JNEPHROL 2013; 26 ( 3 ) : 549-555

ORIGINAL ARTICLE

DOI: 10.5301/jn.5000190

Effects of hemodialysis and vitamin E

supplementation on low-density lipoprotein
oxidizability in end-stage renal failure
Simona Baldi 1, Maurizio Innocenti 2, Silvia Frascerra 1,
Monica Nannipieri 1, Alberto Lippi 2, Paolo Rindi 2,
Ele Ferrannini 1

Abstract

Department of Internal Medicine, University of Pisa

School of Medicine, Pisa - Italy
2
Division of Nephrology, Cisanello Hospital, Pisa - Italy
1

Introduction

Background: Cardiovascular diseases represent the

major cause of mortality in hemodialysis (HD) patients. HD increases oxidative stress and oxidation of
low-density lipoprotein (LDL) is a crucial step in the
development of atherosclerosis. Vitamin E has been
shown to reduce LDL oxidation. Our aim was to test
the effect of a single HD session and chronic vitamin
E supplementation on LDL oxidizability in HD patients.
Methods: LDL susceptibility to copper-induced oxidation (lag-phase, LP) was measured in 19 HD patients,
both immediately before and after hemodialysis;
18 age-matched healthy subjects served as controls.
Both pre-HD and post-HD measurements were repeated after 12 weeks of vitamin E supplementation (800
IU/day) in a placebo-controlled, randomized design.
Results: At baseline, HD patients showed hypertriglyceridemia, a significant triglyceride enrichment in LDL
and HDL and an enhanced LDL resistance to oxidation (186 6 vs. 163 4 min, p<0.003). A single HD
session decreased (to 172 6 min, or -8%, p<0.002),
and chronic vitamin E administration increased, LDL
resistance to oxidation (+19%, p = 0.002 vs. placebo)
without changing the serum lipid profile or lipoprotein
lipid composition.
Conclusions: We conclude that in patients on chronic
hemodialysis, hypertriglyceridemia and triglyceride
enrichment of LDL and HDL particles are associated
with increased resistance of LDL to in vitro oxidation
despite the fact that each dialysis session acutely increases LDL oxidizability. Vitamin E supplementation
improves LDL resistance to oxidation without modifying circulating lipid levels and partitioning.
Key words: Hemodialysis, LDL lipid oxidation, Lipopro-

tein metabolism, Oxidizability, Vitamin E

Atherosclerotic cardiovascular disease (CVD) is the most

common cause of morbidity and mortality in patients maintained on long-term dialysis. CVD prevalence is seven-fold
higher in these patients than in the background population,
and approximately one half of the deaths in dialysis patients
can be attributed to atherosclerotic complications. Major
CVD risk factors are similar to those observed in the general population, including dyslipidemia, hypertension and
smoking (1).
Patients with end-stage renal disease (ESRD) on chronic
dialysis have been reported to have a peculiar lipoprotein
profile, characterized by reduced serum HDL-cholesterol
concentrations, raised plasma triglycerides and increased
lipoprotein remnants and lipoprotein(a) (2). Oxidative stress
is thought to play a relevant role in CVD morbidity/mortality
in patients with ESRD (3-5). Hemodialysis per se has been
suggested to induce oxidative stress by generating oxygen
reactive species on the surface of dialysis membranes following activation of polymorphonuclear leukocytes (6, 7). It
has been documented that even a single session of hemodialysis significantly increases lipid peroxides and decreases
antioxidants (8-10). Evidence for increased oxidative stress
includes antioxidant depletion (8) and increased autoantibody titer to oxidized LDL (5). Increased VLDL and LDL susceptibility to oxidation has also been reported (3-5), although
other groups have failed to confirm this finding (11-14).
Oxidatively modified low-density lipoproteins (ox-LDL) play a
prominent role in atherogenesis. LDL oxidation is a lipid peroxidation process in which polyunsaturated fatty acids are
converted into lipid peroxides and aldehydes. -tocopherol
(vitamin E) is a chain-breaking antioxidant and is the most
abundant lipid-soluble antioxidant present in LDL particles
and tissues. Low vitamin E levels have been associated with

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Baldi et al: Serum lipids and LDL oxidation in ESRF

acceleration of atherosclerosis, and a significant inverse

correlation has been found between -tocopherol levels
and CVD mortality (15). Furthermore, the ability of vitamin E
to protect LDL particles from oxidation has been proven in
several in vitro and in vivo studies (15, 16). The conjugated dienes method (CD method) has become the assay of
choice to assess LDL susceptibility to oxidation (17). With
the use of this method, we aimed at assessing the acute
effect of a single session of hemodialysis and the effect of
chronic vitamin E supplementation on LDL susceptibility to
oxidation in patients with ESRD on long-term hemodialysis.

Materials and methods

Patients
Nineteen ESRD patients were recruited from the Hemodialysis Unit, 18 completed the chronic vitamin E supplementation trial. The cause of renal failure was chronic glomerulonephritis in 13 subjects, polycystic kidney disease in
two subjects and lupus glomerulopathy, rapidly progressive
glomerulonephritis, membrano-proliferative glomerulonephritis and renal carcinoma in the remaining four subjects.
All patients were on a thrice-weekly hemodialysis regimen
performed with biocompatibile membranes (polysulfone
and polyamide). The duration of hemodialysis sessions was
gauged in each patient to obtain an adequate depuration index (KT/V1.2). Inclusion criteria were aged between 35-80
years and duration of hemodialysis treatment >10 months (3
1 years, mean SEM). No subject had either clinical history or laboratory evidence of diabetes at the time of study.
Exclusion criteria were drug or alcohol abuse and current
treatment with lipid-lowering agents, non-steroidal or steroidal anti-inflammatory drugs and antioxidant supplements.
Four subjects had a diagnosis of arterial hypertension and
were on anti-hypertensive treatment. Eighteen age-, sexand BMI-matched subjects with normal kidney function
were recruited from the outpatient clinic and laboratory personnel. According to the Declaration of Helsinki, approval
by the local Ethics Committee and informed consent was
obtained by all participants.

Study design and experimental protocol

All examinations were performed between 2.00-6.00 PM
at the time of the scheduled hemodialysis session. Food,
tea, coffee, alcohol and tobacco had been discontinued
from 8-9 am of the study day. The morning dose of usual
medication was regularly taken. Two double-needle cannu550

las were introduced into an arterio-venous fistula of an arm

and a blood sample was obtained for the determination of
LDL susceptibility to oxidation (lag-phase = LP) initially just
before (LP pre-HD) and again at the end (LP post-HD) of
the dialysis session. Subjects were then randomized to oral
supplementation with vitamin E (800 IU/die, 10 subjects,
Vit-E group) or placebo (eight subjects, placebo group), and
LDL susceptibility to oxidation was assessed again pre- and
post-dialysis 12 weeks later.

Measurement of LDL oxidation and lipid parameters

LDL oxidation was measured in vitro according to the experimental protocol of Esterbauer et al (17) with some modifications. In short, blood was collected in tubes containing EDTA (1 mg/mL) and immediately centrifuged at 3000
rpm at 4C. Very-low density-intermediate density (VLDLIDL), low-density (LDL) and high-density (HDL) lipoproteins
(ds = 1.006-1.019, 1.019-1.063 and 1.063-1.210, respectively) were isolated by sequential ultracentrifugation at
42,000 rpm, at 4C (OPTIMA L-90 K, Beckman) in sodium
bromide solutions with EDTA to avoid oxidation during
isolation. All solutions were degassed and samples were
kept at 4C in a dark environment. To remove EDTA,
the LDL fraction was gel-filtered on a Sephadex column
(Econo-Pac 10 DG columns; Bio-Rad) and eluted in PBS
buffer, pH = 7.4. To quantitate LDL susceptibility to copperinduced oxidation, the protein concentration of the LDL
fraction was adjusted to 50 g/mL by measuring proteins
with the bicinchoninic acid method. Finally, freshly prepared CuSO4 (final concentration 0.25 M) was added and
the kinetics of conjugated dienes formation were followed
spectrophotometrically at 234 nm at 37C every 1.5 min for
seven hours. A typical LDL oxidation curve (Fig. 1) shows
three consecutive phases: the lag-phase (LP), the propagation phase and the decomposition phase. The lag-phase
is defined as the x-axis intercept of the cross-point of the
tangents to the first (slope A) and second phase (slope B).
This time lag depends on intrinsic properties of the LDL
particle (antioxidants content, size, preformed lipid peroxides) as well as experimental conditions (17). During this
phase, the LDL particle gradually loses its antioxidant contents without undergoing major oxidation. In separate experiments using 30 replicates, we estimated the precision
of the method to be 8%.
Total cholesterol and triglycerides (Tg) concentration in plasma and lipoprotein fractions, and plasma HDL-cholesterol
levels were determined by enzymaticcolorimetric methods
using an ERIS Analyzer. Plasma LDL-cholesterol concentration was calculated using Friedewalds formula.

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Statistical analysis
Results are expressed as mean SEM. Data were analyzed
by paired or unpaired Student t test and ANCOVA as appropriate, two-way ANOVA for repeated measures and linear
regression.

Results

Fig. 1 - Mean time-courses of conjugated dienes formation

from LDL particles incubated with copper in patients before
(white circles) and after (black circles) a single haemodialysis.
The lag-phase is obtained as the time on the x-axis intercept
of the cross-point of slope A and slope B for each curve. Values are mean SEM.

The clinical characteristics of the study subjects are given

in Table I together with the serum lipid profile. Patients had
higher plasma Tg levels, a relative enrichment of LDL particles with Tg and a longer lag-phase as compared to controls. The HDL lipoproteins were also relatively enriched in
Tg, whereas the VLDL + IDL fraction was slightly enriched
in cholesterol.
After a single hemodialysis, total, LDL- and HDL-cholesterol
concentrations all showed modest (~15%) but statistically
significant increments. Although Tg were reduced by 20%
post-dialysis, this was not associated with changes in the Tg
content of LDL, while the Tg /cholesterol ratio in VLDL + IDL
and HDL was normalized. The hemodialysis session caused

Table I
Characteristics of the study subjects
Controls

Pts pre-HD

Pts post-HD

P#

18

19

18

Sex (M/F)

9/9

9/10

55 1

61 3

BMI (kg/m2)

25.8 0.5

25.4 0.9

Serum total cholesterol (mmol/L)

5.21 0.13

5.01 0.13

5.68 0.26

<.001

Serum LDL-cholesterol (mmol/L)

3.50 0.18

2.95 0.16*

3.58 0.23

<.001

Serum HDL-cholesterol (mmol/L)

1.24 0.10

1.09 0.10

1.32 0.13

<.001

Serum triglycerides (Tg) (mmol/L)

1.00 0.09

2.22 0.21

1.79 0.20

<.03

VLDL+IDL

2.50 0.24

1.86 0.13

2.15 0.12

.055

LDL

0.09 0.01

0.16 0.01

0.15 0.01

n.s.

HDL

0.08 0.01

0.13 0.01*

0.10 0.01

<.007

163 4

186 6

172 6

<.002

Age (y)

Tg/cholesterol ratio in:

LDL lag-phase (min)

* P<.04, P<.03, P<.003 for the difference from controls.

# for the difference between pre- and post-HD.
BMI = body mass index; F = female; HDL = high density lipoprotein; IDL = intermediate density lipoprotein; LDL = low density
lipoprotein; M = male; VLDL = very low density lipoprotein; y = years.

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Baldi et al: Serum lipids and LDL oxidation in ESRF

Fig. 2 - Relationship between lag-phase and the triglycerideto-cholesterol ratio in LDL particles.

a decrease in LDL resistance to oxidation (lag-phase) (cf,

mean time-course of conjugated dienes formation, Fig. 1).
In the whole dataset (patients + controls), there was a direct relationship between the lag-phase and Tg both as total
plasma concentration (r = 0.46, P<.005) and relative content
in the LDL subfraction (Fig. 2). The lag-phase shortening induced by dialysis, in contrast, was not related to changes in
either total or LDL-Tg.
After 12 weeks of vitamin E supplementation, LDL lagphase was prolonged in the vitamin E group by 19%, while
it remained unchanged in the placebo group (Fig. 3). Neither the serum lipid profile nor lipoprotein composition
was changed by either treatment nor were the other kinetic parameters different at 12 weeks vs. baseline. Chronic
vitamin E supplementation did not prevent the acute effect
induced by a single hemodialysis on the lag-phase (Tab. II).

Discussion
Potentially atherogenic abnormalities of lipoprotein composition and metabolism may contribute to the high incidence
of CVD in subjects on hemodialysis. Reduced lipolysis of
VLDL particles, resulting in hypertriglyceridemia and lower
levels of HDL, has been demonstrated previously (1, 18).
Hypertriglyceridaemia has been associated with the presence of a small, dense LDL phenotype, characterized by
lower cholesterol/Tg ratios both in uremic patients (19) and
in the healthy population (20). Accordingly, in our patients
plasma Tg concentrations were higher and HDL-cholesterol tended to be lower than in control subjects pre-dialysis
(Tab. I) and both LDL and HDL fractions were enriched in
552

Fig. 3 - Lag-phase values (mean SEM) in hemodialysis patients pre-HD (grey bars) and post-HD (black bars) at baseline
and after 12 weeks of treatment with vitamin E or placebo.
*P<.05 vs. baseline.

Tg. In uremic patients, the Tg enrichment of LDL has been

attributed to a prolonged LDL residence time by means of
an enhanced exposure to CETP activity (21).
Our finding of a reduced susceptibility to oxidation in the
ESRD patients as compared to healthy controls is in contrast with some previous studies reporting an enhanced
level of oxidative stress and a shorter LDL lag-phase
(3-5) but agrees with other studies that have reported
similar or lower LDL oxidizability in these patients (13, 14,
22, 23). The heterogeneity of the published results might be
related to inadequate control for LDL composition and/or
different experimental conditions. Particularly with regard to
copper sulphate, the higher concentrations used in some
studies yield shorter lag-phases, thereby reducing the sensitivity of the method.
With regard to the influence of LDL lipid composition, in a
large cross-sectional dataset we observed that LDL resistance to oxidation is positively related to the LDL Tg enrichment (24). This association was also found in this series and
is in line with clinical and experimental evidence (25-27). Our
finding of a longer lag-phase in ESRD does not, however,
necessarily imply that the uremic condition is characterized
by a reduced oxidative stress but only that LDL oxidizability
may reflect LDL lipid composition. This is not surprising given the characteristics of this ex vivo test, which specifically
explores the ability of LDL particles to resist an artificial oxidative aggression. The test does not assess the balance of
oxidative and anti-oxidative forces of the environment where
LDL live (i.e., the plasma and subendothelial space) nor does
it estimate other crucial factors that affect LDL oxidation in
vivo, such as the particle mean residence time in each envi-

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Table II
Influence of a single hemodialysis (HD) and vitamin E supplementation on lipid parameters and
lag-phase
Treatment

Week 0

Week 12

Pre-HD

Post-HD

Pre-HD

Post-HD

Serum total C

Vit E

4.97 0.28

5.52 0.34

4.79 0.23

5.62 0.44

(mmol/L)

Placebo

5.00 0.34

5.91 0.47

5.39 0.52

5.80 0.54

Serum Tg

Vit E

2.23 0.38

1.91 0.40

1.80 0.36

1.65 0.32

(mmol/L)

Placebo

2.08 0.23

1.57 0.14

1.94 0.17

1.53 0.13

Serum HDL-C

Vit E

0.85 0.05

0.98 0.10

0.85 0.05

1.11 0.10

(mmol/L)

Placebo

1.19 0.16

1.53 0.21

1.17 0.21

1.48 0.21

Serum LDL-C

Vit E

3.11 0.28

3.65 0.36

3.13 0.23

3.78 0.41

(mmol/L)

Placebo

2.88 0.23

3.68 0.34

3.34 0.39

3.65 0.41

Vit E

1.84 0.16

2.03 0.18

2.01 0.20

1.95 0.14

Placebo

1.75 0.24

2.15 0.15

1.70 0.10

2.17 0.19

Vit E

0.15 0.02

0.14 0.01

0.16 0.02

0.14 0.02

Placebo

0.17 0.02

0.16 0.02

0.16 0.02

0.15 0.02

Vit E

0.13 0.02

0.10 0.02

0.10 0.01

0.08 0.01

Placebo

0.14 0.02

0.10 0.02

0.13 0.02

0.09 0.02

Vit E

192 9

174 11

228 19*

206 22*

Placebo

177 8

172 8

179 5

164 8

Tg/chol ratio in:

VLDL+IDL

LDL

HDL

Lag-phase (min)

*P = .002 for the effect of a single hemodialysis and P<.04 for the effect of vitamin E by two-way ANOVA for repeated measures.
HDL = high density lipoprotein; IDL = intermediate density lipoprotein; LDL = low density lipoprotein; VLDL = very low density
lipoprotein.

ronment. Noteworthy, the relative enrichment in triglycerides

of LDL particles only determines in part the LP value (r2 =
0.24) and it contributes only partially to account for the higher LP values in hemodialysis patients with respect to control
subjects. Other factors, such as elevated levels of oxidized
phospholipids in apoB carrying lipoproteins (OxPL/apoB ratio), oxidized circulating LDL and related immune complexes
(28), by limiting the accessibility of copper to the LDL moiety,
could in fact be responsible for an increased resistance to
oxidation of LDL particles in ESRD patients. After a single
HD we observed an increase in serum total, LDL- and HDLcholesterol, which can be explained well by the acute hemoconcentration because of the procedure. This interpretation

is supported by the fact that the differences between postand pre-HD values were positively related to the weight loss
(r values of 0.46-0.57, P<.05 for all). In contrast, serum Tg
levels were significantly lower after a single dialysis probably
as a consequence of the stimulated activity of the lipoprotein
lipase induced by heparinization. Although these changes
in total serum cholesterol and Tg were not associated with
significant changes in LDL composition, the lag-phase was
reduced by 10%, suggesting that dialysis caused a reduction in the antioxidants normally resident on LDL. The only
two studies (11, 13) that have assessed the in vitro LDL resistance to copper-mediated oxidation after a single session
of hemodialysis have reported no acute effect.

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Baldi et al: Serum lipids and LDL oxidation in ESRF

Vitamin E is the major antioxidant present in LDL and its

role in inhibiting LDL susceptibility to copper-induced oxidation is well documented both in vitro and in vivo (15).
After three months of vitamin E supplementation in our patients, the lag-phase increased by 19% above baseline values (P<.04); this result is in agreement with a previous report demonstrating a 21% increment by the same vitamin
E dose (29). On the other hand, and contrary to expectation, chronic vitamin E treatment failed to prevent the acute
lag-phase reduction induced by each hemodialysis, indicating that the latter phenomenon may not be consequent
upon chronic vitamin E consumption. A dialysis session,
by imposing a severe oxidative stress, leads to an acute
reduction of all LDL antioxidants (not only vitamin E); by
removing water soluble antioxidants (30), it slows down the
recovery of lipid soluble antioxidants (31), thereby resulting in a more vulnerable LDL particle. Enhancing the basal
LDL resistance to oxidation by chronic vitamin E supplementation in ESRD patients might nevertheless be helpful

to prevent acute exhaustion of anti-oxidants and very low

lag-phase values during prolonged, frequent hemodialysis
sessions. Clearly, the value of this intervention in the progression of atherosclerosis remains to be demonstrated.
Financial support: The study was supported by institutional
research funds.
Conflict of interest statement: None of the authors has any conflict
of interest.

Address for correspondence:

Simona Baldi, MD
Dipartimento di Medicina Interna
Via Roma 67
56100 Pisa, Italy
sbaldi@ifc.cnr.it

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Accepted: May 10, 2012

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