Yuichi Torii,Satoko Yamada,Mayumi Yajima,Toru Sugata
Polymethylmethacrylate Membrane Dialyzer: Historic but Modern
Polymethylmethacrylate,Polymethylmethacrylate hollow fiber membrane,Filtryzer,Patient-reported outcomes,Adsorption
Polymethylmethacrylate (PMMA) hollow fiber membranes are one of the synthetic polymer hollow fiber membranes used to the hollow fiber artificial kidney. A PMMA hollow fiber membrane (PMMA membrane) has unique properties including the uniform structure and the adsorption property. Hemodialyzers using PMMA membranes, Filtryzer®, were approved in Japan in 1977 and have been used worldwide for over 40 years and so is a historical hemodialyzer. Various types in Filtryzer® having different pore sizes are developed and used in the clinical field. Filtryzer® B3 is a low-flux dialyzer. Filtryzer® BK has three types having different pore sizes, and above all, BK-F has the largest pores in the Filtryzer® series. Filtryzer® BG has a more uniform membrane structure by using weak anionic polymers compared with the earlier Filtryzer® series to remove β2-MG more. Filtryzer® NF is the latest Filtryzer® series and was developed as a dialyzer having improved antithrombogenicity compared with previous models and having protein adsorption property as the same with them. There have been many reports concerning Filtryzer® including improvement of patients' symptoms such as pruritus and nutrition on the advantages for dialysis patients. Although PMMA membranes are historic dialysis tools used for over 40 years, they are also modern dialysis membranes that have been updated to respond to dialysis therapy at those time.
Polymethylmethacrylate Membrane Dialyzer: Historic but Modern

Polymethylmethacrylate (PMMA) hollow fiber membranes are one of the synthetic polymer hollow fiber membranes used to the hollow fiber artificial kidney. A PMMA hollow fiber membrane (PMMA membrane) has unique properties including the uniform structure and the adsorption property. Hemodialyzers using PMMA membranes, Filtryzer®, were approved in Japan in 1977 and have been used worldwide for over 40 years and so is a historical hemodialyzer. Various types in Filtryzer® having different pore sizes are developed and used in the clinical field. Filtryzer® B3 is a low-flux dialyzer. Filtryzer® BK has three types having different pore sizes, and above all, BK-F has the largest pores in the Filtryzer® series. Filtryzer® BG has a more uniform membrane structure by using weak anionic polymers compared with the earlier Filtryzer® series to remove β2-MG more. Filtryzer® NF is the latest Filtryzer® series and was developed as a dialyzer having improved antithrombogenicity compared with previous models and having protein adsorption property as the same with them. There have been many reports concerning Filtryzer® including improvement of patients' symptoms such as pruritus and nutrition on the advantages for dialysis patients. Although PMMA membranes are historic dialysis tools used for over 40 years, they are also modern dialysis membranes that have been updated to respond to dialysis therapy at those time.

In hemodialysis therapy, various dialysis membranes made with different raw materials are used for end-stage renal disease patients to remove accumulated waste products. The removal performance and biocompatibility of the membrane are important features when choosing a dialyzer and are being continuously improved. Polymethylmethacrylate (PMMA) hollow fiber membranes are one of synthetic polymer hollow fiber membranes used to the hollow fiber artificial kidney and are made from two kinds of stereoregular polymers [1]. A PMMA hollow fiber membrane (PMMA membrane) has unique properties including the uniform structure characterized with uniform pore size in whole membrane and the adsorption property removing proteins [2, 3]. Hemodialyzers using PMMA membranes, Filtryzer®, were approved in Japan in 1977. Filtryzer® has been used worldwide for over 40 years and is a historical hemodialyzer. Further, regarding Filtryzer®, there have been many reports including improvement of patients' symptoms such as pruritus and nutrition on the advantages for dialysis patients [4, 5, 6]. Patient-reported outcomes (PROs) have become more important in various medical venues instead of evidence-based medicine that uses mortality and biochemical parameters as evaluation indices. This movement has occurred similarly for hemodialysis therapy, as noted in the Standardized Outcomes in Nephrology-Hemodialysis [7, 8]. In the Standardized Outcomes in Nephrology-Hemodialysis, outcomes, including PROs, have been classified into core outcomes, middle tier, and outer tier, in keeping with the importance to all hemodialysis stakeholders. PRO improvements will be spotlighted more frequently for future dialysis membranes. There are some reports that the biocompatibilities of dialysis membranes affect PROs such as fatigue [9, 10]. We consider that PMMA membranes would contribute to PRO improvements, considering the many reports regarding Filtryzer®. This article reviews basic information about PMMA membranes and the clinical benefits of the Filtryzer® series.

PMMA membranes are made from two kinds of stereoregular polymers, isotactic and syndiotactic PMMA, that form stereocomplexes [1]. Stereocomplex PMMA membranes exhibit superior antithrombogenicity relative to membranes made from isotactic or syndiotactic PMMA alone [11], and denaturing of adsorbed albumin is negligible [12]. Many synthetic polymer hollow fiber membranes, including polysulfone (PS) and polyethersulfone, have an asymmetric structure where the pore size enlarges from inside to outside. The asymmetric structure membrane has a thin skin layer with very small pore sizes that control solute separations (shown in Fig. 1). A PMMA membrane has a uniform structure that pore size is uniform and solute separations are controlled by the entire membrane (shown in Fig. 1). Therefore, the separation characteristics of PMMA are broader relative to PS membranes. Generally, hollow fiber membranes remove uremic toxins from the blood via diffusion and filtration. However, PMMA membranes also use adsorption to remove the uremic toxins in addition to diffusion and filtration [2, 13]. Adsorption can remove various proteins including middle- and large-molecular weight ones that are difficult to remove via diffusion and filtration. In vitro evaluation of protein removal by PMMA membranes indicated that the removal rates (RRs) for proteins larger than interleukin-6 were higher than those removed by PS membranes (shown in Fig. 2). Regarding adsorption observed in PMMA, there is a report that it may be due to the occlusion of protein molecules into the pores of the membrane [14]. In this way, PMMA membranes have unique properties in membrane structure and solute removal [3, 15]. In hemodialysis therapy using semipermeable membranes, there are some risks of endotoxin inflows into the patients' blood from the dialysate because of back filtration and back diffusion. The homogenous structure and adsorption characteristics of PMMA membranes prevent endotoxin inflows from the dialysate [2].

Filtryzer® is a dialyzer using PMMA membranes, was approved in Japan in 1977 as the world's first dialyzer using synthetic polymer hollow fiber membranes, and is still used clinically. There are various types in Filtryzer® having different pore sizes and hole-opening rates. There are various beneficial clinical reports such as improvement of dialysis pruritus [4, 5], anti-inflammatory effect [16, 17], improvement of nutritional status [6], and improvement of immune response [18, 19]. Patients who are dialyzed with synthetic dialysis membranes using hydrophilic polymer polyvinylpyrrolidone sometimes show allergic symptoms [20]. Filtryzer® is probably prescribed to those patients because the raw materials of PMMA membranes do not contain this hydrophilic polymer. In synthetic hollow fiber membranes such as PS and polyethersulfone, bisphenols including bisphenol A and bisphenol S, which are environmental hormones [21], are often noticed because their effects to the patients' health are concerned. In Filtryzer®, PMMA and polystyrene, which are respectively the raw material of hollow fiber and dialyzer housing, do not have bisphenol chemical structure. Filtryzer® is one of bisphenol-free dialyzers. Abe et al. [22, 23] reported two cohort studies using a nationwide registry of hemodialysis patients in Japan to evaluate the association of mortality rates with different dialyzer membranes. The hazard ratio for patients treated with PMMA membranes was substantially lower relative to those treated with PS membranes, when the data were adjusted for basic factors, dialysis-related factors, and nutrition- and inflammation-related factors. As for this result, it was discussed in the articles that polyvinylpyrrolidone-free membranes and the removal of middle- and high-molecular weight proteins via adsorption were preferred.

Filtryzer® B3 is a low-flux dialyzer, and its PMMA membrane (B3 membrane) is a weak anionic membrane. Filtryzer® B3 is a reliable option for acute and chronic dialysis, where a lower fluid RRs or ultrafiltration coefficient is desired, from characteristic of low-flux dialyzer [24].

Filtryzer® BK was developed to aim at improving various long-term complications in dialysis by removing low-molecular weight proteins accumulated in the blood. The PMMA membrane used in this device (BK membrane) is a nonionic membrane. In Filtryzer® BK, there are three types of products having different pore sizes (BK-U, -P, and -F). BK-F has the largest pores in the Filtryzer® series, and it is reported that BK-F can remove protein-bound uremic toxins, including 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, homocysteine, and large-molecular weight proteins such as immunoglobulin-free light chains and soluble CD40 ligands [16, 17, 25, 26, 27]. BK-F is thus called a protein-leaking dialyzer, by the removal property, and it is reported as the improvement of response to vaccine [18, 28], suppression of the decrease in count of natural killer cell [19], and improvement of anemia [25].

Filtryzer® BG is a dialyzer using PMMA membrane (BG membrane) that the removal performance for proteins such as β2-macroglobulin (β2-MG) was improved via uniformizing more pore size by using weak anionic polymers. It is reported that the weakly anionic PMMA membrane (BG membrane) has possibly superior adsorption characteristics for basic proteins compared with the nonionic PMMA membrane (BK membrane), by in vitro circulating study using minimodules [5]. Considering the experimental conditions that test solutions were simply circulated, this result might especially show adsorption characteristics of membrane surface. There are some reports showing that dialysis itchiness was improved by the use of this device [4, 5, 29]. By investigating blood components of patients with itchiness, it was reported that components exhibiting degranulation effects on mast cells were found in large molecular weight range of 160 kDa that were not removed by diffusion and filtration [5]. BG membranes adsorbed that component [5].

The latest PMMA membrane (NF membrane) was developed based on BG membrane and is used to the latest product Filtryzer® NF. The amount of protein adsorption is in comparable levels with BG membrane, and antithrombogenicity of NF membrane is improved relative to BG membrane by suppressing platelet adhesion.

It is known that the PMMA membrane adsorbs various proteins. In previous PMMA membrane, BG membrane, the adsorbed proteins would be easily recognized by platelets because their structure is changed by the influence of the membrane. This phenomenon would correlate with the occurrence of blood clotting during dialysis (shown in Fig. 3a). In keeping with this hypothesis, the NF membrane was developed to improve antithrombogenicity by reducing structural changes of adsorbed proteins (shown in Fig. 3b) [30]. It is reported that the amide II infrared band of proteins can be used for secondary structure determination [31]. Therefore, protein structural changes can be analyzed via the maximum wavenumber in the infrared adsorption band of amide II (1,515–1,650 cm–1), obtained by attenuated total reflection. When compared with that for albumin in water, this amide II peak for albumin adsorbed on a PMMA membrane was shifted to lower wavenumbers. It is considered that this shift of peak wavenumbers shows that the structure of adsorbed protein is changed by influence of membrane. The peak shift for NF membrane was less than that for BG membrane, which is the previous PMMA membrane (shown in Fig. 3c). This result suggests that structural changes of the albumin adsorbed on the NF membrane would be smaller than BG membrane. Platelet adhesion on NF membrane was also lower relative to that on the BG membrane when both were incubated in human blood in vitro (shown in Fig. 3d, e). The electrophoresis of proteins adsorbed on the NF membrane was comparable with that for BG membrane (shown in Fig. 3f), and this result indicate that the property of protein adsorption, which is the characteristics of PMMA membrane can be maintained in the NF membrane. In measurement of membrane negative charges by titration method using generation of complex ion [32], those of NF and BG membrane were −80 mEq/g and −110 mEq/g, respectively [30]. Thus, membrane charge of the NF membrane was slightly more neutral relative to that of the BG membrane. It is considered that this difference in membrane charge would contribute to improve antithrombogenicity in the NF membrane [30]. In vitro evaluation of protein removal using minimodules indicated that the RR of β2-MG classified to low-molecular weight proteins by the NF membrane was comparable with PS membranes. However, RRs for proteins larger than β2-MG were higher with the NF membrane than the PS membrane (shown in Fig. 2c). Hence, the NF membrane has the same removal properties as previous PMMA membranes.

There are various clinical reports about NF membranes. In a crossover study in a single dialysis facility, it is reported that platelet activation by the NF membrane is lower, NF membrane has a potential to maintain peripheral blood circulation and improve PROs, compared with BG membrane [33]. Uchiumi et al. [34] compared NF and BG membranes in a year-long multicenter, randomized, and controlled pilot study. In this study, it was mentioned that the NF membrane had the potential to improve or maintain nutritional status according to before and after weight-change rates, as well as percent creatinine generation rates that are an evaluation index for muscle quantity. In addition, there was a substantial decrease in dialysis itchiness with the NF membrane relative to that with the PS membrane. Thus, it is expected that NF membranes, as well as previous PMMA membranes, will decrease dialysis itchiness. Masakane et al. [35] reported a 1-year randomized, controlled study comparing the nutritional status and PROs of NF and PS membranes used on patients that were older than 70 years. There were no notable differences in nutritional status and PROs; however, when the PROs were compared within each membrane group, remarkable improvement was observed for the NF membrane group, suggesting that the NF membrane could improve PROs. There have been other clinical reports regarding improvement of responses to influenza vaccines by NF membrane [36] and improvement of nutritional status and PROs, especially dialysis fatigue, for older dialysis patients by the NF membrane [9].

It has become increasingly important that patients participate in medical treatments because of increases in chronic diseases and because reports from the patients are affecting outcomes. Therefore, attention is shifting from evaluation methods using outcomes based on medical indices to those considering subjective factors of the patients. Hence, PMMA membranes that improve PROs subjectively evaluated by patients will play important roles in future dialysis therapies. Although PMMA membranes are historic dialysis tools used for over 40 years, they are also up-to-date, modern dialysis membranes that meet important aspects for future therapies.

All the authors, Yuichi Torii, Satoko Yamada, Mayumi Yajima, and Toru Sugata, are employed by the Toray Medical Corporation Limited.

The study did not receive financial support.

Yuichi Torii wrote the original and draft manuscript. Satoko Yamada, Mayumi Yajima, and Toru Sugata reviewed and edited the manuscript; have read the manuscript; and have agreed to submit it for publication.