**Review of the Effectiveness of Cellulose- and Polysulfone-Based Vitamin E-Bonded Dialysis Membranes**

Masaharu Aritomi1 and Francesco Galli2 *1Asahi Kasei Kuraray Medical Co., Ltd. Tokyo 2Dept of Internal Medicine, University of Perugia 1Japan 2Italy* 

### **1. Introduction**

294 Technical Problems in Patients on Hemodialysis

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Reduction of the stressful effects of extracorporeal circulation is a major target in hemodialysis (HD) therapy. These effects can be attributed to the HD-associated uremic comorbidity and the oxidative and non-oxidative events that occur because of the extracorporeal treatment. Anemia, cardiovascular disease, chronic inflammation, immunosuppression and intradialytic hypotension are among the most common complications in patients receiving HD, which show a causal relationship with oxidative stress (Galli, 2002 and Del Vecchio et al., 2011). During HD, the patient's blood is repeatedly exposed to components of the extracorporeal circulation, a key component of which is the hollow-fiber dialyzer membrane. This phenomenon may lead to leukocyte and platelet activation, thereby causing oxidative stress. Moreover, bioactive contaminants, e.g., bacterial endotoxins in the dialysis fluids, to which the patient's blood is eventually exposed through the dialyzer membrane, may further sustain leukocyte activation. These variables, which are usually included under the definition of "bio-incompatibility," should be carefully monitored by dialysis centers because these variables are responsible for causing proinflammatory events, oxidative stress, and pro-thrombotic effects. Leukocyte activation and oxidative stress are also reported to cause erythrocyte damage that is further aggravated by shear stress and other mechanical injuries. Plasma proteins and lipids show signs of oxidative damage (Piroddi et al., 2007 and Galli, 2007), and this may influence the burden of uremic toxicity by inducing cell and tissue reactions, abnormal metabolism of these oxidation products, vascular and immune reactions, etc. To reduce the risk of oxidative stress and other adverse reactions that can be caused by poor biocompatibility of HD treatment, highly purified dialysis fluids and dialyzer membranes with greater biocompatibility have been developed, and are currently under investigation for further improvement.

The bio-incompatibility of prototypical dialyzer membranes made of regenerated cellulose has been associated with the contact of blood components with the hydroxyl groups of beta-D-glucose. These groups trigger intradialytic activation of the complement

Review of the Effectiveness of Cellulose-

and polymethylmethacrylate.

**3.1 Development** 

**3.2 Improvement of anemia** 

who underwent treatment with the unmodified dialyzers.

**3. Polysulfone-based vitamin E-bonded dialyzer membranes** 

mechanism of vitamin E and is of putative relevance in its biological function.

On the basis of the early evidence obtained in the Excebrane studies described in section 2.2, VitabranE was proposed as a more biocompatible dialyzer membrane to achieve a better control of anemia in HD patients. This aspect was investigated in clinical trials that

and Polysulfone-Based Vitamin E-Bonded Dialysis Membranes 297

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,

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

Synthetic membrane dialyzers have been developed by many manufacturers in the past decades to achieve higher depurative and biocompatibility standards. Polysulfone has shown better performance among these synthetic biomaterials; as a result, it has become popular in clinical practice (Bowry, 2002). In order to achieve the synergistic effect of the biocompatibility of synthetic membranes and the antioxidant activity of vitamin E, polysulfone-based vitamin E-coated membranes were developed and introduced in the market in 1998. These dialyzers were initially developed by Terumo Corporation; subsequently, they were produced using a new technique and are now manufactured by Asahi Kasei Kuraray Medical Co. Ltd., with the membrane name of VitabranE. Preliminary *in vitro* analyses on these membranes were reported by Sasaki, 2006; the antioxidant capacity of VitabranE was recently confirmed and quantified by Floridi A, et al., 2009, by means of *in vitro* re-circulation tests carried out on mini-module dialyzers. These tests, which used an unbiased procedure, showed that at least one-third of the vitamin E present on the membrane participates in the one-electron transfer reaction with transition metals. This reaction, together with scavenging of peroxyl radicals, characterizes the antioxidant

system and cause leucopenia (Rousseau et al., 1999). Biocompatibility of regenerated cellulose dialyzer membranes was tentatively improved by the chemical modification of the hydroxyl groups, e.g., by acetylation to obtain tri-acetate cellulose, or by adding polyethylene glycol (PEG) chains to obtain PEG-grafted cellulose. Another and more successful approach was the de novo development of synthetic polymer membranes such as polysulfone or polyether sulfone membranes with no bio-incompatible groups in their chemical structures (Bowry, 2002). At present, high-flux synthetic membranes are more frequently used, and represent a cost-effective solution with proven clinical superiority over cellulosic membranes (Krane et al., 2007).

Antioxidants such as vitamin C, vitamin E, and glutathione have been used as oral supplements to alleviate HD-induced oxidative stress (Galli and Azzi, 2010). The clinical course of chronic kidney disease (CKD) includes a progressive decrease in the levels of blood antioxidants such as vitamins C, vitamin E, and glutathione. As a result, CKD patients who undergo regular HD treatment show severe deficiencies, particularly of water-soluble antioxidants (such as vitamin C). Few studies, however, provided clear evidence of the clinical advantage of oral antioxidants. The most convincing evidence was obtained from the randomized clinical trial on vitamin E supplementation in HD patients. This trial, known as SPACE study (Boaz et al., 2000), showed a significant reduction (54%) of the primary endpoint variable (a composite variable including myocardial infarction, ischemic stroke, peripheral vascular disease, and unstable angina) and 70% reduction in myocardial infarction.

One of the most original approaches for antioxidant therapy in HD involved the use of vitamin E as a lipophilic modifier of the surface of the dialysis membrane. The bonded vitamin E on the surface of the dialyzer membrane is expected to reduce the production of reactive oxygen species (ROS) at the site where blood cells are exposed to the dialyzer membrane, thereby providing the blood cells with antioxidant protection in a timely and targeted manner. Two generations of vitamin E-bonded dialyzers based on this concept, namely, cellulosic- and polysulfone-based membrane dialyzers, have been successfully developed and launched in the market over the last 2 decades. This chapter provides a review of the literature and a critical examination of the available clinical data on vitamin Ebonded dialyzer membranes.
