Journal of the American Society of Nephrology 1703 High-Flux Dialysis Membranes Improve Lipid Profile in Chronic Hemodialysis Patient&’2 Peter J. Blankestijn,3 Pieter F. Vos, Ton J. Rabelink, Herman J.M. van Rijn, Hans Jansen, and Hem A. Koomans P.J. Blankestijn. T.J. Rabelink. HA. Koomans. Depart- ment of Nephrology, University Hospital, Utrecht, The Netherlands H.J.M. van Rijn, Department of Clinical Chemistry, University Hospital, Utrecht, The Netherlands P.F. Vos. Home Dialysis Foundation, Utrecht, The Netherlands H. Jansen, Department of Internal Medicine Ill and Biochemistry. Erasmus University. Rotterdam , the Netherlands (J. Am. Soc. Nephrol. 1995; 5:1703-1708) ABSTRACT In a controlled prospective trial, the effect of a switch from cellulose-based, low-flux dialysis membranes to polysulphone, high-flux membranes on lipid param- eters was evaluated. Baseline values of lipid param- eters were identical in the study group and the control group in which the dialysis membrane remained unchanged. After 6 wk, total triglyceride, very low- density lipoprotein (VLDL) triglyceride, and VLDL cho- lesterol decreased, respectively, 28 ± 17 (P < 0.01), 38 ± 17 (P < 0.01), and 24 ± 21% (P < 0.05), and the proportion of total cholesterol that was high-density lipoprotein cholesterol increased from 15 ± 5 to 18 ± 5% (P < 0.05) in the high-flux polysulphone group, whereas these variables remained unchanged in the control group. Low-density lipoprotein and total cho- lesterol as well as Kt/V, protein catabolic rate, para- thyroid hormone, albumin, and body weight did not change. No change in Iipoprotein Iipase activity was found. In a second study, the effects of a single hemodialysis session with high-flux polysulphone and low-flux, cellulose-based membranes on lipid param- eters and lipolytic activity were compared in a cross- over fashion. Treatment with both membranes re- suIted in a significant decrease in plasma triglyceride, VLDL triglyceride, and VLDL cholesterol. Lipoprotein lipase activity increased during hemodialysis. 1 ReceIved June 28, 1994. Accepted November 30, 1994. 2 Part of this study has been presented at the 26th Annual Meeting of the American Society of Nephrology, November 14-17, 1993, Boston, and published in abstract form In JASN (1993:4:334). 3 correspondence to Dr. P.J. Blankestlin, Room F03.226. Department of Nephrol- ogy, UnIversity Hospital, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. 1044.6673/0509-1 703$03.00/0 Journal of the American Society of Nephrology copyght C 1995 by the American Society of Nephrology Changes in lipid parameters and lipolytic activity were identical during the two treatments. These data indicate a favorable change in lipid parameters after the switch from low-flux, cellulose-based to high-flux, polysulphone dialysis membranes that appeared not to be caused by an enhancement of lipoprotein lipase activity. Changes are of similar magnitude as can be obtained with dietary and pharmacologic treatments. Key Words: Hemodialysis, high flux, lipid abnormallties T he typical lipid profile of patients undergoing chronic hemodlalysis treatment demonstrates a moderate increase in triglyceride, normal cholesterol, decreased high-density lipoprotein (HDL) cholesterol, and increased lipoprotein (a) (1 ). At present, it Is not completely clear to what extent these abnormalities contribute to the high Incidence of cardiovascular morbidity and mortality in these patients. However, in the normal population, this profile is associated with an increased risk of cardiovascular disease, and a decrease of triglyceride levels might reduce this risk (2). The concentrations of lipoproteins in renal failure patients may be increased as a consequence of in- creased synthesis, decreased catabolism, or a combi- nation of both processes. There is some evidence of an increased synthesis (3). However, most studies indi- cate that decreased breakdown predominates ( 1), which has been ascribed, at least in part, to reduced lipid catabolism, secondary to reduced activity of lipo- lytic enzymes, i.e. , lipoprotein lipase (LPL) and hepatic lipase (HL) (4). LPL Is bound to the luminal surface of the capillary endothellal cells, where hydrolysis takes place. It can be released Into the bloodstream by heparin, which causes an acute decrease in triglycer- ide (4,5). This heparin-induced lipolysis is markedly diminished In hemodlalysis patients (4,5). Suggested underlying mechanisms of the reduced lipolytic activ- ity include depletion of LPL stores by repeated admin- istration of heparin (5), the existence of LPL inhibi- tor(s) in uremic plasma (6), and increased levels of apolipoprotein CIII (7), whIch is an inhibitor of lipolytic activity. Also, hyperparathyroidism might play a role, although the exact mechanism is unclear (8). Finally, cytokines produced during dialysis might be able to reduce LPL activity (9). The type of dialysate buffer, that is, acetate or bicarbonate, does not seem to influence lipid parameters (10), whereas dialysate glu- cose concentration up to 11 mmol/L does not contrib- ute to the dyslipidemla ( 1 1). Some data suggest that
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Journal of the American Society of Nephrology 1703
High-Flux Dialysis Membranes Improve Lipid Profile inChronic Hemodialysis Patient&’2Peter J. Blankestijn,3 Pieter F. Vos, Ton J. Rabelink, Herman J.M. van Rijn, Hans Jansen, and
Hem A. Koomans
P.J. Blankestijn. T.J. Rabelink. HA. Koomans. Depart-ment of Nephrology, University Hospital, Utrecht, TheNetherlands
H.J.M. van Rijn, Department of Clinical Chemistry,University Hospital, Utrecht, The Netherlands
P.F. Vos. Home Dialysis Foundation, Utrecht, TheNetherlands
H. Jansen, Department of Internal Medicine Ill andBiochemistry. Erasmus University. Rotterdam , theNetherlands
(J. Am. Soc. Nephrol. 1995; 5:1703-1708)
ABSTRACTIn a controlled prospective trial, the effect of a switch
from cellulose-based, low-flux dialysis membranes topolysulphone, high-flux membranes on lipid param-
eters was evaluated. Baseline values of lipid param-eters were identical in the study group and the controlgroup in which the dialysis membrane remainedunchanged. After 6 wk, total triglyceride, very low-
density lipoprotein (VLDL) triglyceride, and VLDL cho-
lesterol decreased, respectively, 28 ± 17 (P < 0.01), 38± 17 (P < 0.01), and 24 ± 21% (P < 0.05), and theproportion of total cholesterol that was high-densitylipoprotein cholesterol increased from 15 ± 5 to 18 ±5% (P < 0.05) in the high-flux polysulphone group,whereas these variables remained unchanged in thecontrol group. Low-density lipoprotein and total cho-lesterol as well as Kt/V, protein catabolic rate, para-thyroid hormone, albumin, and body weight did not
change. No change in Iipoprotein Iipase activity wasfound. In a second study, the effects of a singlehemodialysis session with high-flux polysulphone and
low-flux, cellulose-based membranes on lipid param-
eters and lipolytic activity were compared in a cross-over fashion. Treatment with both membranes re-
suIted in a significant decrease in plasma triglyceride,VLDL triglyceride, and VLDL cholesterol. Lipoproteinlipase activity increased during hemodialysis.
1 ReceIved June 28, 1994. Accepted November 30, 1994.
2 Part of this study has been presented at the 26th Annual Meeting of the
American Society of Nephrology, November 14-17, 1993, Boston, and publishedin abstract form In JASN (1993:4:334).
3 correspondence to Dr. P.J. Blankestlin, Room F03.226. Department of Nephrol-ogy, UnIversity Hospital, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
1044.6673/0509-1 703$03.00/0Journal of the American Society of Nephrologycopy�ght C 1995 by the American Society of Nephrology
Changes in lipid parameters and lipolytic activity
were identical during the two treatments. These dataindicate a favorable change in lipid parameters afterthe switch from low-flux, cellulose-based to high-flux,
polysulphone dialysis membranes that appeared notto be caused by an enhancement of lipoproteinlipase activity. Changes are of similar magnitude as
can be obtained with dietary and pharmacologic
treatments.
Key Words: Hemodialysis, high flux, lipid abnormallties
T he typical lipid profile of patients undergoing
chronic hemodlalysis treatment demonstrates a
moderate increase in triglyceride, normal cholesterol,
decreased high-density lipoprotein (HDL) cholesterol,and increased lipoprotein (a) ( 1 ). At present, it Is not
completely clear to what extent these abnormalities
contribute to the high Incidence of cardiovascular
morbidity and mortality in these patients. However, in
the normal population, this profile is associated
with an increased risk of cardiovascular disease, and
a decrease of triglyceride levels might reduce this
risk (2).
The concentrations of lipoproteins in renal failure
patients may be increased as a consequence of in-
creased synthesis, decreased catabolism, or a combi-
nation of both processes. There is some evidence of an
increased synthesis (3). However, most studies indi-
cate that decreased breakdown predominates ( 1),
which has been ascribed, at least in part, to reduced
lipid catabolism, secondary to reduced activity of lipo-
lytic enzymes, i.e. , lipoprotein lipase (LPL) and hepatic
lipase (HL) (4). LPL Is bound to the luminal surface of
the capillary endothellal cells, where hydrolysis takes
place. It can be released Into the bloodstream by
heparin, which causes an acute decrease in triglycer-
ide (4,5). This heparin-induced lipolysis is markedly
diminished In hemodlalysis patients (4,5). Suggested
underlying mechanisms of the reduced lipolytic activ-
ity include depletion of LPL stores by repeated admin-
istration of heparin (5), the existence of LPL inhibi-
tor(s) in uremic plasma (6), and increased levels of
apolipoprotein CIII (7), whIch is an inhibitor of lipolytic
activity. Also, hyperparathyroidism might play a role,
although the exact mechanism is unclear (8). Finally,
cytokines produced during dialysis might be able to
reduce LPL activity (9). The type of dialysate buffer,
tion, and diet were not changed and were evaluated. In
addition, we compared the acute effects of a single
hemodialysis treatment with either membrane on LPL
activity and lipids.
PATIENTS AND METHODS
Patients
The total population of our institution comprises approxi-mately 1 20 chronic hemodialysis patients. Of this popula-tion, we included 28 consecutive, stable, long-term (>6months on hemodialysis) patients ( 10 male), who were onlow-flux, cuprophane membranes (Asahi AM 140 and 160Nova: Asahi Medical Co, Tokyo, Japan). All were white and
gave informed consent. Patients were excluded when theywere diabetic or were on medications that raise or lowerlipids. Bicarbonate dialysate containing 1 1 mmol/L glucosewas used throughout. The diet comprised 1 .0 to 1 .2 g/kgbody wt of protein, 30 to 35% of caloric Intake as fat, and 50to 55% as carbohydrates. Primary renal diagnosis was un-known in six patients, chronic pyelonephritis with or without
urolithiasis in seven, glomerulonephritis in five, Alport’sdisease in one, polycystic kidney disease in five, glomerulo-
sclerosis in two, and hypertension in two. The median age(range) was 63 (22 to 80) yr, duration on hemodialysistreatment was 24 (6 to 1 76) months, two patients weredialyzed twice, and the remainder were dialyzed thriceweekly. Mean ± SD duration of therapy per week was 1 1 ±
1 .4 h. Total amount of heparmn administered during dialysiswas 15.247 ± 3.462 U/wk. Regular heparmn was used. The28 patients were randomly divided in two groups. Before thestart of the study, it was ascertained that the two groupswere comparable with respect to lipid parameters by com-paring the mean values of cholesterol and triglyceride mea-surements, which were done routinely every 4 months. Four-teen patients (Group A) were studied before and after switchto high-flux membranes: in the remaining 14 patients (GroupB), the dialysis membrane remained unchanged.
Protocols
The two groups were studied according to the followingprotocol. After an overnight fast, blood was collected from thearteriovenous fistula before dialysis for lipid parameters and
parathyroid hormone. Subsequently, 50 U/kg body wt ofregular heparin was injected iv in the contralateral arm. After20 mlii, blood was collected from the arteriovenous fistula ina chilled tube for LPL. In the week before the blood collection,calculated Kt/V and protein catabolic rate were recorded.Residual renal function was taken into account. From thenext dialysis session onward, the patients in Group A weredialyzed with a F6OS polysulphone, high-flux dialyzer (Fre-senlus AG, Bad Homburg, Germany). In both groups, bloodand dialysate flow, length and number of weekly sessions,and total amount of heparmn used during dialysis, as well asmedication and diet, were not changed during the studyperiod. Six weeks after the first measurements of lipid pa-rameters, blood was collected by the use of the same proto-col. Dialysis membranes were used only once. Diet adher-ence was evaluated by the use of a diet diary at baseline andafter 6 wk.
In a second study, six chronic hemodialysis patients (3
men) were randomly selected from the previous study group.In random order, 1 wk apart, they were treated with thehigh-flux, polysulphone or the low-flux, cuprophane mem-brane after an overnight fast. They were not allowed to eat ordrink during the dialysis session. Blood was sampled before,during, and at the end of the dialysis. After blood samplingfor basal values, a bolus injection of 2,500 U of heparin wasgiven at the start of dialysis. Then, a continuous infusion ofheparin was instituted: the dose was adjusted according tothe results of periodic partial thromboplastin time determi-nations but was the same during both studies. All patientswere treated three times for 3.5 h a week.
Methods
Lipid parameters were measured as described previously(16). In brief, for the separation of lipoproteins, plasmasamples were subjected to a single ultracentrifugation stepat 4#{176}Cfor 20 h in a 50.3 Ti rotor (Beckman Instruments, PaloAlto, CA). Cholesterol and triglyceride were measured with afully automated Hitachi 7 1 7 analyzer from Boehringer
Mannheim GmbH (Mannheim, Germany) with the enzymaticapplications with reagents obtained from the same company.The phosphotungstlc acid-magnesium chloride precipitationmethod was used to measure HDL cholesterol together withthe cholesterol-cholesteroloxidase-phenol 4-aminophenazonemethod. Lipoprotein (a) was measured as described elsewhere(17).
LPL and HL were determined separately by an immuno-chemical method, essentially as described by Huttunen et a!.(18), with a gum acacia-stabilized l3Hltrioleoylglycerol emul-
sion. HL activity was determined as the salt-resistant lipasein the presence of 1 M NaC1. LPL activity was determinedafter the Inhibition of HL with a goat antibody raised againstHL purified from postheparin human plasma. Fasted ratserum was added as a source of apolipoprotein CII. A traceramount of I ‘4Cloleate was added to the substrate as aninternal standard for the extraction of l3Hjoleate liberatedfrom [3Hltrioleoylglycerol substrate. In each series of deter-minations, pooled plasmas with high and low LPL and HLwere included as a reference. The normal values of LPL are>70 U/L in men and >80 U/L in women and ofHL are >300U/L in men and >225 U/L in women.
Kt/V was calculated with the urea values determinedbefore and after hemodialysis (19). Data are presented asmean ± SD. Results of both studies were analyzed by atwo-way analysis of variance. If the variance ratio obtainedby the analysis of variance reached statistical significance,
75
50
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0a)Ca)0
a)
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-50
-75
I**
LT��rr
Blankestijn et al,
Journal of the American Society of Nephrology 1705
the differences between the means of the observations were
analyzed at the 5 and 1% significance levels by the least
significance difference test.
RESULTS
The patients who were switched to the high-flux
membrane (Group A) and the control patients (GroupB) did not differ with regard to age, duration on
chronic hemodialysis therapy, frequency (in both
groups, one patient twice weekly and the remainder
thrice weekly), length of weekly sessions ( 10.0 ± 1.5
versus 10.8 ± 1 .4 h/wk), and total amount of heparin
administered during the hemodialysis session (14.835
± 2,230 versus 16.398 ± 3,900 U/week). The switch
did not cause any clinically detectable changes or side
effects, although the study was not specifically de-
signed to address this question. Lipid parameters at
baseline did not differ (Table 1 ). After 6 wk of treat-
ment with a high-flux membrane, fasting total triglyc-
eride, very low-density lipoprotein (VLDL) triglyceride,
and VLDL cholesterol were significantly decreased In
Group A, respectively, by 28 ± 17 (P < 0.01), 38 ± 17
a Data are means ± SD. control, low-flux, cellulose based; 1G. triglycerIde; LDL. low-density lipoprotein; cI. confidence Interval.
b p < 0.05, comparison with value at start of hemodialysis.C p < 0.01 . comparison with value at start of hemodialysis.
.J
E.�,-
E
-J
0.-J
Figure 2. Effects of a single hemodialysis on LPL Data aremeans ± SD at baseline and after 1, 2, and 3.5 h (end) ofdialysis. Triangles, high-flux polysulphone; squares, low-flux,cellulose based.
cellulose-based membranes to high-flux, polysul-
phone membranes in patients on maintenance hemo-
dialysis. The baseline lipid abnormalities in our pa-
tients are similar to those described in the literature
( 1). Hemodialysis with the high-flux, polysulphone
membrane was associated with a decrease in total
triglyceride, VLDL triglyceride, and VLDL cholesterol
and an Increase In the proportion of total cholesterol
that was HDL cholesterol. An effect of confounding
factors such as dialysis characteristics, medication,
diet, change in parathyroid hormone levels, or heparin
dosage could be excluded, because these factors werenot different in the treatment group and the control
group and did not change throughout the study.
These results establish that hemodialysis with a high-
flux membrane has a favorable effect on lipid param-
eters.
Dumler et a!. ( 13) found a decrease in triglyceride
and cholesterol when their patients were switched
from conventional hemodialysis therapy with cellu-
lose-based membranes to hemodialysis with high-
flux, polysulphone membranes. However, because
this study was designed to evaluate the safety and
efficacy of short-time dialysis, several other dialysis
characteristics were changed as well, making it diffi-
cult to define the contribution of the dialysis mem-
brane. Josephson et a!. ( 14) found, in a cross-sec-
tional study, lower triglyceride and identical total
cholesterol and HDL cholesterol in 18 patients who
were treated with high-flux membranes (polysulphone
or cellulose triacetate) as compared with 1 6 patients
undergoing dialysis using low-flux, cellulose-based
membranes. However, in many oftheir patients, blood
was sampled while the patients were not in fasting
state. Finally, Seres et a!. ( 15) demonstrated lower
triglyceride and higher LPL in patients on high-flux,
polysulphone dialysers as compared with patients
Blankestijn et al,
Journal of the American Society of Nephrology 1707
dialyzed with cellulose-based membranes. However,
their study was mainly cross-sectional. Moreover, be-
cause blood samples were obtained immediately after
dialysis, the steady-state effects on lipids and LPL
were not evaluated in that study.
The change in lipid variables In this study could very
well fit with an enhancement of lipolytic activity (5).
However, we found that the decrease in predialysis
triglyceride did not coincide with an increase in pre-
dialysis lipolytic activity. Therefore, we studied in a
subset of patients the effects of a single dialysis on
lipid parameters and lipolytic activity. Both dialysis
treatments caused similar decrements in triglyceride,
VLDL triglyceride, and VLDL cholesterol and an incre-
ment in low-density lipoprotein, presumably the re-
sult of the increased VLDL catabolism during dialysis.
This triglyceride-lowering effect of hemodialysis was
also found by others (20,2 1) and is probably caused by
the increase in plasma LPL activity. LPL is bound to
the endothelium and released by heparin (5). Teraoka
et a!. (20) found that lipolytic activity increased and
triglyceride levels decreased during hemodialysis with
heparmn, but not when heparin was omitted. We also
found a transient increase in LPL during hemodialy-
sis, but importantly, this effect was similar with the
two membrane types. Therefore, our data make It
unlikely that the long-term triglyceride-lowering effect
of high-flux membranes Is due to LPL stimulation. A
possible explanation is offered in a recent report by
Otsubo et a!. (22). They showed that treatment with
dLfl, when in the presence ofcoexisting coronary heart
disease, diabetes mellitus, chronic renal failure, or
low levels of HDL cholesterol, should be treated (2).
One or more of these conditions usually exist in
hemodialysis patients. Studies in uremic patients
have documented the efficacy of dietary modulations
(27-29) or drugs such as clofibrate, gemfibrozil, and
bezafibrate (30-32). Of note, the presenily described
switch in dialysis membrane is equally effective as
dietary modifications (27-29) and almost as effective
as fibrates (30-32). The latter, however, can have
serious side effects in renal failure patients (33,34),
which limits their clinical use. This study indicates
that the choice of dialysis membrane offers an oppor-
tunity to reduce the dyslipidemla without adverse
effects and without problems with the compliance of
the patients.
ACKNOWLEDGMENTST.J. Rabelink is sponsored by a fellowship of the Royal Dutch Acad-
emy of Sciences (KNAW).
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Lipid Profile During High-Flux Dialysis
1708 Volume 5 ‘ Number 9 ‘ 1995
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