title: Redox state, antioxidative activity and lipid peroxidation in erythrocytes and plasma of chronic ambulatory peritoneal dialysis patients. Vitamin E‐‐Bonded Cellulose Membrane, Lipoperoxidation, and Anemia in Hemodialysis Patients Long-term use of vitamin E-coated polysulfone membrane reduces oxidative stress markers in haemodialysis patients. Effects of a vitamin E-modified dialysis membrane and vitamin C infusion on oxidative stress in hemodialysis patients. Effects of erythropoietin and vitamin E-modified membrane on plasma oxidative stress markers and anemia of hemodialyzed patients. Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial Evaluation of a Novel Vitamin E Coated Cellulosic Membrane Hollow Fiber Dialyzer Vitamin E-bonded hemodialyzer improves neutrophil function and oxidative stress in patients with end-stage renal failure. Prospective crossover trial of the influence of vitamin E-coated dialyzer membranes on T-cell activation and cytokine induction. Intradialytic granulocyte reactive oxygen species production: a prospective, crossover trial. Oxidative damage during hemodialysis using a vitamin-E-modified dialysis membrane: a preliminary characterization.
abstract: Red blood cells and plasma reduced and oxidized glutathione levels , glutathione peroxidase ( GSH-Px ) activity , thiobarbituric acid reactants ( TBAR ) of both chronic ambulatory peritoneal dialysis ( CAPD ) patients and a matched control group were investigated in this study . Oxidized and reduced pyridinic nucleotides in red blood cells ( RBC ) , in which NADPH is a direct expression of hexose monophosphate shunt function , were also studied . The results obtained indicate that RBC and plasma are exposed to oxidative stress in CAPD . This condition is characterized by a decreased GSH/GSSG ratio , particularly evident in RBC as a consequence of the GSSG accumulation . Lipid peroxidation is increased , as indicated by raised TBAR levels , and reduced pyridinic nucleotides are decreased . Increased GSH-Px levels and unmodified or slightly increased GSH content were observed in the RBC but not in plasma , which showed decreased GSH and unmodified peroxidase activity . Peroxidase correlated positively with TBAR levels in the RBC lysates . In a subgroup of patients treated with erythropoietin ( vs. untreated patients and controls ) no differences were observed in the glutathione-related parameters studied . These data suggest that a mechanism for adaptation to oxidative conditions may be present in CAPD and its effects on RBC integrity are discussed in comparison with the hemodialysis conditions previously studied 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 BACKGROUND  Asymmetric dimethylarginine ( ADMA ) is an endogenous inhibitor of nitric oxide synthase and an independent predictor of overall mortality and cardiovascular outcome in haemodialysis ( HD ) patients . In the present study , we compared the effects of a vitamin E-coated polysulfone membrane ( PSE ) and a non-vitamin E-coated polysulfone membrane ( PS ) on oxidative stress markers such as ADMA . METHODS Thirty-one HD patients were enrolled to this investigation . They were allocated into two groups : in the PSE group ( n = 16 ) , PSE was used for 6 months , followed by PS for an additional 12 months ; in the PS group ( n = 15 ) , PS was used for the entire observation period . Plasma ADMA , oxidized low density lipoprotein ( Ox-LDL ) and malondialdehyde LDL ( MDA-LDL ) levels were measured at baseline , 3 , 6 , 12 and 18 months . Plasma ADMA in peritoneal dialysis ( PD ) patients and in healthy individuals was also measured . RESULTS Predialysis concentrations of ADMA ( 0.72+/- 0.13 nmol/ml ) were significantly higher in the HD group than in both PD patients ( 0.63+/-0.10 nmol/ml , P<0.01 ) and healthy individuals ( 0.44+/-0.01 nmol/ml , P<0.0001 ) . Treatment with PSE for 6 months significantly reduced predialysis levels of ADMA ( 0.54+/-0.09 nmol/ml ) compared with baseline ( 0.74+/-0.12 nmol/ml ; P<0.01 ) . Predialysis levels of Ox-LDL and MDA-LDL after 6 months therapy with PSE were also significantly lower than baseline values . Treatment with PS subsequent to treatment with PSE again increased ADMA , Ox-LDL and MDA-LDL back to baseline levels . In the PS group , ADMA , Ox-LDL and MDA-LDL levels remained unchanged during the entire treatment period of 18 months . CONCLUSIONS We confirmed that use of PSE reduced ADMA that had accumulated in HD patients . This finding indicates that PSE exerts anti-oxidant activity . A r and omized controlled study will be required to determine whether PSE prevents cardiovascular diseases and other dialysis-related complications by reducing oxidative stress 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 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 Intravenous iron application to anemic patients on hemodialysis leads to an " oversaturation " of transferrin . As a result , non-transferrin-bound , redox-active iron might induce lipid peroxidation . To test the hypothesis that vitamin E attenuates lipid peroxidation in patients receiving 100 mg of iron(III ) hydroxide sucrose complex intravenously during a hemodialysis session , 22 patients were investigated in a r and omized cross-over design , either with or without a single oral dose of 1200 IU of all-rac-alpha-tocopheryl acetate taken 6 h before the hemodialysis session . Blood was drawn before and 30 , 60 , 90 , 135 , and 180 min after the start of the iron infusion , and areas under the curve ( AUC0 - 180 min ) of ratios of plasma malondialdehyde ( MDA ) to cholesterol and plasma total peroxides to cholesterol ( two markers of lipid peroxidation ) were determined as the outcome variables . At baseline of the session without vitamin E supplementation , plasma alpha-tocopherol concentrations ( 27.6 + /- 1.8 micromol/L ) and ratios of alpha-tocopherol to cholesterol ( 5.88 + /- 1.09 mmol/mol ) were normal , plasma MDA concentrations were above normal ( 1.20 + /- 0.28 micromol/ L ) , and bleomycin-detectable iron ( BDI ) , indicating the presence of redox-active iron , was not detectable . Upon iron infusion , BDI and MDA concentrations increased significantly ( P < 0.001 ) . BDI concentrations explained the increase over baseline in MDA concentrations ( MDA = 1.29 + /- 0.075 x BDI ) . Vitamin E supplementation , leading to a 68 % increase in plasma alpha-tocopherol concentrations , significantly reduced the AUC0 - 180 min of MDA to cholesterol ( P = 0.004 ) and peroxides to cholesterol ( P = 0.002 ) . These data demonstrate that a single oral dose of vitamin E attenuates lipid peroxidation in patients on hemodialysis receiving intravenous iron .  Given that intravenous iron is applied repeatedly to patients on hemodialysis , this therapeutic approach may protect against oxidative stress-related degenerative disease in the long term BACKGROUND Excess cardiovascular mortality has been documented in chronic haemodialysis patients . Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without , suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis . We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease . METHODS Haemodialysis patients with pre-existing cardiovascular disease ( n=196 ) aged 40 - 75 years at baseline from six dialysis centres were enrolled and r and omised to receive  800 IU/day vitamin E or matching placebo . Patients were followed for a median 519 days . The primary endpoint was a composite variable consisting of : myocardial infa rct ion ( fatal and non-fatal ) , ischaemic stroke , peripheral vascular disease ( excluding the arteriovenous fistula ) , and unstable angina . Secondary outcomes included each of the component outcomes , total mortality , and cardiovascular-disease mortality . FINDINGS A total of 15 ( 16 % ) of the 97 patients assigned to vitamin E and 33 ( 33 % ) of the 99 patients assigned to placebo had a primary endpoint ( relative risk 0.46 [ 95 % CI 0.27 - 0.78 ] , p=0.014 ) . Five ( 5.1 % ) patients assigned to vitamin E and 17 ( 17.2 % ) patients assigned to placebo had myocardial infa rct ion ( 0.3 [ 0.11 - 0.78 ] , p=0.016 ) . No significant differences in other secondary endpoints , cardiovascular disease , or total mortality were detected . INTERPRETATION In haemodialysis patients with prevalent cardiovascular disease , supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infa rct ion 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 We evaluated the biocompatibility of a newly developed vitamin E hemodialyzer ( CL-EE ; Terumo Co Ltd , Tokyo , Japan ) by neutrophil function and oxidant stress in patients with end-stage renal failure in a r and omized crossover study . Ten patients underwent hemodialysis using either the CL-EE  or a control dialyzer membrane identical to the CL-EE except for vitamin E binding for 12 weeks in a crossover fashion after a 1-month washout period with hemophane membranes . White blood cell counts , serum oxidized low-density lipoprotein ( Ox-LDL ) levels , and malondialdehyde ( MDA ) levels during hemodialysis sessions were measured at the initiation and end of the CL-EE and control trials . Superoxide anion production by neutrophils just before and 4 hours after starting the session also was measured . Leukocytopenia at 1 hour after starting the session was detected to a similar extent in both membranes . However , the degree of reduction was less in the CL-EE trial after repeated use . Superoxide anion production by neutrophils just before a hemodialysis session was reduced after repeated use of the CL-EE membrane .  Serum Ox-LDL levels increased , whereas serum MDA levels decreased during sessions to a similar extent in both trials . However , these parameters were significantly lower in the CL-EE trial after repeated use . Serum LDL concentrations significantly decreased with repeated use of the CL-EE membrane . These data suggest that repeated use of the CL-EE membrane for 3 months improves neutrophil function , oxidant stress , and LDL concentrations in patients with renal failure . This membrane may be useful to reduce the incidence of cardiovascular events in patients with renal failure Cytokine induction by dialyzer membranes has been related to several acute and chronic side effects of hemodialysis treatment , among them being immune dysfunction and progressive atherosclerosis . Surface modification of cuprophane dialyzers with the antioxidant vitamin E is a new approach to enhance biocompatibility and improve cytokine levels , as well as immune function .  Twenty-one patients undergoing treatment with hemophane ( HE ) dialyzers were enrolled onto a crossover study with a vitamin E-coated ( VE ) dialyzer or a synthetic polyamide ( PA ) dialyzer . In vitro assays of lymphocyte activation and measurements of cytokine induction were performed to evaluate biocompatibility . Four weeks of treatment with either VE or PA dialyzers enhanced in vitro proliferation of peripheral blood leukocytes in comparison to treatment with HE membranes used before study entry . Enhancement of lymphocyte function was independent of dialysis efficiency , which was kept constant during the study . In the interdialytic interval , preactivation of monocytes for the production of interleukin-6 ( IL-6 ) did not differ between VE or PA dialysis . In contrast , the VE membrane reduced acute production of IL-6 during a dialysis treatment , whereas the PA membrane did not . Unlike IL-6 , the regulatory cytokine IL-10 is not inhibited by either membrane . This is important because IL-10 is believed to have a beneficial effect on immune function in dialysis patients . The VE membrane , despite being based on a cuprophane backbone , is similar to the highly biocompatible PA dialyzer in terms of its effect on lymphocyte function , whereas it exerts an additional suppressive effect on the overproduction of proinflammatory cytokines By the use of flow cytometric techniques , this prospect i ve , r and omized crossover study was design ed to analyze intradialytic granulocyte reactive oxygen species ( ROS ) formation in whole blood with complement-activating and noncomplement-activating hollow fiber membranes . Dialysis with a complement-activating membrane result ed in a 6.5-fold increase in granulocyte hydrogen peroxide production 15 min after dialysis initiation and remained significantly elevated ( P < 0.01 ) through the first 30 min with this membrane in comparison to both predialysis values and simultaneous values with a noncomplement-activating membrane . Further studies demonstrated that blood obtained at 15 min with a complement-activating membrane generated significantly less granulocyte ROS production in response to Staphylococcus aureus incubation than blood obtained either predialysis or at the same time in dialysis with a noncomplement-activating membrane . Both complement-activating and noncomplement-activating dialysis membranes caused slightly decreased granulocyte responsiveness to phorbol myristate acetate . It was concluded that hemodialysis with complement-activating membranes results in increased granulocyte ROS production and decreased responsiveness to S. aureus challenge during the dialysis procedure . These results document the potential role of ROS in hemodialysis-associated pathology and susceptibility to infection A comparison of the oxyradical exposure during  hemodialysis ( HD ) carried out with vitamin-E-modified cellulose ( CL-E ) or conventional membranes  , study ing red blood cell ( RBC ) and plasma lipoperoxidation and RBC glutathione metabolism , was done . In this preliminary characterization of a new and original approach to the prevention of free radical damage in HD , the results obtained indicate that lipoperoxidation in plasma and RBC is decreased and therefore oxidative damage can be significantly decreased using CL-E dialysis membranes instead of conventional membranes
target: 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: 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 .