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Nephrol Dial Transplant (2003) 18: 23822386 DOI: 10.

1093/ndt/gfg410

Original Article

Comparison of the new polyethersulfone high-ux membrane DIAPES HF800 with conventional high-ux membranes during on-line haemodialtration
Walter Samtleben1, Christina Dengler1, Birgit Reinhardt2, Annekatrin Nothdurft2 and Horst-Dieter Lemke2
Department of Nephrology, University Hospital Munich-Grosshadern, Munich and 2Membrana Research, Obernburg, Germany
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1

Abstract Background. Current modalities of renal replacement therapy allow only a limited removal of larger, possibly toxic molecules, which accumulate in uraemia. Recently, a haemodialter has been made available with the new, high-ux, polyethersulfone-based membrane DIAPES HF800. We performed a study to compare DIAPES HF800 with two conventional high-ux membranes in on-line haemodialtration (HDF), with respect to the removal properties for the two marker proteins, 2-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 ow rate was 250 ml/min and treatment time was 240 min. Pre-treatment 2m 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 haemodialtrate. Results. Tolerance of all treatments was very good, without any side-effects for all lters. The mean plasma reduction rate of 2m was 77 1% for DIAPES HF800 and polysulfone whereas it was 71 1% for polyamide (P < 0.05). The mean 2m amount removed and found in the haemodialtrate 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 haemodialtrate per session for the three membranes: 5.7 0.4, 3.5 0.4 and 1.0 0.4 g, respectively.
Correspondence and offprint requests to: Horst-Dieter Lemke, Forschungsstrasse, Membrana GmbH, D-63785 Obernburg, Germany. Email: horstdieter.lemke@membrana.de

Although DIAPES HF800 showed the highest value for albumin in haemodialtrate the mean posttreatment 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 2m of up to 77% for the DIAPES HF800 membrane and for polysulfone. The amounts of 2m and albumin in haemodialtrate 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; 2-microglobulin; haemodialtration; high-ux membrane; polyethersulfone; post-dilution

Introduction
The introduction of a newly developed, highly permeable haemodialysis (HD) membrane arises interest in todays nephrological community. The question is often considered as to whether a membrane with higher permeability may full an improved balance between a higher removal of uraemic toxins in the molecular weight range from urea to small proteins such as 2-microglobulin ( 2m) and a clinically tolerable albumin loss. In recent years, the choice of membranes of either synthetically modied 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

Nephrol Dial Transplant 18(11) ERAEDTA 2003; all rights reserved

Comparison of DIAPES HF800 and conventional high-flux membranes during HDF Table 1. Characteristics of treatment parameters DIAPES HF800 Membrane manufacturer Haemodialter Manufacturer Membrane surface area Number of patients Treatment time (min) QB (ml/min) Qout (l/4 h) UF volume (Weight loss) (l/4 h) Substitution uid volume (l/4 h)
a

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Polysulfone Fresenius HF80S Fresenius 1.8 m2 10 240 0 250 0 123.3 0.7 3.10 0.72 14.9 0.7

Polyamide S Gambro Polyux 17S Gambro 1.7 m2 10 240 0 250 0 123.6 0.7 3.35 0.71 14.7 0.7

Membrana BLS819SD Bellco 1.8 m2 9a 240 0 250 0 123.6 0.5 3.38 0.48 14.6 0.5

One drop-out.

witnessed [1,2]. The reason for such a trend may be derived from a revived interest in the eld 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 2m (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 specic 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-ux membranes. This leads to an in vitro ultraltration rate of 80 ml/h mmHg for DIAPES HF800 in the BLS819SD haemodialter (Bellco) compared with 55 ml/h mmHg for the polysulfone membrane in the Hemoow HF80S (Fresenius Medical Care). In this study, we evaluated the removal of 2m and albumin in patients undergoing postdilutional on-line haemodialtration (HDF) using DIAPES HF800 in comparison with two other synthetic membranes.

(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 haemodialters 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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Determination of albumin and 2m


In order to study the removal of 2m and albumin with the haemodialtrate, a T-connector was introduced into the efuent haemodialtrate line allowing continuous collection of haemodialtrate at a ow rate of 1 ml/min into a separate beaker during the entire duration of the treatment (Figure 1). Samples were drawn from this haemodialtrate pool after each hour of treatment. Before sampling, the pool was mixed well by a magnetic stirrer. The mass of solute transferred to the haemoltrate after a given time t was calculated from: mass of solute Qout * t * ct where Qout is the outlet haemoltrate ow rate, consisting of the dialysate ow rate Qdial/in, the substitution uid ow rate Qsub and the net ultraltration ow rate QUF as shown in Figure 1. ct is the concentration of the solute in the cumulated haemodialtrate pool after time t. The plasma levels of 2m and albumin were measured directly before (pre, t 0) and after (post, t 240 min) the treatment. 2m and albumin in haemodialtrate and in plasma were measured by laser nephelometry (BN 100 Analyzer, Dade-Behring Marburg GmbH, Marburg, Germany) using N Latex 2-microglobulin and N Antiserum to human albumin (Dade-Behring Marburg GmbH), respectively. The 2m post-haemodialter concentration was corrected for haemoconcentration according to Bergstrom and Wehle [7].

Subjects and methods


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 3370 years); 42 37 months on dialysis (range 5118 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 (Polyux 17S, Gambro, Lund, Sweden) and polysulfone (Hemoow HF80S, Fresenius Medical Care, Bad Homburg, Germany), respectively, in a 4-h post-dilutional on-line HDF regime

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

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

Table 2. 2M, albumin and blood pressure pre- and post-HDF (mean SEM) DIAPES HF 800 2m in haemodialtrate (mg) Albumin in haemodialtrate (g) Plasma albumin concentration pre-HDF (g/l) Plasma albumin concentration post-HDF (g/l) Systolic/diastolic blood pressure (mmHg) pre-HDF Systolic/diastolic blood pressure (mmHg) post-HDF
a b

Polysulfone 18613a 3.50.4a 35.60.4 40.90.5 1427/785 1349/794

Polyamide S 14713a 1.00.4a 35.70.4 41.20.5 1377/785 13011/795

23014a 5.70.4a 35.80.4 43.40.6b 1469/864 1238/815

Signicantly different from each other (P < 0.05). Signicantly different from polysulfone and polyamide S (P < 0.05).

Results
The absolute amount of 2m and of albumin detectable at the end of the treatment in the cumulative haemodialtrate pool as well as the pre- and posttreatment plasma values for albumin are shown in Table 2. Both total 2m and total albumin found in the haemodialtrate decreased in the sequence DIAPES HF800 > polysulfone > polyamide. There was a signicant difference for both, 2m and albumin in the haemodialtrate between the three membranes. All other data, especially the respective pre-treatment values, showed no signicant differences between the three membranes. While the DIAPES HF800 haemodialter reduced the plasma 2m 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. The amount of 2m in haemodialtrate corresponded with the amount of albumin in haemodialtrate. All membranes showed an increase of the

albumin concentration in haemodialtrate during the last 2 h of treatment. Pre-dialysis plasma albumin values and ultraltration volumes were comparable for the three membranes, the latter despite the fact that in all cases the ultraltration rates were set individually in order to achieve the patients dry weights (see Table 1). Although DIAPES HF800 showed the highest albumin loss into haemodialtrate, interestingly, the post-dialysis plasma albumin level after the DIAPES HF800 treatments was signicantly higher compared with the other two haemodialters (Table 2).

Discussion
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

Comparison of DIAPES HF800 and conventional high-flux membranes during HDF

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

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haemodialtrate ow rates, ultraltration and infusion volumes, pre-treatment 2m and albumin concentrations were not signicantly different between the three membranes under investigation. Therefore, these factors did neither inuence the removal of 2m nor of albumin during treatment. In conventional HD with high-ux polysulfone and a blood ow of 300 ml/min a 2m plasma reduction rate of $50% has been reported whereas on-line HDF in post-dilution mode with 100 ml/min substitution uid resulted in a reduction rate of 73% [8]. With a substitution rate of 120 ml/min and a blood ow of 350 ml/min 2m plasma reduction rate could not be raised further [8]. In our study, a higher 2m plasma reduction rate was observed for both DIAPES HF800 and polysulfone with a substitution uid ow rate of only 60 ml/min and a blood ow of only 250 ml/min. In another report on conventional HDF (22 ml/min substitution ow rate, 402 ml/min blood ow rate) and for online HDF (120 ml/min, 434 ml/min) using polysulfone as well as AN69 membranes a removal rate of 2m from plasma of 56 and 71% was observed, respectively [2]. On the other hand, during high-ux HD with a blood ow 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 2m 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 $4.26.6 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 inuenced by several different factors such as age, nutritional status, inammation, plasma volume expansion and

decreased protein synthesis, the latter possibly related to inammation. 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 inammation [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 ow rate of 250 ml/min and limited the ltration/substitution volume to 60 ml/min. If the membranes, however, will be used at higher blood ow rates and substitution volumes albumin loss will presumably increase. A previous study from an Italian group with two different PMMA membrane-based lters, 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 lters 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, 2m removal into haemodialtrate was directly related to albumin loss (Table 2). Thus, a higher loss of albumin

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W. Samtleben et al. 4. Bonomini M, Fiederling B, Bucciarelli T, Manfrini V, Di Ilio C, Albertazzi A. A new polymethacrylate membrane for hemodialysis. Int J Artif Organs 1996; 19: 232239 5. Buoncristiani U, Galli F, Benedetti S, Bianchi J, Floridi A, Canestrari F. Dramatic improvement of uremic anemia over a 6-month treatment with protein-leaking dialysers. J Am Soc Nephrol 2000; 11: 259A (Abstract) 6. Colton CK, Henderson LW, Ford CA, Lysaght MJ. Kinetics of hemodialtration. I. In vitro transport characteristics of a hollow-ber blood ultralter. J Lab Clin Med 1975; 85: 355371 7. Bergstrom J, Wehle B. No change in corrected 2-microglobulin concentration after Cuprophan hemodialysis. Lancet 1987; 1: 628629 8. Lornoy W, Becaus I, Billiouw JM, Van Malderen P, DHaenens P. On-line haemodialtration. Remarkable removal of 2-microglobulin. Long term clinical observation. Nephrol Dial Transplant 2000; 15 [Suppl 1]: 4954 9. Sombolos K, Tsitamidou Z, Kyriazis G, Karagianni A, Kantaropoulou M, Progia E. Clinical evaluation of four different high-ux hemodialysers under conventional conditions in vivo. Am J Nephrol 1997; 17: 406413 10. Hoenich NA, Stamp S. Clinical performance of a new high-ux synthetic membrane. Am J Kidney Dis 2000; 36: 345352 11. Leavey SF, Strawderman RL, Jones CA, Port FK, Held PJ. Simple nutritional indicators as independent predictors of mortality in hemodialysis patients. Am J Kidney Dis 1998, 31: 9971006 12. Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR, Oreopoulos DG, Page D for the Canada-USA (CANUSA) Peritoneal Dialysis Study Group: increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. J Am Soc Nephrol 1998; 9: 12851292 13. Caravaca F, Arrobas M, Dominguez C. Serum albumin and other serum protein fractions in stable patients on peritoneal dialysis. Perit. Dial Int 2000; 20: 703707 14. Yamada S, Kataoka H, Kobayashi H, Ono T, Minakuchi J, Kawano Y. Identication of an erythropoietic inhibitor from the dialysate collected in the haemodialysis with PMMA membrane (BK-F). Contrib Nephrol 1999; 125: 159172 15. Krieter DH, Canaud B. High permeability of dialysis membranes: what is the limit of albumin loss? Nephrol Dial Transplant 2003; 18: 651654

seems to be unavoidable to remove more effectively certain uraemic toxins, e.g. proteins with a molecular weight higher than 2m [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 sufcient dietary protein intake, a loss of 6 g albumin/treatment in patients free of symptoms of inammation 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 2m in haemodialtrate), a general conclusion regarding serum albumin levels, treatment conditions and patients 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 benet.
Conict 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.

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References
1. Canaud B, Bosc JY, Leray H et al. On-line haemodialtration: state of the art. Nephrol Dial Transplant 1998; 13 [Suppl 5]: 311 2. Maduell F, del Pozo C, Garcia H et al. Change from conventional haemodialtration to on-line haemodialtration. Nephrol Dial Transplant 1999; 14: 12021207 3. Kabanda A, Jadoul M, Pochet JM et al. Determinants of serum concentrations of low molecular weight proteins in patients on maintenance hemodialysis. Kidney Int 1994; 45: 16681696

Received for publication: 18.11.02 Accepted in revised form: 13.6.03

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