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      Medium Cut-Off (MCO) Membranes Reduce Inflammation in Chronic Dialysis Patients—A Randomized Controlled Clinical Trial

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          Abstract

          Background

          To increase the removal of middle-sized uremic toxins a new membrane with enhanced permeability and selectivity, called Medium Cut-Off membrane (MCO-Ci) has been developed that at the same time ensures the retention of albumin. Because many middle-sized substances may contribute to micro-inflammation we hypothesized that the use of MCO-Ci influences the inflammatory state in hemodialysis patients.

          Methods

          The randomized crossover trial in 48 patients compared MCO-Ci dialysis to High-flux dialysis of 4 weeks duration each plus 8 weeks extension phase. Primary endpoint was the gene expression of TNF-α and IL-6 in peripheral blood mononuclear cells (PBMCs), secondary endpoints were plasma levels of specified inflammatory mediators and cytokines.

          Results

          After four weeks of MCO-Ci the expression of TNF-α mRNA (Relative quantification (RQ) from 0.92 ± 0.34 to 0.75 ± 0.31, -18.5%, p<0.001)-α and IL-6 mRNA (RQ from 0.78 ± 0.80 to 0.60 ± 0.43, -23.1%, p<0.01) was reduced to a significantly greater extent than with High-flux dialyzers (TNF mRNA-RQ: -14.3%; IL-6 mRNA-RQ: -3.5%). After retransformation of logarithmically transformed data, measurements after MCO were reduced to 82% of those after HF (95% CI 74%–91%). 4 weeks use of MCO-Ci resulted in long-lasting change in plasma levels of several cytokines and other substances with a significant decrease for sTNFR1, kappa and lambda free light chains, urea and an increase for Lp-PLA2 (PLA2G7) compared to High-flux. Albumin levels dropped significantly after 4 weeks of MCO dialysis but increased after additional 8 weeks of MCO dialysis. Twelve weeks treatment with MCO-Ci was well tolerated regarding the number of (S)AEs. In the extension period levels of CRP, TNF-α-mRNA and IL-6 mRNA remained stable in High-flux as well as in MCO-Ci.

          Conclusions

          MCO-Ci dialyzers modulate inflammation in chronic HD patients to a greater extent compared to High-flux dialyzers. Transcription of pro-inflammatory cytokines in peripheral leukocytes is markedly reduced and removal of soluble mediators is enhanced with MCO dialysis. Serum albumin concentrations stabilize after an initial drop. These results encourage further trials with longer treatment periods and clinical endpoints.

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          Most cited references15

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          Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway.

          Vascular calcification is an ectopic calcification that commonly occurs in atherosclerosis. Because tumor necrosis factor-alpha (TNF-alpha), a pleiotropic cytokine found in atherosclerotic lesions, is also a regulator of bone formation, we investigated the role of TNF-alpha in in vitro vascular calcification. A cloned subpopulation of bovine aortic smooth muscle cells previously shown capable of osteoblastic differentiation was treated with TNF-alpha, and osteoblastic differentiation and mineralization were assessed. Treatment of vascular cells with TNF-alpha for 3 days induced an osteoblast-like morphology. It also enhanced both activity and mRNA expression of alkaline phosphatase, an early marker of osteoblastic differentiation. Continuous treatment with TNF-alpha for 10 days enhanced matrix mineralization as measured by radiolabeled calcium incorporation in the matrix. Pretreatment of cells with a protein kinase A-specific inhibitor, KT5720, attenuated cell morphology, the alkaline phosphatase activity, and mineralization induced by TNF-alpha. Consistent with this, the intracellular cAMP level was elevated after TNF-alpha treatment. Electrophoretic mobility shift assay demonstrated that TNF-alpha enhanced DNA binding of osteoblast specific factor (Osf2), AP1, and CREB, transcription factors that are important for osteoblastic differentiation. These results suggest that TNF-alpha enhances in vitro vascular calcification by promoting osteoblastic differentiation of vascular cells through the cAMP pathway.
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            Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure

            Background Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an abnormal κ to λ FLC ratio (reference range 0.26–1.65). Previous work, however, has demonstrated that in patients with renal failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population the range should be extended (reference range 0.37–3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoassays in patients with severe renal failure. Methods Sera from 142 patients with new dialysis-dependent renal failure were assessed by serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma; by receiver operating characteristic curve analysis. Results Forty one patients had a clinical diagnosis of multiple myeloma; all of these patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed. Conclusion Measurement of serum FLC concentrations and calculation of the serum κ/λ ratio is a convenient, sensitive and specific method for identifying monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.
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              MCO Membranes: Enhanced Selectivity in High-Flux Class

              Novel MCO high-flux membranes for hemodialysis have been developed with optimized permeability, allowing for filtration close to that of the natural kidney. A comprehensive in vitro characterization of the membrane properties by dextran filtration is presented. The sieving profile of pristine membranes, as well as that of membranes exposed to blood for 40 minutes, are described. The effective pore size (Stokes-Einstein radius) was estimated from filtration experiments before and after blood exposure, and results were compared to hydrodynamic radii of middle and large uremic toxins and essential proteins. The results indicate that the tailored pore sizes of the MCO membranes promote removal of large toxins while ensuring the retention of albumin.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 January 2017
                2017
                : 12
                : 1
                : e0169024
                Affiliations
                [1 ]Charité-Universitaetsmedizin Berlin, Campus Virchow Clinic, Department of Nephrology and Intensive Care Medicine, Berlin, Germany
                [2 ]Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
                [3 ]NMI Technology Transfer GmbH, Reutlingen, Germany
                [4 ]Department of Research and Development, Gambro Dialysatoren GmbH, Hechingen, Germany
                [5 ]Institute for Chemistry, Food Chemistry, Martin-Luther-University Halle, Halle an der Saale, Germany
                [6 ]Department of Internal Medicine II, Martin-Luther-University Halle, Halle an der Saale, Germany
                Medizinische Universitat Graz, AUSTRIA
                Author notes

                Competing Interests: We have the following interests: Markus Storr, Torsten Boehler, Michael Hulko, and Kristin Werner are employees of Gambro Dialysatoren GmbH, Research & Development, Hechingen, Germany. Gambro AB (including all direct and indirect subsidiaries) is part of Baxter International Inc. Markus Pawlak and Michael Templin are employees of the NMI Technology Transfer GmbH. Financial support for this study comes in part from Gambro Dialysatoren GmbH, Hechingen. ( http://www.gambro.de/). There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

                • Conceptualization: DZ RS MG PM MS.

                • Data curation: PM.

                • Formal analysis: DZ RS MG PM MS RF.

                • Funding acquisition: DZ RS MG PM RF MS.

                • Investigation: DZ RS K. Willy PM MS MP MS MH TB MAG KL CH MT BT CU K. Werner RF MG.

                • Methodology: DZ RS MG MS PM.

                • Project administration: K. Werner TB.

                • Visualization: DZ RS MG PM.

                • Writing – original draft: DZ RS MG PM MS.

                • Writing – review & editing: DZ RS K. Willy PM MS MP MS MH TB MAG KL CH MT BT CU K. Werner RF MG.

                Article
                PONE-D-16-33563
                10.1371/journal.pone.0169024
                5234772
                28085888
                937cb611-ddf0-4170-911d-c57da264fa49
                © 2017 Zickler et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 August 2016
                : 8 December 2016
                Page count
                Figures: 2, Tables: 5, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: FKZ 13N11796-99
                Award Recipient :
                Funded by: Gambro Dialysatoren GmbH
                Award Recipient :
                Funded by: NMI Technology Transfer GmbH
                Award Recipient :
                Funded by: NMI Technology Transfers GmbH
                Award Recipient :
                Financial support for the study came from the German Ministry for Education and Research (FKZ 13N11796-99, https://www.bmbf.de/ and in part from Gambro Dialysatoren GmbH, Hechingen. ( http://www.gambro.de/). Gambro Dialysatoren GmbH provided support in the form of salaries for authors Markus Storr, Michael Hulko, Torsten Boehler and Kristin Werner, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. NMI Technology Transfers GmbH provided support in the form of salaries for authors Markus Pawlak & Markus Templin, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
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