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      Increased Binding of Beta-2-Microglobulin to Blood Cells in Dialysis Patients Treated with High-Flux Dialyzers Compared with Low-Flux Membranes Contributed to Reduced Beta-2-Microglobulin Concentrations

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          Abstract

          Background: Patients on long-term dialysis eventually develop amyloid deposits with β<sub>2</sub>-microglobulin as a predominant component. Although several studies have suggested that high-flux membranes reduce β<sub>2</sub>-microglobulin in plasma compared with low-flux dialyzers, the mechanisms underlying this observation are still discussed. Methods: We revisited this important subject and measured β<sub>2</sub>-microglobulin in the plasma of healthy individuals (n = 8), and patients undergoing hemodialysis (n = 20) who for assigned periods of time were either treated with a low-flux membrane (cuprophan) or high-flux (polyamide) dialyzer with an ELISA. The number of blood cells was determined by FACS. β<sub>2</sub>-Microglobulin was also measured on the surface of granulocytes, lymphocytes, and monocytes before, directly after, and 4 h after hemodialysis. Expression of β<sub>2</sub>-microglobulin, c-fos, tumor necrosis factor-α (TNF-α), and interleukin-1 mRNA was determined in whole blood samples with quantitative RT-PCR using an internal standard in parallel. In the second part of the study, patients were assigned in a two-group cross-over design either to low- or high-flux dialyzers (n = 9 in each group), and dialyzer membranes were changed every 4 weeks for two consecutive periods. Serum β<sub>2</sub>-microglobulin concentrations were measured at the end of each period. Results: Healthy controls had a low plasma β<sub>2</sub>-microglobulin level of 1.2 ± 0.3 mg/l. Before hemodialysis, patients on low-flux dialyzers had a plasma β<sub>2</sub>-microglobulin level of 42.0 ± 14.0 mg/l, patients treated with high-flux dialyzers 21.5 ± 10.8 mg/l (p < 0.05 vs. low-flux dialyzers). In contrast, there was no significant difference in plasma concentrations of active transforming growth factor-β1 with the two different membrane types. The difference in serum β<sub>2</sub>-microglobulin between low- and high-flux membranes was more prominent directly after hemodialysis as well as 4 h after hemodialysis compared with the values directly before the start of treatment. At all studied time-points, leukocytes and platelets were significantly higher in patients on low-flux membranes. Healthy control persons exhibited a significantly higher amount of β<sub>2</sub>-microglobulin bound to granulocytes, lymphocytes, and monocytes compared with dialysis patients. Interestingly, β<sub>2</sub>-microglobulin bound to granulocytes, lymphocytes, and monocytes was significantly increased in patients treated with high-flux membranes compared with low-flux filters. Quantitative RT-PCR revealed no significant difference in β<sub>2</sub>-microglobulin expression in whole blood before hemodialysis, directly after hemodialysis, and 4 h after hemodialysis. However, TNF-α and c-fos transcripts were significantly higher in whole blood obtained from patients treated with low-flux membranes compared to high-flux dialyzers. The two-group cross-over study over three periods of 4 weeks revealed that switching from low-flux to high-flux dialyzers significantly reduced serum β<sub>2</sub>-microglobulin levels. Conclusion: Patients treated with a polyamide high-flux membranehad lower β<sub>2</sub>-microglobulin concentrations compared with those patients on low-flux dialyzers. This difference might not be mediated by an increase in β<sub>2</sub>-microglobulin mRNA, but may be caused by less β<sub>2</sub>-microglobulin released from the blood cells in patients treated with high-flux dialyzers, in addition to a better β<sub>2</sub>-microglobulin clearance.

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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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              The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta2microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis.

              An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta2microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta2M. We demonstrate here that the interaction of AGE-beta2M with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of dialysis-related amyloidosis, is mediated by the receptor for AGEs, or RAGE. 125I-AGE-beta2M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (Kd approximately 53.5 and approximately 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade. AGE-beta2M-mediated monocyte chemotaxis was prevented by excess sRAGE or anti-RAGE IgG. Induction of tumor necrosis factor-alpha (TNF) expression by MPs exposed to AGE-beta2M resulted from engagement of RAGE, as appearances of TNF transcripts and TNF antigen release into culture supernatants were prevented by addition of sRAGE, a process mediated, at least in part, by oxidant stress. AGE-beta2M reduced cytochrome c and the elaboration of TNF by MPs was inhibited by N-acetylcysteine. Consistent with these data, immunohistochemical studies of AGE-laden amyloid deposits of a long-term hemodialysis patient revealed positive staining for RAGE in the MPs infiltrating these lesions. These data indicate that RAGE is a central binding site for AGEs formed in vivo and suggest that AGE-beta2M-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of long-term hemodialysis patients, a process which may ultimately lead to bone and joint destruction.
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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
                2007
                January 2008
                23 October 2007
                : 25
                : 5-6
                : 432-440
                Affiliations
                aDepartment of Internal Medicine III, University of Jena, Jena, bDivision of Nephrology, Helios Klinikum, Erfurt, and cGambro Research, Hechingen, Germany
                Article
                110069 Blood Purif 2007;25:432–440
                10.1159/000110069
                17957097
                2d298cb3-6d60-4a29-983c-d158f777e9e8
                © 2007 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.

                History
                : 23 May 2007
                : 23 August 2007
                Page count
                Figures: 4, Tables: 2, References: 25, Pages: 9
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Beta-2-microglobulin,Polyamide,Cuprophan,Amyloidosis,c-fos
                Cardiovascular Medicine, Nephrology
                Beta-2-microglobulin, Polyamide, Cuprophan, Amyloidosis, c-fos

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