Oxidative stress and erythrocyte integrity in end-stage renal failure patients hemodialysed using a vitamin E-modified membrane. Evaluation of a Novel Vitamin E Coated Cellulosic Membrane Hollow Fiber Dialyzer Vitamin E‐‐Bonded Cellulose Membrane, Lipoperoxidation, and Anemia in Hemodialysis Patients Effects of a vitamin E-modified dialysis membrane and vitamin C infusion on oxidative stress in hemodialysis patients. Effect of dialysis flux and membrane material on dyslipidaemia and inflammation in haemodialysis patients. Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial Effects of vitamin C infusion and vitamin E-coated membrane on hemodialysis-induced oxidative stress. The vitamin E debate: implications for ongoing trials of pre‐eclampsia prevention A Vitamin E-Coated Polysulfone Membrane Reduces Serum Levels of Inflammatory Markers and Resistance to Erythropoietin-Stimulating Agents in Hemodialysis Patients: Results of a Randomized Cross-Over Multicenter Trial Effects of erythropoietin and vitamin E-modified membrane on plasma oxidative stress markers and anemia of hemodialyzed patients. Vitamin C Supplementation Decreases Oxidative Stress Biomarker F2-Isoprostanes in Plasma of Nonsmokers Exposed to Environmental Tobacco Smoke Vitamin E-coated dialyzer reduces oxidative stress in hemodialysis patients.
Oxidative stress has been implicated in a range of disease states , including end-stage renal failure treated with hemodialysis . Hemodialysis with vitamin E-modified membranes reduces lipid peroxidation , but the effect on erythrocyte integrity has not been determined . This study compared antioxidant defense parameters and the resistance of erythrocytes to free radical-mediated hemolysis in patients dialysed with cellulose acetate membranes at baseline and with a vitamin E-modified membrane ( Excebrane Clirans ; Terumo Corporation ) for 13 wk .  Resistance of erythrocytes to free radical attack was assessed in vitro using the peroxyl hemolysis test . The time to 50 % hemolysis ( T50 % ) increased significantly during the first 6 wk of Excebrane use ( p < 0.05 ) , but this parameter returned to baseline by 13 wk . Glutathione concentration and erythrocyte superoxide dismutase activity were unchanged during the study , but glutathione peroxidase activity increased from low levels at baseline and became significantly higher at 6 and 13 wk ( p < 0.001 ) . Total erythrocyte polyunsaturated fatty acid content and C18:2 level increased ( p < 0.001 ) and saturated fatty acids ( total , C16:0 , C18:0 , C22:0 and C24:0 ) decreased ( p < 0.03 ) . Total monounsaturated fatty acid content was unchanged . The increased resistance of erythrocytes to hemolysis , the increased glutathione peroxidase activity , and the increased degree of unsaturation of fatty acids in the erythrocyte membrane are compatible with a reduction of oxidative stress during hemodialysis with vitamin E-modified membranes Adverse physiologic effects accompany hemodialysis . Biocompatible dialyzer membranes may both limit oxidative stress and decrease & bgr;2-microglobulin production , thereby reducing patient morbidity . We compared st and ard solute clearance , lipid , and antioxidant effects of a novel cellulosic membrane dialyzer modified with covalently bonded vitamin E ( Excebrane Clirans E15 , Terumo Australia ) with st and ard cellulosic and polysulphone membrane dialyzers .  Stable adult hemodialysis patients taking no lipid lowering or antioxidant therapy ( n = 17 ; 9 male , 8 female ) were recruited into a 10 week , prospect i ve , unblinded study . Measurements were made at baseline on their usual dialyzer and after 2 , 4 , and 10 weeks of Excebrane use . Excebrane demonstrated good in vivo clearance of st and ard solutes relative to surface area . Predialysis & bgr;2-microglobulin levels were unchanged with time and were significantly lower postdialysis than with cellulose acetate ( p < 0.05 ) . Oxidized low density lipoprotein levels as measured by nitrotyrosine residues were high predialysis , but tended to decrease with both membranes ( p > 0.05 ) . Total antioxidant status fell during dialysis ( p < 0.0005 ) , but plasma vitamin A and E concentrations increased ( p = 0.007 and p = 0.02 , respectively ) . Baseline vitamin A levels were high in all patients and , along with vitamin E , total antioxidant status and lipid profiles did not change over time with Excebrane use . Excebrane is an efficient , biocompatible membrane with no deleterious effects on & bgr;2-microglobulin or lipids . More long-term study is merited In hemodialysis patients , oxidative stress results from an imbalance between the production of reactive oxygen species and antioxidant defense mechanisms . Recently , a new dialysis multi‐‐layer membrane has been developed , by modifying the inner surface of regenerated cellulose to support a vitamin E coating . The aim of our study was to investigate the effects of hemodialysis treatment with vitamin E‐‐modified membrane on anemia and erythropoietin requirement in a group of chronic uremic patients . Ten uremic , non diabetic , patients on st and ard bicarbonate dialysis were treated with vitamin E‐‐bonded dialysis membrane for 12 months . Hematological parameters , erythropoietin requirement , serum vitamin E and serum malonyldialdehyde ( ( MDA ) ) were evaluated before starting the study and monthly . No significant changes in hemoglobin level , RBC count , hematocrit and EPO requirement were observed . Basal vitamin E levels were in the normal range ( ( 13.0±2.88 mg//L vs. 14.79±3.12 mg//L ; NS ) ) . On the contrary , basal MDA levels were higher than those observed in the control group ( ( 1.87±0.36 vs. 1.13±0.18 mmol//mL ; p < 0.01 ) ) and a significant decrease of MDA levels was found after 1 month of Excebrane ® treatment ( ( 1.39±0.25 nmol//mL ; p < 0.02 ) ) . In conclusion , the role of the “ oxidative hemolysis ” in the pathogenesis of anemia in CHD patients is still not clearly defined , but it could be of minor clinical relevance . Although the effectiveness of vitamin E‐‐coated membranes as a scavenger of ROS allows a better control of intradialytic oxidative stress , it does n't seem to contribute to clinical management of anemia in these patients Hemodialysis deteriorates oxidative stress . Vitamin E is an antioxidant whose regeneration is provided for by vitamin C. The authors tested the effects of a vitamin E-modified membrane ( E ) , nonmodified cellulose membrane ( O ) , and vitamin C infusion ( 500 mg , C ) into the arterial blood line during dialysis on parameters of oxidative stress . In a short-term study , 24 patients were subjected to a single dialysis session  with E , O , E with C , and O with C protocol s. In a long-term study ( 12 weeks ) , 20 patients were r and omized into groups with C and without C on each dialysis , and both groups had dialysis using O , E , and again O membrane for 4 weeks each . In the short-term study , thiobarbituric acid reacting substances ( TBARS ) in plasma rose after dialysis ( p < 0.02 ) with O , and no changes were observed in the other 3 protocol s. In the long-term study , predialysis TBARS declined when using E both in the groups with C ( p < 0.02 ) and without C ( p < 0.05 ) . A switch over to O result ed in TBARS returning to baseline levels . The E membrane prevented an increase in lipid peroxidation during single dialysis , and long-term use of the E membrane also result ed in a decrease in the predialysis lipid peroxidation level . The antioxidant capacity of the E membrane was not enhanced by vitamin C infusion . High doses of vitamin C administered during dialysis using a nonmodified cellulose membrane prevented an increase in lipid peroxidation , most probably due to the enhanced rate of endogenous vitamin E regeneration BACKGROUND Dyslipidaemia , inflammation and oxidative stress are prominent risk factors that potentially cause vascular disease in haemodialysis patients .  Dialysis modalities affect uraemic dyslipidaemia , possibly by modifying oxidative stress , but the effects of dialyser flux and membrane material on atherogenic remnant particles and oxidized low-density lipoproteins ( LDL ) are unknown . METHODS We performed a r and omized crossover study in 36 patients on haemodialysis  to analyse the effect of dialyser flux and membrane material on plasma lipids , apolipoproteins and markers of inflammation and oxidative stress . Stable patients on low-flux dialysis with polysulphone for > /=6 weeks were assigned to high-flux polysulphone or high-flux modified cellulose with similar dialyser surface area and permeability characteristics and crossed over twice every 6 weeks . RESULTS Thirty patients completed the study per protocol . Treatments with high-flux polysulphone and modified cellulose lowered serum triglyceride ( by 20 % and 10 % , respectively ; P<0.05 ) and remnant-like particle cholesterol by 32 % ( P<0.001 ) and 11 % ( NS ) after the first 6 weeks of treatment . Oxidized LDL decreased significantly with high-flux polysulphone , but not with modified cellulose . Apolipoproteins CII and CIII were reduced , whereas the ratio CII/CIII was increased ( all P<0.05 ) . Acute-phase proteins and LDL and high-density lipoprotein cholesterol remained unaffected . CONCLUSIONS This r and omized crossover study demonstrates a potent effect of high-flux haemodialysis on uraemic dyslipidaemia .  Polysulphone membrane material showed superiority on oxidatively modified LDL , an indicator of oxidative stress in haemodialysis patients Simvastatin reduces the blood concentration of cholesterol by inhibiting hydroxymethylglutaryl-coenzyme A reductase , the rate-limiting enzyme in cholesterol synthesis , and thereby reduces the risk of cardiovascular disease . In addition , simvastatin treatment leads to a reduction in fluxes in mitochondrial respiratory complexes I and II and might thereby reduce the formation of reactive oxygen species , which have been implicated in the pathogenesis of arteriosclerosis . Therefore , we hypothesized that simvastatin may reduce oxidative stress in humans in vivo . We conducted a r and omized , double-blinded , placebo-controlled study in which subjects were treated with either 40 mg of simvastatin or placebo for 14 days . The endpoints were six biomarkers for oxidative stress , which represent intracellular oxidative stress to nucleic acids , lipid peroxidation and plasma antioxidants , that were measured in urine and plasma sample s. A total of 40 participants were included , of which 39 completed the trial . The observed differences between simvastatin and placebo groups in the primary outcomes , DNA and RNA oxidation , were small and nonsignificant ( p=0.68 ) , specifically , 3 % in the simvastatin group compared to 7.1 % in the placebo group for DNA oxidation and 7.3 % in the simvastatin group compared to 3.4 % in the placebo group . The differences in biomarkers related to plasma were not statistically significant between the treatments groups , with the exception of total vitamin E levels , which , as expected , were reduced in parallel with the reduction in plasma cholesterol . In healthy young male volunteers , short-term simvastatin treatment , which considerably reduces cholesterol , does not lead to a clinical ly relevant reduction in a panel of measures of oxidative stress . Whether simvastatin has effects on oxidative stress in diseased population s , such as diabetes or hemochromatosis , where oxidative stress is prominent , is unknown but seems unlikely Chronic hemodialysis ( HD ) patients manifest anemia and atherosclerosis with associated oxidative stress . We explored whether intravenous infusion of vitamin C ( VC ) and /or use of vitamin E (VE)-coated dialysis membrane could palliate HD-evoked oxidative stress . Eighty patients undergoing chronic HD were enrolled and r and omly assigned into four groups : HD with intravenous VC ( n=20 ) , HD with VE-coated dialyzer ( n=20 ) , HD with both ( n=20 ) , and HD with neither ( n=20 ) . We evaluated oxidative stress in blood and plasma , erythrocyte methemoglobin/ferricyanide reductase ( red blood cells (RBC)-MFR ) activity , plasma methemoglobin , and pro-inflammatory cytokines in these patients . All patients showed marked increases ( 14-fold ) in blood reactive oxygen species ( ROS ) after HD . The types of ROS were mostly hydrogen peroxide , and in lesser amounts , O2 * - and HOCl . HD result ed in decreased plasma VC , total antioxidant status , and RBC-MFR activity and increased plasma and erythrocyte levels of phosphatidylcholine hydroperoxide ( PCOOH ) and methemoglobin . Intravenous VC significantly palliated HD-induced oxidative stress , plasma and RBC levels of PCOOH , and plasma methemoglobin levels and preserved RBC-MFR activity . The VE-coated dialyzer effectively prevented RBCs from oxidative stress , although it showed a partial effect on the reduction of total ROS activity in whole blood . In conclusion , intravenous VC plus a VE-coated dialyzer is effective in palliating HD-evoked oxidative stress , as indicated by hemolysis and lipid peroxidation , and by overexpression of proinflammation cytokines in HD patients . Using VE-coated dialyzer per se is , however , effective in reducing lipid peroxidation and oxidative damage to RBCs A potential role for oxidative stress in the pathophysiology of pre-eclampsia was first proposed by Stark in 1993 . Synthesis of free radicals by a dysfunctional placenta , and possibly by maternal leucocytes and endothelium , seems to play a central role in this association . Free radicals , through oxidative damage of biomolecules and lipid peroxidation , can initiate maternal vascular endothelial dysfunction and leucocyte activation . A comprehensive review of the role of oxidative stress in pre-eclampsia has been recently published . Antioxidants such as vitamin C and vitamin E have been proposed as potential therapeutic or prophylactic treatment for pre-eclampsia .  This suggestion was supported by the observation that women with pre-eclampsia have lower plasma vitamin C concentrations . Both in vitro and in vivo studies suggest that there is an interaction between vitamin C and vitamin E , with vitamin C possibly exerting a ‘ redox ’ recycling effect on oxidised vitamin E within lipoproteins and membranes . The vitamin C to E ratio may be of central importance in protecting against the damaging effects of reactive oxygen species . To date , three placebo-controlled trials have assessed the effect of vitamins C and E on  pre-eclampsia .  Although no benefits were found when supplementation was given to women with diagnosed pre-eclampsia , a combination of 1 g/day of vitamin C and 400 IU/day of vitamin E given as prophylaxis to high risk women demonstrated a reduction in the risk of pre-eclampsia from 17 % in the control group to 8 % in the active treatment group . In this same double-masked r and omised controlled trial , women receiving vitamins C and E showed a reduction in biological markers of oxidative stress . Since this report , a number of multicentre r and omised clinical trials have been initiated both in low risk and in high risk population s , with the goal of testing the hypothesis that antioxidants reduce the incidence of pre-eclampsia ( Table 1 ) . In the UK , a multicentre trial is currently recruiting pregnant women with diabetes . The NIH has funded two antioxidant trials , one that is under way in Brazil and the second that is being conducted among nulliparous women in the NICHD Maternal Fetal Medicine Network . The International Trial of Antioxidants for the Prevention of Preeclampsia ( INTAPP ) , funded by the Canadian Institutes of Health Research , is enrolling nulliparas without additional risk factors ( Stratum I ) and multiparas and nulliparas with clinical risk factors for gestational hypertension ( Stratum II ) . Collectively , these trials should provide an answer to the question of the role of antioxidants in the prevention of pre-eclampsia and its related disorders . Recently , a meta- analysis of 19 clinical trials of  vitamin E  , for the most part secondary prevention trials , conducted in elderly population s at increased risk for a number of diseases ranging from lung or gastrointestinal cancer to cardiovascular disease , Alzheimer ’s disease or cataract , was published in the Annals of Internal Medicine . The authors of the meta- analysis concluded that high doses of vitamin E may be associated with an increased risk of all-cause mortality . What are the implication s of this meta- analysis for the ongoing pre-eclampsia prevention trials ? It is the responsibility of the Principal Investigators , the Steering Committees and Data Safety Monitoring Committees ( DSMC ) of ongoing clinical trials to take into account information generated from studies that arise in the course of their trial . They must assess the quality of the new evidence and determine how this information influences the balance of risks to benefits of the ongoing trials . In the case of the Canadian trial , both the DSMC and the hospital Ethics Committee have review ed the information and made their recommendations to the trial Steering Committee . The following is our evaluation of the quality of the evidence of the meta- analysis by Miller et al. , and its implication s for ongoing clinical trials of antioxidants in the prevention of pre-eclampsia Background : Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia . Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species . The aim of this cross-over r and omized study was to compare the effects of a vitamin E-coated polysulfone ( Vit E PS ) membrane and a non-vitamin E-coated polysulfone ( PS ) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents ( ESAs ) . Methods : After a 1-month run-in period of st and ard bicarbonate dialysis with a synthetic membrane , 62 patients of both genders , and older than 18 years , dialysis vintage 48 ± 27 months , BMI 22 ± 3 ( from 13 different dialysis units ) were r and omized ( A-B or B-A ) in a cross-over design to Vit E PS ( treatment A ) and to PS ( treatment B ) both for 6 months . C-reactive protein ( CRP ) and interleukin-6 ( IL-6 ) concentrations were determined by a s and wich enzyme immunoassay at baseline and every 2 months ; red blood cell count , ESA dose and ESA resistance index ( ERI ) were assessed monthly . Results : Hemoglobin ( Hb ) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months ( p < 0.001 ) and remained unchanged in the PS group . Although ESA dosage remained stable during the observation periods in both groups , ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months ( p < 0.001 ) . No significant variation of ERI was observed in the PS group . A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS  group : CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l ( p < 0.001 ) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml ( p < 0.05 ) . In the PS group , CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7 , and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 ( p = n.s . ) . Conclusions : Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients ; in addition , a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements BACKGROUND Oxidant stress has a pathogenic role in uremic anemia , possibly interfering with erythropoietin ( EPO ) function and red blood cell ( RBC ) survival . Therefore , it is expected that antioxidant therapy might exert a beneficial effect on these parameters . METHODS To test this hypothesis , we investigated some oxidant stress indices , anemia levels , and RBC survival in 47 hemodialysis ( HD ) patients r and omly assigned to three groups . Patients in groups A ( n = l8 ) and B ( n = 20 ) were on dialysis therapy using conventional cellulosic and synthetic membranes and were administered high and low doses of recombinant human EPO ( rHuEPO ) , respectively . Patients in group C ( n = 9 ) were dialyzed with vitamin E-modified membranes ( CL-Es ) and investigated in a two-step prospect i ve study . In step Cl , patients were administered rHuEPO doses similar to those of group A. In step C2 , rHuEPO doses were reduced to those of group B. As oxidant stress markers , we determined in plasma the susceptibility of lipids to undergo iron-catalyzed oxidation ( reactive oxygen molecules [ ROMs ] test ) and malondialdehyde-4-hydroxynonenal ( MDA-4HNE ) , alpha-tocopherol ( alpha-T ) , total thiol ( -SH ) , and total antioxidant activity . RBC survival was measured using the chromium 51 T/2 technique in 22 patients . RESULTS Results show that : ( 1 ) high rHuEPO doses ( groups A and C1 ) were associated with decreased ROM production , low alpha-T levels , and slightly increased -SH levels compared with corresponding groups on low rHuEPO doses ( groups B and C2 ) ; ( 2 ) treatment with CL-Es ( group C ) increased plasma alpha-T and decreased -SH levels ; these data were associated with decreased indices of lipid peroxidation , particularly MDA-4HNE 1evels , only in patients administered low rHuEPO doses ; ( 3 ) alpha-T concentration influenced RBC survival , which was remarkably decreased in HD patients ; patients treated with CL-Es showed a better degree of anemia correction ; and ( 4 ) alpha-T level correlated negatively with -SH level and seemed to be independent of the extent of peroxidation and oxidizability of plasma lipids . CONCLUSION Both EPO and CL-E can influence plasma antioxidants and , to an extent , lipid peroxidation processes . However , this study shows that even in patients treated with low rHuEPO doses , RBC survival close to normal and sufficient correction of anemia are achieved only when appropriate alpha-T levels are reached Exposure to environmental tobacco smoke ( ETS ) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers . Current research suggests that some of these diseases are associated with elevated oxidative stress . We investigated the effect of antioxidant ( AO ) intervention on the lipid peroxidation biomarker F2-isoprostanes ( F2-IsoPs ) , an index of oxidative stress , in plasma of nonsmokers exposed to ETS ( passive smokers).We measured free F2-IsoP concentrations in plasma of 67 passive smokers at baseline and after 2 mo of daily intervention with AOs or placebo .  The study subjects ( 47 females , 20 males ; mean age 46 ± 15 ) were r and omized into one of three treatment groups : vitamin C , " mixture " ( vitamin C , vitamin E , and α-lipoic-acid ) , and placebo . Investigated confounders included plasma baseline AO levels , lipid and total cholesterol profiles , transferrin saturation , and C-reactive protein . Plasma F2IsoP concentrations of subjects in the vitamin C and mixture groups decreased significantly by 17.2 pmol/l ( P = 0.0105 ) and 19.2 pmol/l ( P = 0.0083 ) when compared with the placebo group ( 11.4 % and 12.7 % , respectively ) . Daily AO supplementation ( especially with vitamin C ) decreases this oxidative stress biomarker in passive smokers . This finding might be of importance for the prevention of ETS-associated adverse health effects in nonsmokers The high incidence of cardiovascular disease in hemodialyzed ( HD ) patients is well established and oxidative stress has been involved in this phenomenon . The aim of our study was to evaluate if a vitamin E-coated dialyzer could offer protection to HD patients against oxidative stress . Sixteen HD patients were successively assessed for one month ( i ) on a high biocompatible synthetic dialyzer ( AN ) and ( ii ) on a vitamin E-coated dialyzer ( VE ) .  Blood sample s were taken before and after the dialysis session at the end of each treatment period . HD session conducted with the AN dialyzer was responsible for acute oxidative stress , significantly assessed after HD by a decreased plasma vitamin C level and an increased ascorbyl free radical (AFR)/vitamin C ratio used as an index of oxidative stress . Plasma elastase activity , reflecting neutrophil activation , was also increased ; soluble P-selectin , reflecting platelet activation , did not show any variation . The use of the VE dialyzer was associated with a less extended oxidative stress compared with the AN membrane : basal vitamin C level was higher , and after the HD session AFR/vitamin C ratio and elastase activity were not significantly increased . Plasma vitamin E levels were not affected . Our study demonstrates that HD is associated with oxidative stress , which can be partially prevented by the use of a vitamin E-coated dialyzer . Our data suggest that this dialyzer may exert a site-specific scavenging effect on free radical species in synergy with a reduced activation of neutrophils
The conversion of dialysis patients to a vitamin E-coated dialyser is associated with an improvement in circulating biomarkers of lipid peroxidation , which is of potential clinical benefit
BACKGROUND Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anaemia .
We conducted a systematic review and meta- analysis to examine the effect of Excebrane , a vitamin E-coated cellulose-based dialyser , on circulating biomarkers of lipid peroxidation , as surrogate markers of oxidative stress .