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      Reduced Cytokine Induction and Removal of Complement Products with Synthetic Hemodialysis Membranes

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          Abstract

          The increasing use of high-flux membranes for hemodialysis (HD) has raised concerns that these membranes may confer a higher risk of exposure to cytokine-inducing, bacterial substances (CIS) in the dialysate. Several studies, however, reported higher transfer of CIS through low-flux cellulosic than high-flux synthetic membranes. This surprising paradox was explained by adsorption of CIS to certain high-flux membranes. In order to investigate flux and membrane type independently, we studied two synthetic Polyflux (PF) membranes of the same type but with different flux properties and compared them to a cellulosic membrane (Cuprophan). Three different approaches were employed: (1) cytokine induction in whole blood during in vitro HD contaminated with bacterial filtrates, (2) removal of recombinant C5a, and (3) transfer of purified lipopolysaccharide (LPS). After 90 min recirculation of whole blood, the appearance of IL-6-inducing substances on the blood side was lowest with high-flux PF (1.1 ± 0.2 ng/ml), slightly higher with low-flux PF (1.9 ± 0.7 ng/ml) and highest with Cuprophan (4.1 ± 1 ng/ml). Recombinant C5a added to plasma on the blood side was markedly removed by high-flux PF (by 83%), to a lesser degree and only in the presence of ultrafiltration with low-flux PF (by 54%) and not significantly with Cuprophan (by 11%). Significant transfer of purified LPS from the dialysate onto the blood side was only observed with the cellulosic membrane. We conclude that in contrast to cellulosic membranes, certain synthetic membranes do not permit transfer of LPS. Cytokine induction on the blood side is further reduced by the use of high-flux membranes due to removal of activated complement factors.

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          Most cited references 14

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          The dark side of C5a in sepsis.

           C. Ward (2004)
          Sepsis is a major clinical problem for which therapeutic interventions have been largely unsuccessful, in spite of promising strategies that were successful in animals, especially rodents. There is new evidence that sepsis causes excessive activation of the complement system and that this induces paralysis of innate immune functions in phagocytic cells due to effects of the powerful complement-activation product, C5a. This review describes our present understanding of how and why sepsis is a life-threatening condition and how it might be more effectively treated.
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            Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO study.

            Among the 1846 patients in the HEMO Study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks (RR) for the high-flux arm, compared with the low-flux arm, were 0.80 [95% confidence interval (CI), 0.65 to 0.99] for cardiac death and 0.87 (95% CI, 0.76 to 1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary, depending on the duration of prior dialysis. This report presents secondary analyses to further explore the relationship between the flux intervention and the duration of dialysis with respect to various outcomes. The patients were stratified into a short-duration group and a long-duration group, on the basis of the mean duration of dialysis of 3.7 yr before randomization. In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of ACM (RR, 0.68; 95% CI, 0.53 to 0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR, 0.74; 95% CI, 0.60 to 0.91; P = 0.005), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P = 0.016), compared with low-flux dialysis. No significant differences were observed in outcomes related to infection for either duration subgroup, however, and the trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the years of dialysis during the follow-up phase were combined with the prestudy years of dialysis in the analysis. For the subgroup of patients with <3.7 yr of dialysis before the study, assignment to high-flux dialysis had no significant effect on any of the examined clinical outcomes. These data suggest that high-flux dialysis might have a beneficial effect on cardiac outcomes. Because these results are derived from multiple statistical comparisons, however, they must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation.
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              Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients.

              The use of a high-flux membrane, which eliminates larger molecular weight solutes with better biocompatibility, has steadily increased since the discovery of beta-2 microglobulin (beta 2m) amyloidosis in 1985. The long-term effects of a dialyzer membrane on morbidity and mortality are not completely understood. To examine the membrane effect as a factor of carpal tunnel syndrome onset and mortality, multivariate Cox regression analysis with time-dependent covariate was conducted on 819 patients from March 1968 to November 1994 at a single center. Two hundred and forty-eight of the patients were either switched from the conventional to high-flux membrane or treated only with a high-flux membrane. Fifty-one patients underwent a CTS operation and 206 died. Membrane status (on high-flux or on conventional) was considered as time-dependent covariate and risk was adjusted for age, gender, type of renal disease and calendar year of dialysis initiation. The relative risk of CTS was reduced to 0.503 (P < 0.05) and mortality 0.613 (P < 0.05) by dialysis on the high-flux membrane, compared to the conventional membrane. Serial measurements of beta 2m indicated significantly lower beta 2m to persist in patients on the high-flux membrane. The high-flux membrane decreased the risk of morbidity and mortality substantially. Larger molecule elimination was shown important not only for preventing beta 2m amyloidosis, but for prolonging survival of dialysis patients as well.
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                0253-5068
                1421-9735
                2006
                February 2006
                15 February 2006
                : 24
                : 2
                : 203-211
                Affiliations
                aDepartment of Nephrology and Internal Intensive Care Medicine, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, bGambro Corporate Research, Hechingen, and cDepartment of Immunology, Georg August University, Göttingen, Germany
                Article
                90520 Blood Purif 2006;24:203–211
                10.1159/000090520
                16373999
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 3, References: 25, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/90520
                Categories
                Original Paper

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