Randomized trial of high-flux vs low-flux haemodialysis: effects on homocysteine and lipids

Andrew A. House1,, George A. Wells2, James G. Donnelly3, Steven P. Nadler4 and Paul C. Hébert2,5

1 Division of Nephrology, London Health Sciences Centre, London, Ontario, 2 Clinical Epidemiology Unit, Ottawa Civic Hospital Loeb Research Institute, Ottawa, 3 Division of Biochemistry, Ottawa Hospital, Ottawa, 4 Division of Nephrology, Ottawa Hospital, Ottawa, and 5 Divisions of Respirology and Critical Care, Ottawa Hospital, Ottawa, Ontario, Canada



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Uncontrolled studies have found that high-flux haemodialysis favourably modifies homocysteine and lipid profiles. We sought to confirm these findings by carrying out a randomized prospective comparison of high-flux and low-flux polysulphone in chronic, stable dialysis patients.

Methods. Forty-eight patients were randomly assigned to either high or low-flux dialysis for 3 months. Serum levels of homocysteine, lipoprotein (a), and lipids were compared between the treatment groups at monthly intervals.

Results. All patient characteristics and laboratory variables were equally distributed between the groups at baseline. Over the study duration, we observed no differences between high- and low-flux treatment groups for the following outcomes: pre-dialysis homocysteine, lipoprotein (a), total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides (all P>0.05). Geometric mean (interquartile range) homocysteine at baseline was 20.0 (16.8–24.5) and 19.5 (15.3–22.0) µmol/l for the high-and low-flux groups respectively (P=0.80), and levels did not change significantly during the study. We did demonstrate a more pronounced intradialytic effect of high-flux dialysis on homocysteine levels, which fell during dialysis by 42%, compared to 32% with low-flux dialysis (P<0.001).

Conclusions. In this randomized controlled trial, the effects of high-flux and low-flux haemodialysis on homocysteine and lipid profiles were comparable. The greater intradialytic effect of high-flux dialysis on homocysteine did not translate into a significant difference in pre-dialysis levels after 3 months of study.

Keywords: haemodialysis; homocysteine; polysulphone; prospective studies



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD), accounting for almost half of the reported causes of patient deaths [1]. Traditional risk factors, such as total cholesterol or hypertension, do not appear to explain this excess disease burden. Numerous studies have appeared in the literature in recent years supporting a link between elevations of homocysteine and lipoprotein (a) and cardiovascular mortality and morbidity in ESRD patients [24] and have demonstrated that patients with ESRD are more likely than age- and sex-matched controls to have elevated values of these risk factors [5,6]. Conventional lipid profiles have also been well described in ESRD patients, with emphasis on perturbations of apolipoproteins, hypertriglyceridaemia and inefficient lipolysis, probably secondary to the presence of lipase inhibitors [7,8]. Some studies have suggested that high-flux haemodialysis improves lipid profiles or homocysteine; however, many of these studies were uncontrolled, retrospective, or compared haemodialysis membranes with different degrees of biocompatibility, membrane thickness, or surface area [914]. Other studies have concluded that high-flux haemodialysis has no significant impact on homocysteine levels; however, the subject numbers used in these trials may have limited statistical power [15,16].

The limitations of current published data prompted us to design a randomized controlled clinical trial. In this study, we have examined the effect of maintenance haemodialysis with high-flux polysulphone compared to low-flux polysulphone on pre-dialysis homocysteine, lipoprotein (a), and conventional lipid profiles (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol). We also compared the intradialytic effect of high-flux vs low-flux haemodialysis on plasma homocysteine.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study design
We undertook a prospective, randomized trial of haemodialysis with a high-flux or low-flux dialysis membrane, employing a two-group parallel study design. Forty-eight patients from the in-centre haemodialysis units of two tertiary care hospitals in Ottawa, Ontario, Canada were randomly allocated to two treatment groups of 24, each receiving the pre-specified intervention for 3 consecutive months. High-flux polysulphone (F80, Fresenius AG, Bad Homburg, Germany) and low-flux polysulphone (F8, Fresenius) membranes were compared, since both are made from the same biocompatible synthetic material and have the same surface area, membrane thickness, and inner diameter, resulting in near-identical clearances of low-molecular-weight solutes such as urea. Any observed differences could thus be more readily attributed to the higher ultrafiltration coefficient and clearance of larger molecules by the high-flux membrane. The study was initiated in June 1997, and was completed in December 1997.

Study population
We included patients above 18 and below 80 years of age, requiring haemodialysis treatments for more than 3 months to a maximum of 18 months. Patients were excluded for the following reasons: diabetes mellitus, use of lipid-lowering medication, recent coronary syndrome (unstable angina or myocardial infarction in the previous 3 months), adverse reaction to polysulphone, life expectancy less than 6 months, imminent renal transplantation or other major surgery, hypercoagulable state, malabsorption, refusal or inability to provide informed consent. Patients with diabetes were excluded, since they would have added significant biochemical and clinical heterogeneity to the study population, and thus reduce statistical power. The study was approved by the Research Ethics Boards of both participating institutions.

Intervention and treatment protocols
Randomization was carried out in a blinded fashion by a random-number generator, stratified only for centre. For a minimum of 3 weeks prior to randomization, multivitamin therapy was standardized (Nephro-Vite®Rx, R&D Laboratories Inc., Marina del Rey, CA) to include folic acid (1 mg), vitamin B6 (10 mg), and vitamin B12 (6 µg) daily. This preparation continued for the duration of the study. A random subset of 12 patients from each study group took part in a 1-month randomized cross-over trial described elsewhere [17], which compared the short-term effects of high- and low-flux polysulphone membranes on homocysteine, and found no carry-over, period effect or treatment effect of the study dialysers on the outcome. Following the cross-over, these patients immediately commenced the 3-month parallel group study, and any references to baseline parameters in this subset refer to this point in time.

All haemodialysis treatments were carried out with a volumetric control machine allowing for a precise rate of fluid removal. Specifics of treatment, including duration, blood flow, ultrafiltration rate, dialysate temperature and flow were prescribed by the attending nephrologist, but no changes were made during the study period with the exception of target weight and dialysate potassium. Patients were weighed before and after each treatment, to determine the volume of ultrafiltration. All treatments utilized bicarbonate-based dialysate, and were carried out three times per week. The dialysis membranes were single-use only.

Data collection and laboratory measurements
Baseline demographic data were collected, including age, sex, duration of haemodialysis, aetiology of renal failure, history of renal transplantation, medications, co-morbid illnesses, and type of vascular access.

Blood samples were drawn at baseline and monthly for all variables with the exception of erythrocyte-folate and vitamin B12, which were measured only at baseline and the conclusion of the study. Pre-dialysis samples, drawn prior to the administration of heparin, were analysed for homocysteine, lipoprotein (a), fibrinogen, urea, haemoglobin, albumin, triglycerides, total cholesterol and HDL cholesterol. LDL cholesterol was calculated for each patient using the Friedewald formula. It was not feasible to have subjects fasting for 12 h prior to sampling. Rather, they were encouraged to eat lightly prior to blood sampling, and each individual was sampled at roughly the same time of day each month to minimize intra-subject variability in such parameters as triglycerides. Samples for homocysteine and fibrinogen were placed immediately on ice, and transported to the laboratory to be centrifuged and frozen. Other samples were handled in standard fashion.

Homocysteine and urea were repeated immediately after dialysis, using a slow-flow or stop-pump technique to allow for rebound secondary to access recirculation. Urea reduction ratio was calculated from the pre- and post-dialysis urea samples as follows: (ureapre-ureapost)/ureapre. Homocysteine reduction ratio was calculated in the same manner.

The high-performance liquid chromatography assay for total plasma homocysteine has been described elsewhere [18]. Lipoprotein (a) was measured using the Macra(TM) enzyme linked immunoassay (Strategic Diagnostics, Newark, DE). Erythrocyte-folate was measured using a radioligand assay (Bio-Rad Laboratories, Mississauga, ON). Vitamin B12 was measured on the Abbott AxSYM analyser (Mississauga, ON). HDL cholesterol was quantitated using the Randox Laboratories homogeneous assay (Mississauga, ON) adapted to the Boehringer–Mannheim/Hitachi 917 analyser (Laval, PQ). All other chemistry assays were performed on the Boehringer–Mannheim/Hitachi 917 analyser using Boehringer–Mannheim reagents.

Statistical strategy and sample size
The primary treatment outcome was change in homocysteine over the 3-month study period. The intradialytic effect of high-or low-flux dialysis on levels of homocysteine was also sought. Secondary outcomes were changes in lipoprotein (a), lipids, fibrinogen, erythrocyte-folate, and vitamin B12. The sample size estimate was based upon an ability to detect a 25% difference in homocysteine levels between the two haemodialysis membranes with a level of significance of 0.05 and power of 80%. Since homocysteine is non-Gaussian, our sample size was initially based upon the best available untransformed data in haemodialysis patients. To confirm that the appropriate number were enrolled, the pre-dialysis homocysteine levels for all subjects at study entry were log-normalized, revealing a log10(homocysteine)±SD of 1.30±0.14. A 25% difference corresponds to an absolute difference in log10(homocysteine) of 0.125 (i.e.-log10(0.75)) between high- and low-flux groups. Using these data and standard sample size formulae yielded a sample size of 20 subjects per group.

Patient characteristics and laboratory measures were analysed by Fisher's exact test for categorical variables, analysis of variance, or Mann–Whitney test for continuous variables depending upon their distribution. A two-way analysis of variance was used to examine differences between high- and low-flux groups compared monthly over 3 months. Analysis of variance was also utilized to compare vitamin B12 and folate status at the beginning and end of the study. Skewed variables homocysteine and triglycerides were log-normalized to allow parametric analyses. Lipoprotein (a) was analysed by the Kruskal–Wallis test.

Analyses were performed using SPSS 8.0 software (SPSS Inc., Chicago, IL). All study outcomes were described using arithmetic mean and standard deviation for normally distributed variables or geometric mean with interquartile range for variables with non-Gaussian distribution.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Forty-five patients (22 high-flux, 23 low-flux) completed the 3-month study. One patient in the high-flux group was withdrawn after his third treatment for a presumed reaction to the dialysis membrane, and another changed to continuous ambulatory peritoneal dialysis 6 weeks before completing the study. One patient in the low-flux group died from spontaneous rupture of the oesophagus.

Patient characteristics were similar in both groups at baseline (Table 1Go), although the difference in triglycerides approached statistical significance. Due to the study design, where half of the subjects had participated in a randomized cross-over trial prior to commencing the parallel group study, there was an imbalance in the type of membrane being used immediately prior to the study, with more patients in the high-flux group being dialysed with low-flux membranes and vice versa. Use of cyclosporin, which may influence homocysteine levels, was limited to two patients in the high-flux group. Genotyping for a mutation (C677T) in the gene coding for methylenetetrahydrofolate reductase was available for 44 of 48 patients. Three patients (one high-flux, two low-flux) were homozygous for this mutation, which may cause elevated homocysteine in a folate-deficient state. Twenty-one heterozygotes (11 high-flux, 10 low-flux) were evenly distributed amongst the study groups (P=0.83). This was quite comparable to the gene frequency described in dialysis patients by Födinger et al. [19] where 44% of subjects were heterozygous for the mutation.


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Table 1. Baseline characteristics

 
There were no differences between treatment groups in all laboratory measures over time (Table 2Go), with the exception of homocysteine reduction ratio (higher for the high-flux group; P<0.001) and a strong trend for a difference in post-dialysis homocysteine (lower for the high-flux group; P=0.08). Homocysteine reduction ratio ranged between 41 and 44% for the high-flux patients, and between 29 and 32% for the low-flux patients (Figure 1Go). At no time during the study did the study groups differ significantly in terms of total cholesterol, HDL or LDL cholesterol, and lipoprotein (a). The magnitude of the difference in triglycerides observed at baseline remained consistent and failed to reach significance throughout the study (P=0.11).


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Table 2. Repeated measures table for study parameters

 


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Fig. 1. Homocysteine reduction ratio (HRR) expressed as percent intradialytic change in homocysteine for high-flux (dark bars) and low-flux (light bars) at baseline and monthly intervals (P<0.001). Error bars represent one standard error of the mean.

 
The geometric mean (interquartile range) pre-dialysis homocysteine at baseline was 20.0 (16.8–24.5) µmol/l for the high-flux group, and 19.5 (15.3–22.0) µmol/l for the low-flux group (P=0.80). The pre-dialysis homocysteine fell by approximately 2.5±4.5 µmol/l for the high-flux group by the third month of treatment, while the homocysteine for low-flux patients fell by 0.5±8.1 µmol/l. This difference of 2.0 µmol/l was not statistically significant (P=0.31).

Repeated measures analysis of variance comparing levels of vitamin B12 and erythrocyte-folate for both treatment groups revealed no differences throughout the duration of the study (P=0.38 and 0.96 respectively), and no patients were below the lower limits of the reference intervals. At the conclusion of the study, vitamin B12 levels for high- and low-flux groups were 405±181 pmol/l and 484±226 pmol/l (P=0.21), while the corresponding erythrocyte-folate levels were 2641±869 nmol/l and 2707±1097 nmol/l (P=0.83).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our results indicate no benefit of 3 months of high-flux haemodialysis compared with low-flux haemodialysis in terms of various cardiovascular risk factors in a study population of chronic, stable haemodialysis patients. This is the first randomized controlled trial to compare haemodialysis with two biocompatible membranes whose characteristics are virtually identical, with the exception of ultrafiltration capacity and clearance of solutes of higher molecular weight, to seek the impact of high- vs low-flux haemodialysis on homocysteine, lipoprotein (a), and lipid profiles.

We did demonstrate a greater intradialytic effect of high-flux haemodialysis on homocysteine, as reflected in the consistently lower post-dialysis homocysteine and the larger homocysteine reduction ratio. However, at the conclusion of the study, the pre-dialysis homocysteine levels decreased only modestly from baseline values in the high-flux patients, which did not prove to be statistically significant. The intradialytic effects of haemodialysis on homocysteine have been described by others [11,20], though a direct, randomized comparison of high- and low-flux polysulphone has not been previously reported. Despite the low molecular weight of homocysteine (~135 Da), it is highly protein bound, making it unlikely that diffusive clearance of free homocysteine or its disulphides is the principal route of elimination. This is supported by the work of Arnadottir et al. [21] who failed to demonstrate significant amounts of homocysteine in dialysate. This observation suggests that adsorption to the membrane, or removal of a uraemic inhibitor of homocysteine metabolism plays a significant role in the intradialytic lowering of homocysteine, and a high-flux dialysis membrane might be expected to perform this function with greater efficiency. This hypothesis is the subject of ongoing investigation.

The lack of a long-term effect of high-flux haemodialysis on lowering the pre-dialysis homocysteine was also noted in uncontrolled studies [15,16]. Recently, daily or nocturnal haemodialysis has been suggested as a means to lower homocysteine levels without allowing for significant interdialytic rebound, or perhaps again by providing augmented clearance of uraemic inhibitors of homocysteine metabolism [22]. Whether high-flux daily haemodialysis would confer any advantage over low-flux daily haemodialysis remains unanswered.

In our study, the finding that homocysteine levels were approximately 2 µmol/l lower in the final month of follow-up for high-flux compared to low-flux treatment groups was not statistically significant (P=0.31). A study with over 300 patients would have the statistical power to detect a 10% difference, but prospective evidence from Moustapha et al. [2], demonstrating a 1% increase in the relative risk of subsequent cardiovascular events for each 1 µmol/l increase in homocysteine in patients with end-stage renal disease, suggests that such a small absolute difference would probably have little clinical impact.

Baseline pre-dialysis homocysteine levels were lower in the study groups (20.0 µmol/l and 19.5 µmol/l for the high- and low-flux groups respectively) than other published data [5,23]. It may have been possible to detect a greater effect of high-flux haemodialysis had the homocysteine levels been higher at baseline. However, it is our contention that the mainstay of therapy for elevated homocysteine should begin with folate-based multivitamin therapy, which quickly and reliably lowers homocysteine to a mean of approximately 21 µmol/l [23], after which additional interventions should be evaluated. Furthermore, mortality ratios associated with varying levels of homocysteine demonstrate a large incremental increase above 20 µmol/l [24], suggesting that a strategy that can reduce levels below this threshold would be of greatest potential value.

Another objective of this study was to examine the effect of high- vs low-flux haemodialysis on lipoprotein (a) levels. There were no differences between the dialysis membranes over the 3-month duration of the study. To our knowledge, only two studies have sought this effect, and neither was designed to elucidate the effect of membrane permeability on lipoprotein (a) levels, as the membranes studied also differed in biocompatibility [9,10].

Our study contradicts previous observations that high-flux haemodialysis membranes improve plasma lipoprotein profiles and triglycerides. Seres and colleagues [13] demonstrated that haemodialysis with a high-flux polysulphone membrane caused a greater decrease in triglycerides and a greater rise in HDL cholesterol when compared to a low-flux cellulosic membrane, and suggested that improved clearance of larger molecules with the high-flux membrane may have removed circulating inhibitors of lipoprotein lipase. This is an attractive theory, since several putative inhibitors have been described, and changes in levels of inhibitors such as apolipoprotein CIII and pre-ß-HDL have been shown with high-flux membranes [7,12]. It is of note, however, that apolipoprotein CIII levels did not change in the study by Seres et al., and with the use of membranes of differing biocompatibility, the possibility remains that the differential release of cytokines and other inflammatory mediators may have had an influence on lipid profiles independent of membrane flux.

Any of the studies examining the long-term effects of high-flux haemodialysis on lipid profiles that have suggested an improvement in the patients treated with high-flux haemodialysis, suffer from the same inability to separate the effect of membrane flux with membrane biocompatibility, as they compare high-flux polysulphone with low-flux cellulosic membranes [9,10,14]. In a recent cross-over trial, Ingram and colleagues [25] compared dialysers composed of cellulose acetate, which had the same flux characteristics for ultrafiltration (11 ml/h/mmHg transmembrane pressure), but differing sieving coefficients for larger molecules. While lipoprotein profiles improved immediately after dialysis using the membrane with greater clearance of larger molecules, this advantage appeared to be transient, as no differences in pre-dialysis lipid profiles emerged during the follow-up period. Our study confirms this finding. This also would suggest that the long-term benefits demonstrated in previous studies might be attributable to superior membrane biocompatibility, and not clearance of circulating lipase inhibitors.

In conclusion, 3 months of haemodialysis using a high-flux polysulphone membrane did not result in any favourable changes in homocysteine, lipoprotein (a), or lipid profiles, despite theoretical benefits of clearance of larger molecular weight solutes on the metabolism of these cardiovascular risk factors. High-flux haemodialysis does not improve the cardiovascular risk profile in this group of patients who are at significant risk of cardiovascular mortality and morbidity.



   Acknowledgments
 
This study was supported by Fresenius Medical Care Canada Inc., who provided an unrestricted research grant, and Schein Pharmaceutical Canada Inc., who provided Nephro-Vite®Rx for each study patient. These results were presented at the 31st Annual Meeting of the American Society of Nephrology, Philadelphia, 1998, and published as an abstract in the Journal of the American Society of Nephrology, 1998. The authors wish to thank all patients who participated in this study, and acknowledge the help of the laboratory and dialysis unit personnel. We also thank Cynthia House for administrative assistance and data collection, and Deborah Manley-Bakker for secretarial support.



   Notes
 
Correspondence and offprint requests to: Dr Andrew A. House, Division of Nephrology, London Health Sciences Centre, University Campus, PO Box 5339, Stn Ctr CSC, London, Ontario, Canada N6A 5A5. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 21. 9.99
Revision received 6. 1.00.