology of the increase in blood pressure, the risk of encephalopathy and the possibly somewhat higher risk of thrombosis remain to be elucidated. Nevertheless, the first recombinant hematopoietic hormone has passed its first clinical trials with success.

Topics: Anemia; Antihypertensive Agents; Blood Transfusion; Blood Viscosity; Clinical Trials as Topic; Drug Evaluation; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

Topics: Adult; Anemia; Blood Pressure; Clinical Trials as Topic; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Random Allocation; Recombinant Proteins

[Figure: see text].

Topics: Animals; Blood Pressure; Coronary Artery Disease; Cross-Sectional Studies; Erythropoietin; Female; Humans; Hypertension; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Middle Aged; Prospective Studies; Receptor, Platelet-Derived Growth Factor alpha; Serine Endopeptidases; Vasoconstriction

This case demonstrates an underrecognized cause of posterior reversible encephalopathy syndrome (PRES).. We report a 51-year-old male with a history of essential hypertension without preexisting renal impairment who presented with 3 days of occipital headache and convulsive status epilepticus in the setting of refractory hypertension. He had been receiving outpatient human recombinant erythropoietin injections for virally mediated bone marrow suppression, which worsened his baseline hypertension. Magnetic resosnance imaging (MRI) of the brain on admission showed diffuse bilateral, symmetric signal hyperintensities and patchy enhancement involving the cortex and white matter in both cerebral hemispheres. His blood pressure and seizures were successfully treated during hospital admission, with complete resolution of his neurological deficits. MRI brain performed 6 weeks from initial scan showed normalization of his prior findings.. Recombinant human erythropoietin (RhEPO) may be an underrecognized cause of PRES and should be considered in patients receiving this treatment regardless of the absence or presence of renal impairment. RhEPO-mediated precipitation/exacerbation of hypertension, alterations in cerebral blood flow, and changes in endothelial integrity may underlie this association. MRI signal changes are reversible and typical for that of PRES, and significant improvement of symptoms can be expected.

Topics: Brain; Erythropoietin; Humans; Hypertension; Male; Middle Aged; Posterior Leukoencephalopathy Syndrome; Seizures

Prolyl hydroxylase (PHD) inhibitors are being developed as alternatives to recombinant human erythropoietin (rHuEPO) for the treatment of anemia in patients with chronic kidney disease (CKD). However, the effects of PHD inhibitors and rHuEPO on blood pressure and CKD in animal models susceptible to hypertension and nephropathy have not been studied. The present study compared the effects of dimethyloxaloylglycine (DMOG), a PHD inhibitor, and rHuEPO on the development of hypertension and renal injury in Dahl salt-sensitive rats fed an 8% salt diet for 3 weeks. DMOG and rHuEPO were equally effective at raising hemoglobin levels. Systolic blood pressure rose to a greater extent in rHuEPO-treated rats (267 ± 10 vs. 226 ± 4 mm Hg) than in rats given DMOG (189 ± 8 mm Hg). Urinary protein excretion increased to 568 ± 54 versus 353 ± 25 mg/day in rats treated with rHuEPO and vehicle; however, it only rose to 207 ± 21 mg/day in rats receiving DMOG. DMOG significantly attenuated the degree of glomerulosclerosis and renal interstitial fibrosis as compared with that in vehicle and rHuEPO-treated rats. This was associated with lower renal levels of monocyte chemoattractant protein-1 and interleukin-1

Topics: Amino Acids, Dicarboxylic; Anemia; Animals; Blood Pressure; Dose-Response Relationship, Drug; Erythropoietin; Fibrosis; Hemoglobins; Hypertension; Kidney; Male; Oxidative Stress; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Rats; Rats, Inbred Dahl; Recombinant Proteins; Renal Insufficiency, Chronic; Sodium Chloride, Dietary; Vascular Endothelial Growth Factor A

Recent studies indicate that erythropoietin (EPO) is present in many areas of the brain and is active in the restoration of impaired neurons. In this study, we examined the presence of EPO and its role in bulbospinal neurons in the rostral ventrolateral medulla (RVLM). Hypoxia is often accompanied by a high blood pressure (BP). We hypothesized that EPO is produced in response to hypoxia in RVLM neurons and then activates them. To investigate whether RVLM neurons are sensitive to EPO, we examined the changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole cell patch-clamp technique during superfusion with EPO. A brainstem-spinal cord preparation was used for the experiments. EPO depolarized the RVLM neurons, and soluble erythropoietin receptor (SEPOR), an antagonist of EPO, hyperpolarized them. Furthermore, hypoxia-depolarized RVLM neurons were significantly hyperpolarized by SEPOR. In histological examinations, the EPO-depolarized RVLM neurons showed the presence of EPO receptor (EPOR). The RVLM neurons that possessed EPORs showed the presence of EPO and hypoxia-inducible factor (HIF)-2α. We also examined the levels of HIF-2α and EPO messenger RNA (mRNA) in the ventral sites of the medullas (containing RVLM areas) in response to hypoxia. The levels of HIF-2α and EPO mRNA in the hypoxia group were significantly greater than those in the control group. These results suggest that EPO is produced in response to hypoxia in RVLM neurons and causes a high BP via the stimulation of those neurons. EPO may be one of the neurotransmitters produced by RVLM neurons during hypoxia.

Topics: Action Potentials; Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Blood Pressure; Cell Hypoxia; Erythropoietin; Hypertension; Hypoxia; In Vitro Techniques; Medulla Oblongata; Neurons; Rats, Wistar; Receptors, Erythropoietin; Up-Regulation

Hypertension is the leading cause of death worldwide. Chronic high blood pressure induces inflammation. Tumor necrosis factor (TNF)-α plays a major role in inflammation and also depresses the synthesis of erythropoietin, which exerts protective effects on tissue; however, the mechanism is still unclear. We investigated the protective effect of erythropoietin against tissue damage caused by hypertension in the kidney and whether this effect was suppressed by TNF-α.. First, we detected the optimum chronic dose for darbepoetin-α (Depo), which is a long-acting erythropoietin analog for rats. We separated 60 female adult rats into 6 groups: control, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), L-NAME+Depo, L-NAME+Remicade (an anti-TNF-α antibody), L-NAME+Depo+Remicade, Depo, and control. After 1 month of treatment, we measured cardiovascular parameters, took blood samples, sacrificed the rats, and removed kidneys for analyses.. The apoptotic index and the plasma and kidney mRNA levels of TNF-α increased in the L-NAME group and decreased in all other treatment groups. Macrophage accumulation increased in the L-NAME and L-NAME+Remicade groups, while it decreased in the Depo group. The mRNA abundance of TNF receptor 1 (TNFR1) decreased slightly in the Depo group and TNFR2 increased significantly in the same group.. Erythropoietin protects kidney tissue against hypertension by preventing the apoptotic effects of TNF-α by blocking macrophage accumulation, decreasing TNF-α levels, and switching the TNF-α receptors from the apoptotic receptor TNFR1 to the proliferative receptor TNFR2.

Topics: Animals; Darbepoetin alfa; Erythropoietin; Female; Hypertension; Kidney; NG-Nitroarginine Methyl Ester; Protective Agents; Rats; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD-anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3-week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real-time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO-treated groups, compared to the CRF group, but increased in a dose-dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short-term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro-hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.

Topics: Anemia; Animals; Blood Pressure; Body Weight; Cell Hypoxia; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Inflammation; Kidney; Kidney Failure, Chronic; Male; Organ Size; Rats; Recombinant Proteins; Risk; Risk Assessment

Our aim was to study the effect of a broad range of recombinant human erythropoietin (rHuEPO) doses on hematological and biochemical parameters, blood pressure (BP), renal function and damage in the rat, focusing on endothelial nitric oxide synthase (eNOS) and hypoxia-inducible factors (HIFs). Male Wistar rats were divided in 5 groups receiving different doses of rHuEPO (100, 200, 400 and 600IU/kg body weight (BW)/week) and saline solution (control), during 3weeks. Blood and 24h urine were collected to perform hematological and biochemical analysis. BP was measured by the tail-cuff method. Kidney tissue was collected to mRNA and protein expression assays and to characterize renal lesions. A dose-dependent increase in red blood cells count, hematocrit and hemoglobin levels was found with rHuEPO therapy, in rHuEPO200, rHuEPO400 and rHuEPO600 groups. Increased reticulocyte count was found in rHuEPO400 and rHuEPO600 groups. BP raised in all groups receiving rHuEPO. The rHuEPO200 and rHuEPO600 groups presented increased kidney protein levels of HIF2α, a reduction in kidney protein levels of eNOS, and the highest grade of vascular and tubular renal lesions. Our study showed that rHuEPO-induced hypertension is present before significant hematological changes occur and, therefore, might involve direct (renal) and indirect (hematological) effects, which varies according to the dose used. The presence of renal hypoxia reduces eNOS activity. Excessive erythrocytosis increases blood hyperviscosity, which can be modulated by an increase in reticulocytes. Hypertension leads to early renal damage without alterations in traditional markers of renal function, thus underestimating the serious adverse effects and risks.

Topics: Animals; Blood Cell Count; Blood Pressure; Dose-Response Relationship, Drug; Erythropoietin; Gene Expression; Hemoglobins; Hypertension; Kidney; Male; Nitric Oxide Synthase Type III; Polycythemia; Rats; Rats, Wistar; Recombinant Proteins; Reticulocytes

A 38-year-old woman, obese (219 kg), diabetic, hypertensive, chronic kidney disease (CKD) stage 4, with low plasma albumin level (2.9 g dl(-1)) and marked proteinuria (22 g per day) was studied. Given the advanced-stage CKD with nephrotic proteinuria, we supplemented low-protein diet with high doses of a tailored essential amino acid mixture (AAs: 44 g per day) to improve weight reduction in the patient. After 20 months of conservative therapy, the patient lost 43 kg; despite two episodes of infection, albumin plasma levels increased up to 3.7 g per day. After a further 20 months of dialysis, the patient maintained a diet of 1800 kcal supplemented with 32 g of AAs and lost 47 kg, whereas both albumin (3.89±0.12 g dl(-1)) and C reactive protein returned to normal. During the follow-up period, anemia improved, erythropoietin was thus discontinued and insulin requirement decreased to 105 IU. This therapeutic option may be beneficial in advanced CKD patients with obesity and diabetes resulting from malnutrition.

Topics: Adult; Amino Acids, Essential; Amphetamine; Anemia; Body Mass Index; C-Reactive Protein; Diet, Protein-Restricted; Dietary Supplements; Energy Intake; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Obesity, Morbid; Patient Compliance; Proteinuria; Quality of Life; Renal Insufficiency, Chronic; Serum Albumin; Treatment Outcome; Waist Circumference

Approximately 30% of the chronic kidney disease patients using recombinant human erythropoietin (rhuEPO) have an increase in blood pressure (BP). Its mechanism and whether it depends on renal function remain unclear. There is early evidence that acetylsalicylic acid (ASA) prevents the rhuEPO-induced increase in BP. This study aims to verify whether very high doses of rhuEPO can increase BP in nonuremic rats and whether the co-administration of ASA can prevent it.. Forty male Wistar rats were divided into four groups: placebo/placebo; placebo/rhuEPO 200 UI/kg thrice weekly; placebo/ASA 50 mg/kg daily; rhuEPO 200 UI/kg thrice weekly/ASA 50 mg/kg daily. Hematocrit was measured before and after and systolic BP was measured weekly by tail-cuff technique. Direct measurement of the BP was obtained at the end.. The rhuEPO groups had higher final hematocrit (rhuEPO/placebo 56.7 ± 7.6, rhuEPO/ASA 56.7 ± 7.7; p < 0.001 versus placebo/placebo, 42.2 ± 4.7 and ASA/placebo 41.2 ± 4.2); and also increase in systolic BP (rhuEPO/placebo 135.1 ± 15.0, p = 0.01 and rhuEPO/ASA 127.2 ± 6.8, p = 0.02), whereas BP in rats from placebo/placebo (120.9 ± 5.0, p = 0.18) and placebo/ASA (124.6 ± 13.3, p = 0.12) groups remained unchanged. By direct measurement, the final BP was higher in rhuEPO/placebo (DBP 123.1 ± 12.0; SBP 157.4 ± 12.5; MBP 139.8 ± 11.9) than placebo/placebo (DBP 105.1 ± 11.5; SBP 141.0 ± 12.6; MBP 122.1 ± 12.1) and placebo/ASA groups (DBP 106.6 ± 8.1; SBP 141.5 ± 8.4, MBP 122.1 ± 7.2) (p < 0.05 by post hoc Bonferroni test ANOVA). The rhuEPO/ASA group (PAD 115.1 ± 11.4, PAS 147.4 ± 9.1, MBP 130.1 ± 10.3) was not different from other groups.. The administration of very high doses of rhuEPO is associated with an increase in hematocrit and BP in nonuremic rats. The concomitant use of ASA mitigates the rhuEPO-associated BP increase.

Topics: Anemia; Animals; Aspirin; Blood Pressure; Disease Models, Animal; Drug Monitoring; Erythropoietin; Hematinics; Hypertension; Kidney Failure, Chronic; Male; Rats; Rats, Wistar; Treatment Outcome

In chronic kidney disease (CKD), anemia and hypertension are significant co-morbidities that contribute to cardiovascular and renal disease progression.. The purpose of the study was to identify correlations between changes in hematologic variables against markers of renal function, blood pressure, and erythropoietin (EPO) in a naturally occurring hypertensive model of CKD, the Lewis polycystic kidney (LPK) rat.. Complete blood count, systolic blood pressure, urea and creatinine concentration, urinary protein to creatinine ratio, and plasma EPO concentration were determined in control Lewis (n = 51) and LPK rats (n = 56) aged 6-24 weeks. Renal EPO gene expression and RBC osmotic fragility were also documented. Hematopoiesis in spleen and bone marrow were assessed.. Lewis polycystic kidney rats had increasing urea and creatinine concentrations, concurrent with the development of a nonregenerative normocytic/normochromic anemia and hypertension, with a significant negative correlation between both HGB and HCT with urea concentration and blood pressure (P < .01). HCT was also significantly negatively correlated with creatinine concentration (P = .014). WBC was significantly negatively correlated with urea (P < .01). Plasma EPO concentration was increased and renal EPO mRNA expression was significantly upregulated in LPK animals. The former was significantly positively correlated with blood pressure and platelet count (P < .05). RBC osmotic fragility was normal in LPK rats and there was no evidence for increased RBC elimination or extramedullary hematopoiesis.. Marked anemia in the LPK CKD rodent model in the presence of elevated EPO suggests inefficient erythropoiesis that is correlated with plasma urea concentration and blood pressure.

Topics: Anemia; Animals; Blood Cell Count; Blood Pressure; Blood Urea Nitrogen; Cohort Studies; Creatinine; Disease Models, Animal; Disease Progression; Erythropoietin; Female; Hypertension; Kidney; Kidney Function Tests; Male; Polycystic Kidney Diseases; Rats; Rats, Inbred Lew; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients.. This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated.. No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA.. It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Humans; Hypertension; Male; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies

Erythropoietin (ERO) is known to be the main regulator of proliferation and terminal dissociation of erythroid cells. Its receptors are expressed not only in hematopoietic cells but also in the tissues of the cardiovascular system. The aim of this work was to study specific features of circadian rhythm in erythropoietin synthesis and estimate the predictive informative value of serum ERO level variations as regards the risk of developing cardiovascular complications in patients with stage II essential arterial hypertension (EAH). ERO, neopterin, and interleukin-1 levels were measured in 200 such patients. It was shown that ERO levels increased (p < 0.001) compared with normal values (12.6 pg/ml, 95% CI 11.8-13.4 and 68 pg/ml, 95% CI 6.4-7.2 respectively). Analysis of circadian rhythm demonstrated that enhanced probability of complications in the absence of reduction of the ERO level at night time correlated with the decreased number of CD34 cells (p < 0.001) and the increased neopterin level (p < 0.001). It is concluded that these dependences suggest the necessity of further studies of yet unknown effects of ERO and ways of their application for the treatment of EAH.

Topics: Biomarkers; Blood Pressure; Circadian Rhythm; Disease Progression; Erythropoietin; Essential Hypertension; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Prognosis

Clinical guidelines recommend concurrent treatment of anemia in end-stage renal disease with erythropoiesis-stimulating agents (ESAs) and iron. However, there are mixed data about optimal iron supplementation. To help address this gap, the relationship between iron markers and hemoglobin (Hb) response to ESA (Epoetin alfa) dose was examined. Electronic medical records of 1902 US chronic hemodialysis patients were analyzed over a 12-month period between June 2009 and June 2010. The analysis included patients who had at least one Hb value during each 4-week interval for four consecutive intervals (k - 2, k - 1, k, and k + 1; k is the index interval), received at least one ESA dose during intervals k - 1 or k, had at least one transferrin saturation (TSAT) value at interval k, and at least one ferritin value during intervals k - 2, k - 1, or k. Effect modification by TSAT and ferritin on Hb response was evaluated using the generalized estimating equations approach. Patients had a mean (standard deviation) age of 62 (15) years; 41% were Caucasian, 34% African American, 65% had hypertension, and 39% diabetes. Transferrin saturation, but not ferritin, had a statistically significant (P < 0.05) modifying effect on Hb response. Maximum Hb response was achieved when TSAT was 34%, with minimal incremental effect beyond these levels. Of the two standard clinical iron markers, TSAT should be used as the primary marker of the modifying effect of iron on Hb response to ESA. Long-term safety of iron use to improve Hb response to ESA warrants further study.

Topics: Diabetes Mellitus; Electronic Health Records; Epoetin Alfa; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Models, Biological; Practice Guidelines as Topic; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis; United States

Erythropoietin used to correct anaemia in chronic kidney disease (CKD) has been shown to increase blood pressure (BP) in CKD patients and experimental animals. Endothelin (ET)-1 expression is increased in CKD animals and patients, and enhanced by erythropoietin. Erythropoietin-induced BP rise was blunted by ETA receptor blockers. This study was designed to determine whether preexisting endothelin (ET)-1 overexpression is required for erythropoietin to cause adverse vascular effects and whether this could be prevented by exercise training.. Eight to 10-week old male wild-type mice and mice with endothelial-specific ET-1 overexpression (eET-1) were treated or not with EPO (100  IU/kg, SC, 3  times/week). eET-1 was subjected or not to swimming exercise training (1  h/day, 6 days/week) for 8 weeks. SBP, mesenteric artery endothelial function and remodelling, NADPH oxidase activity, reactive oxygen species (ROS) generation, vascular cell adhesion protein (VCAM)-1, monocyte/macrophage infiltration, T regulatory cells (Tregs) and tissue ET-1 and plasma endothelin were determined.. Erythropoietin increased SBP by 24  mmHg (P < 0.05) and decreased by 25% vasodilatory responses to acetylcholine (P < 0.01) in eET-1 mice. Erythropoietin enhanced ET-1 induced increase in resistance artery media/lumen ratio (31%, P < 0.05), aortic NADPH oxidase activity (50%, P < 0.05), ROS generation (93%, P < 0.001), VCAM-1 (80%, P < 0.01) and monocyte/macrophage infiltration (159%, P < 0.001), and raised plasma and aortic ET-1 levels (≥130%, P < 0.05). EPO had no effect in wild-type mice. Exercise training prevented all of the above (P < 0.05).. Erythropoietin-induced adverse vascular effects are dependent on preexisting elevated ET-1 expression. Exercise training prevented erythropoietin-induced adverse vascular effects in part by inhibiting ET-1 overexpression-induced oxidative stress, inflammation and immune activation.

Topics: Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Immune System; Inflammation; Male; Mice; Mice, Transgenic; NADPH Oxidases; Oxidative Stress; Physical Conditioning, Animal; Reactive Oxygen Species; Swimming; Systole

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Drug Evaluation; Epoetin Alfa; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Hematocrit; Humans; Hypertension; Kaplan-Meier Estimate; Male; Multicenter Studies as Topic; Myelodysplastic Syndromes; Prognosis; Proportional Hazards Models; Recombinant Proteins; Retrospective Studies; Thrombosis

Management of hypertension is one of the fundamental interventions in dialysis patients. However, the profile of interdialytic blood pressure (BP) in Chinese dialysis patients remains elusive. We aim to investigate this issue as well as the effect of antihypertensive medication in this population. We performed 44-h ambulatory BP in 90 patients on maintenance hemodialysis. Patients were classified as 'dipping', 'non-dipping' or 'reverse-dipping' based on night/day ratio (N/D) of systolic BP on nondialysis day. The prevalence of blunted circadian BP pattern was strikingly high (92.2%), with more than half of the patients (55.6%) classified as reverse-dipping. There was a close association between high erythropoietin (EPO) dose used and deteriorated circadian rhythm. Patients in the dipping group also displayed a dipping state for heart rate (HR) compared with the other two groups (N/D of HR: 81.5 ± 6.6 vs 92.1 ± 6.0 and 91.3 ± 10.7, P=0.02). Only 26.7% patients had a controlled nocturnal BP. Patients with bedtime dosing had lower N/D of systolic BP compared with patients without (100.1 ± 7.0 vs 105.2 ± 7.1, P=0.01). Non-dipping and reverse-dipping are highly prevalent in Chinese patients. EPO use and autonomic dysfunction may contribute to the blunted circadian rhythm. More tightly control of nighttime BP is an urgent need and bedtime dosing may be beneficial.

Topics: Adult; Aged; Antihypertensive Agents; Asian People; Autonomic Nervous System; Blood Pressure; China; Circadian Rhythm; Cross-Sectional Studies; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Humans; Hypertension; Male; Middle Aged; Prevalence; Renal Dialysis; Risk Factors; Time Factors

Anemia is among the most important complications of chronic kidney disease (CKD) and a lot of symptoms and signs are due to this problem. Erythropoietin injection may improve anemia, but it may cause hypertension in these patients. The aim of this study is to evaluate erythropoietin injection effects on blood pressure of hemodialysis and predialysis patients.. Forty hemodialysis patients and 40 predialysis patients with end-stage renal disease were enrolled in the study. The studied patients were comparable in terms of age, sex, hemoglobin, serum calcium, and baseline blood pressure. Erythropoietin was injected for all of the patients with anemia (4000 U, twice weekly). The effect of erythropoietin on their blood pressure was evaluated for each group by comparison of systolic, diastolic, and mean arterial blood pressure values before and 1 hour after the injection.. After erythropoietin injection, systolic, diastolic, and mean arterial blood pressure values increased significantly in the hemodialysis group, and the increases were significantly greater in this group than the predialysis group (P = .02, P = .01, and P = .02, respectively). Blood pressure increase was significant only for the systolic component in the predialysis group.. Erythropoietin injection increases blood pressure levels in both groups. However, this is more significant in the hemodialysis patients as compared with patients with end-stage renal disease who have not started dialysis. Monitoring of blood pressure after erythropoietin injection is recommended.

Topics: Adult; Anemia; Arterial Pressure; Erythropoietin; Female; Hematinics; Humans; Hypertension; Injections; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors; Treatment Outcome

Erytropoietin (EPO) has cytoprotective and angiogenic properties and has a beneficial effect in ischaemic conditions. Since the development of renal interstitial abnormalities are often associated with ischaemia, we studied the effects of the long-acting EPO analogue darbepoetin alpha (DA) on kidney damage in TGR(mRen2)27 (Ren2) rats.. Ren2 rats were randomised to DA or vehicle (VEH) or to DA + angiotensin converting enzyme inhibitor (ACEi) or VEH + ACEi. Sprague Dawley (SD) rats served as controls. Blood pressure was measured weekly and 24-h urine was collected to measure proteinuria. Blood samples were collected for creatinine and haematocrit. Kidneys were studied for inflammation and pre-fibrosis. Renal mRNA expression was studied for EPO, EPO-receptor, collagen-3α1 and kidney injury molecule-1 (KIM-1).. DA had no effect on SBP, serum creatinine and proteinuria. Interstitial and glomerular α-SMA expression was significantly increased in Ren2. ACEi but not DA improved the increased renal inflammatory and pro-fibrotic profile in Ren2 rats. DA on top of ACEi further reduced glomerular α-SMA and KIM-1 expression.. Long-term DA treatment has no beneficial effects on renal structural and functional changes in TGR(mRen2)27 rats in the time frame studied and the dose provided.

Topics: Actins; Animals; Cell Adhesion Molecules; Cell Count; Collagen Type III; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Hypertension; Kidney; Kidney Glomerulus; Macrophages; Male; Rats; Receptors, Erythropoietin; RNA, Messenger; Time Factors

Erythropoietin (EPO), used clinically for renal anemia, reportedly exerts beneficial pleiotropic effects in various tissues. Recent studies suggest that nitric oxide (NO) plays an important role in EPO-induced tissue protection. The present study investigated whether recombinant human EPO (rHuEPO) exhibits vasoprotective effects even in the NO synthase-inhibited state. Rats that received a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in drinking water (0.7 mg/ml) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. The administration of rHuEPO to L-NAME-treated rats had no effect on hematocrit values or increased blood pressure. Vasodilation in response to acetylcholine in the aortic ring was impaired in the L-NAME-treated rats, and improved by rHuEPO. Immunohistochemical staining revealed that infiltration by macrophages and expression of osteopontin were enhanced in the L-NAME-treated rat aorta, and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Activation of Akt signaling was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt. rHuEPO enhanced the expression of antioxidant enzymes such as Cu/Zn-superoxide dismutase and heme oxygenase-1 in the aorta. In addition, rHuEPO reduced NADPH oxidase-dependent superoxide production and enhanced the expression of suppressor of cytokine signaling-1(SOCS-1) in the L-NAME-treated rat aorta. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function and vascular inflammation beyond hematopoiesis even in a pharmacologically NO synthase-inhibited state. These effects might be due to the antioxidant properties of rHuEPO. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation.

Topics: Acetylcholine; Adventitia; Animals; Aorta; Blood Pressure; Body Weight; Erythropoietin; Gene Expression Regulation; Hematocrit; Heme Oxygenase-1; Humans; Hypertension; Inflammation; Macrophages; Male; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Osteopontin; Phosphoproteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Superoxide Dismutase; Superoxides; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins

Increased ferritin concentrations are associated with metabolic syndrome (MetS). The association between ferritin as well as hemoglobin level and individual MetS components is unclear. Erythropoietin levels in subjects with MetS have not been determined previously. The aim of this study was to compare serum erythropoietin, ferritin, haptoglobin, hemoglobin, and transferrin receptor (sTFR) levels between subjects with and without MetS and subjects with individual MetS components.. A population based cross-sectional study of 766 Caucasian, middle-aged subjects (341 men and 425 women) from five age groups born in Pieksämäki, Finland who were invited to a health check-up in 2004 with no exclusion criteria. Laboratory analyzes of blood samples collected in 2004 were done during year 2010. MetS was defined by National Cholesterol Education Program criteria.. 159 (53%) men and 170 (40%) women of study population met MetS criteria. Hemoglobin and ferritin levels as well as erythropoietin and haptoglobin levels were higher in subjects with MetS (p < 0.001, p = 0.018). sTFR level did not differ significantly between subjects with or without MetS. Hemoglobin level was significantly higher in subjects with any of the MetS components (p < 0.001, p = 0.002). Ferritin level was significantly higher in subjects with abdominal obesity or high TG or elevated glucose or low high density cholesterol component (p < 0.001, p = 0.002, p = 0.02). Erythropoietin level was significantly higher in subjects with abdominal obesity component (p = 0.015) but did not differ significantly between subjects with or without other MetS components. Haptoglobin level was significantly higher in subjects with blood pressure or elevated glucose component o MetS (p = 0.028, p = 0.025).. Subjects with MetS have elevated hemoglobin, ferritin, erythropoietin and haptoglobin concentrations. Higher hemoglobin levels are related to all components of MetS. Higher ferritin levels associate with TG, abdominal obesity, elevated glucose or low high density cholesterol. Haptoglobin levels associate with blood pressure or elevated glucose. However, erythropoietin levels are related only with abdominal obesity. Higher serum erythropoietin concentrations may suggest underlying adipose tissue hypoxemia in MetS.

Topics: Biomarkers; Case-Control Studies; Chi-Square Distribution; Cross-Sectional Studies; Dyslipidemias; Erythropoietin; Female; Ferritins; Finland; Glucose Metabolism Disorders; Haptoglobins; Hemoglobins; Humans; Hypertension; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Receptors, Transferrin; Up-Regulation; White People

The objective of this study was to examine the hypothesis that hypertensive hypertrophy is vulnerable to infarction and defective in cytoprotective mechanisms by modification of intracellular signaling and mitochondrial proteins. Myocardial infarction was induced by 20-minute coronary occlusion/reperfusion in spontaneously hypertensive stroke-prone rats (SHR-SPs) and their controls (Wistar-Kyoto rats [WKYs]). Infarct size expressed as a percentage of area-at-risk was larger by 29% in SHR-SPs than in WKYs. Pretreatment with erythropoietin (EPO) significantly limited infarct size in WKYs but not in SHR-SPs. Ca(2+) retention capacity of mitochondria, an index of the threshold for opening of the mitochondrial permeability transition pore, on reperfusion was reduced in SHR-SPs compared with that in WKYs. Suppression of reactive oxygen species by N-(2-mercaptopropionyl)-glycine increased Ca(2+) retention capacity after reperfusion and limited infarct size in SHR-SPs to levels in WKYs. EPO induced phosphorylation of Akt, extracellular signal-related kinase, and glycogen synthase kinase-3β in the myocardium in both WKYs and SHR-SPs. EPO enhanced interaction of phospho-glycogen synthase kinase-3β and adenine nucleotide translocase on reperfusion in WKYs, although such an effect of EPO was not detected in SHR-SPs. The results suggest that enhanced opening of mitochondrial permeability transition pores by reactive oxygen species and modification of the signal downstream of phospho-glycogen synthase kinase-3β in the mitochondria underlie the increased vulnerability to infarction and the lack of anti-infarct tolerance by EPO, respectively, in hypertensive hypertrophied hearts.

Topics: Animals; Calcium; Cardiomegaly; Erythropoietin; Hypertension; Male; Mitochondria, Heart; Mitochondrial ADP, ATP Translocases; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Infarction; Myocardium; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Risk Factors; Tiopronin

Heart failure (HF)-associated anemia is common and has a poor outcome. Because bone marrow (BM) dysfunction may contribute to HF-associated anemia, we first investigated mechanisms of BM dysfunction in an established model of HF, the transgenic REN2 rat, which is characterized by severe hypertrophy and ventricular dilatation and SD rats as controls. Secondly, we investigated whether stimulation of hematopoiesis with erythropoietin (EPO) could restore anemia and BM dysfunction. After sacrifice, erythropoietic precursors (BFU-E) were isolated from the BM and cultured for 10 days. BFU-E were quantified and transcript abundance of genes involved in erythropoiesis were assayed. Number of BFU-E were severely decreased in BM of REN2 rats compared to SD rats (50 ± 6.2 vs. 6.4 ± 1.7, p < 0.01). EPO treatment increased hematocrit in the SD-EPO group (after 6 weeks, 49 ± 1 vs. 58 ± 1%, p < 0.01); however, in the mildly anemic REN2 rats, there was no effect (43 ± 1 vs. 44 ± 1%). This was paralleled by a 67% decrease in BFU-E in BM of REN2 rats compared to SD (p < 0.01). EPO significantly improved BFU-E in both SD and REN2 but could not restore this to control levels in the REN2 rats. Expression of several genes involved in differentiation (LMO2), mobilization (SDF-1), and iron incorporation (transferrin receptor) of the BM were differentially expressed in REN2 rats compared to SD rats, and EPO did not normalize this. Altogether, these results suggest that BM dysfunction is an important contributor to HF-associated anemia and that EPO is not an effective agent to treat HF-associated anemia.

Topics: Anemia; Animals; Bone Marrow; Cell Differentiation; Erythroid Cells; Erythropoietin; Gene Expression Regulation; Heart Failure; Hematopoiesis; Hematopoietic Stem Cells; Hypertension; Iron; Male; Random Allocation; Rats; Rats, Sprague-Dawley

Recombinant human erythropoietin (rHuEPO), used clinically for renal anemia, reportedly exhibits pleiotropic properties in various tissues. To test whether it ameliorates vascular injury, rHuEPO (75U/kg) was administered subcutaneously every 3days for 10days to 5/6 nephrectomized hypertensive rats (5/6Nx) treated with 1% NaCl. rHuEPO had no effect on increased systolic blood pressure or decreased hematocrit values, but normalized levels of proteinuria and creatinine clearance. Vasodilation in response to acetylcholine in the aortic ring was impaired in the 5/6Nx, and improved by treatment with rHuEPO. Immunohistochemical analysis revealed that the infiltration of adventitial areas by macrophages and expression of osteopontin were enhanced in the 5/6Nx aorta and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Akt signaling was activated by the increased expression of phosphorylated Akt and GSK-3β in aorta from rHuEPO-treated 5/6Nx. rHuEPO restored plasma NOx (NO(2)(-)+NO(3)(-)) levels and endothelial nitric oxide synthase (eNOS) content in the 5/6Nx aorta. Treatment with an eNOS substrate, l-arginine, which caused a similar increase in plasma NOx levels as the rHuEPO treatment, resulted in a normalization of endothelial dysfunction and vascular inflammation. These results suggest that a low dose of rHuEPO exerted vasoprotective effects in rats with hypertensive renal failure.

Topics: Acetylcholine; Animals; Aorta; Aorta, Thoracic; Blood Pressure; Body Weight; Connective Tissue; Dose-Response Relationship, Drug; Endothelium, Vascular; Erythropoietin; Gene Expression Regulation, Enzymologic; Hematocrit; Hematopoiesis; Humans; Hypertension; Macrophages; Male; Nephrectomy; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrogen Dioxide; Nitrogen Oxides; Nitroprusside; Osteopontin; Phosphoproteins; Rats; Rats, Wistar; Recombinant Proteins

To ascertain mechanisms of development of left ventricular hypertrophy (LVH) and possible cardioprotective action of anemia correction in patients with end-stage renal disease.. A total of 98 patients (53 females and 45 males aged 49.4 +/- 14 years) on hemodialysis participated in the study. The patients were examined clinically with estimation of the levels of parathormone, calcium, phosphorus, erythrocytic indices, serum ferritin, blood transferrin. Echocardiography with dopplerography on Aloka-4000 unit were made. Left ventricular geometry was assessed by J. Gottdiener classification. Therapeutic policy aimed at correction of anemia, arterial hypertension, phosphorus-calcium metabolism.. The patients were treated and followed up for 18 months. The examination was done before treatment, 12 and 18 months later. After the trial the patients were divided into 4 groups depending on the results obtained on LVH development. Blood pressure, hemoglobin, echocardiographic parameters changed according to the patient's group. After 18 months of observation and treatment with erythropoietin and iron preparations, ACE inhibitors, angiotensin II receptor blockers, beta-adrenoblockers, drugs regulating phosphorus-calcium metabolism some cases were seen of reduction of systolic blood pressure, achievement of target hemoglobin level, regression of LVH.. Combined treatment of hemodialysis patients including antianemic, antihypertensive drugs promoted improvement of LVH or its regression in some cases.

Topics: Adrenergic beta-Antagonists; Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Combined Modality Therapy; Erythropoietin; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Iron; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Blood Pressure; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Myocardial Infarction; Myocardial Reperfusion; Recombinant Proteins; Stents; Thrombosis

Traditionally, erythropoietin (EPO) is described as a hematopoietic cytokine, regulating proliferation and differentiation and survival of the erythroid progenitors. The recent finding of new sites of EPO production and the wide spread distribution of EPO receptors (EPO-R) on endothelial cells, cardiomyocytes, renal cells as well as the central and peripheral nervous system raised the possibility that EPO may exert pleiotropic actions on several targets. Indeed studies (mainly preclinical) have documented protective, non-hematopoietic, abilities of EPO in a variety of tissue. However, the data obtained from clinical studies are more skeptical about these properties. This article provides a comprehensive overview of EPO and its derivatives.

Topics: Anemia; Cardiotonic Agents; Cytoprotection; Erythropoietin; Hypertension; Kidney; Neoplasms; Neuroprotective Agents; Receptors, Erythropoietin; Thrombosis

Erythropoietin (EPO) administration in uremic rats leads to an increase in blood pressure (BP). Because chronic renal failure has been associated with oxidative stress, we hypothesize that EPO treatment could accentuate this condition and contribute to hypertension. The present study was designed to investigate the role of reactive oxygen species in EPO-induced hypertension and the effect of tempol, a superoxide dismutase-mimetic.. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 3-week stabilization period. Uremic rats were divided into four groups and received for 4 weeks: vehicle; EPO (100 U/kg, subcutaneously, three times per week); vehicle + tempol (1 mmol/l in drinking water); and EPO + tempol. Systolic BP and biochemical parameters were assessed before and at the end of the treatment. Renal histology, creatinine clearance rate, endothelin-1 (ET-1) concentrations and superoxide anion production were assessed at the end of the study.. The uremic rats developed anemia and hypertension. ET-1 concentrations and superoxide anion production were increased. EPO administration corrected anemia, but accentuated hypertension and renal injuries such as glomerulosclerosis, interstitial fibrosis, and inflammation. EPO therapy further increased tissue levels of ET-1 and superoxide anion production. Tempol treatment improved hypertension and renal injury, and reduced ET-1 concentrations and superoxide anion production.. Oxidative stress contributes to the development of hypertension and to the progression of renal injuries in uremic rats. EPO administration further increases oxidative stress, which might partly account for the accentuation of hypertension and renal injury.

Topics: Anemia; Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hypertension; Kidney Failure, Chronic; Male; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins; Uremia

Topics: Anemia; Animals; Chronic Disease; Erythropoietin; Humans; Hypertension; Kidney Diseases; Oxidative Stress; Rats; Recombinant Proteins

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

Endothelial nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) contribute to erythropoietin (EPO)-induced hypertension, a major adverse reaction associated with EPO therapy. To investigate the mechanism of EPO-induced hypertension, we examined circulating endothelial progenitor cells (EPCs) taken from 56 hemodialysis (HD) patients. Among these EPCs (which reflect the condition of the endothelium), we looked for EPO receptor (EPOR) mRNAs. A truncated form of EPOR acts as a dominant negative regulator of EPO signaling, leading to hypertension. We found that the ratio of truncated EPOR mRNA in EPCs has a correlation with EPO-induced increase in blood pressure (r = 0.36, P = 0.02). The ratio of truncated to total EPOR mRNA in EPCs had an inverse correlation with EPO-induced cGMP production in vitro (r = -0.31, P = 0.02). A similar correlation was observed in cultured human endothelial cells after transfection of the full-length or truncated forms of EPOR (r = -0.92, P < 0.001). It follows, therefore, that evaluation of EPOR isoform mRNA in EPCs can predict EPO-induced hypertension. The termination of the EPO signal by truncated EPORs may decrease NO/cGMP production after EPO exposure, thereby raising blood pressure.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cells, Cultured; Cyclic GMP; DNA, Complementary; Endothelial Cells; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Nitric Oxide; Polymerase Chain Reaction; Receptors, Erythropoietin; Recombinant Proteins; Renal Dialysis; RNA, Messenger; Signal Transduction; Stem Cells; Transfection; Up-Regulation

Deferasirox is a new iron chelator approved recently for chelation therapy in iron-overloaded patients. It is considered safe and efficacious in most patients, but has not been tested formally in patients with end-stage renal disease. We report a case of a patient with end-stage renal disease secondary to sickle cell nephropathy who developed recurrent symptomatic hypocalcemia while on therapy and later reexposure with this medication for iron overload from long-term blood transfusions. This is the first case report of this complication with deferasirox therapy in a patient with end-stage renal disease.

Topics: Adult; Anemia, Sickle Cell; Benzoates; Deferasirox; Erythropoietin; Female; Humans; Hypertension; Hypocalcemia; Iron Chelating Agents; Iron Overload; Kidney Failure, Chronic; Peritoneal Dialysis; Transfusion Reaction; Triazoles

Hypertension is an uncommon but significant problem in high-risk neonates and infants, and the spectrum of potential causes is broad. Here, we describe an extremely premature infant (birth weight, 728 g; gestational age, 27 weeks) with multiple complications and hypertension. During admission, umbilical artery catheters were used for a period of time, and he suffered from respiratory distress syndrome, intraventricular hemorrhage, pulmonary hemorrhage, patent ductus arteriosus, pericardial effusion, heart failure, repeated sepsis, anemia, thrombocytopenia, chronic lung disease, and progressive liver damage. He was treated with multiple medications, including erythropoietin, indomethacin, epinephrine, dopamine, aminophylline, multiple antibiotics, amphotericin B, and total parenteral nutrition. Hypertension was first noted when he was 41 days old, with spontaneous remission. It then recurred, reaching higher than 100 mmHg when he was almost 4 months old. After stopping erythropoietin, hypertension subsided for a short period of time and went up again. Multiple factor-related hypertension in this premature infant was considered. Related literature on hypertension in premature infants is reviewed. In conclusion, multiple factors can influence blood pressure and may induce hypertension in high-risk premature infants. Thus, blood pressure should be closely monitored in high-risk premature infants. Judicious use of all medications and interventions are crucial to decrease the incidence of hypertension in high-risk premature infants.

Topics: Bronchopulmonary Dysplasia; Ductus Arteriosus, Patent; Erythropoietin; Humans; Hypertension; Infant, Newborn; Infant, Premature; Male

Angiotensin-converting enzyme inhibitors (ACI) and angiotensin II receptor blockers (ARB) have been reported to increase recombinant human erythropoietin (rHuEPO) requirements. We performed a cross-sectional study to investigate an association of antihypertensive agents including these two with the rHuEPO dose in chronic hemodialysis patients.. We studied 625 patients undergoing hemodialysis therapy in 11 dialysis units. The association between the rHuEPO dose and antihypertensive agents was statistically analyzed.. The mean hemoglobin (Hb) level and rHuEPO dose corrected by body weight were 10.5 g/dl and 95.2 U/kg/week, respectively. When the patients were subdivided into four groups according to the number of prescribed antihypertensive agents (G-0, G-1, G-2, and G-3; patients prescribed with no medication, 1, 2, and >3 drugs, respectively), a significantly low dose of rHuEPO was observed in G-0 compared to the other groups. Unpaired t test showed a higher dose of rHuEPO in the presence of ARB, alpha-blockers, or calcium channel blockers (CCB). The rHuEPO dose was higher in the elderly, in females, and in patients with diabetes or hypertension. In multiple regression analysis, age, sex, rHuEPO dose, serum albumin level, and duration of dialysis therapy but not antihypertensive drugs were independent factors for the Hb level. In contrast, the rHuEPO dose was significantly associated with a low level of Hb, age, females, and CCB use. However, since CCB use was strongly associated not only with rHuEPO dose but also with systolic blood pressure and the use of alpha-blockers and ARB, these findings might be caused by erythropoietin (EPO)-induced hypertension.. There was an association between the number of antihypertensive agents and rHuEPO dose in chronic hemodialysis patients. However, no significant relation was indicated between ARB/ACI use and EPO requirements.

Topics: Anemia; Antihypertensive Agents; Comorbidity; Cross-Sectional Studies; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Erythropoietin; Female; Humans; Hypertension; Incidence; Japan; Male; Middle Aged; Renal Dialysis

Anaemia and hypertension are common in patients with chronic renal insufficiency. The correction of anaemia with erythropoiesis stimulating agents (ESA) can improve survival and decrease the decline of renal function. Angiotensin converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (AIIRA) can also slow the progression of renal failure, but the blockade of the renin-angiotensin system can worsen anaemia. The aim of our study was to assess the impact of antihypertensive therapy (ACEI plus AIIRA) in the requirements of darbepoietin in a group of elderly predialysis patients. We included 71 patients (m = 39, f = 32), mean age of 76.3 years with a mean creatinine clearance of 17.5 ml/min. Patients were divided in two groups according to their antihypertensive therapy: G-I patients under ACEI or AIIRA therapy and G-II normotensive patients or hypertensive patients under antihypertensive drugs other than ACEI or AIIRA. The groups were compared regarding demographic, nutritional, biochemical and inflammatory parameters. We also compared the mean darbepoietin dose. In GI the mean dose of darbepoietin was higher than in GII (0.543 vs. 0.325 microg/kg/week, P = 0.032). We did not find any difference regarding other parameters analysed. We conclude that ACEI and AIIRA can increase the needs of darbepoietin in predialysis elderly patients. However, when formally indicated to treat hypertension in a specific patient, they should not be switched to another antihypertensive agent. Instead, in such cases, higher doses of ESA should be used, if necessary.

Topics: Aged; Aged, 80 and over; Anemia; Antihypertensive Agents; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Hypertension; Kidney Diseases; Male

Correction of anemia by erythropoietin (EPO) is often associated with a rise in blood pressure (BP; EPO-induced hypertension). Most studies regarding EPO-induced hypertension have involved evaluation using office/clinic BP (OBP). However, recent investigations suggest that BP measured at home (HBP) may be of more importance for clinical practice in hypertension. In this context, the present study addressed whether or not HBP measured in the morning could be useful to predict EPO-induced hypertension.. The study involved patients with mild to moderate renal impairment who had renal anemia requiring EPO treatment. BP control was evaluated based on the relationship between OBP and HBP in the morning. The BP categories used were well-controlled BP, poorly controlled BP, hypertension with a white-coat effect (white-coat hypertension), and masked hypertension. Comparison was made of the BP categories before and after EPO treatment.. Before EPO treatment, 38% of patients had well-controlled BP, 30% had poorly controlled BP, 20% had masked hypertension, and 12% had white-coat hypertension, revealing a predominance of morning hypertension (poorly controlled BP plus masked hypertension). Following EPO treatment, the prevalence of morning hypertension in patients with masked hypertension and poorly controlled BP increased significantly, by 5% (HBP in those with masked hypertension increased from 152 +/- 18 mmHg to 162 +/- 25 mmHg, and HBP in those with poorly controlled BP increased from 157 +/- 18 mmHg to 168 +/- 25 mmHg; P < 0.05 by paired t-test). And there was a significant decrease in the prevalence of the well-controlled category, by 8%, with an increased level of morning HBP (from 128 +/- 14 mmHg to 137 +/- 16 mmHg; P < 0.05 by paired t-test). In contrast, OBP remained unchanged in all groups. The development of EPO-induced hypertension was effectively predicted by HBP in the morning (from 62% to 72% before and after EPO treatment; P = 0.0031 by Wilcoxon's analysis), but not by OBP (from 42% to 47% before and after treatment; P = 0.1399).. The present study indicates that, despite receiving concurrent antihypertensive therapy, the majority of patients with renal disease had morning hypertension. Furthermore, HBP in the morning can be more useful than OBP to predict the development of EPO-induced hypertension in patients with renal anemia.

Topics: Aged; Aged, 80 and over; Anemia; Blood Pressure Determination; Erythropoietin; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Time Factors

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Meta-Analysis as Topic

Hypertension is the most significant complication from treatment with erythropoietin (Epo). Can Epo-induced hypertension be eliminated? We examined systemic and local effects of our genetically engineered products, Epo-binding protein (Epo-bp) and anti-Epo-bp antibodies, on randomly assigned Sprague-Dawley rats at midnight, 4 am, 8 am, noon, 4 pm, and 8 pm. Blood pressure, hematocrit, and body weight were measured immediately before and after the completion of a 4-week, twice-weekly course of Epo (50 U/kg), Epo-bp, anti-Epo-bp antibodies, or physiological saline injections. Epo treatment increased hematocrit markedly overall as compared with the saline, Epo-bp, and anti-Epo-bp antibody groups (0.616 versus 0.427, 0.439, and 0.441, respectively) and at each of the 6 test times (all P<0.0001). Epo-bp and anti-Epo-bp antibody treatment with Epo had almost no effect on the Epo-induced hematocrit increase (0.616 versus 0.580 or 0.591, respectively). Circadian blood pressures for Epo versus saline, Epo-bp, and anti-Epo-bp antibody groups were 136.2+/-2.3 versus 116.2+/-1.7, 118.4+/-2.1, and 116.6+/-2.1 mm Hg, respectively (each P<0.0001). Significantly increased blood pressure was detected at noon, 4 pm, 8 pm, and midnight in Epo treatment. When Epo was given with Epo-bp or anti-Epo-bp antibodies, blood pressure was maintained at similar levels as in saline treatment (each P<0.0001) as compared with Epo treatment alone. Overall, body, brain, and heart weights were significantly lower in Epo treatment than those of other groups. Thus, Epo-bp and anti-Epo-bp antibodies eliminate Epo-induced hypertension without affecting hematocrit and blood volume.

Topics: Animals; Blood Pressure Determination; Body Weight; Circadian Rhythm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematocrit; Hypertension; Probability; Protein Binding; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reference Values; Risk Factors; Sensitivity and Specificity

Ghrelin is a recently discovered protein hormone mainly synthesized in the gastric endocrine cells. This hormone not only is a potent growth hormone secretagogue but also is involved in the regulation of food ingestion and energy metabolism. Derangements in ghrelin secretion in patients with chronic renal failure (CRF) have not been fully evaluated.. Our aim has been to quantify serum concentrations of total ghrelin in a group of patients with CRF on chronic therapy with both haemodialysis (HD) and peritoneal dialysis (PD) in comparison with a group of patients on conservative management (predialysis).. We studied 68 CRF patients treated by HD (n = 30, 16 men, age 61.2 +/- 1.8 years) and PD groups (n = 38, 21 men, age 54.4 +/- 1.7 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of ghrelin, leptin, insulin, IGF I and GH were measured in all subjects.. Patients undergoing HD showed similar concentrations of ghrelin in comparison with the control group (9491 +/- 787 vs 9280 +/- 918 pg/ml, NS). However, PD patients exhibited baseline ghrelin concentrations significantly lower than those found in patients on conservative management (3230 +/- 216 pg/ml, P < 0.0001). Men and women showed similar serum ghrelin levels in both HD (9845.9 +/- 1071 vs 9085 +/- 1194 pg/ml) and PD patients (3214 +/- 297 vs 3250 +/- 324 pg/ml). Hypertension and diabetes mellitus did not influence ghrelin levels. Serum GH levels were positively correlated with serum ghrelin concentrations in both HD (r = 0.46, P < 0.05) and PD (r = 0.53, P < 0.001) patients; however, no relationships between ghrelin, leptin, insulin and IGF I were found.. These results suggest that PD is accompanied by a striking decrement in baseline ghrelin concentrations in comparison with values found both in HD and control patients. Further studies are necessary to determine mechanisms involved in ghrelin regulation in uraemic patients.

Topics: Adult; Case-Control Studies; Diabetes Complications; Erythropoietin; Female; Ghrelin; Growth Hormone; Humans; Hypertension; Insulin; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Leptin; Lipids; Male; Middle Aged; Peptide Hormones; Peritoneal Dialysis; Recombinant Proteins; Regression Analysis; Renal Dialysis

Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy.. Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study.. The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction.. Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Captopril; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Hydralazine; Hydrochlorothiazide; Hypertension; Kidney; Kidney Failure, Chronic; Losartan; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Renin-Angiotensin System; Reserpine; Time Factors; Uremia

Topics: Aged; Aged, 80 and over; Anemia; Antihypertensive Agents; Comorbidity; Erythropoietin; Female; Home Care Services, Hospital-Based; Hospitalization; Hospitals, University; House Calls; Humans; Hypertension; Kaplan-Meier Estimate; Male; Middle Aged; Nephrology; Palliative Care; Prospective Studies; Pruritus; Severity of Illness Index; Spain; Survival Rate; Terminal Care; Uremia; Water-Electrolyte Imbalance

Normochromic normocytic anemia is common in children with chronic renal failure (CRF) when their glomerular filtration rate is below 35 ml/min/1.73 m2 BSA, but it may develop earlier in some forms of renal disease. An inadequate erythropoiesis due to insufficient erythropoietin synthesis in the kidneys is the main cause of renal anemia. Other reasons include reduced red blood cell lifespan, chronic blood loss, iron deficiency, inhibitors of erythropoiesis, and malnutrition. The presence of anemia contributes to many of the symptoms of uremia, including decreased appetite, decreased energy, poor cardiac function, and poor school performance. Therefore, correction of anemia dramatically improves the life of the child with CRF. Presently, the goal of anemia management is to maintain hematocrit concentrations at 33% to 36% and a hemoglobin concentration of at least 11 g/L. This can be accomplished by intravenous or subcutaneous administration of recombinant erythropoietin (rHuEPO, 100-300 U/kg/week) and iron preparations. If adequate iron stores cannot be maintained with oral therapy (2-3, max 6 mg/kg/day), intravenous iron should be administered. In order to optimize anemia management in children with CRF, future research should be concentrated on the normalization of hemoglobin early in the course of CRF, and the long-term effects on the child's development.

Topics: Anemia; Child; Erythropoietin; Hemoglobins; Humans; Hypertension; Iron; Kidney Failure, Chronic; Uremia

Current guidelines give evidence-based advice on how best to manage anaemia in patients with renal disease, but these guidelines do not consider individual patient needs, so tailoring anaemia management to each patient still remains a challenge for the treating physician. Two case studies are described that illustrate some of the key factors that need to be considered. The first case emphasizes that haemoglobin (Hb) targets recommended in current guidelines may not suit all patients. The patient had been stably maintained on subcutaneous epoetin therapy with an average Hb concentration of >13.0 g/dl because he developed angina symptoms when his Hb level fell to 12.2 g/dl. Iron deficiency was identified as the likely cause of falling Hb in this patient. After the patient's iron supplementation was increased, his Hb level was normalized back to >13.0 g/dl without increasing the epoetin dose, and the angina symptoms were resolved. The second case involved a pre-dialysis patient with diabetes, who required a higher dose of epoetin after beginning concomitant antihypertensive treatment with an angiotensin-converting enzyme inhibitor. Previously, the treatment of renal anaemia in pre-dialysis patients has not been the focus of attention. Two ongoing randomized controlled trials have been designed to study early initiation of epoetin treatment in pre-dialysis patients and will provide much needed information in this area.

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Epoprostenol; Erythropoietin; Humans; Hypertension; Kidney Cortex; Kidney Function Tests; Male; Mesenteric Arteries; Rats; Rats, Wistar; Recombinant Proteins; Thromboxane B2; Uremia

To determine the changes in serum erythropoietin with age in patients with and without anemia and to assess the importance of certain comorbidities on changes in erythropoietin level and the development of anemia.. Clinical history, hematological parameters, and serum erythropoietin levels were examined at 1- to 2-year intervals for 8 to 30 years.. Baltimore Longitudinal Study on Aging (BLSA), National Institute on Aging.. One hundred forty-three BLSA participants.. Complete blood count and serum chemistries were performed at the time of each visit, and archived serum samples were used for erythropoietin level.. Although all subjects were healthy and without anemia at the time of initial evaluation, some developed chronic illness-most notably hypertension and diabetes mellitus. Erythropoietin levels rose significantly for the group as a whole, and the slope of the rise was found to be greater for those who did not have associated diabetes mellitus or hypertension. During the subsequent years, subjects who developed anemia but did not have hypertension or diabetes mellitus had the greatest slope in erythropoietin rise over time, whereas those with hypertension or diabetes mellitus and anemia had the lowest erythropoietin slope.. The increase in serum erythropoietin with aging may be compensation for subclinical blood loss, increased red blood cell turnover, or increased erythropoietin resistance of red cell precursors. It is suspected that, with very advanced age, or in those with compromised renal function (e.g., diabetes mellitus or hypertension), the compensatory mechanism becomes inadequate and anemia results.

Topics: Adult; Aged; Aged, 80 and over; Aging; Anemia; Diabetes Complications; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged

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

An obese 76-year-old woman with type II diabetes, hypertension, coronary artery disease, and gastroesophageal reflux was found to have a 6-cm lower-pole mass in a solitary functional right kidney. Because her religious beliefs prohibited blood transfusion, minimally invasive surgery--a laparoscopic partial nephrectomy--was performed, with a good result. Minimally invasive surgery, perhaps with administration of erythropoietin, iron-dextran, or both, is often a good option for severely anemic patients or those whose religious beliefs are opposed to transfusion. Methods of minimizing blood loss intraoperatively are reviewed.

Topics: Aged; Carcinoma, Renal Cell; Coronary Disease; Diabetes Mellitus, Type 2; Erythropoietin; Female; Gastroesophageal Reflux; Humans; Hypertension; Iron-Dextran Complex; Jehovah's Witnesses; Kidney Neoplasms; Laparoscopy; Nephrectomy

The purpose of the present study was to compare fetal and neonatal outcomes with amniotic fluid erythropoietin (EPO) levels obtained in the antepartum period in pregnancies complicated by preeclampsia, pregnancy-induced hypertension or chronic hypertension.. Erythropoietin concentrations were measured in amniotic fluid within 2 days before delivery and in cord blood at birth in 75 hypertensive women and in 23 healthy controls delivered by cesarean section before labor contractions. Erythropoietin levels did not influence clinical decisions.. Amniotic fluid erythropoietin levels correlated highly significantly with cord plasma EPO levels and were significantly higher in pregnancies complicated by hypertension than in control pregnancies. Umbilical arterial pH, acid-base and blood gas values at birth were not different from controls. Both cord plasma and amniotic fluid erythropoietin levels correlated with cord blood pH, acid-base and blood gas values at birth in the study group. Newborn infants admitted to the newborn intensive care unit had significantly higher fetal erythropoietin levels and were more acidotic, hypoxemic and hypoglycemic than infants admitted to the normal care nursery.. Our findings suggest that elevated amniotic fluid erythropoietin levels are markers of chronic or subchronic fetal hypoxia and are associated with neonatal morbidity in pregnancies complicated by hypertension.

Topics: Adult; Amniotic Fluid; Biomarkers; Case-Control Studies; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; ROC Curve

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48 U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P < 0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P < 0.01). Compared with U, UH has lower HW/BW and LV/BW (P < 0.05) and UE has normal HW/BW but lower LV/BW than U (P < 0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal a- actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta1, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure-overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.

Topics: Actins; Anemia; Animals; Atrial Natriuretic Factor; Erythropoietin; Gene Expression; Heart Ventricles; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

Hypertension is a potentially dangerous side effect of erythropoietin treatment; however, extreme elevations in blood pressure are rare. A 75-year-old woman with chronic renal insufficiency was treated with subcutaneous erythropoietin. Three weeks before she started receiving erythropoietin, her hematocrit was 27.2%; after 5 weeks of treatment, it rose to 45.7%. The patient came to the emergency department and was admitted with hypertensive urgency. During her hospital stay she was treated with nitroglycerin and nitroprusside infusions, extended-release nifedipine, a variety of beta-blockers, clonidine, and furosemide. By day 3, her blood pressure was adequately controlled. Her renal insufficiency may have progressed as a result of the hypertensive episode, which probably was related to erythropoietin administration and the resultant rapid increase in her hematocrit. Erythropoietin dosing should be titrated to increase the hematocrit gradually, and blood pressure should be monitored closely to avoid serious side effects such as hypertensive emergencies.

Topics: Aged; Emergency Treatment; Erythropoietin; Female; Hospitalization; Humans; Hypertension; Injections, Subcutaneous; Kidney Failure, Chronic

Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto-PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly decreased tissue TXB concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA probably serves as a mediator of the vascular effect of ET-1.

Topics: Animals; Eicosanoids; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Humans; Hypertension; Male; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Recombinant Proteins; Uremia

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB2), prostacyclin (6-keto-PGF1alpha), and cyclic guanosine 3',5'-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB2, and 6-keto-PGF1alpha were measured by radioimmunoassay. Plasma NOx was measured by high-performance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB2, 6-keto-PGF1alpha, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Biomarkers; Blood Pressure; Cyclic GMP; Endothelin-1; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Thromboxane B2; Time Factors; Treatment Outcome

Secondary hyperparathyroidism is a common complication of renal failure. The exact prevalence in chronic hemodialysis patients in not known. We evaluated 122 patients who were receiving maintenance hemodialysis for at least 12 months in 2 dialysis centers in mid Michigan. Seventy-eight percent of the patients had iPTH above 200 pg/mL (mean 481 pg/mL), 19% had iPTH within the accepted normal range (mean 155 pg/mL), while 3% had level below 100 (mean 53 pg/mL). Phosphate, calcium, calcium phosphate product, age and time on dialysis are the important factors correlating with elevated iPTH. There was no significant difference in iPTH between diabetic and nondiabetic patients with mean iPTH of 403 pg/mL and 407 pg/mL respectively. Black patients had a statistically significant elevated iPTH compared with white patients with a mean iPTH of 438 pg/mL and 283 pg/mL respectively (p < or = 0.004). Factors that predict the response to vitamin D therapy need to be evaluated to help reduce the high prevalence of secondary hyperparathyroidism. The patterns of bone disease in black patients need to be evaluated to further define the accepted normal iPTH range for this population.

Topics: Adult; Age Factors; Calcium Phosphates; Diabetes Complications; Diabetes Mellitus; Erythropoietin; Female; Humans; Hyperparathyroidism, Secondary; Hypertension; Kidney Failure, Chronic; Male; Michigan; Middle Aged; Parathyroid Hormone; Prevalence; Racial Groups; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Time Factors; Urea

Thrombocytopenia is a frequent hematological complication in patients with liver cirrhosis, but its pathogenesis is not clearly understood. We evaluated the effect of iron depletion by phlebotomy on platelet count in 62 consecutive iron overloaded patients with liver cirrhosis and thrombocytopenia. After a median follow-up of 30.2 months we observed a significant increase of platelet count in all patients (from mean baseline levels of 110.1 up to 168.22109/l at the end of follow-up, P<0.001) with platelet count normalization in 42 of them (67.7%). In addition, we observed a significant improvement of serum ALT levels (from pretreatment mean values of 126.7 up to 59.7 U/l at the end of follow-up, P<0.001) along with the reduction of serum ferritin levels and transferrin saturation during phlebotomy. Different pathogenetic mechanisms involving both humoral (erythropoietin and thrombopoietin, TPO) and physical (portal hypertension and hypersplenism) factors are here discussed to explain the platelet count increase following phlebotomy. Our results show that phlebotomy is effective not only in lowering iron overload, but also in improving liver function and thrombocytopenia in patients with liver cirrhosis.

Topics: Aged; Erythropoietin; Female; Follow-Up Studies; Humans; Hypersplenism; Hypertension; Iron Overload; Liver Cirrhosis; Male; Middle Aged; Phlebotomy; Platelet Count; Retrospective Studies; Thrombocytopenia; Thrombopoietin; Treatment Outcome

A recent observation that antiplatelet-aggregation drugs, including ticlopidine hydrochloride, may prevent erythropoietin (EPO)-induced rise in blood pressure in hemodialysis (HD) patients remains a subject of particular interest. The aim of the present study was to determine the effect of ticlopidine hydrochloride on EPO-induced rise in blood pressure of HD patients with special reference to blood levels of vasoactive substances.. HD patients who showed hypertension or aggravation of preceding hypertension with EPO treatment were selected for this study. Ticlopidine hydrochloride was administered at a dose of 200 mg daily for 4 weeks. Blood pressure and serum levels of nitric oxide (NO), atrial natriuretic peptide (ANP) and endothelin (ET) were determined before and after drug administration. Patients were divided into two groups, one of which showed a drop in mean blood pressure (MBP) of >10 mm Hg (group I) and one which did not (group II), and a comparison was made between them with respect to the blood parameters.. Five of 15 patients showed a drop of MBP of >10 mm Hg (group I), and 10 patients did not show any change in MBP (group II). In group I, there was a significant increase in blood NO levels compared to the concentrations before ticlopidine administration, while there was no change in group II. With respect to ANP and ET, there was no significant change in either of the groups.. The findings suggest that the preventive effect of ticlopidine hydrochloride on EPO-induced rise in blood pressure may partly be related to the enhancement of NO production in patients on maintenance HD.

Topics: Adult; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation Inhibitors; Renal Dialysis; Ticlopidine

Maintenance hemodialysis (HD) patients were studied to assess the effect on hemoglobin (Hb) concentration induced by the cyclic variation in hydration status.. Forty-nine HD patients were examined in three consecutive HD sessions in a 1-week treatment period. In a subgroup of 23 patients, Hb levels also were investigated during the long interdialytic interval.. Hb levels at the end of the long interdialytic interval were significantly lower by 0.5 to 0.6 g/dL (5 to 6 g/L) than those at the end of short intervals. Among all pre-HD and post-HD Hb values, levels measured at the end of short intervals were closest to the mean Hb value of the week, derived from calculation of the area under the curve (12.0 +/- 0.2 g/dL [120 +/- 2 g/L]). Intradialytic Hb increments were different in the three sessions (+1.6 +/- 0.1 g/dL [+16 +/- 1 g/L] after the long interval, +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] and +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] after short intervals [P < 0.001] and proportionate to weight loss [-3.4 +/- 0.1, -2.7 +/- 0.1, and -2.6 +/- 0.1 kg, respectively; P < 0.001]). Hb level increment and weight loss correlated directly (r = 0.527; P < 0.0001); each 1 L of ultrafiltration (UF) led to an increase in Hb level of approximately 0.4 g/dL (4 g/L). Plasma refilling accounted for an approximately 45% decrement in the intradialytic increase in Hb level 2 hours post-HD.. This study suggests that: (1) the end of the short interdialytic period is the most appropriate timing for anemia assessment, and (2) the remarkable hemodiluting effect of post-HD plasma refilling protects against excessive increments in Hb levels induced by UF.

Topics: Body Water; Drug Administration Schedule; Erythrocyte Indices; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Thrombosis; Time Factors; Urination

Although the majority of patients with end stage renal failure have anemia, some have relative erythrocytosis. Patients treated with continuous ambulatory peritoneal dialysis (CAPD) having relative erythrocytosis were studied in order to determine the factors that would be responsible.. Nine out of 89 CAPD patients (10%) were identified as having relative erythrocytosis. Age-, sex- and duration of disease-matched eight patients undergoing CAPD were taken as control. Beside factors of etiologies of renal failure, smoking, renal cysts, viral hepatitides, residual renal function, the adequacy of CAPD, nutritional status, hypertension, serum levels of erythropoietin, IL-1, IL-6, TNF-, and IGF-1 levels were also investigated.. Relative erythrocytosis occurred most often in diabetic and amyloidosis patients. None of the parameters studied were found to be significantly different between groups. During 2-year follow-up, although statistically non-significant, patients having relative erythrocytosis seemed to have higher mortality rate due to vascular complications.. No single factor seemed to explain erythrocytosis in patients undergoing CAPD. Being diabetic or with amyloidosis may increase the risk.

Topics: Adult; Amyloidosis; Antigens, CD; Diabetes Complications; Erythropoietin; Female; Hepatitis, Viral, Human; Humans; Hypertension; Insulin-Like Growth Factor I; Interleukin-1; Interleukin-6; Kidney; Kidney Diseases, Cystic; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Polycythemia; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Risk Factors; Smoking

The preliminary data of a small group of voluntary patients in daily short dialysis according to Buoncristiani are reported. After only one month of therapy an increase of haemoglobin and of haematocrit was obtained so that it was possible to reduce the EPO dose. The arterial pressure was better controlled with a smaller dose of antihypertensive drugs, facilitated in one case by a marked reduction of the body weight. The improvement in well-being and libido has been better than expected. The good results achieved encourage to go on with this experience, reported in the literature as an advantageous method both from the theoretic and clinical point of view, despite some difficulties that have still to be minimised.

Topics: Adult; Anemia; Antihypertensive Agents; Caregivers; Erythropoietin; Female; Hemodialysis, Home; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Patient Education as Topic; Patient Satisfaction; Pilot Projects; Program Evaluation; Self Care

Chronic hepatitis C virus (HCV) infection is quite prevalent in long-term hemodialysis (HD) patients. Patients who are candidates for renal transplantation might be treated, before grafting, with interferon-alpha (IFN-alpha). Among 39 HCV-positive long-term HD patients treated with IFN-alpha, we observed three cases of reversible posterior leukoencephalopathy syndrome (PLES). PLES included headaches in three patients, confusion in three patients, cortical blindness in two patients, visual hallucinations in one patient, seizures in three patients, and respiratory distress in one patient in a context of fluid overload and severe hypertension in all cases. The three patients were receiving IFN-alpha and recombinant erythropoietin therapies simultaneously for de novo anemia. Contrast-enhanced computed tomography scan or magnetic resonance imaging showed low-density areas in the occipital lobes (in three patients), frontal lobes (in one patient), and temporal lobes (in one patient). After withdrawal of IFN-alpha and recombinant erythropoietin therapies, hemodiafiltration, and symptomatic treatment of seizures and hypertension, PLES was reversible within 1 week in one patient, 10 days in one patient, and 2 months in the third patient. Our case reports show the occurrence of reversible PLES in HCV-positive long-term HD patients treated with IFN-alpha. Physicians caring for HCV-positive long-term HD patients treated with IFN-alpha need to be particularly cautious when these patients receive simultaneously recombinant erythropoietin and when IFN-alpha therapy induces a weight loss, which indicates a reduction in dry weight.

Topics: Adult; Anemia; Brain Diseases; Comorbidity; Erythropoietin; Hepatitis C; Humans; Hypertension; Interleukin-1; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Syndrome

The correction of anemia with human recombinant erythropoietin (rHuEPO) in end stage renal disease is associated with hypertension in about one third of hemodialysis patients. The pathogenesis of the rHuEPO-induced hypertension is still uncertain, though evidence of the involvement of endothelial cells has emerged. The aim of this study was to determine plasma endothelin-1 during hemodialysis and to compare the endothelin-1 levels in hemodialysis patients with and without rHuEPO substitution. Nineteen stable patients (13 male and 6 female, mean age 62 +/- 11 years) with end stage renal disease were studied. Cuprophan dialysers (GFS 12, Gambro, Lund, Sweden) were used for hemodialysis in all cases. rHuEPO (40 U/kg s.c.) was administered to 10 patients. Blood pressure (BP; RR mmHg) and blood volume changes (deltaBV; hemoglobinometry %) were serially measured. Samples were taken before and every hour during hemodialysis. Plasma endothelin-1 was measured by ELISA (R&D Systems, Minneapolis, USA) and corrected for hemoconcentration. Endothelin-1 concentration was elevated before commencement of hemodialysis (1.16 +/- 0.36 pg/ml) when compared to healthy controls (ref. 0.3-0.9) and increased to 1.47 +/- 0.51 pg/ml by the end of the session (p<0.05). In patients under rHuEPO-substitution plasma endothelin-1 was higher when compared to patients without substitution before (1.25 +/- 0.3 vs. 1.05 +/- 0.3 pg/ml) and at the end of HD (1.62 +/- 0.5 vs. 1.28 +/- 0.3 pg/ml, p<0.05). There was no difference in BP and deltaBV between the two groups during treatment. Plasma endothelin-1 was higher in hemodialysis patients and there was a continuous rise in plasma endothelin-1 during a session. Comparison of two groups of hemodialysis patients with and without s.c. rHuEPO-replacement treatment revealed a significantly higher plasma endothelin-1 concentration in patients with s.c. rHuEPO treatment. However, the elevated endothelin-1 levels were not accompanied by arterial hypertension.

Topics: Anemia; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric

15 years after recombinant erythropoietin (EPO) has become available for the treatment of renal anemia, the target hemoglobin concentration to be achieved is still controversial. A positive impact of partial correction of renal anemia on quality of life has been conclusively demonstrated. Several more recent studies indicate that further improvement of well-being can be achieved with normalization of hemoglobin levels. In addition, there is increasing evidence that anemia is associated with the progression of left-ventricular hypertrophy and mortality. These findings imply that correction of renal anemia has the potential to improve patient prognosis. However, in patients with advanced cardiac disease, the US normal hematocrit failed to demonstrate a prognostic benefit and instead suggested that the attempt to normalize hemoglobin may be harmful. Nevertheless, in patients with less advanced cardiac disease complete correction of renal anemia may prevent progressive ventricular dilatation. The impact of early anemia correction is currently tested in several trials in predialysis patients. Irrespective of the uncertainties about the upper target range, current US and European guidelines have defined a hemoglobin concentration of 11 g/dl as the lower target range on the basis of both symptomatic and prognostic considerations. In the majority of patients these minimum requirements are not yet achieved. Less then 10% of patients receive EPO prior to the onset of dialysis, the mean hemoglobin level at the start of dialysis is not higher than 9 g/dl and a significant proportion of patients permanently remain below 11 g/dl.

Topics: Aged; Anemia; Erythropoietin; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Insufficiency

Increased endothelin-1 (ET-1) production following recombinant erythropoietin (Epo) administration is a presumed etiology for the hypertension reported in some adults. It is unknown whether Epo has similar effects in preterm infants.. Serum ET-1 and Epo concentrations were measured prior to study, and following the second and third doses in 20 preterm infants receiving intravenous (IV) or subcutaneous (SC) Epo. Blood pressures were monitored prior to Epo administration and during the first, second, and third dose.. Infants (963 +/- 54 g birth weight, 27.4 +/- 0.6 weeks gestational age, 18 +/- 3 days of life; mean +/- SEM) had baseline Epo concentrations of 5.5 +/- 1.3 mU/ml and ET-1 concentrations below the lower limits of detection (<1 pg/ml). Epo concentrations were 1,848 +/- 274 and 1,672 +/- 295 mU/ml following the second and third IV dose, respectively, while Epo concentrations were 420 +/- 92 and 290 +/- 35 mU/ml after the second and third SC dose, respectively (p < 0.005, SC versus IV). ET-1 concentrations remained below the limits of detection in all but 6 infants, whose concentrations were <3.3 pg/ml. Blood pressures did not increase above baseline in either group during the study period.. Despite the wide range of Epo concentrations measured, no correlation was observed between Epo concentrations, ET-1 concentrations, and blood pressure during the 1-week study period. The long-term effects of Epo on ET-1 concentrations and blood pressure in preterm infants require further study.

Topics: Blood Pressure; Endothelin-1; Erythropoietin; Gestational Age; Humans; Hypertension; Infant, Newborn; Infant, Premature; Recombinant Proteins

Decreased sensitivity to the hypoglycaemic action of insulin is an almost universal phenomenon in uraemic patients, and it is attributed either to uraemic toxins or to anaemia or even to secondary hyperparathyroidism. Considering the conflicting data of few existing studies, we examined the influence of erythropoietin (EPO) treatment on insulin resistance and tested the probable correlation of this influence with sympathetic nervous system (SNS) activity.. We studied 8 non-obese, non-diabetic, stable dialysis patients using the euglycaemic insulin clamp technique before administration of EPO (phase A), 10 days after (phase B), and after the correction of the haematocrit level, at least 8 weeks later (phase C). We estimated the indices (glucose infusion rate, mg/kg/min), M/G (glucose clearance), and M/I (tissue sensitivity to insulin), and we measured haematocrit, haemoglobin, triglyceride, ferritin, EPO, and fasting insulin levels in each phase. During each phase, we tested the SNS activity using the response of blood pressure to persistent handgrip and the response of blood pressure to the standing position.. Our patients appeared to have an increased insulin resistance in phase A (M(A) = 6.24 +/- 1.01) which was significantly improved 10 days after the beginning of EPO treatment and before the rise of haematocrit (M(B) = 7.71 +/- 1.54, p < 0.05). There was no further improvement in phase C. Indices M/G and M/I behaved similarly. The serum triglyceride levels decreased in response to the increased insulin sensitivity. The patients studied did not demonstrate fasting hyperinsulinaemia, while the SNS activity was abnormal and remained unchanged throughout the study period in spite of some individual improvement.. Our study proves the beneficial effect of EPO treatment on insulin resistance in dialysis patients which could be attributed to the EPO itself and not to the correction of anaemia and is accompanied by improvement in triglyceride levels. Amelioration of insulin resistance did not influence the SNS activity, making the association between EPO treatment and SNS-derived changes in blood pressure quite improbable.

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Glucose Clamp Technique; Humans; Hypertension; Insulin Resistance; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors

To examine erythropoiesis in renal transplant pregnancies.. Retrospective cohort study of 30 renal transplant cases and 30 age, smoking and parity-matched healthy controls with normal index pregnancy. Retrospective chart review and assay of frozen antenatal serum (for serum erythropoietin concentration [serum EPO]), transferrin receptor protein [TfR], ferritin, folate and B12) were performed. The linear regression equation for normal pregnancy controls was used to calculate predicted [serum EPO] and the observed/predicted (O/P) log [serum EPO] was plotted. The relationship between [serum EPO] and haemoglobin (Hb) among transplant cases was considered to be different from that among controls if the slope of the O/P log [serum EPO] versus Hb regression was significantly different from zero.. The transplant (14 cadaveric) to conception interval was (median [range]) 33.5 [4, 189] months. Immunosuppressants were azathioprine (n = 25), cyclosporine (n = 22) and/or prednisone (n = 25). Cases were more often primiparous (20 vs. 7 [controls]; p = 0.01), had pre-existent hypertension (20 vs. 0 [controls]; p < 0.001), developed new/increased hypertension or pre-eclampsia (28 vs. 0 [controls]; p < 0.001) and an antenatal rise in creatinine (14 vs. 2 [controls]; p < 0.001). In early pregnancy, cases had similar EPO (15.2 [2.6, 84.6] vs. 15.7 [6.4, 41.0] [controls] U/L) but lower Hb (101 [65, 129] vs. 116 [106, 150] g/L; p < 0.001). Twenty-two (73%) cases had Hb < 100 g/L (vs. 4 [controls]; p < 0.0001); Hb was comparable at 6 wk postpartum. With advancing gestational age (GA), Hb remained stable and serum EPO increased in both groups. The slope of the O/P log [serum EPO] versus Hb for transplant cases was significantly different from zero within both the 17-28 wk (slope +/- SEM: 0.010 +/- 0.002; p < 0.0001) and the 29-42 wk GA categories (0.006 +/- 0.003; p = 0.02). Cases showed smaller rises in serum TfR (change 481 [- 1471, 2780]) vs. 1119 [- 698, 4195] [controls] ng/mL; p = 0.005).. Anaemia frequently complicates renal transplant pregnancies, in which serum EPO is inappropriately low and the rate of erythropoiesis blunted.

Topics: Adult; Anemia; Case-Control Studies; Cohort Studies; Creatinine; Erythropoiesis; Erythropoietin; Female; Ferritins; Folic Acid; Gestational Age; Hemoglobins; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Linear Models; Parity; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Receptors, Transferrin; Retrospective Studies; Time Factors; Vitamin B 12

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

Topics: Abdominal Pain; Adult; Analgesics, Non-Narcotic; Anemia, Iron-Deficiency; Appendicitis; Epoetin Alfa; Erythropoietin; Fever; Gastrointestinal Hemorrhage; Glomerulonephritis; Hematinics; Humans; Hypertension; Ibuprofen; Kidney Failure, Chronic; Male; Nursing Diagnosis; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Recombinant Proteins; Renal Dialysis

Aggravation of anemia in chronic renal failure patients by angiotensin-converting enzyme inhibitors (ACEIs) has been attributed to the inhibition of angiotensin II which facilitates erythropoietin(Epo) production. This study was aimed at evaluating whether ACEIs aggravate anemia in maintenance hemodialysis patients and to investigate the influence of ACE gene polymorphism on erythropoiesis in these patients. Ninety-one hemodialysis patients were divided into 2 groups, based on whether or not they were administered ACEIs, into the ACEI group(n = 24) and the non-ACEI group(n = 67), and comparisons were made of the doses of recombinant human Epo(rHuEpo) administered, the hematocrit(Hct) and the plasma Epo concentrations. Among the patients in the non-ACEI group, only 17 did not receive rHuEpo, while all of the patients in the ACEI group received rHuEpo. The average dose of rHuEpo was 102.7 +/- 45.4 IU/kg/week in the ACEI group and 57.8 +/- 55 IU/kg/week in the non-ACEI group and the difference between the two groups was statistically significant. A statistically significant difference in the Hct was also observed between the two groups: the mean Hct in the ACEI group was 28.7 +/- 2.9% while that in the non-ACEI group was 31.1 +/- 3.7%. The plasma Epo concentrations were significantly lower in the ACEI group than in the non-ACEI group. No significant differences in the rHuEpo dose and Hct were observed between the three ACE genotype classes in either the ACEI or the non-ACEI group, however, there was a significant difference among the three genotypes in the non-ACEI group in regard to the plasma Epo concentrations; patients with the DD genotype had higher concentrations than those with the DI or II genotypes. These data suggest that anemia in maintenance hemodialysis patients is worsened by ACEIs as a result of the suppression of Epo production. Although it has been suggested that the endogenous Epo concentrations in maintenance hemodialysis patients are associated with ACE gene polymorphism, no significant influence of the ACE genotype on the rHuEpo dose or Hct was evident. Therefore, it is possible that exacerbation of anemia by ACEIs in the patients receiving rHuEpo is a result of an inhibited bone marrow response to Epo.

Topics: Adult; Aged; Anemia; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Bone Marrow; Depression, Chemical; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Recombinant Proteins; Renal Dialysis

This paper is a summary of results obtained in our studies on leptinemia in patients with chronic renal failure treated with recombinant human erythropoietin (rHuEPO), in kidney transplant patients, in patients with essential hypertension, and in pregnant women with preeclampsia. In this study, we found that rHuEPO treatment has a suppressive effect on leptinemia in patients with endstage renal failure. These results suggest that the appetite stimulating effect of rHuEPO may be mediated by a reduction of leptin synthesis and release. At the early stage of successful kidney transplantation, a significant decline of leptinemia was noticed, which was not related either to the excretory function of the graft or the kind and dose of immunosuppressants. In kidney transplant patients with grafts functioning well for 2.5 years, significantly elevated leptinemia was found. From these results, we may conclude that factors other than the excretory function of the graft and the kind and dosage of immunosuppressants may be involved in the pathogenesis of abnormal leptinemia in these patients. Both in normotensive subjects and patients with essential hypertension, a positive correlation was found between leptinemia and mean blood pressure, suggesting that leptin may be involved in the regulation of blood pressure. Both healthy and preeclamptic pregnant women show higher leptinemia than nonpregnant women. In preeclamptic women, leptin levels in maternal vein blood, umbilical cord blood, and amniotic fluid were significantly higher than respective values found in healthy pregnant women. In contrast to healthy pregnant and nonpregnant women, in women with preeclampsia, no correlation was found between the body mass index (BMI) and leptinemia. In preeclamptic women the abnormally elevated leptinemia was not related to blood pressure. Finally, no correlation was found between leptinemia in maternal and umbilical cord blood. From these studies, it follows that the elucidation of abnormal leptin secretion in the pathogenesis of preeclampsia needs further study.

Topics: Adipose Tissue; Amniotic Fluid; Appetite; Blood Pressure; Blood Proteins; Body Mass Index; Erythropoietin; Female; Fetal Blood; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leptin; Pre-Eclampsia; Pregnancy; Proteins

The observation that antiplatelet therapy may decrease the incidence of Epo-induced hypertension in dialysis patients remains a subject of particular interest. The aim of the present study was to test this hypothesis in patients at the predialysis stage. Predialysis patients with renal anemia were treated with EPO (6000 IU/week) for 6-12 months. Patients were divided into two groups, one of which received antiplatelet therapy and the other did not, and a comparison was made between them with respect to the incidence of EPO-induced hypertension. Logistic regression analysis was used to determine the risk factors for developing hypertension during the EPO therapy. Such predictors included age, gender, antecedent of hypertension, antiplatelet drugs and diabetes mellitus. Overall, 66 patients were enrolled in the study and 18 developed hypertension (27%). Out of the 35 patients not receiving antiplatelet therapy, 15 developed hypertension (43%). In contrast, out of the 31 patients receiving antiplatelet therapy, only 3 (10%) developed hypertension (p=0.003 by Chi square test). Multiple regression analysis showed that the best predictive variables for the development of hypertension were antecedent of hypertension (odds ratio: 0.064, p=0.0118), and use of antiplatelet drugs (odds ratio: 5.081, p=0.0295). The present data provide evidence that antiplatelet therapy may prevent EPO-induced hypertension in predialysis patients. However, the mechanism to explain such an effect still remains to be elucidated.

Topics: Adult; Aged; Anemia; Dilazep; Dipyridamole; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Platelet Aggregation Inhibitors; Recombinant Proteins; Renal Dialysis; Risk Factors

Recombinant human erythropoietin (rHuEpo) is the treatment of choice in anemia associated with end-stage renal disease. Its major side effect is hypertension, which occurs in 8-30% of uremic patients. The exact mechanism of rHuEpo-induced hypertension has not been fully elucidated, and several possibilities have been proposed, such as a direct vascular effect of the drug with a shift in the balance of constrictor and relaxing endothelial factors (endothelins and nitric oxide (NO)). Recent papers suggested an enhanced rather than reduced activity of endogenous NO system in rats with normal renal function and rHuEpo-induced hypertension. Our study was designed to verify whether, in spite of enhanced activity of the renal NO system, rHuEpo may affect endothelium-dependent (acetylcholine-induced) and/or endothelium-independent (sodium nitroprusside-induced) vasorelaxation and to evaluate basal NO release by the infusion of NG-nitro-L-arginine methyl ester (L-NAME) in an isolated and perfused rat kidney model.. To investigate this hypothesis, we have determined systemic and renal NO activity in Wistar rats treated with a hypertensive dose of rHuEpo (150 IU/kg b.w. every other day for 2 weeks) by measuring stable NO metabolites (NO2+NO3) in the urine and have also evaluated variations in renal vascular resistance after the injection of Ach, SNP and the infusion of L-NAME.. Hematocrit, hemoglobin concentration and arterial blood pressure were significantly increased in the treated group as compared with the controls. Urinary excretion of NO2+NO3 was significantly higher in treated than in the controls (438+/-66 vs. 294+/-36 nM/ml/min, p<0.01, respectively). There were no significant differences in the dose-response curves to Ach and SNP between the two groups. The renal vasoconstriction following the infusion of L-NAME was also similar in the two groups.. The analysis of our results seems to indicate that the endogenous NO system activity was enhanced in rHuEpo-induced hypertension in rats with normal renal function and a resistance to NO was not developed in renal circulation. Further studies seem to be necessary to better clarify the exact mechanisms underlying the development of rHuEpo-induced hypertension.

Topics: Animals; Creatinine; Enzyme Inhibitors; Erythropoietin; Humans; Hypertension; Male; Muscle Relaxation; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroprusside; Perfusion; Rats; Rats, Wistar; Recombinant Proteins; Renal Circulation; Vasodilation; Vasodilator Agents

Recently, it was reported that blood vessel immunoreactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET(A) and nonselective ET(A)/ET(B) receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk. In protocol A, half of the rats in each group were simultaneously treated with the ET(A)/ET(B) receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET(A) receptor antagonist LU 135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study. rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160+/-7 mmHg versus 187+/-9 mmHg, P < 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172+/-10 mmHg versus 168+/-9 mmHg, NS). In summary, selective ET(A) but not ET(A)/ET(B) receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ET(A) and ET(B) receptors.

Topics: Animals; Blood Pressure; Bosentan; Creatinine; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Recombinant Proteins; Sulfonamides

Angiotensin-converting enzyme (ACE) inhibitors have the capability of decreasing left ventricular mass index (LVMI) in chronic haemodialysis (HD) patients. On the other hand, recent reports provide conflicting information regarding the impact of ACE inhibitors on responsiveness to recombinant human erythropoietin (rHuEpo), and there are no data about the effect of withdrawing ACE inhibitors both on rHuEpo response and LVMI in HD patients.. ACE inhibitors were switched to another antihypertensive medication in 23 out of 68 patients in our HD unit who were receiving both rHuEpo and an ACE inhibitor for more than 1 year. Blood pressure at the pre- and post-dialysis phases, haematocrit levels and rHuEpo doses were determined at the end of the first and of the third years, and the LVMI was determined at the end of the third year. Statistical analyses were done in 15 patients in whom the study could be completed.. The mean (+/-SD) haematocrit level was increased from 26.3+6.4% to 29.8+/-6.3% at the first year (P<0.05), and to 29.4+/-6.5% at the third year (P<0.05 vs before), while the mean dose of rHuEpo was decreased from 208.3+/-99.0 UI/kg/week to 141.0+/-91.8 at the first year (P=0.01), and to 141.4+/-81.0 at the third year (P=0.01 vs before). Administration of rHuEpo had been stopped in two patients at the end of the first year. The mean blood pressure level and the mean LVMI were not changed (P>0.05 vs before). There were no significant changes in dialysis parameters, iron status, plasma renin activities, and levels of aldosterone, intact parathyroid hormone, aluminum and erythropoietin.. The findings of this small uncontrolled study indicate that withdrawal of ACE inhibitors in hypertensive chronic HD patients receiving rHuEpo may result in an increase in haematocrit level, and a decrease in dose of rHuEpo without any significant changes in the blood pressure level and LVMI. Controlled prospective studies are needed to clarify this issue.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Therapy, Combination; Echocardiography; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Recombinant Proteins; Renal Dialysis

The aim of this study was to compare clinical and biological results in 4 standard hemodialyzed patients originally treated by three 4-5 h sessions per week and converted within one year to daily hemodialysis sessions of 2-2.5 h each 6 times per week. The modalities and the total weekly dialysis times remained the same. With daily hemodialysis, the blood pressure and left ventricular mass index decreased significantly (p < 0.01). A significant decrease in the urea time averaged deviation (TAD) (p < 0.005) and increase in the Kt/V index (p < 0.05) were observed. A gain in dry weight was shown with a rise in caloric intake from 33+/-3.21 to 40.8+/-6.35 kcal/kg/day (p < 0.05), and the normalized protein catabolic rate (nPCR) increased significantly (p < 0.0038). One patient who was receiving erythropoietin (EPO) for anemia could stop his treatment. No arteriovenous fistula complications were observed. Daily hemodialysis seems to be the method of choice to manage hypertension and left ventricular hypertrophy in uremic patients. The increase of the urea TAD to a value closer to that of the healthy kidney due to the increase of the frequency of dialysis is probably the main explanation for clinical improvement.

Topics: Adult; Aged; Anemia; Arteriovenous Shunt, Surgical; Blood Pressure; Energy Intake; Erythropoietin; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Proteins; Renal Dialysis; Time Factors; Ultrasonography; Urea; Uremia; Weight Gain

Topics: Animals; Blood Pressure; Endothelins; Erythropoietin; Hematocrit; Humans; Hypertension; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Topics: Brain Diseases; Erythropoietin; Humans; Hypertension

Long-term administration of erythropoietin (EPO) frequently causes hypertension in humans and animals with chronic renal failure (CRF). We recently demonstrated that EPO-induced hypertension is hematocrit independent and accompanied by elevated cytosolic [Ca2+]i and nitric oxide (NO) resistance. This study was undertaken to examine the effects of therapy with EPO alone or together with calcium channel blockade on NO metabolism. Urinary excretion of NO metabolites (NOx) and thoracic aorta and kidney endothelial and inducible NO synthases (eNOS and iNOS) were studied in 4 groups of 6 nephrectomized rats treated with either placebo, EPO, the calcium channel blocker felodipine, or EPO plus felodipine for 6 weeks. A group of sham-operated placebo-treated animals served as control. The placebo-treated CRF group exhibited moderate hypertension, elevated basal and depressed stimulated platelet [Ca2+]i, reduced urinary NOx excretion, and diminished vascular and renal eNOS and iNOS proteins. EPO therapy further raised blood pressure and increased resting and stimulated [Ca2+]i but did not change NOx excretion or NOS proteins. Concurrent administration of felodipine abrogated EPO-induced hypertension, normalized resting and stimulated [Ca2+]i, and increased NOx excretion and eNOS and iNOS proteins. Thus, EPO therapy leads to marked increases in blood pressure and resting and stimulated [Ca2+]i. These abnormalities are ameliorated by calcium channel blockade, which restores [Ca2+]i to normal and increases vascular and renal NOS expression.

Topics: Animals; Blood Pressure; Blotting, Western; Calcium; Calcium Channel Blockers; Drug Interactions; Erythropoietin; Felodipine; Hypertension; Kidney Failure, Chronic; Male; Nephrectomy; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Vasodilator Agents

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120+/-3 mmHg compared to 161 +/-6 mmHg in the Nx + vehicle group (p <0.01) and 199+/-9 mmHg in the Nx + r-HuEPO group (p <0.01 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels were similar in the Nx + vehicle and Nx + r-HuEPO groups (7.9+/-1.0 and 7.8+/-0.8 pg/ml). In contrast, thoracic aorta ir-ET-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3+/-2.9 vs 13.4+/-1.9 pg, p <0.05). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, p<0.05) and in the mesenteric arterial bed (r= 0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension.

Topics: Animals; Blood Pressure; Creatinine; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Male; Rats; Rats, Wistar; Recombinant Proteins; Uremia

The results of anemia correction by recombinant human erythropoietin (rHuEPO) therapy with regard to cardiac function and left ventricular hypertrophy in dialysis patients are controversially discussed. The aim of the study was to assess the effects of therapy rHuEPO on cardiac morphology and function in dialysis patients. We studied 11 clinically stable hemodialysis patients with severe renal anemia (hematocrit <27%) and increased left ventricular mass index (LVMi) with no history of coronary or valvular heart disease, systemic disease, severe hyperparathyroidism, hypertension stage 2 or higher, transfusion-dependent anemia, and concurrent rHuEPO treatment. The patients were treated with rHuEPO administered subcutaneously once or twice weekly at a mean dose of 80 +/- 31 IU/kg week until the hematocrit was >30% and underwent a complete Doppler echocardiographic study at baseline and at follow-up (after 12.2 +/- 2.9 months). At follow-up, ejection fraction and fractional shortening significantly increased from 62.7 +/- 13.8 to 67.8 +/- 9. 7% (p < 0.05) and from 35.5 +/- 9.8 to 39.4 +/- 7.1% (p < 0.05), respectively, whereas mean velocity of circumferential fiber shortening demonstrated a trend towards amelioration from 1.18 +/- 0. 23 to 1.27 +/- 0.27 circ/s (n.s.). LVMi and morphological data remained unchanged throughout the study. Nevertheless, LVMi changes showed two different behaviors with respect to baseline values: in 6 patients with higher baseline values, LVMi decreased from 229 +/- 36 to 191 +/- 45 g/m2 (p < 0.05), while it worsened in 5 patients with less marked LVMi, increasing from 141 +/- 32 to 186 +/- 40 g/m2 (p < 0.05). Our data demonstrate that partial correction of renal anemia with rHuEPO therapy seems to improve cardiac performance and to induce a regression of left ventricular hypertrophy, particularly in patients with greater baseline hypertrophy, ultimately confirming the multifactorial pathogenesis of left ventricular hypertrophy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Echocardiography, Doppler; Erythropoietin; Female; Heart Function Tests; Hematocrit; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Ventricular Function, Left

Topics: Amniocentesis; Amniotic Fluid; Erythropoietin; Female; Fetal Hypoxia; Humans; Hypertension; Infant, Newborn; Pre-Eclampsia; Pregnancy; Pregnancy Complications

Patients on maintenance hemodialysis with a family history of essential hypertension are at higher risk for increased arterial blood pressure when treated with erythropoietin than patients without family history. This study was performed to elucidate the role of endogenous erythropoietin in essential hypertension. We conducted a study in 42 untreated patients (mean age, 51 +/- 9 years) with essential hypertension World Health Organization stages I or II. Ambulatory 24-hour blood pressure (Spacelab 90207), cardiac output (2D guided M-mode echocardiography and CW Doppler sonography), renal hemodynamics (para-aminohippurate and inulin clearance), and endogenous erythropoietin (radioimmunoassay) together with erythrocyte count, hemoglobin, and hematocrit were measured in parallel. Mean 24-hour systolic blood pressure was 145 +/- 13 mm Hg, and mean diastolic blood pressure was 93 +/- 8 mm Hg. The average erythropoietin concentration was 15.3 +/- 3.7 mU/mL and within the normal range. We found that the higher erythropoietin concentrations, the more elevated was both 24-hour ambulatory systolic (r = 0.51, P < 0.005) and diastolic blood pressure (r = 0.49, P < 0.005). Also, the concentration of endogenous erythropoietin was correlated with total peripheral resistance as noninvasively determined by echocardiographic and Doppler sonographic measurements (r = 0.40, P < 0.02 and r = 0.49, P < 0.02, respectively). With increasing erythropoietin concentrations, renal plasma flow and renal blood flow were found to be progressively reduced (r = -0.32, P < 0.05 and r = -0.35, P < 0.05, respectively) and renal vascular resistance increased (r = 0.41, P < 0.01). Neither hematocrit nor hemoglobin nor erythrocyte count were related to endogenous erythropoietin concentrations. In human essential hypertension, the level of arterial blood pressure is related to endogenous erythropoietin, which is hemodynamically mediated by an increase of total peripheral resistance. Because erythropoietin has shown proliferative and vasoconstricting effects on the endothelium in experimental studies, we suggest that endogenous erythropoietin might be an aggravating or even a promoting factor in the pathogenesis of essential hypertension.

Topics: Adult; Blood Pressure; Circadian Rhythm; Echocardiography; Echocardiography, Doppler; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged

Hypertension complicating the therapy of renal anemia with rHU-EPO is characterized by an increase in total peripheral vascular resistance, but the mechanisms underlying arteriolar vasoconstriction remain unclear. To assess the role of altered cellular calcium metabolism, resting platelet cytosolic calcium was measured in 12 previously normotensive patients with end-stage renal disease before and after 12 weeks of EPO-therapy, after 12 weeks of combined antihypertensive pharmacotherapy of EPO-induced hypertension, and after 12 weeks of concurrent administration of EPO and indomethacin. Patients with EPO-induced hypertension showed a significant raise in platelet calcium by comparison with calcium levels prior to EPO (179 +/- 15 vs 120 +/- 8 nmol/l), and there was a positive correlation between their blood pressure and platelet calcium levels (r = 0.9, p < 0.001). Antihypertensive therapy of EPO-induced hypertension resulted in a reduction of blood pressure and a reduction of platelet calcium to near normal levels (128 +/- 6 nmol/l). The non-steroidal antiinflammatory drug indomethacin prevented EPO-induced hypertension and EPO-associated alterations in platelet calcium. The results of the present study suggest that EPO-induced hypertension might be related to altered cellular calcium homeostasis. If EPO therapy induces alterations in calcium metabolism not only in platelets but also in vascular smooth muscle cells, these changes in calcium influx may contribute to arteriolar vasoconstriction during EPO therapy.

Topics: Anemia; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Calcium; Cytosol; Erythropoietin; Female; Humans; Hypertension; Indomethacin; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Adolescent; Blood Pressure; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Platelet Count; Platelet Transfusion; Recombinant Proteins; Thrombocytopenia

Arterial hypertension in end-stage renal disease (ESRD) patients is characterized by an altered nycthemeral blood pressure (BP) rhythm and an increased pulse pressure, and it could be suggested that this association of risk factors plays a major role in the cardiovascular prognosis of this population. The aim of this study was to determine the influence of nycthemeral BP pattern on arterial distensibility and pulsatile components of BP in treated hypertensive patients on regular hemodialysis. Forty-two hypertensive patients were included, and all underwent ambulatory BP and pulse wave velocity (PWV) measurements between the femoral and carotid arteries. The patients were divided into two groups according to the magnitude of the nocturnal fall in BP: dippers and non-dippers. The groups were similar in gender, age, duration of hemodialysis, body mass index, body size, history of cardiovascular complications, class and number of antihypertensive drugs used per patient. PWV was significantly higher in non-dippers. For the whole population, a stepwise regression analysis showed that PWV and erythropoietin therapy were independently related to the impaired nycthemeral BP pattern. In addition to its pressor effect, erythropoietin could have a deleterious influence on the ambulatory BP profile of treated hypertensive patients in ESRD. Arterial distensibility and nycthemeral BP impairment are linked, and these cardiovascular risk factors should be taken into account together for the management of hypertensive hemodialysis patients.

Topics: Adult; Aged; Blood Pressure; Circadian Rhythm; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Pulse; Renal Dialysis

Regular administration of recombinant erythropoietin (EPO) in patients with chronic renal failure (CRF) is frequently complicated by a rise in arterial blood pressure. Clinical studies intended to discern the possible role of endothelin (ET) in the pathogenesis of EPO-induced hypertension have produced contradictory results. Given the limitations of the clinical studies, this placebo-controlled study was carried out in CRF (5/6 nephrectomized) rats treated with either EPO, 150 U/kg intraperitoneally, or the vehicle alone twice weekly for 6 wk. Plasma ET was measured at baseline, and weeks 2, 4, and 6. In addition, plasma arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) were determined at the conclusion of the study period. As expected, blood pressure rose markedly after 1 wk of EPO therapy as compared with the placebo therapy. However, there was no significant difference in plasma ET levels between the EPO- and placebo-treated groups during the study period. Likewise, EPO therapy had no effect on plasma ANP level but depressed plasma AVP concentration. Thus, this placebo-controlled animal study revealed that EPO therapy markedly raised arterial blood pressure but had no effect on plasma ET in the CRF rats. This observation suggests that EPO-induced hypertension in this model is not mediated by an increased circulating ET level. However, the possible effect, if any, of EPO on local vascular tissue ET level is uncertain and awaits further investigation.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelins; Erythropoietin; Hypertension; Longitudinal Studies; Male; Rats; Rats, Sprague-Dawley; Vasopressins

Recent experimental studies have found that erythropoietin elicits vasoconstriction and proliferation of endothelial cells. We conducted the following study to assess the possible interactions between endogenous erythropoietin, systemic and renal haemodynamics at different stages of essential hypertension.. We examined 47 patients with borderline essential hypertension (age 26 +/- 3 years) and 49 patients with established essential hypertension WHO stage I-II (age 52 +/- 10 years), and compared them to 42 normotensive individuals (age 26 +/- 3 years). The concentration of erythropoietin (radioimmunoassay), 24-h ambulatory blood pressure (Spacelab 90207), systemic haemodynamics (Doppler sonography) and renal haemodynamics (para-aminohippuric acid and inulin clearance) were determined.. Erythropoietin was within normal range and similar among the three groups. In patients with established essential hypertension, a close correlation was found between erythropoietin and systolic (r = 0.45, P < 0.002) and diastolic (r = 0.51, P < 0.001) ambulatory blood pressure. In contrast, ambulatory blood pressure was not correlated with erythropoietin in subjects with borderline hypertension. Total peripheral resistance (r = 0.41, P < 0.02) was linked to erythropoietin in established but not in borderline hypertension. However, erythropoietin was inversely correlated with renal plasma flow in both established and borderline hypertension (r = -0.33, P < 0.05, and r = -0.34, P < 0.05 respectively). In normotensive subjects, in contrast, erythropoietin was not correlated with any of the determined variables. In neither group erythropoietin was linked to the haematocrit or hemoglobin concentration.. The correlation between erythropoietin and renal vascular changes which is already present in borderline hypertension and is confirmed in established hypertension indicates an involvement of erythropoietin in the development of essential hypertension. The presence of normal concentrations of endogenous erythropoietin in all groups suggests a dysregulation of erythropoietin in patients with essential hypertension as the pathophysiological link between erythropoietin and vascular changes.

Topics: Adult; Blood Pressure; Erythropoietin; Hematocrit; Hemodynamics; Hemoglobins; Humans; Hypertension; Middle Aged; Renal Circulation; Renal Plasma Flow

Human recombinant erythropoietin is used to treat chronic anemia in patients with end-stage renal failure. Erythropoietin causes hypertension, and hypertensive encephalopathy has been associated with its use. We describe six dialysis-dependent, chronic renal failure patients who developed hypertension, headache, and seizures while on erythropoietin. Four of the six patients had posterior white matter changes on neuroimaging. The encephalopathy was managed by prompt antihypertensive and anticonvulsant treatment and by discontinuation of erythropoietin. Hypertensive posterior leukoencephalopathy is associated with erythropoietin use.

Topics: Adult; Anemia; Anticonvulsants; Brain Diseases; Child; Drug Administration Schedule; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Magnetic Resonance Imaging; Middle Aged; Recombinant Proteins

This study compared the status and adequacy of blood pressure (BP) control in 21 ESRD patients treated with HD and CAPD at different time periods. Patients were considered to be hypertensive it they were receiving antihypertensive medications during the study period. During HD, 9 of the 21 patients (43%) required antihypertensive drugs to control their hypertension; whereas, during CAPD, the number of patients taking antihypertensive drugs increased to 15 (71%) (p < 0.05). Adequate control of hypertension (systolic BP < 150 mmHg and/or diastolic BP < 90 mmHg) was achieved in 17 patients (81%) during HD compared to 11 patients (52%) during CAPD (p < 0.05). Average ultrafiltration rate was 1.28 +/- 0.1 l/day during HD and 1.30 +/- 0.2 l/day during CAPD (p = NS). Mean Kt/V during HD was 1.24 +/- 0.1; whereas, mean weekly Kt/V during CAPD was 1.81 +/- 0.2. There were no significant differences in hematocrit or usage of recombinant human erythropoietin (rHuEPo) between the two treatment modalities. However, the weekly dose of rHuEpo was higher during HD than during CAPD (p < 0.05). Mean body weight was significantly higher (p < 0.01) and serum albumin was lower (p < 0.05) during CAPD than during HD in the same group of patients. We conclude that hypertension appears to be controlled better by HD than by CAPD in ESRD patients. The gain in body weight observed with CAPD treatment may reflect an increase in total body fluid volume which may partly explain why hypertension is less adequately controlled during CAPD than during HD treatment.

Topics: Blood Pressure; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Water immersion (WI) is followed by hypoxemia and hemodilution, and induces alterations in renal hemodynamics (increase in tubular sodium load). These facts justified the performance of studies which aimed to assess the influence of WI on erythropoietin (EPO) secretion. Serum EPO and atrial natriuretic peptide (ANP) concentrations as well as plasma renin activity (PRA) were estimated in 18 patients with essential hypertension (EH) and in 9 healthy subjects (HS): before, after 2 h of WI and 2 h after discontinued WI. WI was followed by a significant increase in plasma volume and decrease in PRA, which were of similar magnitude in both examined groups. Patients with EH showed significantly higher basal levels of serum EPO (66.7+/-11.4 mU/ml in EH vs. 20.0+/-3.4 mU/ml in HS) and ANP (110.6+/-15.4 pg/ml in EH vs. 75.6+/-8.2 pg/ml in HS). WI was followed by a significant increase in both EPO (by 34.0+/-8.9 mU/ml in EH and 17.0+/-5.4 mU/ml in HS) and ANP (by 106.9+/-19.2 pg/ml in EH and 149.4+/-16.9 pg/ml in HS). Only in EH, a significant correlation was found between serum EPO level and mean arterial pressure post WI and natriuresis during WI, respectively.. (1) water immersion induced increase in plasma EPO both in healthy subjects and patients with essential hypertension. (2) Patients with EH are characterized by elevated basal plasma levels of ANP and EPO. (3) Participation of the renin-angiotensin system and ANP in the regulation of EPO secretion could not be proven both in normotensive subjects and hypertensive patients.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Immersion; Male; Plasma Volume; Radioimmunoassay; Renin; Sodium; Water

1) Does erythropoietin (EPO) reduce the need for transfusion of red blood cells in patients receiving chemotherapy for a nonhematologic cancer? 2) Does the administration of EPO improve the quality of life of these cancer patients?. To make recommendations regarding the use of EPO to reduce the need for transfusion of red blood cells in patients receiving chemotherapy for a nonhematologic cancer.. First transfusion requirement from the start of chemotherapy is the main outcome of interest. Quality of life and costs are also considered.. Evidence was selected and reviewed by 5 members of the Ontario Cancer Treatment Practice Guidelines Initiative (OCTPGI) and the Systemic Treatment Program Committee (STPC). Drafts of this document have been circulated to and reviewed by members of the STPC. The STPC comprises medical oncologists, pharmacists, supportive care personnel and administrators. No community representative participated in the development of this practice guideline.. Eleven randomized controlled trials (RCTs), most placebo-controlled, were available for review. A meta-analysis was performed with 8 trials that shared a clinically relevant outcome measure. Only 1 trial assessed quality of life.. The meta-analysis showed a relative risk for transfusion among EPO patients of 0.64 (95% confidence interval 0.53-0.78), which translates into a 36% relative reduction in the proportion of patients requiring transfusion (p = 0.00001). Reduction in transfusion requirements was similar across strata defined by methodological quality, EPO dose, hematologic status, tumour type at trial entry and chemotherapy regimen. In the 1 trial that assessed quality of life, EPO was associated with improved quality of life.. Hypertension has been noted rarely in EPO-treated cancer patients. The RCTs did not report adverse effects in EPO-treated patients compared with control patients during the follow-up period. Long-term adverse effects are unknown. EPO is more costly than transfusion, but formal cost-effectiveness studies are unavailable.. For patients receiving chemotherapy for nonhematologic cancer in whom symptoms of anemia are expected and in whom transfusion of red blood cells is not considered an acceptable treatment option, EPO can be recommended as a safe, effective treatment alternative. The evidence in support of using EPO is stronger for patients receiving platinum-based chemotherapy regimens that for those receiving non-platinum-based regimens. CLINICAL PRACTICE GUIDELINE DATE: Apr. 4, 1997.

Topics: Anemia; Antineoplastic Agents; Drug Costs; Erythrocyte Transfusion; Erythropoietin; Follow-Up Studies; Humans; Hypertension; Meta-Analysis as Topic; Neoplasms; Outcome Assessment, Health Care; Platinum Compounds; Quality of Life; Randomized Controlled Trials as Topic; Risk Factors

Topics: Anemia; Antineoplastic Agents; Cisplatin; Double-Blind Method; Erythrocyte Volume; Erythropoietin; Follow-Up Studies; Hemoglobins; Humans; Hypertension; Kidney; Neoplasms; Recombinant Proteins

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Drug Therapy, Combination; Enalapril; Erythropoietin; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nephrotic Syndrome; Recombinant Proteins; Reoperation; Tissue Donors

The treatment of uraemic patients with recombinant human erythropoietin (rHuEpo) often leads to an increase in blood pressure. Indirect and direct effects of the hormone are probably involved. We explored the possibility of a direct action on the vascular smooth muscle cell (VSMC).. Rat VSMC were isolated from aortas of spontaneously hypertensive rats (SHR) and normotensive control rats (WKY) and maintained in culture. They were exposed to rHuEpo under various experimental conditions, and cells proliferative index was measured by [3H]-thymidine incorporation. Binding studies and Northern blots were performed in an attempt to identify a specific erythropoietin receptor (EpoR). In the latter experiment, Epo-responsive Rauscher Reds cells (Reds cells) were used as a positive control for mRNA EpoR expression.. VSMC growth index of SHR was enhanced up to 1.6-fold by rHuEpo concentrations of 16 U/ml or more, in the presence of 1% fetal calf serum. No such stimulation was observed in VSMC of WKY. Binding studies with radiolabelled rHuEpo showed either extremely low or no specific binding of radiolabelled rHuEpo by VSMC. However, Northern blot analysis revealed the expression of EpoR mRNA in VSMC of either rat strain.. The present report provides preliminary evidence in favour of a direct action of the hormone on vascular smooth muscle via a specific EpoR.

Topics: Animals; Aorta; Blotting, Northern; Blotting, Southern; Cell Division; Cells, Cultured; DNA; DNA Replication; Erythropoietin; Hypertension; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enalapril; Erythropoietin; Female; Follow-Up Studies; Fosinopril; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Topics: Blood Pressure; Erythropoietin; Humans; Hypertension; Plasma Volume; Platelet Aggregation Inhibitors; Uremia

The stimulatory effect of spa therapy on erythropoiesis is well documented. The present study aimed to elucidate the pathogenesis of this effect. The influence of spa therapy on plasma erythropoietin and erythropoiesis was studied in four groups of patients: 35 patients with essential hypertension, 35 patients with inflammatory renal diseases at a stabilized stage and normal excretory renal function. 25 patients with gastrointestinal pathology or cholelithiasis and 33 patients with neurovegetative neurosis. Spa therapy for 20 days in Wysowa was accompanied by a significant increase of plasma erythropoietin, iron, ferritin and saturation of transferrin with iron and by an increase of blood haemoglobin and haematocrit value. These alterations were especially marked in patients with essential hypertension.. 1. Spa therapy exerts a stimulatory effect on erythropoiesis caused, among other factors, by increased erythropoietin secretion and iron mobilization. 2. This stimulatory effect is especially marked in patients with essential hypertension.

Topics: Autonomic Nervous System Diseases; Balneology; Circadian Rhythm; Erythropoiesis; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Hematocrit; Hemoglobins; Humans; Hypertension; Iron; Male; Middle Aged; Nephritis

Topics: Anemia, Hemolytic; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Renal Dialysis

Regular administration of recombinant erythropoietin (EPO) is frequently complicated by a rise in arterial blood pressure. We therefore asked if prolonged stimulation of endogenous EPO production has the same effect. To this end, male Sprague-Dawley rats were placed in a hypobaric chamber (390 mm Hg) for 24 days. The control (NL) group was placed in the chamber at normobaric condition. The animals were then removed from the chamber and monitored through day 108. Plasma EPO peaked within 24 hours and returned to baseline by day 7 and remained so thereafter. Hematocrit rose steadily during the hypoxic phase and declined steadily during the normobaric phase, reaching the baseline on day 45. This was accompanied by parallel changes in erythrocyte mass and blood volume. The rise in hematocrit during hypoxia was accompanied by a parallel rise in blood pressure which peaked on day 24. Despite the restoration of normal hematocrit, erythrocyte mass and blood volume following resumption of normoxia, blood pressure remained elevated throughout the observation period. To dissect the role of hypoxia from that of the associated rise in hematocrit, the experiments were repeated using a group of rats whose hematocrits were kept constant by repeated phlebotomies. These animals exhibited a sustained rise in blood pressure identical to that found in the original group. Thus, prolonged hypobaric hypoxia leads to a severe hematocrit-independent systemic hypertension (HTN) that persists long after the restoration of normoxia. Given the transient nature of the rise in its plasma concentration, endogenous EPO does not appear to play a role in the genesis of the observed systemic HTN. The authors believe that this animal model can be used for future studies of the mechanism, consequences and treatment of acquired HTN.

Topics: Air Pressure; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Disease Models, Animal; Erythropoietin; Hematocrit; Hypertension; Hypoxia; Male; Rats; Rats, Sprague-Dawley; Time Factors

We studied the mechanism of erythropoietin (EPO)-induced hypertension (HTN) in rats with chronic renal failure (CRF). After partial nephrectomy, rats were randomized into four groups. Group A received EPO, 150 U/kg, two times weekly for 6 wk to prevent anemia; group B received placebo injections and became anemic; group C received EPO but was kept anemic by dietary iron deficiency; and group D received placebo and regular transfusions to match hematocrit (Hct) in group A. Blood pressure (BP), Hct, platelet cytosolic calcium ([Ca2+]i) and magnesium concentration, and pressor and vasodilatory responses were determined. By design, Hct in groups A and D were comparable and significantly greater (P < 0.01) than in groups B and C. Despite divergent Hct values, the EPO-treated groups A and C showed a significant rise in BP compared with the placebo-treated groups B and D. HTN occurred whether EPO therapy was begun immediately or 4 wk after nephrectomy. EPO therapy augmented the elevation of basal [Ca2+]i and restored the defective thrombin-mediated rise of platelet [Ca2+]i in CRF animals. EPO therapy did not alter caudal artery contraction in response to either 68 mM K(+)-induced depolarization, angiotensin II or alpha 1-agonist, methoxamine in vitro, or the pressor response to angiotensin II in vivo. However, EPO therapy impaired the hypotensive response to nitric oxide (NO) donors, sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine, and reversed the CRF-induced upregulation of guanosine 3',5'-cyclic monophosphate production by thoracic aorta in vitro. Thus EPO-induced HTN in CRF rats is Hct independent and is associated with and perhaps causally related to increased basal and stimulated [Ca2+]i and impaired vasodilatory response to NO.

Topics: Angiotensin II; Animals; Blood Pressure; Calcium; Cyclic GMP; Drug Resistance; Erythropoietin; Hematocrit; Hypertension; Intracellular Membranes; Kidney Failure, Chronic; Male; Nitric Oxide; Nitroprusside; Osmolar Concentration; Penicillamine; Rats; Rats, Sprague-Dawley; S-Nitroso-N-Acetylpenicillamine; Vasodilation; Vasodilator Agents

The mechanism of erythropoietin-induced hypertension in dialysis patients is unclear. Intracellular calcium ([Ca2+]i) may be altered in both hypertension and uraemia, and the effects of both uraemia and r-HuEPO on vascular smooth muscle [Ca2+]i and blood pressure (BP) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were therefore studied. Male WKY and SHR underwent partial nephrectomy or sham operation. Three weeks later a 28-day period of treatment with either r-HuEPO 100 U/kg, s.c., 3 times/week or buffer was commenced (n = 10-12 for each subgroup). BP was measured weekly, by noninvasive Doppler tail-cuff assessment. [Ca2+]i was measured following loading with fura-2 in pooled, primary aortic vascular smooth muscle cells (VSMC). Serum urea and creatinine rose 3- to 4-fold after partial nephrectomy. Treatment with r-HuEPO did not change renal function further in either uraemic or control WKY or SHR. Haemoglobin increased in both non-uraemic WKY (16.2-20.3 g/dl) and SHR (16.4-20.5 g/dl) and uraemic animals (WKY 13.9-20.9; SHR 13.8-18.8 g/dl; p < 0.01 for all changes) following 4 weeks of r-HuEPO treatment. BP was unaffected by r-HuEPO in WKY but increased in nonuraemic SHR (210-250; p < 0.01) and in uraemic SHR (224-251 mm Hg; p < 0.001) at 4 weeks. VSMC [Ca2+]i was higher in SHR than WKY (121 vs. 83 nmol/l; MANOVA p < 0.05) but no effect of uraemia or r-HuEPO on [Ca2+]i was detected. In conclusion, the hypertensive effects of r-HuEPO are augmented both in a genetic model of hypertension and in uraemia. Although VSMC [Ca2+]i was elevated in SHR, the further increase in BP induced by r-HuEPO was not associated with alterations in VSMC cytosolic calcium.

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Blood Pressure; Calcium; Creatinine; Cytosol; Erythropoietin; Hemoglobins; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins; Urea; Uremia

Hypertension complicates the treatment of anaemia of chronic renal failure with recombinant human erythropoietin (EPO) in some patients. We conducted a prospective study measuring changes in cardiac index (CI) and systemic vascular resistance index (SVRI) in 29 patients from before commencement of EPO to attainment of target haemoglobin concentration. We used the operator-independent technique of trans-thoracic bioimpedance. The group of patients who developed EPO-induced hypertension (EpHT) were separately analysed and compared with the group who had no change in blood pressure (NC). Our results showed there was a significant rise in SVRI after treatment in EpHT group patients but in the NC group there was a small fall. CI increased significantly in the NC group after treatment but no change was recorded in the EpHT group. These findings clearly demonstrate how the cardiovascular changes differ in patients who develop EPO-induced hypertension.

Topics: Adult; Anemia; Blood Pressure; Cardiography, Impedance; Erythropoietin; Female; Heart Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Posture; Prospective Studies; Recombinant Proteins; Renal Dialysis; Vascular Resistance

Topics: Blood Pressure; Erythropoietin; Humans; Hypertension

Persistent hypertension after nephrectomy is in most cases due to increased fluid volume. Endothelin-1 is a potent endogenous vasoconstrictor peptide. Its role in the development and maintenance of hypertension is not completely understood, but it might be significant in some cases. We report a case of stage IV hypertension after nephrectomy with elevated endothelin-1 levels and no volume overload.

Topics: Adult; Blood Pressure; Endothelin-1; Erythropoietin; Female; Humans; Hypertension; Nephrectomy; Renal Dialysis

Topics: Adrenal Gland Neoplasms; Adult; Erythropoietin; Female; Humans; Hypertension; Male; Osmolar Concentration; Pheochromocytoma; Reference Values

Erythropoietin (EPO) has been reported to induce hypertension in hemodialysis patients with family history of hypertension. In this study, to reveal the mechanism of EPO-induced hypertension, we examined the acute effect of EPO on blood pressure (BP) and renal hemodynamics in genetically hypertensive rats, and we also tested the effect of BQ-123, an endothelin ETA-receptor blocker, on EPO-induced changes in hemodynamics. Male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), aged 9-12 wk, were anesthetized, and BP was monitored through the carotid artery. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after an intravenous injection of EPO (1,000 U/kg body wt). In another group of SHR, BQ-123 was continuously infused (1.2 mg.kg body wt-1.h-1) during the experiments. The acute injections of EPO increased BP significantly in SHR in a dose-dependent manner, whereas WKY did not show a significant increase in BP after EPO injections. The effect of EPO on BP in SHR was blocked by BQ-123. In SHR, an acute injection of EPO decreased RPF significantly (from 1.78 +/- 0.16 to 1.49 +/- 0.18 ml.min-1.100 g body wt-1, P < 0.05) without a change in GFR, whereas WKY did not show significant changes in either RPF or GFR. The effect of EPO on RPF in SHR was completely blocked by BQ-123 (from 1.92 +/- 0.26 to 1.88 +/- 0.28 ml.min-1.100 g wt-1, NS). EPO caused a significant increase in plasma endothelin ET-1 in SHR (from 2.3 +/- 0.6 to 6.3 +/- 1.6 pg/ml, P < 0.05), but not in WKY. In conclusion, acute administration of EPO raised blood pressure and reduced RPF in SHR, and these vasoconstrictive effects of EPO are mediated via ETA receptors by an enhanced ET-1 release.

Topics: Animals; Blood Pressure; Endothelins; Erythropoietin; Hemodynamics; Hypertension; Male; Osmolar Concentration; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Time Factors

An elevation of blood pressure is observed in approximately 30% of dialysis patients treated with recombinant human erythropoietin (rHuEPO). Various studies have been performed in order to elucidate possible underlying mechanisms, but it is not yet well understood whether there is one major mechanism involved. In this present study, samples were obtained from male normotensive Wistar-Kyoto rats (WKY) and genetically hypertensive rats (SHR) at the age of 5 and 20 weeks. Thoracic aorta rings, with or without endothelium, isolated from WKY and SHR were used to evaluate the direct effect of rHuEPO on vascular smooth muscle by measuring the tension of vascular smooth muscle induced by various concentrations (1-100 IU/ml) of rHuEPO. Also, rHuEPO (10, 100, 1000 and 10,000 IU/kg) was intravenously administrated and the changes in mean blood pressure were recorded for 5-10 min. rHuEPO produced no significant contraction in the rat aortae in any of the preparation studies, in the presence or the absence of endothelium. The intravenous administration of rHuEPO had no immediate effect on mean blood pressure in 5- and 20-week-old WKY and SHR. These results suggest that the elevation of blood pressure observed in the clinical setting following the administration of rHuEPO is not due to a direct pressor effect on vascular smooth muscle.

Topics: Animals; Aorta; Blood Pressure; Disease Models, Animal; Erythropoietin; Hypertension; Infusions, Intravenous; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction

Systemic hypertension may develop, or worsen, in 20-30% of haemodialysis patients treated with recombinant human erythropoietin (r-HuEPO). No particular group of patients, however, should be excluded from r-HuEPO treatment because of this increased risk. In the vast majority of cases, hypertension can be managed effectively by reducing dry weight, and by adding an antihypertensive agent if necessary. Only if these approaches are ineffective should the dose of r-HuEPO be reduced. Patients on dialysis are likely to be intolerant of cardiac ischaemia, as a result of coronary artery disease, microvascular occlusive disease, inadequate neo-vascularization in cardiac hypertrophy, or reduced glucose uptake (which impairs non-oxidative metabolism of the heart). Treatment with r-HuEPO can significantly reduce cardiac risk, as measured by surrogate endpoints such as left ventricular hypertrophy. More studies are urgently needed to investigate the potential beneficial effects of r-HuEPO on hard endpoints such as cardiac morbidity and mortality. In addition, dose-response data for target haematocrits in the range 30-40% are needed before an appropriate target haematocrit can be determined for patients with symptomatic vascular and cardiac disease.

Topics: Erythropoietin; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Ischemia; Peripheral Vascular Diseases; Recombinant Proteins

The aim of this study was to investigate the mechanism of erythropoietin-induced hypertension in respect to its action on blood serotonergic system. The experiment was carried out on healthy rats and animals with experimental chronic renal failure. Erythropoietin (rHuEPO) injected into the healthy and uremic rats caused an increase in systolic blood pressure. This effect was completely abolished by ketanserin, an antagonist of 5-HT2 receptors. Concomitantly a rise in blood and platelet serotonin concentration was observed. It is concluded that serotonin may play a role in the development of hypertension caused by rHuEPO. Moreover, ketanserin may serve as a drug for pharmacological protection of rHuEPO-induced rise of blood pressure in uremia.

Topics: Anemia; Animals; Blood Platelets; Endothelium, Vascular; Erythropoietin; Hypertension; Ketanserin; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Renin-Angiotensin System; Serotonin; Serotonin Antagonists; Uremia; Vasoconstriction

It is well known that the effects of human recombinant erythropoietin (rHuEPO) are dose-dependent. However, when higher doses of rHuEPO are used, the frequency of the side effects also increases. The aim of our study was to analyze the hematologic parameters and blood pressure response in hemodialysis patients treated with low initial and gradually increased rHuEPO. Sixteen regular hemodialysis patients were treated with 3 x 20 U/kg/week of rHuEPO subcutaneously during the first month. Every fourth week the dose was increased by 3 x 20 U/kg/week if the hematocrit did not rise by 2%. If the elevation was 2% or more, the dose of the rHuEPO was not changed. Blood count and blood pressure were checked every week. The antihypertensive treatment was also reviewed weekly. The hematocrit increased significantly from the second week, and 11 patients achieved the target level (30%) between Weeks 8 and 24. Two patients reached the 30% hematocrit level between Weeks 2 and 8, and another 2 patients reached the target level between Weeks 25 and 28. There was 1 nonresponder. The average rHuEPO dose needed to achieve the target hematocrit was 56.3 U/kg/week. We did not observe significant changes in the mean arterial or diastolic blood pressure. It was necessary to increase the doses of antihypertensive drugs, namely nifedipine and captopril, to control blood pressure. Encephalopathy occurred in none of the cases. The low initial dose and the gradual increase of rHuEPO treatment were beneficial to the hemodialysis patients. Although the target hematocrit took longer to achieve, high blood pressure and encephalopathy were prevented by close monitoring and administration of suitable antihypertensive treatment.

Topics: Adult; Aged; Anemia; Blood Pressure; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Adult; Anemia; Anuria; Combined Modality Therapy; Erythropoietin; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Topics: Aged; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Seizures

Meticulous glucose control that begins long before conception is fundamental to protecting the fetus and mother. Maternal hypertension, retinopathy, renal disease, and neuropathy may lead to complications, but optimal education, care, and fetal monitoring can reduce the risks.

Topics: Adult; Algorithms; Antihypertensive Agents; Blood Glucose Self-Monitoring; Cesarean Section; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Fetal Monitoring; Humans; Hypertension; Infant, Newborn; Insulin; Male; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy, High-Risk; Prenatal Care

Conservative use of allogeneic red blood cell (RBC) transfusion is a growing trend in cardiovascular surgery. Recent advances in blood conservation measures have reduced, and in some cases eliminated, the need for allogeneic RBC transfusions in some of these patients. Reduced reliance on allogeneic RBC transfusion requires close collaboration among the clinical pathology, anesthesia, and surgery services managing the patient. Preoperative conservation measures include donation of autologous blood and treatment with recombinant human erythropoietin (Epoetin alfa). Meticulous surgical technique, moderate hemodilution, aprotinin, hemostatic techniques, blood salvage, and autotransfusion are intraoperative measures that can reduce blood loss. Postoperatively, even severe blood deficits can often be restored with adequate diet and rest and the use of actinics.

Topics: Anticoagulants; Aprotinin; Blood Loss, Surgical; Blood Transfusion, Autologous; Cardiac Surgical Procedures; Christianity; Erythrocyte Transfusion; Erythropoietin; Hemodilution; Hemostatic Techniques; Hemostatics; Heparin; Humans; Hypertension; Hypothermia, Induced; Intraoperative Period; Monitoring, Physiologic; Postoperative Care; Preoperative Care; Recombinant Proteins

Hypertension is the most common side-effect of treatment with recombinant human erythropoietin (EPO) for the anemia of chronic renal failure. To elucidate why this occurs in some patients we measured changes in blood volumes and diurnal blood pressure (BP) variation during treatment. Isotope labelled measurements of red cell and plasma volume (RCV and PV) were carried out along with ambulatory BP monitoring before starting EPO and after target hemoglobin (Hb) was reached. RCV did not differ between the patient group developing EPO-induced hypertension (EpHT, n = 11) and the group with no change in BP (NC, n = 13) either before or after treatment. However PV was significantly lower in the EpHT group after treatment (2.97 vs 3.92 litres; p < 0.025). Mean BPs differed little between groups because antihypertensive medications were increased as necessary for clinical safety but after achieving target Hb, day-night difference in diastolic BP was greater in the EpHT than the NC group (11.5 vs 4.6 mmHg; p < 0.025) due to a greater rise in daytime BP. There were significant correlations between high day-night diastolic BP differences after EPO in all the studied patients and low plasma volumes either pre- or post-EPO. The study group was heterogeneous but the changes were in the same direction irrespective of type of renal replacement therapy. These results suggest that EPO-induced hypertension is associated with increased daytime vasoconstriction and greater hemoconcentration due to lower plasma volume.

Topics: Anemia; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Erythrocyte Volume; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Plasma Volume; Prospective Studies

1. There is no experimental proof that renal insufficiency is a necessary condition for hypertension during erythropoietin treatment. 2. The present study compares the effect of 3 weeks treatment with r-hu EPO (50 i.u./kg) on systolic blood pressure (SBP), haematocrit and plasma cGMP in an animal model of chronic renal failure (remnant kidney model excision) and sham-operated rats. 3. Sub-total nephrectomy induced a significant fall in haematocrit and a significant increase in plasma creatinine levels. Treatment with r-hu EPO resulted in a significant haematocrit increase in uraemic as well as in non-uraemic rats. Despite this effect, r-hu EPO treatment had no effect on SBP in sham-operated rats. On the contrary, this treatment caused significant SBP elevation in uraemic rats; in these rats, SBP increase did not correlate with haematocrit increase. 4. Plasma cGMP concentrations were significantly higher in uraemic compared to sham-operated rats and were not modified by r-hu EPO treatment. 5. This study provides evidence that renal insufficiency in rats is a prerequisite for the development of hypertension during erythropoietin treatment.

Topics: Animals; Blood Pressure; Creatinine; Cyclic GMP; Disease Models, Animal; Erythropoietin; Hematocrit; Hypertension; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Wistar; Uremia

The administration of recombinant erythropoietin (rHuEpo) to anemic chronic renal failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood vessels. In the present study, experiments were designed to explore the hypothesis that rHuEpo could enhance vascular resistance through mitogenic effect on vascular smooth muscle cells (VSMCs), and that preexisting hypertension might be a predisposing condition. Cultured VSMCs from the thoracic aortae of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related proto-oncogene expression in the presence of rHuEpo. In cells from both strains, rHuEpo dose-dependently increased DNA synthesis and stimulated phospholipase C activity, as indicated by 3H-thymidine incorporation and 3H-inositol phosphate formation, respectively (EC50 approximately 4 U/ml). Exposure of VSMCs to rHuEpo for various times gradually increased the levels of c-myc and junB and transiently induced c-fos expression, as determined by Northern analysis. rHuEpo-induced DNA synthesis was markedly enhanced in VSMCs from SHR compared to those from WKY. In contrast, rHuEpo-induced phospholipase C activity and proto-oncogene expression did not differ between the two strains. Taken together, these results suggest that rHuEpo may function as a vascular smooth muscle cell growth promoting factor through activation of the phospholipase C cascade and modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension.

Topics: Animals; Aorta; Cells, Cultured; Erythropoietin; Hypertension; Male; Mitogens; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Wistar

Recent data indicated the importance of urinary losses of erythropoietin (Epo) in the pathogenesis of anaemia in patients with nephrotic syndrome. In the present study we aimed to investigate plasma and urinary Epo levels and their renal handling in relation to beta 2-microglobulin (beta 2m), sodium metabolism and the renin-angiotensin-aldosterone system (RAAS), respectively, in patients with sub-nephrotic range proteinuria (SNP), microalbuminuric diabetics and hypertensives, and in healthy subjects studied on a standardized diet containing 120 mmol sodium and 70 g protein per day. We found that patients with SNP were characterized by lower plasma levels of Epo than healthy subjects but no differences were found in urinary excretion of Epo, endogenous Epo clearance and its fractional excretion (FEEpo). There were no differences between groups in FE beta 2m and FENa and plasma aldosterone levels but plasma renin activity was higher in patients with SNP than in the controls. No relationships were found between Epo levels and activity of the RAAS and sodium metabolism, respectively. Our data suggest that lower levels of plasma Epo in patients with SNP and normal renal excretory function are not due to urinary losses of Epo but rather to the decreased production/degradation ratio.

Topics: Adult; Albuminuria; beta 2-Microglobulin; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Hypertension; Nephrotic Syndrome; Proteinuria; Renin-Angiotensin System; Sodium

Erythropoietin therapy for uraemic anaemia is associated with a high rate of hypertensive and thrombotic complications. The mechanism is unknown, but a change in cellular calcium control may be relevant to changes in blood pressure and thrombosis. Platelets were utilized as a model of vascular smooth muscle cells. The effects of erythropoietin therapy on platelet cellular calcium, assessed by fura-2, were measured in 25 patients receiving renal replacement therapy during a 6-month treatment period. Three patients failed to reach a target haemoglobin and were excluded from the analysis. Blood pressure increased in 11 of the remaining 22 subjects, eight requiring an increase in antihypertensive medication. There were no differences in cellular calcium control between the group in whom blood pressure rose and patients with stable blood pressure. Overall there was a fall of 24% in resting cytosolic calcium (baseline 69.2 +/- 5.1 to 52.5 +/- 3.0 nmol/l, P < 0.05) after 3 months of erythropoietin therapy. There was no change in the thrombin-stimulated peak response in the presence of extracellular calcium during therapy, although thrombin-stimulated intracellular release also fell at 3 months (baseline 769 +/- 61 versus 3 months 559 +/- 49 nmol/l, P < 0.01). This study suggests that intracellular free calcium control within platelets improves in response to erythropoietin therapy. However these changes appear not to be related to the development of hypertension.

Topics: Adult; Aged; Anemia; Blood Platelets; Blood Pressure; Calcium; Cytosol; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Thrombosis; Uremia

Topics: beta-Thromboglobulin; Blood Platelets; Blood Pressure; Calcium; Calcium Channel Blockers; Erythropoietin; Humans; Hypertension; Injections, Subcutaneous; Recombinant Proteins; Renal Dialysis; Thrombin

The burden of cardiac disease in dialysis patients is high. Congestive heart failure, ischemic heart disease, left ventricular hypertrophy, and systolic dysfunction occur frequently and are associated with an adverse prognosis. In addition, during dialysis therapy anemia, hypoalbuminemia, low blood pressure, and lower serum creatinine levels are adverse predictors of mortality. Risk factors for systolic dysfunction include older age, ischemic heart disease, hyperparathyroidism, and smoking. Risk factors for left ventricular hypertrophy include older age, hypertension, anemia, and diabetes mellitus. Interventions with potential for improving cardiomyopathy include normalization of hematocrit with erythropoietin, improved uremia therapy, and angiotensin-converting enzyme inhibitors. Trials to determine the most appropriate interventions to reduce the impact of cardiac disease in chronic uremia are urgently required.

Topics: Age Factors; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Canada; Cardiomyopathies; Cohort Studies; Comorbidity; Diabetes Mellitus; Echocardiography; Erythropoietin; Female; Hematocrit; Humans; Hyperlipidemias; Hyperparathyroidism; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Prognosis; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Risk Factors; Smoking; Survival Analysis; Systole

Topics: Adult; Cyclophosphamide; Erythropoietin; Female; Humans; Hypertension; Male; Radioimmunoassay; Time Factors; Vasculitis

The changes in haemoglobin concentration, haematocrit, plasma renin activity (PRA) and atrial natriuretic peptide (ANP) were studied in 10 haemodialysis patients with erythropoietin-associated hypertension. All patients received intravenously 1500 IU of recombinant human erythropoietin (rHuEPO) thrice weekly for 24 weeks. Treatment with rHuEPO induced significant rises in haemoglobin concentration (p < 0.001) and haematocrit (p < 0.01). However, the difference between post- and pretreatment levels of haemoglobin (delta Hb) was not correlated with that between post- and pre-treatment mean blood pressure (delta MBP). No correlation was found between delta Ht (difference between post- and pre-treatment values of haematocrit) and delta MBP. These results indicate that elevation of the haematocrit and haemoglobin concentration of haemodialysis patients does not necessarily lead to an increase in blood pressure. In these patients, no significant differences were observed in PRA and ANP, comparing pre-treatment values with those measured 4, 8, 12 or 24 weeks after commencing rHuEPO. This suggests that neither PRA nor ANP play a central role in the pathogenesis of rHuEPO-induced hypertension.

Topics: Adult; Atrial Natriuretic Factor; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin

We assessed the influence of hyperoxemia on erythropoietin secretion in patients with various etiological forms of arterial hypertension (essential, n = 15; renoparenchymal, n = 16; renovascular, n = 15) and in 15 healthy subjects. On the first day of the study, blood was withdrawn at 1-hour intervals for the estimation of erythropoietin during a total of 6 hours and at 2-hour intervals for the assessment of PO2. Three days later the same parameters were assessed again at identical time intervals, but the subjects were breathing pure oxygen during the first 2 hours. Breathing with pure oxygen resulted in a significant increase of blood PO2 (184.85 +/- 4.47 versus 85.92 +/- 2.28 in essential, 185.21 +/- 5.52 versus 84.55 +/- 3.04 in renoparenchymal, and 181.7 +/- 3.14 versus 87.49 +/- 2.25 in renovascular hypertension groups and 189.84 +/- 5.2 versus 85.89 +/- 1.73 mm Hg in healthy subjects; P < .001 in all groups). Baseline plasma erythropoietin was not different among the groups (29.33 +/- 4.14 in essential, 24.56 +/- 3.09 in renoparenchymal, and 27.77 +/- 3.29 in renovascular hypertension groups and 24.23 +/- 2.70 mU/mL in the control group). The pattern of erythropoietin decline was different in the groups of hypertensive patients. In patients with essential hypertension, unlike in healthy subjects and patients with other etiological forms of arterial hypertension, only a very short-term suppression of erythropoietin levels was observed during hyperoxemia. No significant changes in blood pressure during breathing with pure oxygen were found in any of the studied groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Iron; Male; Middle Aged; Oxygen

We investigated whether the treatment of anemic hemodialysis patients with a low dose of recombinant human erythropoietin (rHEpo) for a short period would increase the blood pressure (BP). Home BP measurements were used to detect minute increases in BP. Fifty-one anemic patients on maintenance hemodialysis with a hematocrit of 25% or less received rHEpo at the dose of 4500 IU/week by the intravenous route for 8 weeks. Overall, rHEpo did not increase the BP whether measured at home or in the clinic (causal BP). Hemoglobin concentration increased significantly from 7.1 +/- 0.7 to 8.8 +/- 0.7 g/dl. Patients were classified into two groups according to the change in mean (M) home BP induced by rHEpo: a pressor group (delta MBP > or = 5 mmHg, n = 17) and a non-pressor group (delta MBP < 5 mmHg, n = 34). The hemoglobin concentration rose significantly in both groups, but there was no change in casual BP. Home blood pressure measurements showed a gradual and continuous rise in BP in the pressor group, but not in the non-pressor group. Patients administered antihypertensive medications before rHEpo treatment accounted for 88% of the former and 50% of the latter groups. Two patients with malignant nephrosclerosis were included in the pressor group. The findings indicate that rHEpo, even given at a low dose for a short period, elevates the BP, as determined by home BP measurement, but not by casual measurements obtained in the clinic.

Topics: Adult; Aged; Anemia; Blood Pressure Determination; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Blood Pressure; Erythropoietin; Hemodynamics; Humans; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Intracellular free calcium concentration ([Ca2+]i) was examined in the platelets of 15 control subjects (NT), 6 predialysis patients with chronic renal failure (CRF), 17 patients on hemodialysis (HD), 20 patients on continuous ambulatory peritoneal dialysis (CAPD), 10 normotensive persons with genetic hypertension (GHT) and 8 essential hypertensive patients (EHT). Levels of [Ca2+] i in the platelets were measured by the fluorescent calcium indicator Fura-2. Resting [Ca2+] i in CRF and HD patients was higher than the value in NT and that in CAPD patients was similar to NT. rHuEPO significantly increased the level of [Ca2+] i in CRF and HD patients compared to those in NT. Under resting and EPO-stimulated conditions, the levels of [Ca2+] i in GHT and EHT were higher than those in NT. rHuEPO increased the levels of [Ca2+] i in the absence of extracellular calcium in NT, GHT and EHT. In addition, EPO-stimulated calcium influx in GHT and EHT was greater than that in NT. Thus, it appears that the mechanism of rHuEPO-induced hypertension may be mainly due to elevation of [Ca2+] i. EPO may contribute to the development of genetic hypertension.

Topics: Adult; Aged; Blood Platelets; Calcium; Erythropoietin; Female; Humans; Hypertension; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

The pathogenesis of hypertension induced by recombinant human erythropoietin (rHuEPO) remains a subject of intense interest. The observation that patients treated with antiplatelet drugs never developed hypertension following rHuEPO therapy prompted us to study retrospectively the incidence and risk factors associated with the development of hypertension in 91 patients on renal replacement therapy who had commenced rHuEPO therapy in the last three years. Logistic regression analysis was used to determine the risk factors associated with the development or aggravation of hypertension during the first six months on rHuEPO therapy. The predictors were: age, gender, number of months on dialysis, antecedent of hypertension, use of antiplatelet drugs, and those parameters related with dose, route and magnitude of the hematological response to rHuEPO. Of the 91 patients studied, 34 developed hypertension (37%). Of the 34 patients who were on antiplatelet treatment, 2 (5.8%) developed hypertension, whereas among 57 who did not receive antiplatelet drugs, 32 (56%) developed it. By multiple logistic regression analysis, the best predictive variables over the development of hypertension were: age (odds ratio: 0.959, P = 0.02), antecedent of hypertension (odds ratio: 6.52, P = 0.002), and use of antiplatelet therapy (odds ratio: 0.030, P < 0.0001). The rest of the studied variables failed to explain the development of hypertension. Antiplatelet therapy may prevent the development of hypertension in patients treated with rHuEPO. Since the antiplatelet drugs used in this study did not have a significant hemodynamic effect, we infer that changes in platelet aggregability induced by rHuEPO may be involved in the pathogenesis of hypertension induced by this hormone.

Topics: Adolescent; Adult; Aged; Catheters, Indwelling; Confounding Factors, Epidemiologic; Erythropoietin; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Platelet Aggregation Inhibitors; Recombinant Proteins; Regression Analysis; Renal Dialysis; Retrospective Studies; Risk Factors; Thrombosis; Uremia

Deliberate self-administration of recombinant human erythropoietin (rHuEpo) in a patient without anemia has never been documented. The case of a 62-year-old man who worked in an allied health care field and surreptitiously injected the drug, causing his hematocrit to increase to a dangerously high level is presented. Resultant complications of the misuse of erythropoietin in this patient included worsening hypertension, exacerbation of chronic lung disease and development of new onset angina. Medical management consisted of endotracheal intubation with mechanical ventilation, intravenous hydration, and serial phlebotomy. The unusual possibility of erythropoietin abuse must be added to the differential diagnosis with a patient with unexplained polycythemia. This case highlights the potential abuse of biological growth factors that may mask medical conditions.

Topics: Angina Pectoris; Bloodletting; Delusions; Diagnosis, Differential; Drug Overdose; Erythropoietin; Fluid Therapy; Hematocrit; Humans; Hypertension; Lung Diseases, Obstructive; Male; Middle Aged; Polycythemia; Respiration, Artificial; Self Medication; Substance-Related Disorders

Topics: Anemia; Animals; Calcium; Cell Line; Endothelium, Vascular; Erythropoietin; Humans; Hypertension; Muscle, Smooth, Vascular; Rats; Recombinant Proteins; Renal Dialysis

Recent studies suggest the existence of a relationship between the renin-angiotensin system and erythropoietin (EPO) secretion. It has been studied whether patients with various forms of arterial hypertension (essential, renal, renovascular, in the course of arteritis) differ with respect to EPO secretion and whether EPO serum levels are related to renin response induced by dietary sodium restriction to 10-20 mmol Na/24 h for 3 days and upright body position for 3 h. Patients with different forms of hypertension and normal renal excretory function and healthy subjects did not differ in hematocrit value, markers of iron metabolism, and EPO secretion except for patients with arteritis who had higher ferritin values. In these patients a positive correlation between EPO levels and hematocrit values suggests the existence of an altered regulation of EPO secretion. In essential hypertension a negative correlation found between changes in EPO and PRA levels in response to sodium restriction and upright body position may also reflect an altered regulation of both EPO and renin production.

Topics: Adult; Blood Pressure; Diet, Sodium-Restricted; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Male; Posture; Renin; Renin-Angiotensin System

Treatment with recombinant human erythropoietin (rHuEPO) successfully reverses anemia in uremic patients. Of major concern, however, are blood pressure increases during rHuEPO therapy, observed particularly in patients with a history of hypertension. The present study was designed to determine whether high-dose rHuEPO elevates blood pressure in nonuremic rats, and if so, whether preexisting hypertension enhances this response. We examined blood pressure responses to high (100 IU/kg) and very high (200 IU/kg) doses of rHuEPO or placebo, given subcutaneously every other day for 3 weeks to male spontaneously hypertensive rats (SHR) and their normotensive genetic controls (Wistar-Kyoto rats, WKY). The high and very high doses of rHuEPO stimulated equivalent increases in hematocrit, and this increase was always larger in SHR than in WKY. In contrast to the pattern of hematocrit changes, blood pressure did not change following high-dose rHuEPO but was elevated in both strains after the very high dose of the drug. Although the rise in blood pressure tended to be greater in SHR than in WKY, this difference was not significant. The data indicate that very high-dose rHuEPO raises blood pressure comparably in normotensive and hypertensive rats and this increase is relatively independent of the increase in hematocrit.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Erythropoietin; Hypertension; Injections, Subcutaneous; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins

Topics: Adult; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Male; Recombinant Proteins; Renal Dialysis

To clarify the effects of correction of anemia with recombinant human erythropoietin (rHuEPO) on blood coagulation, fibrinolysis and endothelium, these markers were examined in 19 regular hemodialysis patients before and 4, 8, 12 weeks on rHuEPO treatment, and 5 weeks after the end of treatment. Hematocrit significantly increased from 22.8 +/- 2.0 to 31.1 +/- 2.7% at 12 week (p < 0.001). Coagulation and fibrinolysis markers did not show significant changes except for minor and transient alteration of protein C, thrombin-antithrombin III complex and alpha 2-plasmin inhibitor plasmin complex (PIC) throughout the treatment. Endothelin and 6-keto-prostaglandin F1 alpha (PGF1 alpha) significantly increased from 6.1 +/- 4.5 to 14.2 +/- 2.9 pg/ml (p < 0.001) and from 51.9 +/- 14.7 to 66.5 +/- 18.5 pg/ml (p < 0.05) at 12 week, respectively. Human atrial natriuretic peptide (ANP) significantly decreased from 277.9 +/- 88.6 to 179.4 +/- 73.3 pg/ml at 12 week (p < 0.001). Endothelin and PGF1 alpha after 6 month treatment with rHuEPO showed high values as same as those of 12 weeks. These data suggests that rHuEPO therapy did not affect blood coagulation and fibrinolysis, however exerts effects on the endothelium. Changes in endothelial function after rHuEPO may be one of the pathogenetic mechanisms of hypertension and may contribute to a decrease in thrombotic complications.

Topics: Blood Cell Count; Blood Coagulation; Blood Coagulation Factors; Endothelins; Erythropoietin; Fibrinolysis; Humans; Hypertension; Recombinant Proteins; Renal Dialysis

Topics: Adult; Aged; Blood Pressure; Catecholamines; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged

To gain an insight into the effect of erythropoietin (Epo) upon cation transporters and cytosolic free Ca2+ concentration ([Ca2+]i) of vascular smooth muscle cells (VSMC), we studied whether 1) Epo, per se, alters Ca2+ Na+, K+ fluxes and [Ca2+]i of VSMC, and 2) Epo may modify the effect of endothelin (ET-1). Using serially passaged quiescent cultured VSMC, the following results were obtained. 1) Epo had no direct effect on steady state Na(+)-K+ transporters (Na(+)-K+ pump, Na(+)-K+ cotransport and Na(+)-H+ antiport). 2) ET-1 alone substantially stimulated Na(+)-K+ pump, Na(+)-H+ antiport and 45Ca uptake, although these effects were not potentiated in the presence of Epo. 3) Epo alone substantially stimulated 45Ca uptake, leading to an increase in [Ca2+]i, which effect was not seen in Ca2+ deficient medium, and was partially inhibited with diltiazem but not with TMB-8. 4) Even in the presence of Epo, ET-1 and angiotensin II (A II) had substantial stimulatory effect on [Ca2+]i of cultured VSMC. The present data indicate that Epo, per se, elicits an increase in [Ca2+]i of VSMC through the stimulation of inward Ca2+ flux without affecting Na(+)-K+ transporters. In contrast, Epo did not potentiate ET-1's stimulatory effect on the transporters. Although the effect of Epo was subtle compared to ET-1 and A II, it may alter an overall characteristic of vascular smooth muscle cell contractility, possibly leading to blood pressure elevation in patients on maintenance dialysis.

Topics: Animals; Biological Transport; Calcium; Erythropoietin; Humans; Hypertension; In Vitro Techniques; Intracellular Membranes; Male; Muscle, Smooth, Vascular; Potassium; Rats; Rats, Wistar; Recombinant Proteins; Sodium

Twenty-seven patients with renal failure (16 on CAPD and 11 predialysis) were treated with erythropoietin. At 12 weeks, the mean haemoglobin concentration (+/- SEM) in the CAPD patients had increased from 7.07 +/- 0.20 to 10.88 +/- 0.45 g/dl (two-tailed paired t test, P < 0.0001) and in the predialysis patients from 6.90 +/- 0.35 to 10.05 +/- 0.47 g/dl (P < 0.0001). Predialysis patients were taking more antihypertensive medication at baseline. No increase was required in either group after erythropoietin; there was no change in blood pressure in the CAPD patients, though in the predialysis patients the systolic blood pressure rose slightly from 132 to 146 mmHg (P = 0.029) and the mean blood pressure from 95 to 103 mmHg (P = 0.028). In 12 patients (6 on CAPD and 6 predialysis) the red cell volume, plasma volume, and total blood volume were measured before and after treatment. In the CAPD patients there was a marked expansion of the red cell volume from 912 +/- 127 to 1471 +/- 222 ml (P = 0.004) and a concomitant contraction of the plasma volume from 3932 +/- 250 to 3178 +/- 326 ml (P = 0.005), leaving the blood volume unchanged from 4843 +/- 352 to 4649 +/- 503 ml. Predialysis patients had a similar expansion of the red cell volume from 733 +/- 59 to 1304 +/- 161 ml (P = 0.017) but no contraction of the plasma volume (from 3417 +/- 354 to 3314 +/- 260 ml), so that the blood volume tended to expand from 4149 +/- 347 to 4618 +/- 414 ml (P = 0.053).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Blood Volume; Erythropoietin; Humans; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

To assess the effect of erythropoietin (EPO) treatment on blood pressure in continuous ambulatory peritoneal dialysis (CAPD) patients, we analyzed in a retrospective study the results of 6 months of EPO treatment in 17 CAPD patients. There were 10 females and 7 males, mean age 52 years, mean duration on CAPD 35 months. They received subcutaneously a mean initial EPO dose of 114 +/- 45 U/kg/week (range 59-209). This dose was adjusted throughout 6 months to achieve and maintain a target Hb of 100 g/L (Hct 30%). Seven of the patients were hypertensive before starting EPO treatment. Fifteen patients (88.2%) achieved the target hemoglobin. For all subjects (n = 17) there was a significant increase in lying mean blood pressure (MBP) from 93.8 +/- 10.0 to 105.2 +/- 14.4 mmHg (p = 0.0024). Four patients required an increase in their antihypertensive medication, and 4 were not treated before we started antihypertensive treatment (Group I). This group represents 46% (8/17) of the patients. There was no change in the antihypertensive medication status of the remaining 9 patients (Group II). The baseline lying MBP was not significantly different for the two groups (98.8 +/- 9.8 mmHg vs 96.1 +/- 7.2 mmHg). The mean weekly dose of EPO during the first 3 months was higher in Group I (126 vs 100 U/kg) and conversely was lower during the last 3 months (mean dose 108 vs 117 U/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Pressure; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Retrospective Studies

Recombinant human erythropoietin (r-HuEPO) was administered in 68 dialyzed patients (32 on acetate hemodialysis, 24 bicarbonate hemodialysis and 12 on hemo-filtration). The mean initial Hb 52.7 +/- 8.0g/L, Ht 19.4 +/- 2.2%, serum ferritin > 100ng/L. Each patients received r-HuEPO intravenously, at the dose of 300U/Kg/w for 6.2 +/- 4.3 months. Target range: Hb 100-120g/L, Ht 30-35%. After r-HuEPO treatment, blood transfusion was not needed for any of the patients, anemia was ameliorated with increase of Hb and Ht levels. It was found that the minimum effective dose of the r-HrEPO was 150-300U/Kg/w. We conclude that r-HuEPO is effective as treatment for the anemia of dialyzed patients. However, hypertension, clotted dialyzers and dialysis access thromboses were been developed in some patients after correction of anemia. There is now a general consensus that these side effects may be minimized if r-HuEPO is initially given in small doses with increments to avoid a too rapid correction of the anemia.

Topics: Adult; Anemia; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

Regulation of renal erythropoietin (EPO) production has not yet been clearly established in physiologic as well as in pathologic conditions. Recent studies suggest a possible role for renin-angiotensin system in control of EPO production. An elevation in blood pressure occurs commonly in patients with various forms of anaemia treated with recombinant human EPO. Furthermore it has been found that EPO can alter secretion of hormones engaged in regulation of intravascular fluid volume and vascular resistance. The aim of this study was to determine whether patients with essential hypertension (EH) and healthy subjects differ in EPO secretion and whether EPO serum level is related to renin response to dietary sodium restriction and upright position of the body. 63 patients with EH and 12 healthy subjects were investigated. Patients with EH were divided into subgroups on the following criteria: renin response to dietary sodium restriction and upright position of the body. 63 patients with EH and 12 healthy subjects were investigated. Patients with EH were divided into subgroups on the following criteria: renin response to dietary sodium restriction and upright position of the body and severity of existing hypertension. In all subjects haematocrit value, haemoglobin concentration, erythrocyte count, sodium, potassium, creatinine, iron, ferritin serum levels, total iron binding capacity, plasma renin activity (PRA), erythropoietin serum level and mean arterial blood pressure (MAP) were measured in basic conditions (normal sodium diet). Additionally PRA, EPO and MAP were measured after dietary sodium restriction for three days and upright position of the body for three hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Erythropoietin; Female; Humans; Hypertension; Male; Renin; Renin-Angiotensin System

There is little experience with the use of various therapies in the end-stage renal disease patient who becomes pregnant. Erythropoietin for the treatment of anemia has become part of the standard treatment regimen of dialysis patients, but experience with its use in pregnancy is limited. We report five cases of its use in dialysis patients during pregnancy. We found no evidence that it crossed the placenta or that it made blood pressure control more difficult. We found that patients required a higher dose of erythropoietin to maintain hematocrit levels than they had before pregnancy. Another therapy involves the treatment for premature labor, which is the most common cause of pregnancy loss in dialysis patients. Two of our patients were successfully treated with indomethacin for premature labor. Both drugs are useful tools in the management of pregnant dialysis patients.

Topics: Abnormalities, Drug-Induced; Adult; Anemia; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Indomethacin; Kidney Failure, Chronic; Obstetric Labor, Premature; Oligohydramnios; Polyhydramnios; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Renal Dialysis

To assess the efficacy of blood pressure control in continuous ambulatory peritoneal dialysis (CAPD), blood pressure was examined sequentially in 63 CAPD patients transferred from hemodialysis (HD), and in 97 patients started de novo on CAPD (NEW), over periods ranging from 3 to 63 months. Blood pressure changes were related to changes in body weight, hematocrit, and treatment with recombinant human erythropoietin (rHu-EPO), as well as to changes in antihypertensive drug requirements. Both groups of patients showed an immediate improvement in blood pressure control at 1 month, as manifested by an absolute decrease in blood pressure in HD patients (-4.3% +/- 2.1% [SEM], P < 0.05) and by a decrease in antihypertensive drug requirements in NEW patients (from 78% to 43.3%). This early improvement in blood pressure appeared to be volume-related, as reflected by changes in body weight. Both groups showed an additional decrement in blood pressure at approximately 6 months (-7.8% +/- 2.6% [SEM], P < 0.05, HD group; -3.4% +/- 2.4% [SEM], P < 0.05, NEW group). Treatment of anemia with rHu-EPO in 22 of the CAPD patients had no effect on blood pressure. CAPD thus appears to be more effective than HD in controlling blood pressure.

Topics: Anemia; Antihypertensive Agents; Blood Pressure; Body Weight; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Time Factors

Hypertension is the most common complication of r-HuEPO therapy in dialysis patients. The aim of this study was to test the hypothesis that hypertension develops in patients who fail to autoregulate adequately their hemodynamic response to correction of anemia. Twenty-five dialysis patients (17-71 yrs, 13 male, 13 CAPD) initially received r-HuEPO 50 U/kg 3 times/week intravenously or subcutaneously. Hypertension, defined as a rise in mean blood pressure (BP) of greater than 15 mmHg during therapy developed in 44% (Group 1: stable BP; Group 2: rise in BP). There was no difference in sex, age, mode of dialysis or route of administration of r-HuEPO between the groups. Before commencement and after 6-12 months of r-HuEPO therapy, assessment of the baroreflex arc was performed using the Valsalva ratio and orthostatic BP testing, sympathetic efferent nerve function was assessed by the cold pressor test and afferent parasympathetic function by the 30:15 ratio and heart rate variation (HRV). No difference was detected prior to r-HuEPO therapy between the two groups in Valsalva ratio (Group 1: 1.26 +/- 0.06 vs Group 2: 1.23 +/- 0.06, mean +/- SEM); 30:15 ratio (1.06 +/- 0.02 vs 1.03 +/- 0.01), or systolic, diastolic, mean BP or pulse rate after standing for 3 minutes or following hand immersion in ice slush. Both groups had a fall in systolic and diastolic BP (p < 0.05) and a rise in pulse rate (p < 0.05) on standing. HRV during deep respiration between the 2 groups was not different (9.6 +/- 2.3 vs 7.1 +/- 1.4 beats/minute).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Autonomic Nervous System Diseases; Blood Pressure; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Pressoreceptors; Recombinant Proteins; Renal Dialysis; Valsalva Maneuver

The purpose of this study is to compare the direct vasopressor effects of erythropoietin between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The aortic rings from SHR or WKY were suspended in tissue baths coupled with tension-recording devices. High concentrations of recombinant human erythropoietin (more than 20 U/ml) induced vasoconstriction in the aortic ring of genetically hypertensive SHR. Furthermore, only in SHR, 10 U/ml erythropoietin enhanced contraction induced by 10(-7) M norepinephrine (+145% vs +121%, p < 0.04) and reduced relaxation by 10(-7) M acetylcholine (-69% vs -96%, p < 0.05). On the other hand, erythropoietin did not influence the contractility of aortic ring in normotensive WKY. These results suggest that erythropoietin exhibits its direct vasopressor effect preferentially in the blood vessels of genetically hypertensive animals.

Topics: Acetylcholine; Angiotensin II; Animals; Blood Pressure; Body Weight; Erythropoietin; Hematocrit; Hypertension; In Vitro Techniques; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction

This study investigated the hypothesis that a genetic predisposition to hypertension is involved in the etiology of the elevation in blood pressure induced by human recombinant erythropoietin (rHuEPO).. Blood pressure changes after 10 weeks of treatment with rHuEPO were compared between 26 patients with a positive family history of hypertension and 27 with a negative family history.. Mean blood pressure was significantly increased in patients with a positive family history of hypertension (+8.8 mm Hg, p < 0.001). In contrast, the change was not significant in those whose family history was negative (+1.8 mm Hg, not significant). The mean blood pressure of 14 of 26 patients with a positive family history of hypertension increased by more than 10%, whereas such an increase occurred in only 2 of 27 patients with a negative family history (p < 0.001). The two groups were similar in terms of the total dose of rHuEPO given, the degree to which their anemia improved, and their basal blood pressures.. It appears that hemodialysis patients with a positive family history of hypertension are susceptible to developing hypertension during treatment with rHuEPO.

Topics: Antihypertensive Agents; Blood Pressure; Body Weight; Causality; Confounding Factors, Epidemiologic; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Male; Medical History Taking; Middle Aged; Renal Dialysis; Weight Gain

Renal erythropoietin production is dependent on local oxygen content of blood which activates so called "oxygen sensors". Taking into consideration altered local renal blood supply in patients with arterial hypertension in the course of arteritis (HA) and from the other side contribution of the renin-angiotensin system in both pathogenesis of hypertension and regulation of erythropoietin production it seemed plausible to undertake this study. The aim of the study was to determine whether and in what extent patients with HA and healthy subjects differ in EPO secretion and whether EPO serum level is related in this patients to renin response to dietary sodium restriction and upright position of the body. 18 patients with HA and 12 healthy subjects were investigated. In all subjects haematocrit value, haemoglobin concentration, erythrocyte count, sodium, potassium, creatinine, iron, ferritin serum levels, total iron binding capacity, plasma renin activity (PRA), erythropoietin serum level and mean arterial blood pressure (MAP) were measured in basic conditions (normal sodium diet). Additionally PRA, EPO and MAP were measured after dietary sodium restriction to 10-20 mmol Na/24 hrs for three days and upright position of the body for three hours. Patients with HA had insignificantly lower serum EPO concentrations than healthy subjects and both studied groups did not differ in haematocrit value and determinants of iron metabolism except of significantly higher ferritin concentration in HA. After dietary sodium restriction and upright position of the body significant rise in PRA and no significant changes in EPO level were found in studied groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arteritis; Blood Pressure; Erythropoietin; Humans; Hypertension; Reference Values; Renin

To investigate the pathophysiology of hypertension in patients receiving recombinant human erythropoietin (rHuEpo) we studied its effects on the renin-aldosterone axis of chronic haemodialysis (HD) patients not receiving antihypertensive drugs. Nine severely anaemic normotensive HD patients received rHuEpo 50 U/kg bodyweight, thrice weekly after each HD. The dose was increased by 25 U/kg bodyweight every 4 weeks to a maximum of 100 U/kg or until an increase of Hb or Hct of 2 g/dl or 7% was achieved. Blood samples were taken after 30 min supine rest and while seated 10 min later after gentle ambulation. Results expressed as mean +/- SEM: therapy in normotensive HD patients by a negative feedback loop, before the development of hypertension.

Topics: Adult; Aged; Aldosterone; Anemia; Erythropoietin; Feedback; Hemoglobins; Humans; Hypertension; Middle Aged; Renal Dialysis; Renin; Renin-Angiotensin System

Systemic hypertension as assessed by causal blood pressure measurements is a frequently reported side-effect of recombinant human erythropoietin (rHuEpo) treatment. We investigated the effect of rHuEpo treatment on the 24-h ambulatory blood pressure and heart rate profiles of 13 chronic haemodialysis patients. After 3-4 months of rHuEpo therapy it was found that the mean haematocrit had increased from 24.5 +/- 1.0% to 32.0 +/- 1.1% (P less than 0.005), while body-weight and control of uraemia as assessed by routine laboratory data remained unchanged. Despite gradual and incomplete correction of anaemia by use of low doses of rHuEpo, increases in the ambulatory systolic and diastolic blood pressure were found. The greatest increases affected day-time systolic blood pressure and night-time diastolic blood pressure, and these increases were significant (P less than 0.05). As a result, pulse pressure increased during day-time (P less than 0.05) while the night-time decline in diastolic blood pressure disappeared. An increase in peripheral resistance after partial correction of renal anaemia might explain these observations. rHuEpo therapy increased the percentage of abnormal ambulatory blood pressure measurements (defined as systolic blood pressure greater than 140 mmHg and/or diastolic blood pressure greater than 90 mmHg) from 33% to 52% (P less than 0.05) while in contrast, mean casual prehaemodialytic and posthaemodialytic blood pressure values remained unchanged. We conclude that changes in 24-h blood pressure profiles should be carefully assessed by ambulatory blood pressure monitoring in haemodialysis patients treated with rHuEpo, since these changes are likely to be missed when only causal blood pressures are measured.

Topics: Anemia; Blood Pressure; Electrocardiography, Ambulatory; Erythropoietin; Heart Rate; Humans; Hypertension; Renal Dialysis

Topics: Anemia; Erythropoietin; Humans; Hypertension; Prevalence; Recombinant Proteins; Renal Dialysis

Topics: Adult; Erythropoietin; Female; Humans; Hypertension; Recombinant Proteins; Serotonin

The major side effect of rHuEPO is hypertension, which is reported to occur in 10-75% of adult patients. The aim of the present study is to evaluate the effect of rHuEPO on blood pressure in pediatric dialysis patients. Nine CAPD patients (mean age 7.4 +/- 3.6 years) and fourteen HD patients (mean age 13.8 +/- 5.5 years) were treated with rHuEPO. The hematocrits increased significantly from 20.7 +/- 1.8 to 28.3 +/- 4.1 in HD patients and from 19.7 +/- 2.9 to 26.7 +/- 4.4 in CAPD patients. The final maintenance dose required to correct the anemia was 47.6 +/- 11.7 units/kg/week for CAPD patients and 122.6 +/- 75.2 U/kg/week foe HD patients. Six (66.6%) out of nine CAPD patients, and five (35.7%) of fourteen HD patients developed or worsened hypertension. Younger CAPD patients tended to develop hypertension. Correction of anemia was poor in two hypertension-exacerbated patients, since rHuEPO dose increase was withheld for fear of aggravating hypertension. A four-year-old girl developed hypertensive encephalopathy after 13 months of rHuEPO therapy. No difference was observed in plasma level of aldosterone or plasma renin activity. Hypertension is observed frequently among pediatric dialysis patients treated with rHuEPO therapy. Careful monitoring and management of hypertension is required, especially in the first three months of rHuEPO therapy.

Topics: Adolescent; Anemia; Child; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

We studied the hemodynamic changes and the incidence of hypertension after correction of anemia with recombinant human erythropoietin (rhEPO) in 25 hemodialysis (HD) and in 27 continuous ambulatory peritoneal dialysis (CAPD) patients with a mean age of 44.6 years and a mean time on dialysis of 43.6 months. We analyzed basal and final hemoglobin concentrations, time elapsed to reach target hemoglobin, rhEPO dosage, and the following echocardiographic parameters: left ventricular end-systolic and end-diastolic diameters and volumes, posterior wall thickness, interventricular septum, ejection fraction, fractional fiber shortening, cardiac output index, and peripheral vascular resistance index. We did not find any significant difference between HD and CAPD patients in basal and final hemoglobin, concentrations, time elapsed to reach target hemoglobin, dose of rhEPO received for response, and incidence of hypertension. Changes were more evident in HD patients, with a decrease of 15% in cardiac output index and an equal increase of peripheral vascular resistance,. In the patients on CAPD, these variations were less important, with a decrease in cardiac output index of 10% and no significant change in peripheral vascular resistance. Despite both techniques showing the occurrence of hypertension, the left ventricular mass stabilized during the study time. We conclude that CAPD seems to modulate the changes observed in hemodynamic parameters after rhEPO treatment.

Topics: Adult; Anemia; Blood Pressure; Echocardiography; Erythropoietin; Hemodynamics; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Topics: Antidepressive Agents, Tricyclic; Contraceptives, Oral; Cyclosporine; Danazol; Erythropoietin; Extracellular Space; Glycyrrhetinic Acid; Glycyrrhizic Acid; Humans; Hypertension; Monoamine Oxidase Inhibitors; Recombinant Proteins; Sodium, Dietary

It is not known whether recombinant human erythropoietin has a direct, clinically apparent pressor effect in hemodialysis patients or whether hypertension developing or aggravated in these patients merely reflects increased hematocrit. We compared blood pressure after three different methods of partial correction of anemia in hemodialysis patients with similar baseline hematocrits (erythropoietin n = 12, intravenous iron alone n = 10, androgens n = 9). Shortly after the start of treatment and with a minimally increased hematocrit, the need for antihypertensive medication increased in the erythropoietin group. No such pressor effect was observed with iron or androgens. These data suggest a direct hypertensive effect of erythropoietin in some patients on hemodialysis.

Topics: Adult; Anemia; Blood Pressure; Erythropoietin; Female; Ferric Compounds; Humans; Hypertension; Male; Middle Aged; Nandrolone; Nandrolone Decanoate; Recombinant Proteins; Renal Dialysis

Two anephric patients in the course of one year erythropoietin therapy improved their anemic status without changes in Mean Arterial Blood Pressure. The discordant time course behaviour of hematocrit and blood pressure points to the importance of residual renal tissue for blood pressure to develop during erythropoietin therapy in the renoprival status.

Topics: Adult; Anemia; Blood Pressure; Combined Modality Therapy; Erythropoietin; Female; Glomerulosclerosis, Focal Segmental; Hematocrit; Humans; Hypertension; Kidney; Male; Nephrectomy; Polycystic Kidney Diseases; Renal Dialysis; Time Factors

The role of the rate of increase in hematocrit (Hct) and changes in vasoactive substances as a cause of hypertension induced by the administration of recombinant erythropoietin (r-EPO) were examined in 20 stable hemodialysis (HD) patients. Measurements were made twice at the start of treatment and when the Hct reached 30%. Patients were divided into 2 groups: Group I: 14 patients received r-EPO, 3000 units intravenously three times a week. Group II: 6 patients, needing repeated blood transfusion, were given 2 to 4 units of washed red blood cells during a HD session. The Hct increased by 0.65%/week in Group I and by 6.7%/2 days in Group II. An elevation in blood pressure was not seen in any patient. There was no difference in the levels of renin, angiotensin II, epinephrine, norepinephrine, dopamine, atrial natiuretic peptide (ANP), BUN, creatinine, cardiac thoracic ratio and body weight in any of the groups. In conclusion, elevation of the Hct in HD patients whatever the rate of increase within the 30% Hct range, does not cause an increase in blood pressure. In addition, the levels of vasoactive substances do not change in partially corrected anemic HD patients. As a result blood pressure control can be helped by aiming at the lower target Hct level of around 30%.

Topics: Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Transfusion; Catecholamines; Dopamine; Epinephrine; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Pilot Projects; Recombinant Proteins; Renal Dialysis; Renin

Two renal transplant patients developed anemia during treatment of hypertension with enalapril medication. Hemoglobin levels normalized after administration of enalapril was stopped. In one patient, it was demonstrated that the discontinuation of enalapril was followed by a decrease in renal blood flow and a significant increase in the plasma erythropoietin levels that preceded the rise in hemoglobin. These observations are consistent with the hypothesis that angiotensin-converting enzyme inhibition may cause anemia by increasing renal blood flow and consequently decreasing erythropoietin levels.

Topics: Adult; Anemia; Enalapril; Erythropoietin; Female; Humans; Hypertension; Kidney Transplantation; Male; Renal Circulation

The effects of erythropoietin (EPO) on cytosolic free calcium concentration ([Ca2+]i) in platelets of 20 essential hypertensive patients (HT) and of 25 normotensive subjects (NT) were investigated using the fura2 technique. In resting platelets [Ca2+]i were not significantly higher in HT compared to NT (74.3 +/- 7.8 nM vs 59.8 +/- 7.0 nM, mean +/- SEM). Addition of EPO significantly increased [Ca2+]i in HT compared to NT (13.8 +/- 5.3 nM vs 0.9 +/- 1.9 nM, p less than 0.01). EPO increased the amount of calcium in intracellular stores. This was confirmed independently using thrombin-induced changes of [Ca2+]i in a calcium-free medium and using chlorotetracycline as a marker of stored calcium. After preincubation with EPO thrombin-induced changes of [Ca2+]i were significantly lower in HT compared to NT (306.1 +/- 30.0 nM vs 407.7 +/- 35.7 nM, p less than 0.05). In a calcium-free medium after preincubation with EPO thrombin-induced changes of [Ca2+]i were significantly lower in HT compared to NT (54.7 +/- 11.8 nM vs 100.9 +/- 10.5 nM, p less than 0.05) indicating lower storage capacity in HT. It is concluded that elevated response to EPO may provide a powerful tool to evaluate diagnosis and underlying pathophysiological mechanisms in essential hypertension.

Topics: Adult; Blood Platelets; Calcium; Chlortetracycline; Erythropoietin; Female; Fura-2; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Thrombin

Topics: Amino Acid Sequence; Anemia; Dialysis; Erythropoietin; Humans; Hypertension; Inflammation; Molecular Sequence Data; Recombinant Proteins

Seventeen haemodialysis patients with renal anaemia were treated with recombinant human erythropoietin (rhEPO) and observed for 30 weeks. The viscosity of whole blood and plasma, the erythrocyte aggregation tendency, and the erythrocyte deformability, measured as fluidity, were analysed every second week. All patients responded with increasing haematocrit and whole-blood viscosity. The plasma viscosity and the erythrocyte aggregation tendency were already increased before the start of treatment, and remained unchanged during treatment. The basal erythrocyte fluidity tended to be impaired, although not significantly so. During treatment, significant impairment of fluidity was observed at the beginning of the treatment period. After 24 weeks the fluidity started to increase, and it later reached values observed before the start of treatment. Hence, the quality of the erythrocytes formed during the corrective phase of rhEPO treatment differs in some respects from that of cells formed at a normal production rate. The impaired fluidity might have important implications for the flow resistance in small vessels, and contribute to the development or aggravation of hypertension that is often seen during rhEPO treatment.

Topics: Anemia; Blood Viscosity; Erythrocyte Aggregation; Erythrocyte Deformability; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Erythropoietin; Female; Humans; Hypertension; Infant; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

The hemodynamic hallmark of hypertension complicating the treatment of renal anemia with recombinant human erythropoietin (rHu-EPO) is increased total peripheral vascular resistance, but the mechanisms underlying the arteriolar vasoconstriction are still an enigma. We studied body fluid volumes, plasma renin activity, plasma norepinephrine, and calcium metabolism in platelets in 40 previously normotensive hemodialysis patients before and after 12 weeks of rHu-EPO treatment. Partial correction of anemia caused a rise in arterial pressure (94 +/- 6 mmHg vs 124 +/- 7 mmHg, p less than 0.05) and in platelet cytosolic calcium concentration (113 +/- 5 nM vs 171 +/- 18 nM, p less than 0.05) in eight patients. Hypertensive patients had significantly higher plasma noradrenaline concentrations, but they did not differ significantly in body fluid volumes and plasma renin activities. There was a close correlation between free calcium concentration in platelets and mean arterial pressure in patients developing rHu-EPO-induced-hypertension (r = 0.95). Short-term antihypertensive treatment resulted in a reduction of free calcium concentrations in platelets and a concomitant fall in blood pressure. The main results of the present studies suggest that rHu-EPO-induced hypertension might be associated with altered cellular calcium homeostasis and hyperactivity of the sympathetic nervous system. If rHu-EPO therapy induces alterations of pressor factors or the hormone itself raises the cytosolic calcium not only in platelets but also in vascular smooth muscle cells, altered cellular calcium influx may contribute to the arteriolar vasoconstriction.

Topics: Anemia; Blood Platelets; Blood Pressure; Calcium; Cytosol; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

The long-term impact of erythropoietin (EPO) treatment on cardiac structures and function was prospectively studied in eight hypertensive (Group I) and seven normotensive (Group II) patients on hemodialysis (HD). Doppler-echocardiograms were done before EPO and at two and twelve months of treatment. Mean hemoglobin (+/- SD) before EPO was 6.4 +/- 0.9; it rose significantly up to two months and then remained constant. At two months, cardiac index (CI) had significantly decreased, while peripheral vascular resistances increased. Five patients required increased antihypertensive drug treatment. No changes were seen in myocardial parameters at this short follow-up. After one year, left ventricular mass index (LVMi) decreased (p less than 0.05) in both groups concomitantly with a decrease in diastolic diameter and septum and posterior wall thicknesses. Basal LVMi was higher in Group I than in Group II, and after one year the regression was more marked in Group II. Left cardiac work showed prompt and steady improvement in both groups. Maintained partial correction of anemia with EPO during one year was associated with a return to normal of high CI, decreased left cardiac work and impressive regression of left ventricular hypertrophy.

Topics: Adolescent; Adult; Anemia; Echocardiography, Doppler; Erythropoietin; Female; Heart; Hemodynamics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Topics: Aldosterone; Blood Pressure; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renin; Vascular Resistance

Nine patients on maintenance hemodialysis and transfusion-demanding renal anemia (group A) were treated with rHuEPO 120 IU/kg i.v. three times per week. Hemoglobin-content was raised from 7.2 +/- 0.9 to 10.4 +/- 0.8 g/dl. In all patients blood pressure rose, three patients developed arterial hypertension. Mean diastoloic blood pressure was 66 +/- 12 and 78 +/- 16 mmHg (p less than 0.001) before and after rHuEPO. Rise in blood pressure was accompanied by a significant fall in plasma-noradrenaline-levels (from 498 +/- 100 to 383 +/- 75 pg/ml; p less than 0.05) and alpha 2-adrenoceptor-density (from 574 +/- 76 to 384 +/- 49; p less than 0.05). Compared to nine patients on maintenance hemodialysis and hematocrit over 30% (group B), patients with severe renal anemia (group A before treatment) had higher densities of alpha 2-adrenoceptors (574 +/- 76 vs. 218 +/- 32; p less than 0.001) despite higher plasma-noradrenaline-levels (498 +/- 100 vs. 399 +/- 63; n.s.). We suppose a anemia-related disturbance of alpha 2-receptor-function with the result of abolished receptor down-regulation and impaired vascular reagibility to vasoconstricting stimuli. With the correction of anemia receptor-function improves, receptor down-regulation as well as vascular reagibility is re-established resulting in augmented vascular resistance and higher blood pressure.

Topics: Adult; Aged; Anemia; Blood Pressure; Blood Viscosity; Epinephrine; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Receptors, Adrenergic; Recombinant Proteins; Renal Dialysis; Vascular Resistance

Recombinant human erythropoietin (rHuEpo) is effective in correcting renal anemia with the development of hypertension as the most frequent side-effect. Compared to hemodialysis patients with normal hemoglobin concentration, nine examined patients with transfusion-dependent renal anemia had low blood pressure in the context of high alpha 2-receptor densities and high plasma levels of catecholamines. This constellation can be explained by a defective receptor-ligand-interaction. During treatment with rHuEpo all patients showed an increase in blood pressure due to increased peripheral resistance, accompanied by a significant fall in plasma noradrenaline and alpha 2-receptor-density. There was a significant negative correlation between hemoglobin concentration and alpha 2-receptor density. We conclude that correction of renal anemia abolishes anemia-mediated disturbance of alpha 2-receptor function with the consequence of receptor down-regulation and increased vasoconstriction, which contributes to the rise in arterial blood pressure.

Topics: Adult; Aged; Anemia; Blood Viscosity; Epinephrine; Erythropoietin; Female; Hemodynamics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Receptors, Adrenergic, alpha; Recombinant Proteins

The neonatal neutropenia after pregnancy-induced hypertension is a function of diminished neutrophil production. These studies test the hypothesis that this diminution is due to decreased production of neutrophilic growth factors, reduced responsiveness of neutrophil progenitors to these factors, or the presence of an inhibitor. While the concentrations of placentally derived colony-stimulating factors were similar in normotensive and hypertensive gestations, bioassay demonstrated less colony-stimulating activity in placental conditioned media from hypertensive gestations. Evaluation of the responsiveness of progenitors to recombinant factors revealed no differences between those from normotensive and hypertensive gestations. However, neutrophilic colony formation in vitro was significantly inhibited after the addition of conditioned media or sera from hypertensive gestations, whereas the addition of these from normotensive gestations had no inhibitory effect. Thus this common maternal-fetal disorder is associated with an inhibitor of neutrophil production, which is elaborated by the placenta and present in cord blood serum.

Topics: Cells, Cultured; Erythropoietin; Female; Fetal Blood; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypertension; Infant; Interleukin-3; Neutropenia; Neutrophils; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Umbilical Veins

To investigate the mechanisms of hypertension induced by recombinant human erythropoietin (rHuEPO) in patients on hemodialysis (HD), mean blood pressure (MBP), plasma renin activity (PRA), whole blood viscosity, blood volume (BV), cardiac index (CI) and total peripheral resistance index (TPRI) were measured before and after treatment with rHuEPO for 3 months in 9 patients on HD. Pressor responsiveness to exogenous norepinephrine (NE) and angiotensin II (AII) were also compared before and after treatment. Four patients were 'responders' (R) whose MBP increased by more than 10 mmHg, and 5 patients were 'non-responders' (non-R) whose MBP was unchanged or increased by less than 10 mmHg. Initial PRA and TPRI were significantly higher and BV was significantly lower in R than in non-R. After treatment, TPRI was increased in both groups, but CI was decreased in non-R. There was a significant correlation between changes in MBP and blood viscosity to rHuEPO. Pressor responsiveness to NE and AII were significantly enhanced after rHuEPO treatment in responders. These results suggest that inappropriate cardiovascular responses to the correction of anemia, increased blood viscosity, and enhanced pressor responsiveness may participate in the development of rHuEPO-related hypertension.

Topics: Adult; Anemia; Blood Pressure; Blood Viscosity; Blood Volume; Cardiac Output; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renin; Vascular Resistance

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Thrombosis

Following the administration of recombinant human erythropoietin (rHuEPO) to 18 patients undergoing hemodialysis, the hematocrit (Ht) increased from 19.7 +/- 1.8 to 31.0 +/- 2.0%. The incidence of hypertension according to the criteria of WHO was 11.1%. The systolic blood pressure (SBP) increased significantly from 120 +/- 21 to 129 +/- 26 mmHg (p less than 0.01) and diastolic blood pressure (DBP) increased from 67 +/- 14 to 73 +/- 12 mmHg (p less than 0.05). The cardiac index (CI) decreased significantly from 4.07 +/- 1.13 to 3.56 +/- 0.88 L/min/m2 (p less than 0.05). Total peripheral resistance index (TPRI) and blood volume (BV) increased significantly from 1,725 +/- 406 to 2,170 +/- 643 dynes/sec/cm-5/m2 (p less than 0.001) and from 78.9 +/- 11.2 to 87.8 +/- 14.8 ml/kg (p less than 0.005) respectively. Pulse rate (PR) decreased significantly from 73.0 +/- 10.7 to 65.9 +/- 7.8 beats/min (p less than 0.01). Patients who developed a blood pressure (BP) elevation of 10% or more for the mean blood pressure (MBP) showed a slight and insignificant decrease in CI from 3.65 +/- 1.12 to 3.49 +/- 1.06 L/min/m2, which clearly contrasted to that in another group of patients who showed a reduced increase in MBP and a significant reduction in CI from 4.50 +/- 1.03 to 3.63 +/- 0.72 L/min/m2 (p less than 0.05). Stroke volume index (SVI) was unchanged in both groups but PR decrease significantly in the latter group. A significant increase in TPRI or BV was observed equally in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Blood Volume; Cardiac Output; Echocardiography; Erythropoietin; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Vascular Resistance

Eighteen patients aged 5-18 years on regular dialysis had a packed cell volume (PCV) less than 0.27. On treatment with epoetin alfa (EA) PCV increased by 0.05 or more in all patients. Iron supplementation was necessary in 13 patients with a ferritinaemia less than 300 micrograms/l before study. During treatment, plasma potassium increased significantly and more vigorous antihypertensive measures were required in 8 patients, 5 of them being already on antihypertensive drugs before EA. Iliofemoral thrombosis occurred in 1 patient 10 days after renal transplant. The data indicate that EA ameliorates the anaemia of chronic renal disease. The main concerns arising during treatment with EA are hyperkalaemia, arterial hypertension and possibly thrombosis.

Topics: Adolescent; Anemia; Child; Child, Preschool; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Topics: Aldosterone; Anemia; Blood Pressure; Enalapril; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Kidney Neoplasms; Male; Middle Aged; Polycystic Kidney Diseases; Renal Dialysis; Renin-Angiotensin System

Topics: Animals; Calcium; Drug Synergism; Erythrocytes; Erythropoietin; Fishes; Humans; Hypertension; Potassium; Reference Values; Uremia

The contractile properties of recombinant human erythropoietin (rHuEPO) on isolated resistance vessels of renal and mesenteric vascular beds were studied in an in vitro model using a small vessel myograph. Under isometric conditions, rHuEPO caused a contraction of this vasculature in a concentration range between 10 U/ml and 200 U/ml. A maximal active wall tension of 1.52 +/- 0.19 mN/mm was obtained under a rHuEPO dose of 200 U/ml. In Ca2+ free solution, the pressor response to high rHuEPO-concentrations was attenuated, and the response to low rHuEPO concentrations was abolished. In the presence of verapamil, phentolamine and saralasin, rHuEPO-induced contractions were not affected significantly. A dose-dependent vasodilatation of mounted vasculature to acetylcholine (ACh) indicated that endothelium remained intact in our preparations. rHuEPO-induced vessel contraction was not abrogated after an enzymatical removal of endothelium by collagenase, confirming that the described contractile responses are endothelial independent. These findings suggest that a direct vasopressor effect of rHuEPO on proximal resistance vessels may contribute to development of hypertension seen in rHuEPO-treated hemodialysis patients.

Topics: Animals; Dose-Response Relationship, Drug; Erythropoietin; Humans; Hypertension; In Vitro Techniques; Kidney; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred WKY; Recombinant Proteins; Vascular Resistance; Vasoconstriction

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Topics: Antihypertensive Agents; Captopril; Combined Modality Therapy; Diet, Sodium-Restricted; Dietary Proteins; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Recombinant Proteins

Using fura-2 cytosolic free calcium concentrations were measured in intact washed platelets from 9 spontaneously hypertensive rats (SHR) and from 9 age-matched normotensive Wistar-Kyoto rats (WKY). In resting platelets cytosolic free calcium concentration was significantly higher in SHR than in WKY (171.8 +/- 64.4 nM vs 93.1 +/- 59.0 nM, p less than 0.05). After preincubation with erythropoietin cytosolic free calcium concentration was significantly higher in SHR than in WKY (197.5 +/- 83.2 vs 93.0 +/- 60.1, p less than 0.01). Using platelets from SHR erythropoietin increased mean resting cytosolic free calcium concentration by 14.9% (p less than 0.05) and mean thrombin induced changes of cytosolic free calcium by 58.3% (p less than 0.01). In contrast, erythropoietin caused no significant increase in the resting calcium concentration or in thrombin induced changes of cytosolic free calcium in platelets from WKY. It is concluded that erythropoietin is involved in the pathogenesis of hypertension by elevating cytosolic free calcium concentration.

Topics: Animals; Blood Platelets; Calcium; Cytosol; Erythropoietin; Fura-2; Hypertension; In Vitro Techniques; Kinetics; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spectrometry, Fluorescence; Thrombin

Topics: Anemia; Blood Pressure; Blood Viscosity; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Ultrafiltration

Recombinant human erythropoietin (rHuEpo) corrects the anemia of end-stage renal disease. However, hypertension has been observed as an adverse effect of increasing red cell mass. In our study, 44 of 63 patients (70%) treated with rHuEpo had an increase in mean arterial pressure greater than 10 mm Hg or required new or additional hypertensive medications. Retrospective analysis disclosed that increasing blood pressure was associated with pretreatment hematocrit level less than or equal to 0.20 (P = .05) and dependency on red cell transfusions (P less than .01). Factors not associated with hypertension included the rate of rise of the hematocrit, the net rise in hematocrit, age, sex, the number of years on dialysis, the presence or absence of kidneys, smoking, or the presence of pretreatment hypertension. Noninvasive hemodynamic studies in eight normotensive patients before and after improvement of the anemia demonstrated a normalization of the decreased peripheral vascular resistance and a reduction toward normal in the elevated cardiac output. In three of these patients, clinical hypertension subsequently evolved. Follow-up hemodynamic studies in nine other patients receiving new or additional antihypertensive medications were difficult to interpret. Although the hypertension can be controlled with routine medication, hypertensive encephalopathy may occur if the blood pressure increases rapidly when the hematocrit increases with rHuEpo therapy.

Topics: Adult; Aged; Anemia; Epilepsy, Tonic-Clonic; Erythropoietin; Female; Hematocrit; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Renal Dialysis

Topics: Adult; Brain Diseases; Erythropoietin; Humans; Hypertension; Injections, Subcutaneous; Male; Recombinant Proteins

Cardiomegaly and impaired cardiac function induced by renal anemia are frequent findings in patients with chronic renal failure. The present investigation was performed to study the cardiac effects of a therapy with recombinant human erythropoietin in patients on maintenance hemodialysis. Echocardiographic examinations showed a decrease in cardiac size and left-ventricular mass continuously over 12 months of effective erythropoietin substitution. Cardiac output was reduced, and ejection fraction and myocardial contractility increased. The development of aggravation of arterial hypertension did not counteract the beneficial effects of erythropoietin on cardiac performance.

Topics: Cardiomegaly; Echocardiography; Erythropoietin; Female; Heart; Humans; Hypertension; Male; Recombinant Proteins; Renal Dialysis; Time Factors

Fourteen patients (aged 5.9-22.1 years) undergoing continuous ambulatory or cycling peritoneal dialysis were treated with recombinant human erythropoietin (rhEPO), which was given intravenously once a week at a dosage of 300 units/kg. The mean haematocrit level increased from 18.5% to 27.5% and the reticulocyte count from 19% to 62% within 1 month. After an average time of 3.1 months rhEPO dosage could be adjusted to 100 units/kg per week to keep the haematocrit level at 30%. Only 1 patient had an exacerbation of hypertension, which required a dosage reduction; other side-effects were not noted.

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Erythropoietin; Female; Humans; Hypertension; Infusions, Intravenous; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Topics: Angiotensin II; Autonomic Nervous System; Drug Resistance; Erythropoietin; Humans; Hypertension; Norepinephrine; Renal Dialysis

The purpose of this study was to evaluate the effect of the partial correction of anaemia with recombinant human erythropoietin (rHuEPO) on the blood pressure (BP) of patients on chronic haemodialysis (HD). A group of 50 patients (26 men and 24 woman, mean age of 50 +/- 19.0 and range of 21 to 67) with basal levels of haemoglobin (Hb) less than or equal to 8 g/dl was evaluated before and during treatment with rHuEPO. Recombinant erythropoietin was started at 50 U/kh I.V. 3 times a week, immediately after each session of HD, for 4 weeks, and this dose was increased in steps of 25 U/kg until and Hb level of 12 g/dl or a maximum dose of 100 U/kg were reached. Before the administration of rHuEPO 33 patients (67.3%) were normotensives and 16 (32.6%) were hypertensives treated and well controlled. During the period of administration of rHuEPO 10 of the normotensives (30.3%) and 5 (31.3%) of the hypertensives patients showed an increase in the B.P. There was no correlation between the frequency of increase in B.P. and sex, age, length of time on HD and previous levels of B.P., but that frequency was higher in the patients with the lowest basal levels of haematocrit (Hct) and with the greatest increases in Hct (delta Hct). An immediate effect of I.V. administration of rHuE-PO on B.P. levels was not found. Finally we discuss the etiopathologic factors eventually responsible for the increase in BP and suggest some rules to be observed in the therapeutic use of rHuEPO.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Adult; Aged; Anemia; Blood Viscosity; Erythrocyte Aggregation; Erythropoietin; Female; Fibrinogen; Hematocrit; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Rheology; Thrombosis

Hemodynamic and volume changes induced by recombinant human erythropoietin (rHuEPO) treatment were investigated in 12 chronic hemodialysis patients with refractory anemia. After rHuEPO administration for 49 to 151 days, hematocrit (Ht) significantly improved from 19.4 +/- 2.3 to 30.1 +/- 1.1% (Mean +/- SD). Mean blood pressure (MBP) increased slightly but significantly from 78.8 +/- 13.2 to 88.9 +/- 16.9 mmHg. Hemodynamically, total peripheral resistance index (TPRI) increased significantly from 1,444 +/- 367 to 2,146 +/- 470 dynes.sec.cm-5.m2, while cardiac index (CI) decreased significantly from 4.49 +/- 0.85 to 3.37 +/- 0.60 l/min/m2. Both pulse rate (PR) and stroke volume index (SVI) also decreased significantly, but blood volume (BV) remained unchanged. Plasma renin activity and plasma norepinephrine decreased significantly. There were positive correlations between the change of MBP and that of CI, and between the change in CI and that of BV, respectively (p less than 0.05 or less). In conclusion the improvement of anemia using rHuEPO is hemodynamically associated with an increase in TPRI and a decrease in CI as well. Blood pressure elevation seems to be caused by an inappropriately minor reduction of CI. The contribution of humoral factors is not suggested.

Topics: Adult; Anemia; Blood Pressure; Erythropoietin; Female; Hematocrit; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Time Factors

Topics: Blood Pressure; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Recombinant Proteins

Administration of recombinant erythropoietin (r-HuEPO) is an effective treatment for the anaemia of chronic renal failure, but in some patients it has been accompanied by elevated blood pressure. This study focuses on seven patients with end-stage renal failure, managed on haemodialysis, who developed probable hypertensive encephalopathy with seizures during treatment with r-HuEPO. All made a full recovery. The events were not clearly related to the haemoglobin concentrations achieved, and four patients have subsequently been restarted on r-HuEPO therapy at a reduced dose, resulting in a slower increase in haemoglobin with no recurrence of episodes of severe hypertension. Close attention needs to be paid to blood pressure in patients commencing erythropoietin therapy, and it seems prudent to aim for a gradual increase in haemoglobin concentration to allow the circulation to adapt to changes in oxygen delivery and haematocrit.

Topics: Adult; Aged; Blood Pressure; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Seizures

Treatment of renal anemia with rhEPO (120 U/kg body weight/hemodialysis) in transfusion-dependent patients on maintenance hemodialysis led to an increase in blood pressure, regional peripheral resistance and whole blood viscosity. Our results are in agreement with earlier findings that partial correction of renal anemia results in hemodynamic changes characterized by a fall in cardiac output together with an increase in blood pressure due to increased vascular resistance. The increase in whole blood viscosity correlated with the increase in regional peripheral resistance but not with the increase in mean arterial blood pressure. Thus, other regulating factors of vascular resistance must be involved. Correction of renal anemia does not influence the reninangiotensin system. However, peripheral responsiveness of vascular smooth muscles may have changed due to improved tissue oxygenation and thus leading to an increase in vasoconstriction.

Topics: Adult; Aged; Anemia; Blood Viscosity; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin-Angiotensin System

Topics: Anemia; Blood Viscosity; Erythrocyte Aggregation; Erythrocyte Deformability; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis; Rheology

Topics: Anemia; Chronic Disease; Erythropoietin; Graft Rejection; Humans; Hypertension; Kidney Transplantation; Recombinant Proteins

18 anemic patients undergoing maintenance hemodialysis were treated with recombinant human erythropoietin (EPO) 1-3 times per week for 10.7 +/- 3 months. 4 patients underwent renal transplantation whereas 14 patients could be followed up during 12 months of EPO treatment. Hemoglobin concentration rose (from 7.0 +/- 0.7 to 11.0 +/- 1.1 g/dl, p less than 0.001) with an EPO maintenance dose of 298 units/kg/week. Blood transfusions were totally eliminated. 12 patients without iron overload required iron supplements. In the course of an infectious episode and notwithstanding an increase in EPO dosage, 2 patients exhibited a fall in hemoglobin which rose again after successful treatment of the infection. The few complications observed in connection with the rise in hemoglobin were: 1. deterioration of arterial hypertension in 7/18 with hypertensive encephalopathy in 3 patients, 2. thrombotic occlusion of the vascular hemodialysis access (a-v fistula) in 3/18, 3. periarticular inflammation with calcified deposits due to an elevated calcium-phosphorus product of 6.8 mmol/l in 4/18, 4. occurrence of hyperkalemia (6.9 +/- 0.3 mmol/l) in 7/18. These complications were more frequent during the first 3 months. They were corrected with close monitoring, drug therapy for hypertension, and intensification of dialysis and of treatment with phosphate binding substances, with the result that no differences were found in 14 patients before and after 12 months of treatment with EPO (blood pressure 133 +/- 25/77 +/- 9 vs 139 +/- 26/79 +/- 13 mm Hg [ns], potassium 5.4 +/- 0.4 vs 5.6 +/- 1.0 mmol/l [ns] and calcium-phosphorus product 4.3 +/- 1.0 vs 4.6 +/- 1.3 [ns]).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia, Hypochromic; Calcium; Erythropoietin; Female; Hemoglobins; Humans; Hyperkalemia; Hypertension; Infections; Male; Middle Aged; Phosphorus; Recombinant Proteins; Renal Dialysis

To investigate the mechanism of blood pressure upward after recombinant human erythropoietin (EPO) administration in patient with chronic renal failure (CRF), hemodynamic changes following on the improvement of anemia was evaluated by the echocardiography. Fourteen (5 males, 9 females) normotensive patients with less than 23% of hematocrit (HT) were administered 1,500 approximately 3,000 units of EPO three times a week. Four patients with systolic (greater than 160 mmHg) or diastolic (greater than 90 mmHg) hypertension after EPO administration was named group H, the remaining patients was named group N. Blood pressure, heart rates and parameters of echocardiography examined after the improvement of anemia were compared to those examined before EPO administration, respectively. Patients had an increase in Ht from 20.0 +/- 1.6% to 33.0 +/- 1.9% (p less than 0.01). LVDd, LVEDV, CO and flow velocity in group N were significantly decreased after EPO administration; while those in group H did not show the significant changes. IVSth and LVPWth in each group were significantly increased after EPO administration. These data showes that decrease in CO maintains the patients normotensive after EPO administration.

Topics: Adult; Anemia; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Bone marrow megakaryocytes and their progenitors were studied in SHR in order to obtain more information about megakaryocytopoiesis in hypertension since it is known that various anomalies of platelet function occur in hypertension. Megakaryocytopoiesis under steady state conditions and following stimulated erythropoiesis and thrombocytopenia was not found to be significantly different in SHR from that in normotensive Wistar controls.

Topics: Animals; Bone Marrow; Cell Count; Erythropoiesis; Erythropoietin; Female; Hypertension; Megakaryocytes; Platelet Count; Rats; Rats, Inbred SHR

Topics: Anemia; Blood Viscosity; Erythropoietin; Humans; Hypertension; Renal Dialysis

Topics: Adult; Blood Pressure; Erythropoietin; Humans; Hypertension; Male; Recombinant Proteins; Status Epilepticus

Topics: Brain Diseases; Erythropoietin; Humans; Hypertension; Nitric Oxide

Topics: Biological Products; Brain Diseases; Erythropoietin; Hemoglobins; Humans; Hypertension; Nitric Oxide; Vasodilation

Fifteen hemodialysis patients suffering from stable anemia were treated with recombinant human erythropoietin (r-HuEPO). Within 16 weeks, hematocrit values increased from 23.7 +/- 1.2 to 35.7 +/- 0.2%. Simultaneously, mean predialytic blood pressure rose significantly from 131/79 to 139/85 mm Hg. Three out of 15 patients developed frank hypertension and had to be put on antihypertensive therapy. When the hematocrit was lowered again from 36.3 +/- 1.8 to 30.5 +/- 1.2% in these 3 patients, blood pressure was attenuated and the antihypertensive medication could be reduced or abolished. With rising hematocrit values, whole blood viscosity increased at both low (+42%) and high shear rates (+33%) without reaching the values seen in healthy subjects. By contrast, plasma viscosity was already elevated in hemodialysis patients prior to r-HuEPO treatment and showed only a slight, but insignificant increase during r-HuEPO treatment. Since whole blood viscosity is one factor that determines vascular resistance, it is conceivable that the development of hypertension during correction of the renal anemia is, at least partly, due to an increment of blood viscosity.

Topics: Adult; Anemia; Blood Viscosity; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Rheology; Vascular Resistance

Post-transplant erythrocythemia (PTE) is a common finding in renal allograft recipients, although the etiology of this disorder has not been clearly established. We identified 22 patients (9.8%) with PTE from among 225 renal transplant recipients followed for an average of 5.5 years. To characterize possible predisposing factors and to study the clinical significance of PTE, these patients were compared with a control group matched for age, race, sex and etiology of renal failure. Plasma volume (PV) and red blood cell mass (RBCM) were measured in the majority of patients with PTE. Peripheral serum erythropoietin (Ep) levels were determined in the majority of patients in the control and PTE groups. PTE occurred an average of 11.4 months after transplantation. Risk factors for the development of PTE were pretransplant hypertension, retention of native kidneys, higher pretransplant hematocrit, and diuretic use for treatment of post transplant hypertension. Ep levels in the PTE and control groups were not significantly different. Twenty of the 22 patients with PTE were receiving concurrent diuretic therapy, and hematocrits fell to normal levels in all of these patients following cessation or dose reduction of diuretic. No other treatment of PTE was utilized, excluding the phlebotomy of a single unit of blood from one patient. No thromboembolic complications were noted during the follow-up period. We conclude that PTE is frequently induced by overzealous diuretic therapy for treatment of post-transplant hypertension. Discontinuation or reduction of diuretic therapy results in resolution of PTE in nearly all patients. From this experience we have developed an algorithm for the investigation and management of PTE.

Topics: Adult; Diuretics; Erythrocyte Volume; Erythropoietin; Female; Humans; Hypertension; Kidney Transplantation; Male; Plasma Volume; Polycythemia; Postoperative Complications

Fifteen long-term hemodialysis patients suffering from stable anemia received recombinant human erythropoietin (r-huEPO). The hormone was given intravenously at the end of each dialysis session starting with a dose of 24 IU/kg. This dose was doubled when hemoglobin levels did not rise within 2 weeks. The number of reticulocytes started to increase after 14 days of treatment. The hematocrit rose from baseline values of 23.7 +/- 1.2% to 32.4 +/- 1.3% after 24 weeks of treatment. In parallel, hemoglobin values increased from 7.3 +/- 0.3 g/100 ml to 10.1 +/- 0.4 g/100 ml. As for side effects, 3 patients developed hypertension and 2 patients suffered from occlusions of their arterio-venous fistulas. There was no evidence of major organ dysfunctions, toxic effects, allergic reactions, or antibody formation. These data show that r-HuEPO is able to correct the anemia of patients undergoing hemodialysis treatment.

Topics: Adult; Anemia; Drug Administration Schedule; Erythrocyte Count; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Platelet Count; Recombinant Proteins; Renal Dialysis; Reticulocytes

Chronic renal disease is frequently characterized by anemia, which may modify systemic and renal hemodynamics. In adult Munich-Wistar rats, the mild anemia (hematocrit, approximately equal to 42 vol/dl) that accompanies five-sixths nephrectomy was either made more severe (approximately equal to 30 vol/dl) by feeding a low iron diet or prevented (approximately equal to 50 vol/dl) by administration of recombinant human erythropoietin (r-HuEpo). In functional studies performed 4 weeks after renal ablation, untreated rats exhibited mild anemia with systemic hypertension and elevation of the single nephron glomerular filtration rate due to glomerular capillary hyperperfusion and hypertension. Preventing anemia with r-HuEpo worsened systemic and glomerular hypertension, effects largely obviated by induction of more marked anemia with the low iron diet. Untreated rats followed for 6 weeks postablation exhibited progressive proteinuria and sclerosis involving 12% of glomeruli, contrasted with 33% in rats given r-HuEpo. Even after 12 weeks, sclerosis involved only 6% of glomeruli in rats with more severe anemia but progressed to 30% in untreated rats. Thus, anemia limits systemic and glomerular hypertension and glomerular injury, whereas its prevention by r-HuEpo severely accelerates hemodynamically mediated glomerular injury in this model. These results suggest that anemia is a hemodynamically favorable adaptation to chronic renal disease and that its overly vigorous correction may have adverse renal hemodynamic and structural consequences.

Topics: Anemia; Animals; Blood Viscosity; Erythropoietin; Glomerular Filtration Rate; Hematocrit; Hypertension; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Rats; Rats, Inbred Strains; Recombinant Proteins

Fourteen patients with uraemic anaemia and having regular haemodialysis were given human recombinant erythropoietin in increasing doses, beginning with 24 U/kg thrice weekly. One patient was dropped from the study because of recurrent thrombosis of vascular access sites. In the other 13 patients, followed up for a mean of 9.1 months (range 8-11), haemoglobin concentrations increased from 62 (SD 8) to 105 (9) g/l. No antierythropoietin antibodies were detected during the study. The correction of anaemia was associated with a tendency to hyperkalaemia and a mild increase of unconjugated bilirubinaemia. In eight previously hypertensive patients antihypertensive treatment had to be reinforced, but in normotensive patients blood pressure did not change. Thrombosis of arteriovenous fistulas occurred in two patients and a cerebral ischaemic lesion in one. Protracted treatment with human recombinant erythropoietin evidently can maintain normal haemoglobin concentrations in uraemic patients over time. Full correction of anaemia, however, may trigger some vascular problems, particularly in hypertensive patients and those with a tendency to thromboembolism.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

In the human fetus, elevated plasma erythropoietin levels have been found in high-risk pregnancies at delivery. We examined the relationship of amniotic fluid erythropoietin and umbilical plasma erythropoietin at delivery in 17 normal pregnancies, 41 hypertensive pregnancies, and 37 insulin-treated diabetic pregnancies terminated by elective cesarean section without labor. An additional 27 insulin-treated diabetic patients were studied after undergoing variable durations (86-1184 minutes) of labor. Erythropoietin was analyzed using a highly sensitive and specific radioimmunoassay technique. Fetal plasma erythropoietin concentrations were elevated above the control upper range (50.3 mU/mL) in 59% of the hypertensives and in 38% of the diabetics. The amniotic fluid erythropoietin values were significantly lower than the umbilical plasma erythropoietin values in each study group. Although the umbilical plasma erythropoietin values in the abnormal pregnancy groups differed considerably from the corresponding levels in the controls, the ratio of amniotic fluid erythropoietin to umbilical plasma erythropoietin was approximately the same in controls, hypertensives, and diabetics. Furthermore, the plasma and amniotic fluid levels (In transformed) correlated highly significantly in all three individual groups in absence of labor. In the diabetic labor group, this relationship was nonsignificant. We conclude that in the absence of labor, amniotic fluid erythropoietin reflects fetal plasma erythropoietin. We speculate that amniotic fluid erythropoietin may be an antepartum indicator of fetal hypoxemia.

Topics: Amniotic Fluid; Erythropoietin; Female; Fetal Blood; Humans; Hypertension; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics

Topics: Adenocarcinoma; Erythropoietin; Humans; Hypertension; Kidney Neoplasms; Nephrectomy; Polycythemia; Renin

Topics: Animals; Erythropoietin; Humans; Hydronephrosis; Hypertension; Male; Middle Aged; Nephrectomy; Polycythemia; Renin

To evaluate the effect of prostaglandin inhibition on the renal blood flow of the ischemic kidney, we administered indomethacin to 10 anesthetized dogs with renal artery stenosis and contralateral nephrectomy. Following the operation to produce renal ischemia, there was an increase of blood pressure associated with an increase of renin and the prostaglandins F1 (PGF1), and E (PGE). The administration of indomethacin to the intact, normotensive animals caused the anticipated decrease of prostaglandin E, renin, and renal blood flow. However, in the hypertensive dogs, indomethacin caused a paradoxical 45 per cent increase in the renal blood flow, despite a 44 per cent decrease of prostaglandin E. PGF1, PGE, renin, and erythropoietin exhibited the anticipated decreased levels. The study suggests that prostaglandins may not be the sole important factor in the regulation of renal blood flow in the presence of ischemia. Other important factors likely include the renin-sensitive angiotensin, the adrenergic, and the kallikrein-kinin systems.

Topics: Animals; Blood Pressure; Dogs; Erythropoietin; Female; Hypertension; Indomethacin; Ischemia; Kidney; Male; Nephrectomy; Prostaglandins E; Prostaglandins F; Regional Blood Flow; Renal Artery Obstruction; Renin

Plasma activities of renin and erythropoietin were determined in the renal veins of the right and left kidneys of hypertensive patients. The patients were divided into the following groups either according to the origin of the hypertension (group 1: control for essential hypertension, group 2: renovascular hypertension) or according to the hormone levels (group 3: renin activity exceeding 10 ng/litre in at least one of the renal veins and group 4: erythropoietin activity higher than 4% 59Fe incorporation in at least one of the renal veins). In groups 1, 2 and 3 a statistically significant difference in renin activity was found between the kidney with the higher renin activity and that with the lower activity. However, in group 4, the side, which showed elevated erythropoietin values also had higher renin activity as compared to the essential hypertensive group. Erythropoietin activity probably does not parallel the increased renin activity found in renovascular hypertension or in some cases of non-renovascular hypertension. However, in several cases of renal vascular alterations, both systems can be activated simultaneously.

Topics: Erythropoietin; Humans; Hypertension; Hypertension, Renal; Renin

Topics: Adult; Blood Viscosity; Erythrocytes; Erythropoietin; Hematocrit; Humans; Hypertension; Male; Methyldopa; Middle Aged; Plasma Volume; Polycythemia; Prospective Studies; Renin

Topics: Acute Disease; Erythropoietin; Feeding and Eating Disorders; Heart Failure; Hemorrhagic Disorders; Humans; Hypertension; Peripheral Nervous System Diseases; Renin; Uremia; Vomiting

Topics: Aldosterone; Angiotensin II; Animals; Dogs; Erythropoietin; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension; Hypoxia; Juxtaglomerular Apparatus; Kidney Transplantation; Renin; Sodium; Transplantation, Homologous; Water-Electrolyte Balance

During the study of an inbred strain of Wistar rats which spontaneously develop hypertension when they reach a weight of approximately 150 g, it was found that these animals also develop an erythrocytosis. A significant increase in red cell count was observed in spontaneously hypertensive (SH) rats (8-11 x 10(6) RBC/mm(3)) when compared with normotensive rats (6-7 x 10(6) RBC/mm(3)) of the same strain. This increase in red cell count paralleled the increase in body weight and the rise in blood pressure. Since the plasma volume, as measured with labeled albumin was normal, there was an absolute increase in red cells. The hematocrit and hemoglobin content of the blood measured in SH rats were only slightly greater than those found in normotensive rats. However, the mean cell volume (MCV) of the red cells in the SH rats was 45-47 mu(3) as compared with 51-53 mu(3) in normotensive rats.A fourfold increase in 24 hr (59)Fe incorporation into the red cells was found in the SH rats when compared with normotensive controls. The bone marrow of the SH rats showed erythroid hyperplasia. When the SH rats were treated with alpha-methyldopa (Aldomet 200 mg/kg daily, i.p.) the red cell count fell in parallel with the drop in blood pressure. No change in red cell count or blood pressure was observed in normotensive rats treated in the same manner. The erythropoietin titer was high in SH rats, and was undetectable in normotensive rats. These observations suggest a direct relationship between the hypertension and the erythrocytosis mediated by erythropoietin; both are genetically controlled.

Topics: Animals; Blood Pressure; Blood Pressure Determination; Body Weight; Cell Survival; Chromium Isotopes; Dihydroxyphenylalanine; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematocrit; Hemoglobins; Hypertension; Hypertension, Renal; Iron; Iron Isotopes; Leukocyte Count; Male; Plasma Volume; Polycythemia; Rats; Rats, Inbred Strains; Serum Albumin, Radio-Iodinated

Topics: Adolescent; Adult; Aged; Angiotensin II; Aortic Coarctation; Blood Pressure; Creatinine; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hyperaldosteronism; Hypertension; Hypertension, Renal; Male; Middle Aged; Polycythemia; Potassium; Renin; Sodium; Urea; Water-Electrolyte Balance

Topics: Adult; Anemia; Animals; Biological Assay; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension; Hyperthyroidism; Male; Mice; Polycythemia; Rats; Renin

Topics: Adult; Blood Pressure; Creatinine; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Glomerulonephritis; Hematocrit; Hemoglobinometry; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Phenolphthaleins; Urea

Topics: Adolescent; Adult; Aged; Anemia; Angiotensin II; Blood Pressure; Blood Volume; Creatinine; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Hypertension, Renal; Injections, Intravenous; Iron Isotopes; Male; Middle Aged; Potassium; Proteinuria; Renin; Sodium

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Brain Neoplasms; Child; Child, Preschool; Dogs; Electric Stimulation; Erythropoiesis; Erythropoietin; Ethacrynic Acid; Haplorhini; Humans; Hydronephrosis; Hypertension; Hypothalamus; Infant; Iron Isotopes; Kidney Diseases; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Middle Aged; Polycythemia Vera; Rats; Testicular Neoplasms; Testosterone; Urinary Calculi; Urologic Diseases; Wilms Tumor; Wounds and Injuries

Topics: Animals; Blood Cell Count; Blood Pressure; Creatinine; Dogs; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hypertension; Kidney Transplantation; Polycythemia; Renin; Reticulocytes; Transplantation, Homologous

Topics: Adult; Aged; Altitude; Arteries; Blood Gas Analysis; Blood Pressure; Body Weight; Bone Marrow Cells; Carbon Dioxide; Colorado; Culture Techniques; Erythropoietin; Female; Hematocrit; Humans; Hydrogen-Ion Concentration; Hypertension; Hypoxia; Male; Middle Aged; Obesity; Oxygen; Oxygen Inhalation Therapy; Partial Pressure; Polycythemia; Posture; Respiratory Function Tests

Topics: Epoetin Alfa; Erythrocyte Count; Erythropoietin; Humans; Hydronephrosis; Hypertension; Kidney; Nephrectomy; Polycystic Kidney Diseases; Polycythemia