Comparison of the new polyethersulfone high-flux membrane DIAPES® HF800 with conventional high-flux membranes during on-line haemodiafiltration

Walter Samtleben1, Christina Dengler1, Birgit Reinhardt2, Annekatrin Nothdurft2 and Horst-Dieter Lemke2

1Department of Nephrology, University Hospital Munich-Grosshadern, Munich and 2Membrana Research, Obernburg, Germany

Correspondence and offprint requests to: Horst-Dieter Lemke, Forschungsstrasse, Membrana GmbH, D-63785 Obernburg, Germany. Email: horstdieter.lemke{at}membrana.de



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Current modalities of renal replacement therapy allow only a limited removal of larger, possibly toxic molecules, which accumulate in uraemia. Recently, a haemodiafilter has been made available with the new, high-flux, polyethersulfone-based membrane DIAPES® HF800. We performed a study to compare DIAPES® HF800 with two conventional high-flux membranes in on-line haemodiafiltration (HDF), with respect to the removal properties for the two marker proteins, ß2-microglobulin 2m, 11.8 kDa) and albumin (66.5 kDa).

Methods. In a prospective, controlled study 10 stable end-stage renal disease patients were randomly allocated to 30 sessions of post-dilutional on-line HDF with three types of steam-sterilized membranes: DIAPES® HF800, polysulfone and polyamide. Blood flow rate was 250 ml/min and treatment time was 240 min. Pre-treatment ß2m and albumin plasma concentrations did not differ between the three groups. The concentration of the two proteins was determined before and after treatment in plasma as well as in the continuously collected haemodiafiltrate.

Results. Tolerance of all treatments was very good, without any side-effects for all filters. The mean plasma reduction rate of ß2m was 77 ± 1% for DIAPES® HF800 and polysulfone whereas it was 71 ± 1% for polyamide (P < 0.05). The mean ß2m amount removed and found in the haemodiafiltrate per session was 230 ± 14 mg for DIAPES® HF800, 186 ± 13 mg for polysulfone and 147 ± 13 mg for polyamide (P < 0.05 between each pair of membranes). The same ranking was obtained for albumin removed and found in haemodiafiltrate per session for the three membranes: 5.7 ± 0.4, 3.5 ± 0.4 and 1.0 ± 0.4 g, respectively. Although DIAPES® HF800 showed the highest value for albumin in haemodiafiltrate the mean post-treatment plasma albumin was higher after the treatment with DIAPES® HF800 compared with the other membranes (P < 0.05).

Conclusions. On-line HDF has shown to achieve plasma reduction rates for ß2m of up to 77% for the DIAPES® HF800 membrane and for polysulfone. The amounts of ß2m and albumin in haemodiafiltrate were much higher for DIAPES® HF800 than for the other two membranes indicating a greater permeability for molecules up to a molecular weight of 66.5 kDa. This could, at least theoretically, offer the advantage also to remove uraemic toxins in the molecular weight range of albumin or of albumin-bound toxins. The future must show whether this will counterbalance the loss of albumin.

Keywords: albumin; ß2-microglobulin; haemodiafiltration; high-flux membrane; polyethersulfone; post-dilution



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The introduction of a newly developed, highly permeable haemodialysis (HD) membrane arises interest in today’s nephrological community. The question is often considered as to whether a membrane with higher permeability may fulfil an improved balance between a higher removal of uraemic toxins in the molecular weight range from urea to small proteins such as ß2-microglobulin 2m) and a clinically tolerable albumin loss. In recent years, the choice of membranes of either synthetically modified cellulosic or synthetic membranes has expanded to a large extent. In parallel, a trend towards treatment modes with higher plasma reduction rates has recently been witnessed [1,2]. The reason for such a trend may be derived from a revived interest in the field of uraemic toxins. Apart from being small, dialysable molecular substances, uraemic toxins may be bound to plasma proteins such as albumin or can be proteins itself, like ß2m (11.8 kDa). The removal of plasma proteins up to the 66.5 kDa range of albumin has been investigated by several authors employing different membranes and dialysis modalities [35]. The factors involved in the removal of low molecular weight proteins depend not only on membrane permeability, but also on the transmembrane pressure applied during treatment [6] and on patient specific variables.

Recently, DIAPES® HF800, a highly permeable membrane made of polyethersulfone (PES) has been developed. DIAPES® HF800 exhibits an increased hydraulic permeability compared with conventional high-flux membranes. This leads to an in vitro ultrafiltration rate of 80 ml/h x mmHg for DIAPES® HF800 in the BLS819SD haemodiafilter (Bellco) compared with 55 ml/h x mmHg for the polysulfone membrane in the Hemoflow® HF80S (Fresenius Medical Care). In this study, we evaluated the removal of ß2m and albumin in patients undergoing post-dilutional on-line haemodiafiltration (HDF) using DIAPES® HF800 in comparison with two other synthetic membranes.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
The study was prospective, randomized and cross-over in nature and the study protocol was approved by the local ethics committee. Ten chronic uraemic patients on a regular thrice weekly HD programme were enrolled after giving informed consent [seven males, three females; aged 51 ± 13 years (range 33–70 years); 42 ± 37 months on dialysis (range 5–118 months)]. The patients were randomly treated once with DIAPES® HF800 (Membrana GmbH, Wuppertal, Germany; BLS819SD, 1.8 m2, steam-sterilized, Bellco S.p.A., Mirandola, Italy), and once with polyamide (Polyflux® 17S, Gambro, Lund, Sweden) and polysulfone (Hemoflow® HF80S, Fresenius Medical Care, Bad Homburg, Germany), respectively, in a 4-h post-dilutional on-line HDF regime (Gambro AK100 Ultra monitor). Treatments under investigation were once a week after the long dialysis-free interval. Details of the HDF treatment parameters and of the haemodiafilters are listed in Table 1. One patient had to be admitted to the hospital after the second study treatment for reasons, which were not related to the study. As a consequence, one treatment with DIAPES® HF800 could not be performed.


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Table 1. Characteristics of treatment parameters

 
Determination of albumin and ß2m
In order to study the removal of ß2m and albumin with the haemodiafiltrate, a T-connector was introduced into the effluent haemodiafiltrate line allowing continuous collection of haemodiafiltrate at a flow rate of 1 ml/min into a separate beaker during the entire duration of the treatment (Figure 1). Samples were drawn from this haemodiafiltrate pool after each hour of treatment. Before sampling, the pool was mixed well by a magnetic stirrer.



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Fig. 1. HDF set-up and haemodiafiltrate collection scheme.

 
The mass of solute transferred to the haemofiltrate after a given time t was calculated from:

(1)
where Qout is the outlet haemofiltrate flow rate, consisting of the dialysate flow rate Qdial/in, the substitution fluid flow rate Qsub and the net ultrafiltration flow rate QUF as shown in Figure 1. ct is the concentration of the solute in the cumulated haemodiafiltrate pool after time t.

The plasma levels of ß2m and albumin were measured directly before (pre, t = 0) and after (post, t = 240 min) the treatment. ß2m and albumin in haemodiafiltrate and in plasma were measured by laser nephelometry (BN 100 Analyzer, Dade-Behring Marburg GmbH, Marburg, Germany) using ‘N Latex ß2-microglobulin’ and ‘N Antiserum to human albumin’ (Dade-Behring Marburg GmbH), respectively. The ß2m post-haemodiafilter concentration was corrected for haemoconcentration according to Bergstrom and Wehle [7].

Statistics
Differences between parameters were tested by multivariate ANOVA and Duncan’s multiple range test. A P value of <0.05 was considered significant. Results are given as mean of all treatments ± SEM.



   Results
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 Subjects and methods
 Results
 Discussion
 References
 
The absolute amount of ß2m and of albumin detectable at the end of the treatment in the cumulative haemodiafiltrate pool as well as the pre- and post-treatment plasma values for albumin are shown in Table 2. Both total ß2m and total albumin found in the haemodiafiltrate decreased in the sequence DIAPES® HF800 > polysulfone > polyamide. There was a significant difference for both, ß2m and albumin in the haemodiafiltrate between the three membranes. All other data, especially the respective pre-treatment values, showed no significant differences between the three membranes.


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Table 2. ß2M, albumin and blood pressure pre- and post-HDF (mean ± SEM)

 
While the DIAPES® HF800 haemodiafilter reduced the plasma ß2m level by 77 ± 1% of the pre-dialysis value (identical to the reduction with polysulfone), polyamide achieved only a reduction rate of 71 ± 1% (P < 0.05) as shown in Figure 2.



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Fig. 2. Plasma concentrations and plasma reduction rates (RR) of ß2m during post-dilutional on-line HDF for three different membranes (mean ± SEM). The plasma reduction rate for ß2m of polyamide is significantly lower (P < 0.05) compared with the other two membranes (*). The post values of each membrane group are significantly different (P < 0.05) from pre values (**).

 
The amount of ß2m in haemodiafiltrate corresponded with the amount of albumin in haemodiafiltrate. All membranes showed an increase of the albumin concentration in haemodiafiltrate during the last 2 h of treatment.

Pre-dialysis plasma albumin values and ultrafiltration volumes were comparable for the three membranes, the latter despite the fact that in all cases the ultrafiltration rates were set individually in order to achieve the patients’ dry weights (see Table 1). Although DIAPES® HF800 showed the highest albumin loss into haemodiafiltrate, interestingly, the post-dialysis plasma albumin level after the DIAPES® HF800 treatments was significantly higher compared with the other two haemodiafilters (Table 2).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Treatments with DIAPES® HF800 used in the HDF mode were tolerated very well without any side-effects and did not differ in this regard from those with established membranes. Average blood pressure was slightly increased before and normalized during treatments in all three groups as expected. Blood and haemodiafiltrate flow rates, ultrafiltration and infusion volumes, pre-treatment ß2m and albumin concentrations were not significantly different between the three membranes under investigation. Therefore, these factors did neither influence the removal of ß2m nor of albumin during treatment.

In conventional HD with high-flux polysulfone and a blood flow of 300 ml/min a ß2m plasma reduction rate of ~50% has been reported whereas on-line HDF in post-dilution mode with 100 ml/min substitution fluid resulted in a reduction rate of 73% [8]. With a substitution rate of 120 ml/min and a blood flow of 350 ml/min ß2m plasma reduction rate could not be raised further [8]. In our study, a higher ß2m plasma reduction rate was observed for both DIAPES® HF800 and polysulfone with a substitution fluid flow rate of only 60 ml/min and a blood flow of only 250 ml/min. In another report on conventional HDF (22 ml/min substitution flow rate, 402 ml/min blood flow rate) and for online HDF (120 ml/min, 434 ml/min) using polysulfone as well as AN69® membranes a removal rate of ß2m from plasma of 56 and 71% was observed, respectively [2]. On the other hand, during high-flux HD with a blood flow of 250 ml/min using a variety of synthetic membranes (Asahi PAN DX-85, Nikkiso FLX-15GW, Renal Systems Primus 2000, Althin Medical Altra-Flux 170G) lower amounts (between 80 and 170 mg) of ß2m compared with our study (e.g. 230 ± 14 mg with DIAPES® HF 800) were measured in dialysate [9,10].

In uraemia, the correlation between hypoalbuminaemia and higher morbidity and mortality is a well-documented fact [11]. In peritoneal dialysis with a mean albumin loss of ~4.2–6.6 g/day, patients with high peritoneal transport displayed lower serum albumin levels and a lower survival compared with patients with a lower peritoneal permeability [12]. Serum albumin levels, however, are influenced by several different factors such as age, nutritional status, inflammation, plasma volume expansion and decreased protein synthesis, the latter possibly related to inflammation. Some studies make the peritoneal loss of albumin responsible for hypoalbuminaemia [12]. On the contrary, as shown recently, CAPD patients with normal albumin, lose more albumin into dialysate compared with hypoalbuminaemic patients. Reduction of plasma albumin was only observed in those patients having a reduced protein catabolic rate even without overt inflammation [13].

In our HDF study, albumin loss was lowest with polyamide (1.0 ± 0.7 g/session), intermediate with polysulfone (3.5 ± 1.4 g/session) and highest with the DIAPES® HF800 membrane (5.7 ± 1.4 g/session). To operate the HDF process under stable conditions during the entire session in all patients, we choose a blood flow rate of 250 ml/min and limited the filtration/substitution volume to 60 ml/min. If the membranes, however, will be used at higher blood flow rates and substitution volumes albumin loss will presumably increase.

A previous study from an Italian group with two different PMMA membrane-based filters, even in HD mode, which is prone to a reduced loss of albumin compared with HDF, revealed a higher loss of albumin compared with the three filters we have examined (Filtryzer BK-P, 5.9 g/session; BK-F, 7.4 g/session, Toray, Tokyo, Japan) [4]. In another study with the Filtryzer BK-F, the dialyser with the highest loss of albumin reported to date, after 6 months of HD the plasma albumin level returned to 3.7 ± 0.2 g/dl after an initial drop. In parallel, renal anaemia improved [5]. It was hypothesized that enhanced removal of some compounds of higher molecular weight (probably having a molecular weight of ~40 kDa), exerting an inhibitory effect on erythroid progenitors, could be responsible [14].

Our study shows that with the three membranes DIAPES® HF800, polysulfone and polyamide, ß2m removal into haemodiafiltrate was directly related to albumin loss (Table 2). Thus, a higher loss of albumin seems to be unavoidable to remove more effectively certain uraemic toxins, e.g. proteins with a molecular weight higher than ß2m [5]. In our study, a loss of albumin with DIAPES® HF800 higher than with the two other membranes was not associated with a decrease of post-treatment albumin concentration. Provided a sufficient dietary protein intake, a loss of 6 g albumin/treatment in patients free of symptoms of inflammation can probably be tolerated as it will be compensated by enhanced albumin synthesis. However, these questions need to be addressed in a separate, long-term study [15].

Taking into account the two aspects of excellent low molecular weight clearances and the high permeability for low molecular weight proteins (indicated by the high ß2m in haemodiafiltrate), a general conclusion regarding serum albumin levels, treatment conditions and patient’s risk cannot be made at the present time. Although, DIAPES® HF800 in HDF mode appears to offer a valuable alternative to conventional membranes long-term experience with this new membrane is needed to show whether its higher removal capacity for low molecular weight proteins is associated with additional clinical benefit.

Conflict of interest statement. B. Reinhardt, A. Northdurft and H.-D. Lemke were at the time of the study employed by Membrana GmbH, the manufacturer of DIAPES® HF800.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 18.11.02
Accepted in revised form: 13. 6.03