losartan-potassium and Acute-Phase-Reaction

Protein-energy malnutrition (PEM) and inflammation are common and usually concurrent in maintenance dialysis patients. Many factors that appear to lead to these 2 conditions overlap, as do assessment tools and such criteria for detecting them as hypoalbuminemia. Both these conditions are related to poor dialysis outcome. Low appetite and a hypercatabolic state are among common features. PEM in dialysis patients has been suggested to be secondary to inflammation; however, the evidence is not conclusive, and an equicausal status or even opposite causal direction is possible. Hence, malnutrition-inflammation complex syndrome (MICS) is an appropriate term. Possible causes of MICS include comorbid illnesses, oxidative and carbonyl stress, nutrient loss through dialysis, anorexia and low nutrient intake, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hyporesponsiveness, high rate of cardiovascular atherosclerotic disease, decreased quality of life, and increased mortality and hospitalization in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, hypocreatininemia, and hypohomocysteinemia, a "reverse epidemiology" of cardiovascular risks can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed. Successful management of MICS may ameliorate the cardiovascular epidemic and poor outcome in dialysis patients. Clinical trials focusing on MICS and its possible causes and consequences are urgently required to improve poor clinical outcome in dialysis patients.

Topics: Acute-Phase Reaction; Anemia; Chronic Disease; Erythropoietin; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Protein-Energy Malnutrition; Quality of Life; Recombinant Proteins; Renal Dialysis; Syndrome; Wasting Syndrome

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Anemia; Animals; Blood Platelets; Cytokines; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Hematopoietic System; Humans; Inflammation; Iron; Liver; Megakaryocytes; Models, Biological

In a prospective observational study, we examined the temporal relationships between serum erythropoietin (EPO) levels, haemoglobin concentration and the inflammatory response in critically ill patients with and without acute renal failure (ARF).. Twenty-five critically ill patients, from general and cardiac intensive care units (ICUs) in a university hospital, were studied. Eight had ARF and 17 had normal or mildly impaired renal function. The comparator group included 82 nonhospitalized patients with normal renal function and varying haemoglobin concentrations. In the patients, levels of haemoglobin, serum EPO, C-reactive protein, IL-1beta, IL-6, serum iron, ferritin, vitamin B12 and folate were measured, and Coombs test was performed from ICU admission until discharge or death. Concurrent EPO and haemoglobin levels were measured in the comparator group.. EPO levels were initially high in patients with ARF, falling to normal or low levels by day 3. Thereafter, almost all ICU patients demonstrated normal or low EPO levels despite progressive anaemia. IL-6 exhibited a similar initial pattern, but levels remained elevated during the chronic phase of critical illness. IL-1beta was undetectable. Critically ill patients could not be distinguished from nonhospitalized anaemic patients on the basis of EPO levels.. EPO levels are markedly elevated in the initial phase of critical illness with ARF. In the chronic phase of critical illness, EPO levels are the same for patients with and those without ARF, and cannot be distinguished from noncritically ill patients with varying haemoglobin concentrations. Exogenous EPO therapy is unlikely to be effective in the first few days of critical illness.

Topics: Acute Kidney Injury; Acute-Phase Reaction; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Transfusion; Critical Illness; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Outpatients; Prospective Studies; Reference Values; Time

An experimental study was conducted to investigate the effects of erythropoietin on the acute phase of esophageal burn damage induced by sodium hydroxide.. A standard esophageal alkaline burn was produced by the application of 10% sodium hydroxide to the distal esophagus in an in vivo rat model. Fifty-six female rats were allocated into three groups: Group BC (baseline control, n = 8) rats were uninjured and untreated, Group PC (positive control, n = 24) rats were injured but untreated and Group EPO (erythropoietin-treated, n = 24) rats were injured and given subcutaneous erythropoietin (1,000 IU/kg per day), 15 min, 24, and 48 h after administration of the NaOH solution. Six animals from Group PC and six from Group EPO were killed at 4, 24, 48, and 72 h after application of NaOH to the esophagus. All of animals in Group BC were killed 4 h after exposure to 0.9% NaCl. Oxidative damage was assessed by measuring levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD) and catalase (CAT) in homogenized samples of esophageal tissue. Histologic damage to esophageal tissue was scored by a single pathologist blind to groups.. MDA levels in the BC and EPO groups were significantly lower than those in the PC group (p < 0.05). CAT and SOD activities, and NO levels in the BC and EPO groups were significantly higher than in the PC group (p < 0.05). Esophageal tissue damage measured at 4, 24, 48, and 72 h after NaOH application was significantly less in the EPO group than in the PC group (p < 0.05).. When administered early after an esophageal burn induced by 10% sodium hydroxide in this rat model, erythropoietin significantly attenuated oxidative damage, as measured by biochemical markers and histologic scoring.

Topics: Acute-Phase Reaction; Animals; Burns, Chemical; Catalase; Caustics; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Esophagus; Female; Injections, Subcutaneous; Malondialdehyde; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Hydroxide; Superoxide Dismutase; Trauma Severity Indices; Treatment Outcome

An acute-phase response is the systemic reaction of an organism to insult (e.g. infection, trauma and burning). It represents the 'first line' of defence of the body to tissue-damaging attacks. In the present work, we used a rat model of an intra-muscular turpentine oil (TO) injection to analyse erythropoietin (EPO) gene expression changes in the liver, one of the main target organs of acute-phase cytokines. EPO began to increase in the serum of TO-treated animals 6 h after injection and reached a maximum at 24 h (125+/-20 pg/ml). The detection of total RNA by polymerase chain reaction analysis showed that the levels of EPO gene expression in the liver were considerably increased between 2 and 12 h by up to 20-fold at the peak after TO administration, followed by a gradual decrease over the next 48 h, although the values remained significantly higher compared with the control group. In the kidney, after a sudden slight increase, the values declined progressively to 3.5-fold decrease at 12 h after the injection. In the liver, a parallel upregulation of the hypoxia-inducible factor-1 (HIF-1) alpha gene was observed (up to 4.7-fold increase), while HIF-2 alpha gene expression remained unaltered. On the other hand, the protein of both genes became detectable after the injection and increased progressively over 24 h, with a subsequent decline. These results suggest that EPO may be added to the increasing group of positive acute-phase proteins and the liver might represent the major source of the hormone under these conditions in the rat.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Animals; Basic Helix-Loop-Helix Transcription Factors; Disease Models, Animal; Erythropoietin; Gene Expression; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Liver; Rats; RNA, Messenger; Solvents; Turpentine; Up-Regulation

The source of circulating erythropoietin (EPO), the mediators and the mechanisms involved in the upregulation of EPO gene expression during acute-phase reaction are still poorly understood. Acute-phase reaction was induced by either intramuscular turpentine oil (TO) or intraperitoneal lipopolysaccharide (LPS) administration into wild-type and interleukin (IL)-6 knockout (KO) mice. Animals were killed at different time points and blood, liver and muscle tissue were collected. Serum levels of EPO were measured by enzyme-linked immunoadsorbent assay; liver and injured muscle samples were processed for RNA isolation and for protein analysis. EPO, hypoxia-inducible factors 1alpha and 2alpha (HIF-1alpha and HIF-2alpha) mRNA were analyzed by RT-PCR and the protein levels were analyzed by western blot and electrophoretic mobility shift assay. HIF-1alpha and HIF-2alpha localization was performed through immunofluorescence staining. EPO, HIF-1 and HIF-2 gene and protein expression levels were also analyzed in isolated mouse hepatocytes after stimulation with IL-6. In the wild-type animals, EPO serum levels increased dramatically at 12 h after the insults together with the hepatic gene expression. In TO-treated animals, the EPO gene expression reached an 8.2-fold increase at 12 h, and in LPS-treated mice a similar induction was recorded at 6 h (about 4.5-fold increase). In the IL-6KO strain, the upregulation after the inflammatory stimuli was much lower (only 2.0-fold increase). A progressive upregulation of HIF-1alpha and HIF-2alpha was detectable until 6 h after the insults, but only HIF-1alpha upregulation was reduced in IL-6KO mice. In isolated hepatocytes, stimulation with a single dose of IL-6 induced a nuclear accumulation of HIF-1alpha, in parallel with an increase of EPO mRNA. No effect on HIF-2alpha expression was found. IL-6 appears to be the main regulator of EPO gene expression and a major contributor for HIF-1alpha induction in hepatocytes and Kupffer cells during acute-phase response. The increase of HIF-2alpha, predominantly expressed in endothelial cells and fibroblast-like cells, seems not to be affected by the lack of IL-6.

Topics: Acute-Phase Reaction; Animals; Enzyme Assays; Erythropoietin; Gene Expression; Genes; Hepatocytes; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Kupffer Cells; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Turpentine; Up-Regulation; Vascular Endothelial Growth Factor A

C-reactive protein (CRP) is an acute phase reactant protein, which becomes elevated in response to inflammation, infections or malignancies. These conditions are well known causes of bone marrow hyporesponsiveness and erythropoietin resistance in dialysis patients. The role of iron-deficiency as a cause of hyporesponsiveness under these conditions is not clear. Reticulocyte haemoglobin content (CHr) is one of several iron indices used to determine iron deficiency in dialysis patients. The aim of this study is to evaluate the role of CRP and CHr in iron administration and anaemia management in dialysis patients.. In 47 haemodialysis patients with ferritin levels of >500 ng/mL, CRP, CHr, transferrin saturation (TSAT), other markers and erythropoietin dose were evaluated. Patients with CRP < 5 mg/L (Group A) were compared to patients with CRP > 5 mg/L (Group B).. Ferritin levels in the two groups were not different. Weekly erythropoietin was significantly different between the two groups. Group B required an average of 121% more erythropoietin than Group A to maintain similar haemoglobin levels of 11-12 g/dL 36% of Group B had CHr < 29 pg versus 7% of patients in Group A. 39% of patients in Group B also had TSAT < 20% versus 0% in Group A. Group A also had more arteriovenous (AV) fistulae as dialysis access than group B.. Data indicate that low CHr, similar to low TSAT, could be associated with inflammatory process and erythropoietin resistance, but not necessarily with iron-deficiency. High CRP association with low CHr and low TSAT levels can explain the lack of response to further IV iron therapy. AV grafts, contrary to AV fistulae, are associated with high inflammatory markers and also with a higher erythropoietin requirement.

Topics: Acute-Phase Reaction; Aged; Anemia; Biomarkers; C-Reactive Protein; Drug Resistance; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Reticulocytes; Transferrin

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

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

In order to investigate whether vascular endothelial growth factor (VEGF) and inflammatory pathways are activated during acute hypobaric hypoxia in subjects who are susceptible to high-altitude pulmonary oedema (HAPE-S), seven HAPE-S and five control subjects were exposed to simulated altitude corresponding to 4000 m in a hypobaric chamber for 1 day. Peripheral venous blood was taken at 450 m (Zürich level) and at 4000 m, and levels of erythropoietin (EPO), VEGF, interleukin-6 (IL-6) and the acute-phase proteins complement C3 (C3), alpha1-antitrypsin (alpha1AT), transferrin (Tf) and C-reactive protein (CRP) were measured. Peripheral arterial oxygen saturation (SaO2) was recorded. Chest radiography was performed before and immediately after the experiment. EPO increased during altitude exposure, correlating with SaO2, in both groups (r = -0.86, P < 0.001). Venous serum VEGF did not show any elevation despite a marked decrease in SaO2 in the HAPE-S subjects [mean (SD) HAPE-S: 69.6 (9.1)%; controls: 78.7 (5.2)%]. C3 and alpha1AT levels increased in HAPE-S during hypobaric hypoxia [from 0.94 (0.11) g/l to 1.07 (0.13) g/l, and from 1.16 (0.08) g/l to 1.49 (0.27) g/l, respectively; P < 0.05], but remained within the clinical reference ranges. No significant elevations of IL-6, Tf or CRP were observed in either group. The post-exposure chest radiography revealed no signs of oedema. We conclude that VEGF is not up-regulated in HAPE-S and thus does not seem to increase critically pulmonary vascular permeability during the 1st day at high altitude. Furthermore, our data provide evidence against a clinically relevant inflammation in the initial phase of exposure to hypoxia in HAPE-S, although C3 and alpha1AT are mildly induced.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Adult; Altitude; Atmospheric Pressure; Disease Susceptibility; Endothelial Growth Factors; Erythropoietin; Humans; Hypoxia; Lymphokines; Male; Middle Aged; Pulmonary Edema; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Haptoglobin knockout (Hp-/-) mice are more sensitive to phenylhydrazine-induced hemolysis than Hp+/+ mice.. Hemolysis was induced in Hp-/- and Hp+/+ mice using phenylhydrazine. Relative renal tissue damage and function were then assessed.. Hp-/- mice had higher basal levels of renal lipid peroxidation, as evidenced by levels of malonaldehyde and 4-hydroxy-2(E)-nonenal (MDA/HNE). After the administration of phenylhydrazine, levels of 8-hydroxyguanine (but not other products of oxidative DNA damage) were significantly elevated in the renal DNA. There was also increased induction of heme oxygenase-1. The more severe renal damage in Hp-/- mice was also evident in the delayed erythropoietin gene expression and poorer renal clearance of 3H-inulin. This reduction in glomerular filtration function in Hp+/+ and Hp-/- mice could be restored to baseline by vasodilators (prazosin or diazoxide), implicating renal vasoconstriction as a major mechanism of acute renal failure during induced hemolysis. Precipitation of hemoglobin in the kidney was not increased in Hp-/- mice.. Haptoglobin appears to play an important physiological role as an antioxidant, particularly during hemolysis.

Topics: Acute-Phase Reaction; Aldehydes; Animals; Antioxidants; DNA; Erythropoietin; Gene Expression Regulation, Enzymologic; Guanine; Haptoglobins; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hemoglobins; Hemolysis; Inulin; Kidney; Kidney Function Tests; Lipid Peroxidation; Liver; Malondialdehyde; Membrane Proteins; Mice; Mice, Knockout; Oxidative Stress; Phenylhydrazines; Tritium

We defined erythropoietin (EPO) resistance by the ratio of the weekly EPO dose to hematocrit (Hct), yielding a continuously distributed variable (EPO/Hct). EPO resistance is usually attributed to iron or vitamin deficiency, hyperparathyroidism, aluminum toxicity, or inflammation. Activation of the acute-phase response, assessed by the level of the acute-phase C-reactive protein (CRP), correlates strongly with hypoalbuminemia and mortality in both hemodialysis (HD) and peritoneal dialysis (PD) patients. In this cross-sectional study of 92 HD and 36 PD patients, we examined the contribution of parathyroid hormone (PTH) levels, iron indices, aluminum levels, nutritional parameters (normalized protein catabolic rate [PCRn]), dialysis adequacy (Kt/V), and CRP to EPO/Hct. Albumin level serves as a measure of both nutrition and inflammation and was used as another independent variable. Serum albumin level (deltaR2 = 0.129; P < 0.001) and age (deltaR2 = 0.040; P = 0.040) were the best predictors of EPO/Hct in HD patients, and serum albumin (deltaR2 = 0.205; P = 0.002) and ferritin levels (deltaR2 = 0.132; P = 0.015) in PD patients. When albumin was excluded from the analysis, the best predictors of EPO/Hct were CRP (deltaR2 = 0.105; P = 0.003) and ferritin levels (deltaR2 = 0.051; P = 0.023) in HD patients and CRP level (deltaR2 = 0.141; P = 0.024) in PD patients. When both albumin and CRP were excluded from analysis in HD patients, low transferrin levels predicted high EPO/Hct (deltaR2 = 0.070; P = 0.011). EPO/Hct was independent of PTH and aluminum levels, PCRn, and Kt/V. High EPO/Hct occurred in the context of high ferritin and low transferrin levels, the pattern expected in the acute-phase response, not in iron deficiency. In well-dialyzed patients who were iron replete, the acute-phase response was the most important predictor of EPO resistance.

Topics: Acute-Phase Reaction; Adult; Aged; Anemia; C-Reactive Protein; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Prognosis; Regression Analysis; Renal Dialysis; Statistics, Nonparametric

Inflammation and hypoxia are frequently associated, but their interaction is poorly understood. In vitro studies have shown that hypoxia stimulates the genes of acute phase proteins (APP) and cytokines known to induce APP. We decided to determine kinetics and potential determinants of an acute phase response after cardiac arrest and to assess whether isolated moderate hypoxia can induce APP in humans in vivo.. Prospective, observational study in patients and human experiment.. Tertiary care university hospital.. 22 patients after primarily successful cardiopulmonary resuscitation (CPR) and 7 healthy volunteers.. None in patients; exposure of volunteers to simulated altitude (460 torr/6 h).. Following CPR, type-1 APP (C-reactive protein, alpha 1-acidglycoprotein, serum amyloid A) and type-2 APP (haptoglobin, alpha 1-antitrypsin) increased consistently within 1-2 days and the 'negative' APP transferrin was downregulated. This APP response occurred irrespective of the cause of arrest, the estimated time of anoxia, clinical course or patient outcome and was not different in patients with and without infectious complications. Exposure of healthy volunteers to less severe but more prolonged hypoxia did not induce APP, although a time dependent increase of serum erythropoietin (EPO) was measurable under these conditions, indicating the activation of oxygen dependent gene expression.. (i) A marked acute phase response occurs regularly after cardiac arrest, but within the complexity of this situation the severity of hypoxia is not a predominant determinant of this response. (ii) Despite in vitro evidence for similarities in the oxygen dependent regulation of APP and EPO production, the oxygen sensitivity of these proteins in vivo is different. (iii) Measurements of APP are not revealing regarding infectious complications in the early phase after CPR.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Adolescent; Adult; Aged; Cardiopulmonary Resuscitation; Erythropoietin; Female; Heart Arrest; Hemoglobins; Humans; Hypoxia; Inflammation; Kinetics; Male; Middle Aged; Prospective Studies

The aim of our study was to evaluate bone marrow stimulation and bone marrow response to post-operative anaemia in children after open heart surgery. In 16 children (age 5.7 +/- 0.9 years, weight 20.1 +/- 3.2 kg) serum erythropoietin, haematocrit, reticulocyte count, ferritin, transferrin saturation and C-reactive protein were assessed perioperatively after cardiopulmonary bypass for surgical repair of atrial septal defect. Erythropoietin increased seven fold from 14 +/- 6.2 (7-30) to 80 +/- 49 (20-171) mU/ml (P < 0.05) and the reticulocyte count a 1.7-fold from 11.1 +/- 3.1 (6-19) to 18.4 +/- 5.9 (10-31) / 1000 (P < 0.05). Transferrin saturation was inversely correlated to C-reactive protein.. These findings suggest adequate bone marrow stimulation but an inadequate bone marrow response during the immediate perioperative period, caused by inhibition of erythropoesis by acute postoperative inflammation in children after open heart surgery.

Topics: Acute-Phase Reaction; Analysis of Variance; Anemia; Bone Marrow; Cardiopulmonary Bypass; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Heart Septal Defects, Atrial; Hematocrit; Hemodynamics; Humans; Iron; Male; Postoperative Complications; Regression Analysis; Reticulocyte Count

This study attempts to evaluate the adequacy of the erythropoietin (EPO) response in 42 anaemic patients with advanced human immunodeficiency virus (HIV) infection [30 with acquired immunodeficiency syndrome (AIDS) and 12 with AIDS-related conditions] by comparing their serum EPO levels with those found in a non-HIV reference population consisting of 36 patients with anaemia of chronic disorders (ACD) and 57 with iron deficiency anaemia (IDA). Although the average Hb concentration was similar in the three groups, the EPO level for HIV patients (mean +/- SEM, 64.3 +/- 7.7 mU/ml) did not differ significantly from that in ACD patients (45.3 +/- 8.3 mU/ml, P > 0.1), and both groups had a lower mean EPO level (P < 0.05 and P < 0.01 respectively) than IDA subjects (133.5 +/- 18.7 mU/ml). Thirteen HIV patients on zidovudine therapy showed similar mean Hb and EPO levels to those in the untreated patients. A significant inverse correlation between the log of serum EPO and the Hb values was observed in the three groups. However, this relationship was found to be stronger in IDA patients than in either HIV or ACD subjects (P < 0.001), with no difference between the two latter groups (P > 0.2). These data suggest that the EPO response is blunted in the anaemia associated with advanced HIV infection.

Topics: Acquired Immunodeficiency Syndrome; Acute-Phase Reaction; Adolescent; Adult; Aged; Anemia; Anemia, Hypochromic; Child; Chronic Disease; Erythropoietin; Female; Hemoglobins; HIV Infections; Humans; Male; Middle Aged