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      uPAR (CD87) as a Biocompatibility Marker of Dialysis Membrane

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          Background/Aims: Hemodialysis (HD) therapy may lead to functional changes in patient leukocytes. For example, the upregulation of inflammatory cytokines, such as IL-1β and TNFα, has been well characterized. However, these findings do not explain the entire response of leukocytes in HD. In this study, we carried out a comprehensive gene expression analysis in leukocytes treated with various dialysis membranes using DNA microarrays. The identified gene has the potential to be a new marker for testing dialysis membrane biocompatibility. Methods: Gene expression profiles were compared between a group of leukocytes treated with various dialysis membranes and an untreated group by using DNA microarray analysis. Expression was confirmed by quantitative RT-PCR. The expression of the gene product (leukocyte surface protein) was examined in 20 chronic HD patients by flow cytometry. Results: In addition to the inflammatory cytokines, the urokinase plasminogen activator receptor (uPAR or CD87) gene was induced in leukocytes treated with each dialysis membrane. The extent of induction depended on the membrane’s material composition. The expression of the uPAR (CD87) protein on leukocytes was markedly increased in patients undergoing dialysis therapy. The magnitude of uPAR (CD87) protein expression was correlated with clinical findings, i.e., the degree of leukopenia and the expression of adhesion molecules. Conclusions: The gene and protein expression of uPAR (CD87) depended on the dialysis membrane material and correlated closely with clinical findings. These results suggest that uPAR has the potential to serve as a marker not only for clinical use but also for the development of new dialysis membranes.

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          Most cited references 17

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          Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis.

          During hemodialysis, cardiopulmonary decompensation may appear in uremic patients, possibly caused by plugging of pulmonary vessels by leukocytes. In 34 patients we noted leukopenia (20% of initial levels) during hemodialysis that in 15 was associated with impaired pulmonary function. When we infused autologous plasma, incubated with dialyzer cellophane, into rabbits and sheep, sudden leukopenia and hypoxia occurred, with doubling of pulmonary-artery pressures and quintupling of pulmonary-lymph effluent. Histologic examination showed severe pulmonary-vessel-leukostasis and interstitial edema. The syndrome was prevented by preinactivation of complement but was reproduced by infusions of plasma in which complement was activated by zymosan. Thus, acute pulmonary dysfunction from complement-mediated leukostasis may play a major part in the acute cardiopulmonary complications of cellophane-membrane hemodialysis.
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            Anticoagulation intensity sufficient for haemodialysis does not prevent activation of coagulation and platelets.

            A single bolus of dalteparin at the start of haemodialysis (HD) may prevent clot formation, but subclinical activation of platelets and coagulation may still occur. Consequently, the relationship between clinical clotting events and activation markers of platelets and coagulation before and during HD is of interest. The effect of tapered doses of dalteparin during 84 HD sessions (4-4.5 h) was prospectively examined in 12 patients. Six of the patients were treated with warfarin. The initial dalteparin dose was reduced to 50% if no clotting was observed. Clinical clotting was evaluated by inspection of the air trap every hour and by inspection of the dialyser after each session. Anti-FXa activity was measured for assessment of dalteparin activity. Markers of activated plasma coagulation, (thrombin-antithrombin (TAT) and prothrombin fragment 1+2 (PF1+2)) and a marker of platelet activation (beta-thromboglobulin, beta-TG), were measured before the start of and after 3 and 4 h of dialysis. Ten pre-dialytic patients with chronic renal failure served as a control group. A total of 230 measurements of each parameter were performed. An anti-FXa activity above 0.4 IU/ml at the end of HD inhibits overt clot formation for 4 h. This was obtained by an intravenous dalteparin dose of about 5000 IU. TAT and PF1+2 correlated to clinical clotting episodes (r=0.50 and 0.47, P<0.001). beta-TG was not significantly correlated to clinical clotting. All parameters increased during the sessions (TAT, PF1+2, beta-TG, P<0.001). When measurements during clinical clotting episodes were disregarded, all parameters were still markedly increased. Warfarin-treated patients had lower TAT and PF1+2. Dialysis patients had higher beta-TG values than pre-dialytic patients. Despite clinically effective anticoagulation, obtained by dalteparin administration, platelets and coagulation are activated by HD, resulting in a potentially thrombophilic state. Warfarin treatment reduces clinical clot formation and subclinical activation of coagulation.
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              Vitamin E-bonded hemodialyzer improves neutrophil function and oxidative stress in patients with end-stage renal failure.

              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 randomized 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.

                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                February 2006
                15 February 2006
                : 24
                : 2
                : 236-246
                aSecond Department, Central Technology Laboratory, Asahi Kasei Corporation and bLaboratory for Biology, Asahi Kasei Pharma, Fuji; cDivision of Nephrology and Hypertension, Jikei University, School of Medicine, Tokyo; dFuji Daiichi Clinic, Fuji; eDialysis Products Division, Asahi Kasei Medical, Tokyo; fFuji City General Hospital, Fuji, Japan
                91028 Blood Purif 2006;24:236–246
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 7, Tables: 2, References: 28, Pages: 11
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