Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging.

BACKGROUND: Inflammaging is a persistent, low-grade, sterile, nonresolving inflammatory state, associated with the senescence of the immune system. Such condition downregulates both innate and adaptive immune responses during chronic disorders as type II diabetes, cancer and hemodialysis, accounting for their susceptibility to infections, malignancy and resistance to vaccination. Aim of this study was to investigate hemodialysis inflammaging, by evaluating changes of several hemodialysis treatments on indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation. METHODS: We conducted a randomized controlled observational crossover trial. Eighteen hemodialysis patients were treated with 3 different hemodialysis procedures respectively: 1) Low-flux bicarbonate hemodialysis, 2) Low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, and 3) Hemodialfitration. The control group consisted of 14 hospital staff healthy volunteers. Blood samples were collected from all 18 hemodialysis patients just after the long interdialytic interval, at the end of each hemodialysis treatment period. RESULTS: Hemodialysis kynurenine and kynurenine/L - tryptophan blood ratio levels were significantly higher, when compared to the control group, indicating an increased indoleamine 2,3-dioxygenase-1 activity in hemodialysis patients. At the end of the low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers period, L - tryptophan serum levels remained unchanged vs both low-flux bicarbonate hemodialysis and hemodialfitration. Kynurenine levels instead decreased, resulting in a significant reduction of kynurenine/L - tryptophan blood ratio and indoleamine 2,3-dioxygenase-1 activity, when matched to both low-flux bicarbonate hemodialysis and HDF respectively. Serum nitric oxide control group levels, were significantly lower when compared to all hemodialysis patient groups. Interestingly, low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers nitric oxide serum levels from venous line blood samples taken 60 min after starting the hemodialysis session were significantly lower vs serum taken simultaneously from the arterial blood line. CONCLUSIONS: The treatment with more biocompatible hemodialysis procedure as low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, reduced indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation when compared to both low-flux bicarbonate hemodialysis and hemodialfitration. These data suggest that low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers lowering hemodialysis inflammaging, could be associated to changes of proinflammatory signalling a regulated molecular level. TRIAL REGISTRATION: NCT Number: NCT02981992; Other Study ID Numbers: 20100014090. First submitted: November 26, 2016. First posted: December 5, 2016. Last Update Posted: December 5, 2016.

Effects of Vitamin E-Coated versus Conventional Membranes in Chronic Hemodialysis Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: Accruing evidence suggests that vitamin E-coated membranes (ViE-m) might improve the clinical management of chronic hemodialysis (HD) patients. METHODS: We conducted a systematic review and meta-analysis of RCTs comparing ViE-m to conventional HD. Endpoints of interest were a series of biomarkers pertaining to anemia status, inflammation, oxidative stress and dialysis efficacy/status. RESULTS: Sixty studies were included. ViE-m significantly improved the Erythropoietin Resistance Index but had no impact on other anemia parameters. As for oxidative stress and inflammation, ViE-m produced a significant decrease in interleukin-6 levels, thiobarbituric acid reactive substances, plasma and red blood cell (RBC) malonylaldehyde and a significant increase in blood and RBC vitamin E. Conversely, ViE-m use had no impact on lipid profile, dialysis adequacy, blood pressure, albumin and uric acid. CONCLUSIONS: ViE-m might ameliorate anemia management by reducing oxidative stress and inflammation. Benefits of these bio-membranes on harder clinical outcomes are uncertain and need to be investigated by future, targeted trials.

Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study.

BACKGROUND: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. METHODS: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. RESULTS: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29). CONCLUSIONS: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.

Vitamin E as a functional and biocompatibility modifier of synthetic hemodialyzer membranes: an overview of the literature on vitamin E-modified hemodialyzer membranes.

Along with one century of history, research has provided many solutions for hemodialysis (HD) biomaterials, encompassing several generations of copolymers that have found wide application in the development of hollow-fiber dialyzer membranes. Polysulfone-based biomaterials have gained increasing consideration and are now the gold standard in the production of biocompatible hemodialyzers. However, even the highest biocompatibility now available cannot exclude that dialyzer membranes and the overall extracorporeal circulation may produce at the subclinical level immunoinflammatory reactions and thus an increased cardiovascular risk of patients on regular HD therapy. The lipophilic antioxidant and radical scavenger vitamin E has been used (as α-tocopherol) to modify cellulosic and synthetic hollow-fiber membranes with the ultimate goal to neutralize harmful reactive species and to mimic lipid structures of blood cell plasmalemma and lipoprotein particles. Besides filtration and biocompatibility, this modifier has introduced a third function of dialyzer membranes, namely 'antioxidant bioactivity'. Vitamin E can also serve as a template molecule to produce synthetic redox-active and -silent (non-antioxidant) modifiers for future generations of dialyzer membranes. This mini-review article describes the evolution of vitamin E-derived copolymers as a generation of biomaterials that has offered a clinical challenge and still represents a chance to further improving the quality of HD therapy.

SARS-CoV-2 Survival on Surfaces and the Effect of UV-C Light.

The aim of this study was to establish the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inanimate surfaces such as plastic, stainless steel, and glass during UV-C irradiation which is a physical means commonly utilized in sanitization procedures. The viral inactivation rate, virus half-life, and percentage of titer reduction after UV-C irradiation were assessed. Infectivity was maintained on plastic and glass until 120 h and on stainless steel until 72 h. The virus half-life was 5.3, 4.4, and 4.2 h on plastic, stainless steel, and glass, respectively. In all cases, titer decay was >99% after drop drying. UV-C irradiation efficiently reduced virus titer (99.99%), with doses ranging from 10.25 to 23.71 mJ/cm2. Plastic and stainless steel needed higher doses to achieve target reduction. The total inactivation of SARS-CoV-2 on glass was obtained with the lower dose applied. SARS-CoV-2 survival can be long lasting on inanimate surfaces. It is worth recommending efficient disinfection protocols as a measure of prevention of viral spread. UV-C can provide rapid, efficient and sustainable sanitization procedures of different materials and surfaces. The dosages and mode of irradiation are important parameters to consider in their implementation as an important means to fight the SARS-CoV-2 pandemic.

Liquid chromatography separation of α- and γ-linolenic acid positional isomers with a stationary phase based on covalently immobilized cellulose tris(3,5-dichlorophenylcarbamate).

α-Linolenic acid (ALA) and its most important positional isomer γ-linolenic acid (GLA), are essential fatty acids (vitamin F). Therefore, ALA- and GLA-rich edible oils hold great potential in human and animal nutrition, as well as in nutraceutics and cosmetics. Quality control and nutritional validation of oil products is thus of increasing importance. In the present study, the cellulose tris(3,5-dichlorophenylcarbamate)-based chiral stationary phase was successfully used for separation of ALA and GLA, a major challenge in the liquid chromatography of these isomers. The chromatographic conditions were firstly optimized on a HPLC system with UV detection, and the use of a reversed-phase eluent system made up of aqueous 10 mM ammonium acetate/acetonitrile (40/60, v/v; wspH6.0) with a 25 °C column temperature resulted optimal for the simultaneous discrimination of the two isomers at a 0.5 mL/min flow rate (α = 1.10; RS = 1.21). The method was then optimized for LC-MS/MS implementation. The proposed innovative separation method holds a great potential for the quantification of ALA and GLA in food and biological matrices, thus opening the way to further investigations involving the two positional isomers.

Effects of erythropoietin and vitamin E-modified membrane on plasma oxidative stress markers and anemia of hemodialyzed patients.

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 randomly 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 prospective 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.

Analysis method and characterization of the antioxidant capacity of vitamin E-interactive polysulfone hemodialyzers.

The lipophilic antioxidant vitamin E was used as a surface modifier (or coating agent) of hollow-fiber hemodialyzer membranes with the aim of increasing their biocompatibility and preventing oxidative stress, which are the main clinical drawbacks in hemodialysis (HD) therapy. At present, the redox chemistry of vitamin E-modified dialyzers is not well characterized and there is no standard method to assess the antioxidant capacity of these biomembranes under conditions that simulate those observed during HD therapy. With this study, we developed an original online method to determine the antioxidant capacity of vitamin E-modified dialyzer membranes during circulation experiments. This method is based on a spectrophotometric assay known as the ferric reducing/antioxidant power assay (FRAP). The principle of FRAP and its application to the qualitative and quantitative assessment of miniaturized polysulfone (PS)-based vitamin E-modified dialyzers (PS-VE) were verified by the accurate in vitro analysis of the iron-catalyzed oxidation of vitamin E. The antioxidant capacity of miniaturized PS-VE samples assessed in this study was of 14.5 microM Fe(2+), which corresponded to the transformation of nearly one-third of the vitamin E bound to the hollow-fiber membrane to its oxidation end product alpha-tocopherol quinone. This method shows good reproducibility and intra- and inter-assay precision, and can be easily adapted to determine the redox activity of every type of vitamin E-modified dialyzers during technological investigation, manufacturing control and clinical research.

Effect of the super-flux cellulose triacetate dialyser membrane on the removal of non-protein-bound and protein-bound uraemic solutes.

BACKGROUND: Uraemic solutes accumulate in haemodialysis (HD) patients and interfere with physiological functions. Low-flux (LF) HD does not efficiently remove all uraemic compounds. We investigated whether large pore super-flux (SF) cellulose triacetate membranes (CTA) result in a better removal of uraemic solutes. METHODS: Eleven patients were dialysed consecutively with LF-CTA and SF-CTA during 3 weeks. Urea (UR), creatinine (CR), uric acid (UA), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), indole-3-acetic acid (IAA), indoxyl sulfate (IS), hippuric acid (HA), pentosidine (PENT), low-molecular weight (MW) AGEs (AGEs) and albumin were determined in pre-HD, post-HD blood and in dialysate. Reduction rate (RR), dialytic clearance and mass transfer-area coefficient (KoA) were calculated. RESULTS: SF-HD resulted in a higher RR than LF-HD for IS and AGEs. Urea RR correlated with HA (r=0.59), IS (r=0.68) and IAA (r=0.67), (P<0.05) for SF. Dialytic clearance ranged from 20+/-5 to 179+/-20 ml/min for LF and from 24+/-6 to 191+/-24 ml/min for SF; being higher with SF for UA, HA, IS and IAA (SF vs LF, P<0.05). KoA was higher for most compounds with SF-HD. Albumin loss per SF session was 3.4+/-1.3 g. The retrieved amount of uraemic solutes in dialysate with LF and SF was comparable. CONCLUSIONS: In conventional HD, SF-CTA was superior to LF-CTA for removal of most protein-bound compounds, especially IS. Reduction rate, dialytic clearance and KoA were higher with SF. The SF-CTA membrane is albumin-leaking; however, this property could not completely explain the amount of retrieved protein-bound compounds in dialysate.

Oxidant and carbonyl stress-related apoptosis in end-stage kidney disease: impact of membrane flux.

Apoptosis is a highly regulated process which mostly affects cell-mediated immunity. In this open-label, randomized, prospective clinical study, we determined the impact in 10 hemodialysis patients treated with high-, medium-, and low-flux membranes on spontaneous or plasma-induced apoptosis, on monocytes, as well as on oxidant and carbonyl stress. High- and medium-flux membranes significantly reduced patients' plasma-dependent proapoptotic activity on U937 monocytic cell lines. Patients who had the highest levels of plasma-induced proapoptotic activity exhibited the highest plasma levels of advanced oxidation protein products (AOPPs) and carbonyls. Plasma carbonyl residues but not AOPPs were significantly lowered. Finally, a significant correlation could be drawn between the extent of plasma-induced proapoptotic activity and both plasma carbonyl and AOPP levels.

Glycoxidation and inflammatory markers in patients on treatment with PMMA-based protein-leaking dialyzers.

BACKGROUND: High-molecular-weight solutes such as glycation and oxidation protein products are putative proinflammatory mediators found in the uremic blood. The elimination of these and other large solutes by protein-leaking dialyzers (PLD) might help to correct the inflammatory status of maintenance hemodialysis (HD) patients. METHODS: Two matched groups of 13 standard 3 times/week HD patients were treated for 6 months with PMMA-based PLD and non-protein-leaking dialyzers (NPLD), respectively. At baseline, 1, 3, and 6 months, we measured the blood levels of the inflammatory cytokines IL-1beta, TNF-alpha, IL-6, the acute-phase protein C-reactive protein (CRP), the adhesion molecules ICAM-1, VCAM-1, and selectine-E, the chemotaxis factors MCP-1, and the glycation and oxidation protein end products pentosidine, protein carbonyls, and AOPP. RESULTS: In all the patients at baseline, pre-HD levels of glycation and oxidation protein markers, and inflammatory parameters were significantly higher than in healthy control subjects (P < 0.01 or greater). After 6 months, in the group on treatment with PLD, but not in that on NPLD, there was a significant decrease (P < 0.05 or greater) of pre-HD values of total pentosidine (mainly represented by pentosidine in serum albumin; -43%), protein carbonyls (-42%), AOPP (-38%), and the inflammatory cytokines IL-1beta (-49%), IL-6 (-39%), and TNF-alpha (-20%), while IL-10 and INF-gamma increased by 67% and 37%, respectively. Proinflammatory cytokines, and particularly IL-6, showed a positive correlation with the levels of circulating pentosidine. Protidemia was not significantly modified at the end of the study in both the groups. CONCLUSION: The results in this pilot study show that the removal of large solutes by PLD can improve some indices of chronic inflammation in HD patients. Further studies are required to determine the relevance of the individual solutes removed with PLD as proinflammatory mediators in the uremic environment.

Vitamin E-loaded dialyzer resets PBMC-operated cytokine network in dialysis patients.

BACKGROUND: In hemodialysis patients the activity of stimulated Th1 lymphocytes is depressed, while Th2 cells are constitutively primed. Such phenomena may depend on monocyte activation and altered release of interleukin (IL)-12 and IL-18, which regulate Th cell differentiation. Reactive oxygen species (ROS) activate monocytes; therefore, a hemodialyzer with antioxidant activity would contrast ROS, prevent monocyte activation, reset IL-12 and IL-18 release, and restore Th1/Th2 balance. METHODS: Ten patients on regular dialysis treatment (RDT) with cellulosic membrane (CM) were shifted to vitamin E-coated dialyzer (VE). During treatment with CM and after 3, 6, and 12 months of treatment with VE, peripheral blood mononuclear cells (PBMC) and purified CD4+ cells were isolated, and cultured, resting, mitogen-stimulated, and interferon gamma (IFNgamma), IL-4, IL-10, IL-12, and IL-18 release was measured. Vitamin E and A plasma levels and the effects of a single dialysis session on peripheral blood NO levels were assayed. RESULTS: The constitutive release of IL-4 and IL-10 by CD4+ cells was abated significantly by treatment with VE (nadir -77.8% and -55.3%, respectively, at 12 months). INFgamma release by mitogen-stimulated CD4+ recovered with VE (zenith +501% at 12 months). PBMC constitutive production of IL-12 and IL-18 was significantly reduced by VE (nadir at 12 months -64.7% and -51.3%, respectively). VE increased plasma levels of vitamins E and A. NO plasma levels fell after a single dialysis treatment with VE (-17%, P < 0.05) in contrast with CU (+27.1%, P < 0.05). CONCLUSION: The network of cytokines released by monocytes and Th cells is reset toward normality by treatment with vitamin E-coated dialyzer.

The effect of PMMA-based protein-leaking dialyzers on plasma homocysteine levels.

BACKGROUND: Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease in end-stage renal disease (ESRD) patients. Since homocysteine (Hcy) largely binds to serum proteins (80 to 90%), in this study we investigated the possibility that polymethylmethacrylate (PMMA)-based protein-leaking dialyzers could reduce total plasma Hcy (tHcy) levels in ESRD patients. METHODS: Two matched groups of patients (N = 13) showing mild to intermediate hyperhomocysteinemia on standard hemodialysis (HD) with conventional non-protein-leaking dialyzers were included. In the control group membranes were maintained the same, while the study group was switched to protein-leaking dialyzers (BK-F series; Toray, Japan) and studied for 6 months. tHcy was measured by high performance liquid chromatography (HPLC) at baseline and after 1, 3, and 6 months. Proteins and Hcy were also measured in the spent dialysate. RESULTS: The pre-HD levels of tHcy in the control group remained close to baseline values (26.6 +/- 5.0 micromol/L), while in the study group at 1, 3, and 6 months they decreased from a baseline value (in micrormol/L) of 25.3 +/- 5.9 to 21.5 +/- 4.5, 16.9 +/- 4.0, and 17.2 +/- 4.2, respectively (P < 0.01 for values at 3 and 6 months vs. baseline). The intra-HD drop of tHcy (Delta HDHcy) slightly but progressively decreased during the 3 steps on protein-leaking dialyzers and a positive correlation was found between Delta HDHcy and pre-HD levels of tHcy. In spent dialysate samples from protein-leaking dialyzer-treated patients, the amount of protein-bound Hcy (bHcy) was approximately 10 times higher than in non-protein-leaking dialyzers, but the Delta HDHcy observed in non-protein-leaking dialyzers and protein-leaking dialyzers was comparable. Serum proteins and albumin were only slightly affected by protein-leaking dialyzers. CONCLUSION: This study demonstrates that protein-leaking dialyzers used with a pure diffusive technique significantly lower pre-HD tHcy (approximately 33% of starting levels after 3 months of treatment) in ESRD patients. A possible underlying mechanism for this effect could be the removal of large molecular weight solutes responsible for a defective metabolism of the Hcy, as the removal of bHcy with protein-leaking dialyzers seems not sufficient, per se, to explain this steady reduction of tHcy levels in pre-HD.

Peroxynitrite-induced oxidation of plasma lipids is enhanced in stable hemodialysis patients.

BACKGROUND: The relationship between end-stage renal disease (ESRD), hemodialysis, and oxidative stress is controversial. To determine whether ESRD causes oxidative stress, we measured basal levels of plasma F2-isoprostanes as a marker of lipid peroxidation in vivo, and peroxynitrite-stimulated formation of F2-isoprostanes, as a marker of the oxidizibility of plasma lipids in vitro, before and after routine hemodialysis. METHODS: Total plasma F2-isoprostanes were measured by gas chromatography-mass spectrometry (GC-MS) before and after the oxidation of plasma lipids with the peroxynitrite-generating compound, 3-morpholino-sydnonimine (SIN-1), in 23 patients with ESRD patients undergoing regular hemodialysis, and 14 controls. Plasma vitamin E concentrations were measured by high-performance liquid chromatography (HPLC). RESULTS: There was no difference in basal plasma concentrations of F2-isoprostanes in the ESRD group prior to hemodialysis, 246 +/- 20 pg/mL, compared to controls, 252 +/- 28 pg/mL, or immediately on completion of hemodialysis, 236 +/- 14 pg/mL. Incubation of control plasma with SIN-1 caused the formation of F2-isoprostanes with plasma concentrations increasing to 987 +/- 54 pg/mL at 6 hours. The formation of F2-isoprostanes stimulated by SIN-1 was markedly enhanced in the plasma obtained from patients undergoing hemodialysis at 1861 +/- 174 pg/mL, P < 0.001, and SIN-1-induced formation of F2-isoprostanes was further increased in plasma obtained immediately after hemodialysis at 2437 +/- 168 pg/mL, P < 0.001. Incubation of plasma with SIN-1 resulted in the net consumption of vitamin E. CONCLUSION: Although basal plasma F2-isoprostanes were similar in patients with ESRD compared with controls, the presence of oxidative stress in patients with ESRD was unmasked when the plasma was stressed by peroxynitrite generated from SIN-1, and this was enhanced further by hemodialysis.