Pre-dilution on-line haemofiltration vs low-flux haemodialysis: a randomized prospective study

Charles H. Beerenhout1, Antinus J. Luik5, Suzan G. J. Jeuken-Mertens5, Otto Bekers4, Paul Menheere4, Linda Hover3, Leny Klaassen6, Frank M. van der Sande1, Emile C. Cheriex2, Natalie Meert7, Karel M. Leunissen1 and Jeroen P. Kooman1

1 Department of Nephrology, 2 Department of Cardiology, 3 Department of Nutrition and 4 Department of Clinical Chemistry, University Hospital Maastricht, The Netherlands, 5 Department of Internal Medicine and 6 Department of Nutrition, Vie Curi, Venlo, The Netherlands and 7 Department of Nephrology, University Hospital Gent, Belgium

Correspondence and offprint requests to: Jeroen P. Kooman, MD PhD, Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Email: jkoo{at}sint.azm.nl



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Accumulation of larger molecular weight uraemic toxins molecules may have a negative effect on the cardiovascular and nutritional state of dialysis patients and influence uraemic symptomatology. Their clearance can be enhanced by the use of haemofiltration (HF).

Methods. The effects of low-flux haemodialysis (HD) (ultrapure dialysate; polyamide membranes) and pre-dilution on-line HF (1:1 blood/substitution ratio; target filtration volume: 1.2 times body weight) on cardiovascular and nutritional parameters, interdialytic levels of uraemic toxins and quality of life (QOL; Laupacis questionnaire) were assessed during 1 year follow-up. Forty patients were randomized.

Results. After 1 year, 27 patients were eligible for analysis (HF: 13 patients; HD: 14 patients). Left ventricular mass index did not change in the HF patients (127±33 -> 131±36 g/m2 after 12 months) or in the HD group (135±34 -> 138±32 g/m2). Also, there were no changes in pulse wave velocity, and 48 h systolic and diastolic blood pressures. Lean body mass, assessed by dual-energy X-ray absorptiometry, increased in the HF group (44.8±8.9 -> 46.2±9.6 kg; P<0.05), but not in the HD group (49.4±9.2 -> 50.6±8.8 kg), although differences between groups were not significant. Insulin-like growth factor-1 levels remained stable in the HF patients, but decreased in the HD group (P<0.05 between groups). QOL for physical symptoms improved in the HF group (4.2±1.2 -> 5.0±1.1; P<0.05 within the HF group and P = 0.06 between groups), but not in the HD group (4.0±1.0 -> 4.4±1.4). ß2-microglobulin, complement factor D and homocysteine decreased significantly in the HF but not in the HD group, whereas L-ADMA, leptin and advanced glycation end-products-related fluorescence did not change.

Conclusions. No changes in cardiovascular parameters were observed during pre-dilution on-line HF compared with low-flux HD. Treatment with on-line HF resulted in marked changes in the uraemic toxicity profile, an improvement in physical well-being and a small improvement in nutritional state.

Keywords: cardiovascular; haemofiltration; homocysteine; left ventricular mass; pre-dilution on-line; pulse wave velocity



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Conventional haemodialysis (HD) is highly efficient in removing small molecular weight (MW) uraemic toxins. However, the clearance of larger MW substances is limited. A greater removal of larger MW substances is achieved by convective therapies, such as haemofiltration (HF) [1]. Despite a burst of initial enthusiasm for HF during the late seventies and early eighties, interest in this technique gradually diminished, among other reasons, because of the limited removal of small MW uraemic toxins due to the relatively small filtration volumes used during conventional HF and the high costs of the prefabricated substitution fluids. However, so-called on-line production of substitution fluid enables the production of bicarbonate-containing, sterile substitution fluid in large quantities, thereby circumventing limitations in small MW removal [1].

From a theoretical point of view, and based on results of retrospective studies with conventional HF, an increased removal of larger MW substances might have beneficial effects on blood pressure control and cardiovascular morbidity [2]. Moreover, a recent study with pre-dilution on-line HF showed an improvement in the quality of life (QOL) [3].

With regard to cardiovascular disease, the prevalence of hypertension and left ventricular hypertrophy is notably high in HD patients. Recent data suggest that accumulation of the endogenous nitric oxide inhibitor L-asymmetric dimethylarginine (ADMA) might play a role in this respect. Removal of ADMA (202 D) during conventional HD is limited. Improved clearance of ADMA in combination with improved blood pressure control was observed during on-line HF [4]. Homocysteine, which is marginally removed by conventional HD, has also been implicated in the increased cardiovascular morbidity in dialysis patients. Lastly, it has been suggested that accumulation of advanced glycation end-products (AGE) might play a role in cardiovascular damage in HD. AGE are inefficiently removed during HD, but a reduction in pre-dialytic levels of AGE was observed during on-line haemodiafiltration [5].

Another important factor in survival of patients on HD is their nutritional state. It has been hypothesized that accumulation of uraemic toxins in the range of 2–5 kDa or leptin may reduce appetite [6].

Prospective randomized studies on the potential benefits of on-line convective therapies are scarce [7,8] and have not yet focused on cardiovascular and nutritional parameters in detail. Moreover, most studies assessed on-line haemodiafiltration, during which the clearance of both smaller and larger MW uraemic toxins is enhanced [1]. As during pre-dilution on-line HF, the highest convective clearance as yet possible can be achieved with a small molecular clearance nearly comparable to that of HD; this modality is an interesting method to study the pathophysiological effects of an increased clearance of larger MW uraemic toxins per se.

The aim of the present prospective randomized study was to compare the effects of on-line pre-dilution HF and low-flux HD on cardiovascular and nutritional parameters, QOL and uraemic toxicity profile.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Approval for the study was obtained from the ethical committees of both centres (University Hospital Maastricht and Vie Curi Medical Center, Venlo, The Netherlands).

Included were patients, treated with low-flux HD three times weekly, who were on dialysis treatment for ≥3 months and had adequate arteriovenous access. Excluded were patients with severe cardiovascular morbidity, defined as a left ventricular ejection fraction <25% and/or coronary heart disease NYHA classification of III–IV and severe intercurrent illness. Patients were enrolled during a period of 2 years.

All patients gave written consent. Baseline characteristics of the patients are displayed in Table 1 (body weight is mentioned in Table 3). In the HF group, the original renal disease was nephrosclerosis/renal vascular disease in four patients, glomerulonephritis in seven patients, diabetic nephropathy in four patients, polycystic disease in one patient and other diagnoses in four patients. In the HD group, the original renal disease was nephrosclerosis/renal vascular disease in three patients, glomerulonephritis in six patients, diabetic nephropathy in five patients, polycystic disease in three patients and other diagnoses in three patients.


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Table 1. Patient characteristics

 

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Table 3. Nutritional parameters

 

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Table 2. Cardiovascular parameters

 
Study design and treatment characteristics
The study was performed in two dialysis centres. Patients were centrally randomized for pre-dilution HF or standard HD using envelopes and were stratified for diabetes. Patients who dropped out of the study within 3 months were replaced. Patients who replaced the drop-outs were also put through the randomization process. All patients were treated with low-flux HD before the start of the study.

On-line HF was performed with the AK 200/200-S ULTRA (Gambro, Lund, Sweden). HD was performed with AK 200 ULTRA or 4008H modules (Fresenius Medical Care, Bad Homburg, Germany).

For the HF treatment, polyamide (Polyflux 24S; Gambro) dialysers were used. The HD group was treated with low-flux polyamide membranes (Polyflux 8L; Gambro) and ultrapure dialysis fluid, manufactured through a double reverse osmosis unit and electrical deionization, followed by filtration (U 8000, Gambro; or Diasafe, Fresenius Medical Care). The minimal target double-pool Kt/V during low flux dialysis was 1.2.

Treatment time was not changed during the study. The dilution of blood in HF was aimed at the ratio 1:1 and the total filtrate volume in the HF group was aimed at 1.2 times body weight [1], the treatment protocol being the same in both participating centres. The composition of both dialysate and substitution fluid was sodium 140 mmol/l, potassium 2 mmol/l, calcium 1.50 mmol/l, bicarbonate 32–36 mmol/l, glucose 1 mmol/l and magnesium 0.5 mmol/l.

Power analysis
Left ventricular mass index (LVMi) was the primary outcome variable.

Assuming a standard deviation of 25 g/m2 for changes in LVMi (extrapolated from [9]), a total number of 22 patients would be needed to detect a difference of 25 g/m2 between the effect of the different treatment modalities [10] with a type I error probability of 0.05 and a type II error probability of 0.10. In order to correct for multiple comparisons and expected drop-outs, we chose to include 40 patients because of expected drop-outs due to transplantation or death during the long follow-up time. Patients who withdrew from the study within 3 months (three patients, due to transplantation) were replaced. In Table 1, the characteristics of the 40 patients who entered randomization and remained in the study for ≥3 months are displayed.

Treatment efficacy
Treatment efficacy was assessed by the urea reduction ratio (URR) and by measurement of Kt/V by partial dialysis quantification (DQM 100 Urea Monitor; Gambro). Kt/V and URR were not necessarily determined during exactly the same treatment, but the difference in timing between Kt/V and URR did not exceed 2 weeks.

Cardiovascular parameters
Blood pressure was measured in all patients using an ambulatory blood pressure device (Spacelabs Medical BV, Utrecht, The Netherlands) during 2 days between dialysis treatments before randomization, after 6 months and after 1 year. Ambulatory blood pressure was assessed during a midweek period, excluding the dialysis treatment itself.

In a subgroup analysis, changes in ambulatory blood pressure measurements were also analysed separately in strictly normotensive patients (mean ambulatory systolic blood pressure <133 mmHg without antihypertensive agents) and hypertensive patients (mean ambulatory systolic blood pressure >133 mmHg with or without antihypertensive agents). In this subanalysis, patients with intermediate blood pressure control (systolic blood pressure <133 mmHg with use of antihypertensive agents) were excluded.

The week before, pre- and post-dialytic blood pressures were assessed by an oscillometric method (HEM 780; Omron Healthcare, Inc., Bannockburn, IL, USA). The mean of three consecutive treatments was calculated and used in the analysis.

Also, the prescription of antihypertensive medication was registered. For each patient, a score was made in which every medication used was given a score of 100. Adding another antihypertensive drug resulted in an increase of 100, cessation of a drug resulted in a decrease of 100. Changing the dose of an already-used drug resulted in an increase of 50 after a rise in dosage, or a decrease of 50 after a lowering of the drug. After assessment and potential correction of dry weight, antihypertensive agents would be reduced if pre-dialytic systolic blood pressure decreased below 110 mmHg and increased if pre-dialytic systolic blood pressure consistently increased above 160 mmHg.

Two-dimensional echocardiography was performed on a midweek interdialytic day using a HP Sonos 5500 ultrasound system (Hewlett Packard, Palo Alto, CA, USA). Left ventricular mass was calculated according to the formula of Devereux and Reichek and corrected for body surface area.

Arterial stiffness was assessed by pulse wave velocity (Complior SP; PMS Instruments, Berkshire, UK), also on a midweek interdialytic day.

Nutritional state
The energy and protein intake was assessed using a 7 day questionnaire. Protein catabolic rate was assessed by the DQM Urea Monitor (Gambro). Subjective global assessment on a seven-point scale was performed.

Dual-energy X-ray absorptiometry (DEXA) was performed for the measurement of body composition by a QDR 4500 densitometer (Hologic Inc., Waltham, MA, USA). DEXA assesses body composition as a three-compartment model, i.e. fat mass, bone cell mass and lean body mass (comprising muscle, inner organs and body water).

These investigations were performed on a midweek interdialytic day before randomization and after 6 months and 1 year.

Fluid status
Dry weight was adjusted on clinical criteria, aided by echography of the inferior caval vein. Extracellular volume was assessed at baseline and after 6 and 12 months by multifrequency bioimpedance analysis (Xitron: BIS 4000; San Diego, CA, USA). Interdialytic weight gain at baseline and after 6 and 12 months was calculated as the mean of three interdialytic periods, assessed on the week before the other examinations were performed.

Quality of life
The kidney disease questionnaire of Laupacis et al. [11] was used to evaluate the QOL. Patients were asked to identify their specific physical problems, next to questions regarding frustration, depression and well-being. Patients were asked to name their complaints on a scale ranging from 1 (severe) to 7 (none). The questionnaire was performed before randomization, and was repeated after 6 months and 1 year.

Laboratory analysis
The following routine parameters were recorded before randomization, after 6 months and after 1 year: haemoglobin level, C-reactive protein, albumin and serum calcium, phosphorus and parathyroid hormone. At the same time intervals, noradrenalin, endothelin and insulin-like growth factor (IGF) were assessed. All blood samples were taken on a midweek interdialytic day.

The following uraemic toxins were assessed before randomization and after 6 months: ADMA, homocysteine, leptin, complement factor D, ß2-microglobulin (ß2M) and AGE-related fluorescence. For financial reasons, these parameters were only measured at these time points and also because changes in uraemic toxins may be expected in the relatively short term.

Complement factor D was measured by enzyme-linked immunoassay using two monoclonal antibodies directed against human complement factor D as described in [12].

ß2M was assessed by a commercial enzyme-linked immunoassay (Immundiagnostik, Bensheim, Germany; detection limit 0.1 mg/l) using a polyclonal antibody directed against human ß2M. Total (free and protein-bound) homocysteine was analysed by isocratic reversed-phase high-performance liquid chromatography with fluorescence detection. ADMA was analysed by capillary electrophoresis with fluorescence detection as described in [13].

IGF-1 was determined with an immunoradiometric assay with kits from Nichols (Bad Vilbel, Germany). Leptin measurements were performed with a radioimmunoassay (Mediphos Medical Supplies, Renkum, The Netherlands). Noradrenalin was measured with cation-exchange high-performance liquid chromatography using electrochemical detection. For the study of antioxidants (total antioxidant state, glutathione peroxidase and superoxide dismutase), kits from Randox (Crumlin, UK) were used and measured on a Cobas Mira (Radiometer, Copenhagen, Denmark).

The determination of AGE-related total fluorescence was performed by quantitative total fluorescence analysis [14].

Statistical analysis
Changes in measured variables with time were assessed by repeated measure analysis of variance, with the mode of treatment (HF or HD) as a between-subjects factor. If changes within groups were significant, differences were analysed further using the paired Student's t-test. Data were analysed using SPSS version 12.01. P-values of <0.05 were considered significant.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
After randomization, 20 patients were enrolled in the HF group and 20 patients in the HD group. Both participating centres included 20 patients. Baseline characteristics, as reported in Table 1, were not significantly different between both groups. Thirty-six patients (90%) completed the 6 month period (HF: 19 patients; HD: 17 patients). After 1 year, 27 patients (68%) were eligible for analysis (HF: 13 patients; HD: 14 patients).

During the study period, two patients died, one after a rupture of an aortic aneurysm (HF) and one due to an acute myocardial infarction (HD). Four patients were transplanted (one HF; three HD). During the study, three patients in total (all HF) were withdrawn for medical reasons: one patient was starting treatment with chemotherapy for newly diagnosed cerebral and bone metastases of breast carcinoma, one patient after a traumatic (not dialysis-related) spinal cord lesion and one patient after abdominal sepsis. One patient (HF) had an allergic reaction to the dialyser. Three patients (one HF; two HD) decided to withdraw from the study for personal reasons.

Mean filtration volume during HF was 77.3±9.8 l per treatment. Achieved Kt/V, measured by partial dialysis quantification, and URR were not significantly different between the HD and HF groups. URR in the HF group was 0.70±0.08 at baseline (thus, before the start of the study), 0.67±0.07 at 6 months and 0.66±0.05 at 12 months. In the HD group, URR was 0.68±0.05 at baseline, 0.67±0.07 at 6 months and 0.67±0.07 at 12 months. In the HF group, Kt/V was 1.38±0.32 at baseline, 1.33±0.21 at 6 months and 1.14±0.13 at 12 months. In the HD group, Kt/V was 1.41±0.04 at baseline, 1.34±0.20 at 6 months and 1.36±0.26 at 12 months.

Cardiovascular parameters
Data are summarized in Table 2. In the overall group, no significant changes in ambulatory, pre- and post-dialytic blood pressures, echographic parameters and pulse wave velocity were observed, either in the HF or in the HD groups.

When changes in ambulatory blood pressure were separately analysed in normotensive and hypertensive patients (n = 12), no changes were observed in systolic or diastolic blood pressure in the normotensive group (n = 7). In the hypertensive patients, mean systolic blood pressure decreased significantly in the HF group (systolic BP at baseline 149±15 mmHg, after 6 months 136±17 mmHg and after 12 months 134±14 mmHg; P<0.05). However, also in the HD group, mean systolic BP decreased significantly (systolic BP at baseline 153±19 mmHg, after 6 months 141±19 mmHg and after 12 months 141±21 mmHg; P<0.05), without significant differences between the HD and HF groups. No significant changes in diastolic blood pressure were observed.

The change in LVMi in the HF group during the 1 year period was 4±20 g/m2, whereas the change in 48 h systolic blood pressure was 1.2±18 mmHg. The number of antihypertensive agents and medication score also did not change significantly, although there was a tendency towards a rise in both groups. In eight patients (five HF; three HD), angiotensin-converting enzyme inhibitors were started during the study period and were withheld in two patients (one HF; one HD). Noradrenalin levels decreased significantly in both the HD and HF groups, but were not significantly different between both groups. Extracellular water remained constant during the study period (Table 3). Interdialytic weight gain did not change significantly in both treatment groups. In the HF group, interdialytic weight gain was 2.1±0.7 kg at baseline, 1.8±0.9 kg after 6 months and 2.0±0.2 kg after 12 months. In the HD group, interdialytic weight gain was 1.9±0.6 kg at baseline, 2.2±0.6 kg after 6 months and 2.1±0.7 kg after 12 months.

Nutritional parameters
Data are summarized in Table 3. Body weight did not change significantly during the study. In contrast, lean body mass increased significantly in the HF group (1.4±1.9 kg), but not in the HD group, although differences between groups did not reach significance. IGF-1 decreased significantly in the HD group during the study period. In the HF group, IGF-1 levels decreased initially between the 0 and 6 months period, but increased significantly again during the 6 and 12 months period. The difference in IGF-1 levels between the HD and HF groups was significant. No differences in serum albumin, protein catabolic rate (Table 3) or in protein and energy intake assessed by dietary questionnaire were observed between the groups (data not shown). Of note, only 10 patients in the HF group and six patients in the HD group completed all 7 day questionnaires at all time points.

Quality of life
QOL, with regard to physical symptoms, improved significantly in the HF group (4.1±1.4 at baseline, 5.4±0.9 after 6 months and 5.0±1.1 after 12 months; P<0.01), but not in the HD group (4.2±0.9 at baseline, 4.3±1.2 after 6 months and 4.4±1.4 after 12 months), with differences between both groups approaching significance (P = 0.06). QOL for other aspects did not change significantly in any treatment group.

Uraemic toxicity profile
Data are summarized in Table 4. ß2M decreased significantly in the HF but not in the HD group, with significant differences between both groups, the same holding true for complement factor D. Homocysteine decreased significantly in the HF but not in the HD group, whereas the difference was not significant between both groups. ADMA, leptin and AGE-related fluorescence did not change in any group. Of note, leptin levels were significantly related to fat mass (r = 0.65; P<0.01), assessed by DEXA, but also inversely to protein and energy intake (r = –0.44 and –0.48; P<0.05).


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Table 4. Uraemic toxins

 
Other parameters
Haemoglobin levels, serum calcium and phosphate, parathyroid hormone and C-reactive protein did not change within or between groups (Table 5). However, serum sodium increased significantly within the HF group, although the difference with the HD group did not reach significance. Total antioxidant status decreased significantly in the HF group without significant differences between both groups, whereas glutathione peroxidase and superoxide dismutase did not change.


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Table 5. Other laboratory parameters

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present randomized study, the effect of pre-dilution on-line HF on cardiovascular and nutritional state, QOL and the uraemic toxicity profile was compared with low-flux HD using ultrapure dialysate and biocompatible membranes.

With regard to cardiovascular parameters, no significant differences in changes in LVMi, arterial stiffness and 48 h ambulatory blood pressure measurements were observed between HD and HF. No study, as yet, has assessed changes in cardiac parameters during pre-dilution on-line HF. Comparing our data with the only published study to assess cardiac effects of convective techniques, our data are in contrast to those of Schrander-van der Meer et al. [10], who observed a significant decline in LVMi during a follow-up period of 1 year in patients treated with acetate-free biofiltration (AFB) and an increase in LVMi in patients treated with HD. The reason for the discrepant results between their study and the present one is not clear. Convective clearance is much larger during pre-dilution on-line HF as compared with AFB, which is a modified haemodiafiltration technique. It should be noted that volume status, which can have a major influence on cardiovascular parameters, was meticulously controlled and checked in the present study. In our HD patients, LVMi remained stable during the follow-up period.

The absence of changes in structural cardiovascular parameters should be interpreted with caution, as the follow-up time of our study was relatively short and the number of included patients relatively small. However, pronounced changes were observed in even smaller groups of dialysis patients and/or during shorter follow-up periods during quotidian HD [15].

Few studies have assessed the long-term haemodynamic effects of on-line HF. With regard to blood pressure control, our data are in contrast to those obtained by Altieri et al. [3]. Whereas in our study, interdialytic blood pressure control did not differ between the HF and HD groups, Altieri et al. observed an increase in ambulatory blood pressure during pre-dilution on-line HF compared with high-flux HD. However, in this study, reactance and resistance assessed by bioimpedance decreased during the HF period, suggesting an increase in body hydration, whereas the prevalence of patients on antihypertensive treatment appeared to be lower in the HF treatment period [4]. The increase in interdialytic blood pressure during pre-dilution on-line HF was interpreted by Altieri et al. [3] as a beneficial stabilizing effect of the increased convective clearance, contributing to a reduction in intradialytic hypotension.

The results of Altieri et al. [3] suggest that HF might increase blood pressure in hypotensive patients and improve blood pressure regulation in hypertensive patients. Although no patients with severe pre-dialytic hypotension were included in the present study, we also analysed hypertensive patients separately, as potential improvements in blood pressure control might be flawed if only the results of the entire group are presented. Interestingly, in both the HD and HF groups, blood pressure control improved during the year of the study, without significant differences between the groups. This again shows that randomized studies are absolutely necessary if effects of different treatment modalities are to be compared.

Although a slight increase in serum sodium levels was observed within the group of HF-treated patients, the difference with the HD group was not significant. An increased sodium sieving has been observed during HF, due to coating of negative loaded proteins to the haemofilter [16], although in earlier short-term studies, we and others were not able to confirm either a reduced sodium removal or increased sodium sieving during pre-dilution on-line HF [17,18]. As in this study, sodium kinetics were not assessed in detail; more detailed long-term studies are needed to assess the effect of pre-dilution on-line HF treatment on sodium balance. Thus, the discrepant results from the literature remain, as yet, unexplained.

Also, in studies of haemodiafiltration techniques, results regarding blood pressure control are conflicting. Of note, in only a few studies, including the present one, is there objective information on fluid state and was there the use of ambulatory blood pressure monitoring [3,4]. All these discrepant results underline the necessity of strictly standardized procedures for blood pressure analysis and meticulous control of fluid state.

No significant differences in ADMA levels were observed between the HF and HD groups. Noradrenalin levels decreased in both the HF and HD groups. The mechanism behind this observation is not clear, but might be related to the fact that the prescription of angiotensin-converting enzyme inhibitors tended to increase during the study period.

Regarding nutritional state, a small but significant increase in lean body mass was observed within the HF group. Lean body mass, assessed by DEXA, makes no distinction between body cell mass and extracellular water. However, as extracellular water did not change significantly during the study period, the observed changes in lean body mass may reflect an increase in body cell mass. Extracellular water was assessed by multifrequency bioimpedance, which may have shortcomings in HD patients. However, although the assessment of the absolute magnitude of fluid compartments by bioimpedance may be different from ‘gold standard’ techniques, bioimpedance is sensitive in assessing changes in extracellular volume [19].

No significant differences in lean body mass were observed between the HF and HD groups and, thus, these findings should be interpreted with great caution. Still, significant differences between both groups were observed with regard to IGF-1 levels. The mechanism for the potential benefits of HF treatment on nutritional state remains to be elucidated. Changes in leptin levels were not observed, which may be due to the fact that in renal patients, leptin levels are predominantly dependent upon fat mass, as also shown in the present study. Interestingly, however, serum leptin levels were weakly but significantly inversely related to energy and protein intake in our patient cohort.

During HF, no major changes in energy or protein intake were observed. These data should be interpreted with great caution, as various patients did not complete the 7 day questionnaires. However, also protein catabolic rate did not change. Our data are, to a certain extent, in contrast with those of Wizemann et al. [8], who did not observe differences in nutritional status between patients randomized to on-line haemodiafiltration or low-flux HD, although in this study, body composition was not assessed in detail.

In agreement with Altieri et al. [3], we observed an increase in the QOL of patients in the HF group, due to a general improvement in physical well-being. However, it should be noted that patients were not blinded to the treatment modality.

Regarding the uraemic toxicity profile, major improvements were observed in the HF group. ß2M levels, obtained at an interdialytic day, decreased by almost 50%. This reduction appears to be larger compared with earlier studies using on-line haemodiafiltration [7]. However, a direct comparison with previous studies is difficult as patients were often treated with either high-flux dialysis or conventional haemodiafiltration before the on-line treatment was started. Indeed, baseline ß2M levels in patients participating in our study were relatively high compared with previous studies. Also, in addition to the data of Ward et al. [7] using on-line haemodiafiltration, a significant decrease in complement factor D, which stimulates the alternative route of complement, but inhibits the degranulation of polymorphonuclear leukocytes, was observed. In our study, AGE-related fluorescence levels did not change during HF, in contrast to the findings of Lin et al. [5], who observed a decline in total AGE levels in patients treated with on-line haemodiafiltration compared with low-flux dialysis. Differences in methodology to assess AGE may contribute to discrepant results between different studies.

A significant decline in homocysteine levels was observed in HF-treated patients. Whether this change is due to increased protein loss during HF (free and protein-bound homocysteine was measured) or due to increased removal of uraemic toxins responsible for impaired homocysteine metabolism cannot be elucidated from the present study. Thus, the significance of this observation with regard to cardiovascular prevention remains to be determined.

URR and Kt/V were not significantly different between the two treatment modalities, though, especially, Kt/V at 12 months tended to be lower in the HF group. This may be due to the fact that the target filtration volume (1.2 times body weight) was not reached in all patients (mean filtration volume: 77 l, i.e. 1.13 times body weight), given the rise of transmembranous pressure which occurred in some patients. Moreover, intertreatment variations in transmembranous pressure led to some variation in achieved filtration volume, which might explain the small discrepancy between Kt/V and URR in the HF group at t = 12 months.

Lastly, total antioxidant status declined slightly but significantly within the HF group, although the difference with the HD group was not significant. The meaning of this observation is unclear, as the antioxidants superoxide dismutase and glutathione peroxidase did not decrease during HF treatment. However, it is of interest that Morena et al. [20] observed an increase in vitamin C removal in patients treated with on-line haemodiafiltration. Whether this is the explanation of the finding observed in our study remains to be elucidated. Future studies should focus on the potential differences in vitamin requirements between HD and high-volume convective treatments.

Drawbacks of the present study are the relatively small follow-up period and number of included patients (e.g. resulting in a non-significant imbalance in sex ratio, body weight and C-reactive protein levels at baseline). Also, the drop-out ratio was relatively high, although not incomparable with other randomized studies in dialysis patients. Studies in which various parameters are assessed in detail may be demanding for dialysis patients and, indeed, several patients withdrew from our study for personal reasons. Also, the tendency towards a lower Kt/V in the HF group may have exerted an impact on the results.

With regard to the number of studied patients, major changes in cardiac parameters have been observed with smaller numbers of patients or shorter follow-up periods with other interventions, as mentioned previously. Moreover, the standard deviation for the primary outcome variable (i.e. change in LVMi) was comparable to the assumption made in the power analysis. Also, in view of the relatively small standard deviation for changes in, e.g. 48 h systolic blood pressure observed in the present study, clinically important differences could have been detected with the number of patients included. However, it should be admitted that due to the relatively small power of the study, minor changes in some secondary outcome parameters may have gone undetected. Thus, certainly in view of the beneficial effects of on-line HF treatment on the uraemic toxicity profile, larger studies are definitely needed to identify the potential role of convective therapies in the treatment or prevention of cardiovascular morbidity in the dialysis population.

The study focused on stable dialysis patients, eliminating patients with poor cardiovascular function. This was done because the underlying cardiac disease in these patients might have interfered with the outcome parameters, potentially obscuring treatment effects. It was specifically not the aim of the present study to focus on hypotension frequency or intradialytic hypotension, as this issue has been addressed in previous studies by others and our group.

When designing the study, we aimed to assess the effect of on-line HF on erythropoietin requirements. However, due to the label change of the epoetin-alpha brand used in our centres, administration had to be switched from the subcutaneous to the intravenous route, which itself affected erythropoietin requirements.

Concluding, in this prospective randomized study, no significant differences in cardiovascular parameters were observed between patients treated with pre-dilution on-line HF compared with patients treated with low-flux ultrapure HD. However, small but significant improvements were observed in the nutritional state of HF-treated patients, though the difference with the HD group did not reach significance. In addition, treatment with HF resulted in a significant improvement in the physical well-being of dialysis patients and in major improvements in the uraemic toxicity profile.



   Acknowledgments
 
This study was supported by a research grant from Gambro Corporate Research, Lund, Sweden.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Ledebo I. Principles and practice of hemofiltration and hemodiafiltration. Artif Organs 1998; 22: 20–25[CrossRef][ISI][Medline]
  2. Quellhorst EA, Scheunemann B, Mietzsch G. Long-term hemofiltration in ‘poor risk’ patients. Trans Am Soc Artif Intern Organs 1987; 33: 758–764
  3. Altieri P, Sorba G, Bolasco G et al. Predilution hemofiltration – the Second Sardinian Multicentre Study: comparisons between haemofiltration and haemodialysis during identical Kt/V and session times in a long-term cross-over study. Nephrol Dial Transplant 2001; 16: 1207–1213[Abstract/Free Full Text]
  4. Schroder M, Riedel E, Beck W, Deppisch RM, Pommer W. Increased reduction of dimethylarginines and lowered interdialytic blood pressure by the use of biocompatible membranes. Kidney Int Suppl 2001; 78: S19–S24[CrossRef][Medline]
  5. Lin CL, Huang CC, Yu CC, Yang HY, Chuang FR, Yang CW. Reduction of advanced glycation end product levels by on-line hemodiafiltration in long-term hemodialysis patients. Am J Kidney Dis 2003; 42: 524–531[CrossRef][ISI][Medline]
  6. Anderstam B, Mamoun AH, Sodersten P, Bergstrom J. Middle-sized molecule fractions isolated from uremic ultrafiltrate and normal urine inhibit ingestive behavior in the rat. J Am Soc Nephrol 1996; 7: 2453–2460[Abstract/Free Full Text]
  7. Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W. A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol 2000; 11: 2344–2350[Abstract/Free Full Text]
  8. Wizemann V, Lotz C, Techert F, Uthoff S. On-line haemodiafiltration versus low-flux haemodialysis. A prospective randomized study. Nephrol Dial Transplant 2000; 15 [Suppl 1]: 43–48[Medline]
  9. Konings CJ, Kooman JP, Schonck M et al. Effect of icodextrin on volume status, blood pressure and echocardiographic parameters: a randomized study. Kidney Int 2003; 63: 1556–1563[CrossRef][ISI][Medline]
  10. Schrander-van der Meer AM, ter Wee PM, Kan G, Donker AJ, van Dorp WT. Improved cardiovascular variables during acetate free biofiltration. Clin Nephrol 1999; 51: 304–309[ISI][Medline]
  11. Laupacis A, Muirhead N, Keown P, Wong C. A disease-specific questionnaire for assessing quality of life in patients on hemodialysis. Nephron 1992; 60: 302–306[ISI][Medline]
  12. Oppermann M, Baumgarten H, Brandt E, Gottsleben W, Kurts C, Götze O. Quantitation of components of the alternative pathway of complement (APC) by enzyme-linked immunosorbent assays. J Immunol Methods 1990; 133: 181–190[CrossRef][ISI][Medline]
  13. Causse E, Siri N, Arnal JF et al. Determination of asymmetrical dimethylarginine by capillary electrophoresis-laser-induced fluorescence. J Chromatogr B Biomed Sci Appl 2000; 741: 77–83[CrossRef][Medline]
  14. Fagugli RM, Vanholder R, de Smet R et al. Advanced glycation end products: specific fluorescence changes of pentosidine-like compounds during short daily hemodialysis. Int J Artif Organs 2001; 24: 256–262[ISI][Medline]
  15. Chan CT, Floras JS, Miller JA, Richardson RM, Pierratos A. Regression of left ventricular hypertrophy after conversion to nocturnal hemodialysis. Kidney Int 2002; 61: 2235–2239[CrossRef][ISI][Medline]
  16. Di Filippo S, Manzoni C, Andrulli S, Tentori F, Locatelli F. Sodium removal during pre-dilution haemofiltration. Nephrol Dial Transplant 2003; 18 [Suppl 7]: 31–36
  17. David S, Bostrom M, Cambi V. Predilution hemofiltration. Clinical experience and removal of small molecular weight solutes. Int J Artif Organs 1995; 18: 743–750[ISI][Medline]
  18. Beerenhout CH, Dejagere T, van der Sande FM, Bekers O, Leunissen KM, Kooman JP. Haemodynamics and electrolyte balance: a comparison between on-line pre-dilution haemofiltration and haemodialysis. Nephrol Dial Transplant 2004; 19: 2354–2359[Abstract/Free Full Text]
  19. Cox-Reijven PL, Kooman JP, Soeters PB, van der Sande FM, Leunissen KM. Role of bioimpedance spectroscopy in assessment of body water compartments in hemodialysis patients. Am J Kidney Dis 2001; 38: 832–838[ISI][Medline]
  20. Morena M, Cristol JP, Bosc JY et al. Convective and diffusive losses of vitamin C during haemodiafiltration session: a contributive factor to oxidative stress in haemodialysis patients. Nephrol Dial Transplant 2002; 17: 422–427[Abstract/Free Full Text]
Received for publication: 5.11.04
Accepted in revised form: 11. 2.05





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