**2. Cellulose-based vitamin E-bonded dialyzer membranes**

### **2.1 Development**

In 1990, cellulose-based vitamin E-bonded dialyzer membranes (Excebrane) were developed and introduced into the market by Terumo Corporation. The base membrane was made of regenerated cellulose hollow fiber, and the surface of the hollow fiber was covalently modified by hydrophilic polymers as well as by oleic alcohol. Vitamin E (-tocopherol) was then bonded to oleic alcohol via hydrophobic interaction. Sasaki et al., 2000, reported the outline of the production process as well as the results of *in vitro* and *in vivo* studies on Excebrane, which showed much better biocompatibility than the original regenerated cellulose membrane.

#### **2.2 Clinical outcomes**

Early trials using Excebrane indicated that its use would have positive clinical effects (Galli, 2002). The potential therapeutic effects of using this membrane in HD were reduction of oxidative stress and inflammation. Cardiovascular endpoints were investigated in several small clinical trials and in a meta-analysis of 14 peer-reviewed articles by Sosa et al., 2006; these studies concluded that Excebrane treatment was associated with a significant decrease in the plasma levels of lipid-peroxidation biomarkers, thereby suggesting the potential benefit of these membranes in clinical usage. Actually, these biomarkers have a cause-effect relationship with low density lipoprotein (LDL) damage and endothelial dysfunction in CKD. Preliminary evidence of better management of uremic anemia by these dialyzer membranes was obtained in the pioneering studies by Usberti et al., 2002; Nakatani et al., 2003; and Kobayashi et al., 2003. These authors found improved erythrocyte life span and rheology in patients receiving HD with Excebrane. A larger multicenter study (172 patients) reported by Cruz et al., 2008, confirmed that the impact of Excebrane dialyzers on anemia parameters was better than that of other high-flux biocompatible dialyzer membranes, including cellulose acetate, polysulfone, and polymethylmethacrylate.

Other reports demonstrated positive effects such as (1) decreased oxidative stress (Tarng et al., 2000; Miyazaki et al., 2000; Clermont et al., 2001; Westhuyzen et al., 2003; Bufano et al., 2004; Mydlik et al., 2004; Calò et al., 2004; Yang et al., 2006; and Odetti et al., 2006), (2) suppression of leukocyte activation (Omata et al., 2000; Zaluska et al., 2001;Pertosa et al., 2002; Tsuruoka et al., 2002; Libetta et al., 2004; and Kojima et al., 2005), (3) dosage reduction of anticoagulants (Huraib et al., 2000), (4) improved biocompatibility (Yoshida et al., 2002), and (5) decreased levels of advanced glycation end products (AGEs) (Baragetti et al., 2006). Moreover, a recent study reported by Kirmizis D et al., 2010, showed that the levels of inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, and soluble intercellular adhesion molecule (sICAM)-1 in 35 patients treated with Excebrane were lower than those in the baseline evaluation carried out with conventional low- or middle-flux dialyzers. Whereas, no change was observed throughout the experimental period in a matched control group of 25 patients who underwent treatment with the unmodified dialyzers.
