Biomarkers and Genomic Medicine (2015) 7, 125e130

Available online at www.sciencedirect.com

ScienceDirect
journal homepage: www.j-bgm.com

ORIGINAL ARTICLE

Effects of combined supplementation of

vitamins C and E on the oxidative
modification of low-density lipoprotein,
soluble form of CD36, soluble vascular cell
adhesion molecule-1, and nitrite/nitrate
oxide levels in idiopathic nephrotic
syndrome
Omega Mellyana a,*, Edi Dharmana b, Hardhono Susanto c,
Nanan Sekarwana d
a
Division of Nephrology, Department of Child Health, Faculty of Medicine, Diponegoro University/Dr.
Kariadi Hospital, Semarang, Central Java, Indonesia
b
Division of Parasitology Clinical and Immunology, Faculty of Medicine, Diponegoro University/Dr.
Kariadi Hospital, Semarang, Central Java, Indonesia
c
Department of Anatomy, Faculty of Medicine, Diponegoro University, Central Java, Semarang,
Indonesia
d
Division of Nephrology, Department of Child Health, Faculty of Medicine, Padjadjaran University/Dr.
Hasan Sadikin Hospital, Bandung, West Java, Indonesia

Received 23 December 2014; received in revised form 26 February 2015; accepted 1 April 2015

Available online 14 June 2015

KEYWORDS
antioxidant;
atherosclerosis;
inflammation;
scavenging receptor

Abstract This study aimed to investigate whether a combined supplementation of vitamins C

and E was able to modify the oxidized low-density lipoprotein (ox-LDL), soluble form of CD36
(sCD36), soluble vascular cell adhesion molecule-1 (sVCAM-1), and nitrite/nitrate oxide (NOx)
levels in pediatric nephrotic syndrome (NS) cases. The study included 36 children with NS. The
patients were randomly allocated to either the treatment group or the placebo group (18 children each). The treatment group received a combined supplementation of vitamins C and E.
The serum levels of ox-LDL, sCD36, and sVCAM-1 were assayed by enzyme-linked immunosorbent assay. The serum levels of NOx were assayed by colorimetric assay. Results showed that

* Corresponding author. Division of Nephrology, Department of Child Health, Faculty of Medicine, Diponegoro University/Dr. Kariadi
Hospital, Jalan Dokter Sutomo Number 16, Semarang, Central Java 50244, Indonesia.
E-mail address: omegamellyana@gmail.com (O. Mellyana).
http://dx.doi.org/10.1016/j.bgm.2015.04.001
2214-0247/Copyright 2015, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved.

126

O. Mellyana et al.
the levels of ox-LDL, sVCAM-1, and NOx were decreased after treatment with a combined supplementation of vitamins C and E, but there was no statistical difference (p > 0.05). After
treatment, there was an increase in the level of sCD36 in both groups, although this was not
significantly different (p > 0.05). The level of ox-LDL was significantly lower in the
remission-idiopathic NS (remission-INS) group compared with the nonremission-INS group
(p < 0.05). The levels of ox-LDL and sVCAM-1 were significantly lower in the remissiontreated group than in the nonremission-treated group (p < 0.05). In conclusion, the combined
supplementation of vitamins C and E cannot modify the ox-LDL, sCD36, sVCAM-1, and NOx
levels in children with INS. In remission cases, the combined supplementation of vitamins C
and E reduces the ox-LDL and sVCAM-1 levels.
Copyright 2015, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier
Taiwan LLC. All rights reserved.

Introduction
Idiopathic factor is a common cause of nephrotic syndrome
(NS) in children.1 This pathomechanism can be classified
directly from kidney disease (primary NS/idiopathic) or
indirectly via conditions in other parts of the body affecting
the kidney (secondary NS).2,3 Persistent NS is frequently
associated with abnormal lipid profiles, including elevated
levels of total lipids [cholesterol and triglycerides (TGs)],
and an often enormous increase in cholesterol in the lowdensity lipoprotein (LDL)- and very-low-density lipoprotein-cholesterol fraction. Conversely, the concentration of
high-density lipoprotein (HDL)-cholesterol (HDL-C) is
normal or even decreased. This condition constitutes a risk
factor for early atherosclerosis.4,5
Oxidative modification of LDL (ox-LDL) is a central
pathogenesis of atherosclerosis.6 ox-LDL is an early event of
subsequent pathogenetic conditions and is associated with
carotid intimaemedia thickening; release of unstable plaques in vascular, brachial, and coronary endothelial
dysfunction; and coronary artery disease.7 When ox-LDL
loses its ability to bind with LDL receptors, it will interact
with proteins called scavenger receptors.8 CD36, originally
described as a platelet receptor glycoprotein (88 kDa),
belongs to the class B scavenger receptor family.9,10 A soluble form of CD36 (sCD36) can be identified in human
plasma, and its level is shown to increase in atherogenesis.11 A recent study showed that sCD36 is not a proteolytic
product, but is rather associated with a specific subset of
circulating microparticles (MPs) that can readily be
analyzed. These MPs primarily originated from platelets.12
Previous studies have shown that oxidative modification
of LDL was involved in NS. The oxidized form of lipoprotein
levels was significantly higher in acute-period NS and
remission NS compared with control.13 Plasma malondialdehyde as a lipid peroxidation marker was found to increase
in patients with NS compared with controls. Plasma ascorbic
acid was decreased in the nephrotic group than in healthy
controls.14,15 The ratio of vitamin E to LDL was reduced in the
active stage compared with healthy controls.16
Nitric oxide synthase (NOS) is required for the synthesis
of nitric oxide (NO). All three NOS isoforms can be
expressed in the kidney.17 The association of NO level with
idiopathic NS (INS) was inconsistent. One study showed an
increased level of urinary nitrite in children with NS.18
Another study found that the eNOS4 gene polymorphisms

were not associated with the development, frequent

relapse, and response to steroid in nephritic syndrome.19
Besides, the administration of NO-1886 decreased plasma
TGs and increased HDL-C.20
The possible association of atherosclerosis with ox-LDL
suggests that dietary antioxidants may inhibit this process.21,22 Water-soluble antioxidants (vitamin C and flavonoids) and lipid-soluble antioxidants (vitamin E and
carotenoids) were reported to inhibit the development of
atherosclerosis.23 A combined supplementation of vitamins
C and E is the best choice for antioxidant treatment. When
continuous oxidative stress exists, there is an increase in
the concentration of ascorbate radical initially, but this
steadily declines. After the virtual disappearance of the
ascorbate radical, the tocopheroxyl radical appears.24 This
study aimed to investigate whether treatment involving a
combined supplementation of vitamins C and E was able to
modify the ox-LDL, sCD36, soluble vascular cell adhesion
molecule-1 (sVCAM-1), and nitrite/nitrate oxide (NOx)
levels in pediatric NS cases.

Materials and methods

Study patients
The study included 42 children with NS, who were randomly
allocated to either the treatment group or the placebo
group, with each group consisting of 21 children. Patients
were enrolled in this study after informed and written
consent had been obtained. Patients were seen on an
outpatient basis at 2-week intervals. Criteria for eligibility
were as follows: age 1e15 years, persistent proteinuria
(
1 g/m2/d), total cholesterol (T-Chol) more than 200 mg/
dL or LDL-cholesterol more than 160 mg/dL, and glomerular
filtration rate more than 80 mL/min/1.73 m2 (estimated by
the Schwartz formula).

Definitions
Primary (idiopathic) NS was defined by heavy proteinuria
(urinary protein > 50 mg/kg/d or dipstick
2), hypoalbuminemia (serum albumin < 2.5 g/dL), and hypercholesterolemia (serum cholesterol > 5.72 mmol/L or >
200 mg/dL), with or without edema. The initial treatment
includes oral administration of prednisone (2 mg/kg/d;

Effects of vitamins C and E on nephrotic syndrome

maximum 60 mg/d) in three doses for 4 weeks followed by
therapy (three times per week, at Monday-WednesdaySaturday) on alternate days for another 4 weeks. The daily
dose was then tapered down for 4e7 months and finally
stopped. The active stage of NS was defined as increased
urinary protein excretion (Albustix >2 for at least 3
consecutive days or >50 mg/kg/d) and serum albumin
concentration less than 2.5 g/dL. Remission was defined as
normal protein excretion (Albustix trace or negative for at
least 3 consecutive days). Patients were considered steroid
sensitive if their proteinuria disappeared (negative or trace
for 3 consecutive days) following 4 weeks of prednisone
treatment. Patients who still had proteinuria were considered steroid resistant.

Treatment with vitamins C and E

Vitamin C (Sigma-Aldrich, USA) at a dose of 10e15 mg/kg
body weight (maximum dose 400 mg) and vitamin E (D1-atocopherol acetate) at a dose of 10e15 mg/kg body weight
(maximum dose 400 mg) were orally administered for 12
weeks.

Blood samples
Blood sample was drawn from an antecubital vein into 10mL serum Vacutainer tubes. After approximately 45 minutes, the tubes were centrifuged at 3000 rpm (5000g) for
10 minutes at room temperature. Serum was separated
from blood cells and stored at 20 C until further analysis.

Lipid profile analysis

Fasting blood samples (10 mL) were collected in 1 mmol
disodium EDTA and 0.5 mg sodium azide. Level of Total
Cholesterol(T-Chol), LDL-cholesterol (LDL-C), HDL-C and
TGs were measured directly by routine laboratory method
on Dimension RxL (Siemens Dimension, Clinical Chemistry
System, Camberley, UK).

Determination of the ox-LDL level

The ox-LDL level was determined in the serum samples
collected. Enzyme-linked immunosorbent assay (ELISA) for
ox-LDL (Mercodia Oxidized LDL ELISA, Catalog nr-10-114301, Uppsala, Sweden) was performed according to the
manufacturers instructions, with an intra-assay coefficient
of variation (CV) less than 6% and interassay CV less than
7%. ELISA was performed in triplicate.

Determination of the sCD36 level

The sCD36 level was determined in the serum samples
collected. ELISA for sCD36 (human sCD36 ELISA kit; Aviscera
Bioscience, Catalog No. SK000196, Santa Clara, CA, USA)
were performed according to the manufacturers instructions, with an intra-assay CV less than 5% and interassay CV less than 9%. ELISA was performed in triplicate.

127

Determination of the sVCAM-1 level

The sVCAM-1 level was determined in the serum samples
collected. ELISA for sVCAM-1 (Quantikine human sVCAM-1
ELISA kit; R&D systems, Catalon No. DVC00, Shanghai, PRC)
was performed according to the manufacturers instructions, with an intra-assay CV less than 5% and interassay CV less than 8%. ELISA was performed in triplicate.

Determination of the NOx level

The NOx level was determined in the serum samples
collected. Colorimetric assays (ELISA) for NO (Cayman
nitrate/nitrite colorimetric assay kit, Catalog No. 780001,
Cayman Chemical, Ann Arbor, MI, USA) were performed
according to the manufacturers instructions, with an intraassay CV of 2.7% and interassay CV of 3.4%. ELISA was
performed in triplicate.

Ethics
Human experimental procedures were approved by the
Institutional Ethics Committee of University of Diponegoro/
Dr. Kariadi Hospital, Semarang, Central Java, Indonesia.

Statistical analysis
Data are presented as mean  standard deviation and the
differences between groups were analyzed using independent sample t test for normal distribution or ManneWhitney
U test for abnormal distribution with IBM SPSS for Windows
version 20.0 statistical package. A p value less than 0.05
was considered statistically significant.

Results
Patients
Six of the 42 children (14.3%) dropped out of the study.
Thus, we tested our hypothesis on 36 children (18 in each
group). The age, sex, frequency of normotension and prehypertension, and food record at baseline were not significantly different between groups (p > 0.05; Table 1). During
the observation period, there were no side effects due to
the vitamin or placebo treatment. In addition, the remission status, frequency of hypertension, and lipid profile
were not significantly different between the two groups
(p > 0.05; Table 2).

Levels of ox-LDL, sVCAM, NO, and sCD36

The mean ox-LDL level at baseline in the treatment and
placebo groups was 127.2 U/L and 125.2 U/L, respectively
(Table 3). The mean sVCAM-1 level at baseline in the
treatment and placebo groups was 929.4 ng/mL and
1231.23 ng/mL, respectively. The mean NOx level at baseline in the treatment and placebo groups was 8.9mM and
8.2mM, respectively. After treatment, there was a decrease
in the ox-LDL, sVCAM, and NOx levels in both groups, but
this was not significantly different (p > 0.05). The mean

128
Table 1

O. Mellyana et al.
Baseline clinical characteristics and food record among patients.

Parameter

INS

INS vitamins C and E

Age (mo)
Sex (male/female)
Normotension
Prehypertension stage 2
Energy (kcal/d)
Carbohydrate (g)
Carbohydrate (%)
Lipid (g)
Lipid (%)
Protein (g)
Protein (%)
Cholesterol (mg)
PUFA (g)
MUFA (g)
SFA (g)
Fiber (g)
Vitamin E
Vitamin C

80.48  42.24
12/9
8 (38.1%)
13 (61.9%)
1452.6  2777.73
199.9  56.86
54.3  9.50
50.6  15.37
30.5  6.98
53.7  17.6
15.1  5.8
268.7  200.79
5.3  3.3
8.65  4.4
23.5  8.68
6.7  3.68
4.3  2.76
40.8  37.6

87.81  45.10
13/8
9 (42.9%)
12 (57.1%)
1358.8  308.67
186.7  37.75
55.9  8.38
45.94  17.00
28.9  6.79
52.5  19.6
15.3  3.5
196.8  149.34
7.0  4.14
9.89  5.39
21.7  7.97
84
3.7  1.65
62.5  45.26

0.458
0.753
0.753
0.753
0.307
0.378
0.575
0.359
0.456
0.840
0.308
0.704
0.195
0.633
0.491
0.263
0.439
0.061

INS Z idiopathic nephrotic syndrome; MUFA Z monounsaturated fatty acid; PUFA Z polyunsaturated fatty acid; SFA Z saturated fatty
acid.

sCD36 level at baseline in the treatment and placebo groups

was 72.5 ng/mL and 56.9 ng/mL, respectively. After
treatment, there was an increase in the sCD36 level in both
groups, although this was not significantly different
(p > 0.05).
Table 4 presents the ox-LDL, sVCAM, NOx, and sCD36
levels in the remission and nonremission cases. The ox-LDL
level was significantly lower in the remission-INS group
compared with the nonremission-INS group (p < 0.05). The
levels of ox-LDL and sVCAM-1 were significantly lower in the
remission-treated group compared with those in the
nonremission-treated group (p < 0.05).

Discussion
Hyperlipidemia results from hypoalbuminemia due to inhibition of the reaction (conversion of cholesterol of HDLs to
cholesterol esters) catalyzed by lecithin cholesterol acyltransferase and to an inhibition of HDL particle formation

Table 2

from very-low-density lipoproteins due to reduced activity

of lipoprotein lipase.25 In this study, we found that ox-LDL
showed a decreasing trend in both groups, although this
was not significantly different (p > 0.05). This finding
indicated that a combined supplementation of vitamins C
and E cannot affect the lipid peroxidation process in patients with NS. In a previous study of 15 teenage children
with familial hypercholesterolemia and familial combined
hyperlipidemia, treatment with vitamins C (500 mg/d) and
E (400 IU/d) for 6 weeks did not have an effect on biomarkers of oxidative stress; however, this treatment
improved the brachial artery dilatation.26 In addition,
another study showed that the absence of improvement in
urinary isoprostane levels and atherosclerotic lesion area in
vitamin-E-supplemented mice may be due to their high-fatdiet consumption and/or their extreme elevations in
plasma lipid levels.27 Our data show that the level of ox-LDL
was significantly lower in the remission-INS group compared
with the nonremission-INS group (p < 0.05) or in the
remission-treated group than in the nonremission-treated

Clinical and laboratory parameters after treatment with vitamins E and C.

Parameter

INS

INS vitamins C and E

Remission:nonremission
Normotension
Prehypertension stage 2
Total cholesterol (mg/dL)
LDL (mg/dL)
HDL (mg/dL)
VLDL (mg/dL)
Triglyceride (mg/dL)

9:9
9 (50%)
9 (50%)
265.33  158.12
173.05  132.76
45.88  20.18
42.61  22.35
161.89  135.89

10:8
15 (83.4%)
3 (16.6%)
329.05  212.796
211.28  162.5
51.44  16.58
75.67  83.27
203.89  184.24

0.738
0.077
0.443
0.628
0.373
0.563
0.719

INS Z idiopathic nephrotic syndrome; LDL Z low-density lipoprotein; HDL Z high-density lipoprotein; VLDL Z very-low-density
lipoprotein.

Effects of vitamins C and E on nephrotic syndrome

Table 3

129

Levels of ox-LDL, sVCAM-1, sCD36, and NOx before and after treatment.

Biomarkers
Before
ox-LDL (U/L)
sCD36 (ng/mL)
sVCAM-1 (ng/mL)
NOx (mM)

INS vitamins C and E

INS

125.2
56.9
1231.2
8.2

After





57.15
66.20
660.30
4.73

Before

76.7
61.7
1007.96
7.9






61.72
59.04
395.97
3.23

127.2
72.5
929.4
8.9






After
51.69
102.36
225.23
6.80

89.5
123.5
868.4
8.5






63.85
180.97
232.25
5.90

INS Z idiopathic nephrotic syndrome; NOx Z nitrite/nitrate oxide; ox-LDL Z oxidized low-density lipoprotein; sCD36 Z soluble cluster
of differentiation 36; sVCAM Z soluble vascular cells adhesion molecule.

Table 4

Levels of ox-LDL, sVCAM-1, sCD36, and NOx in remission and nonremission cases.

Biomarkers
Nonremission (n Z 9)
ox-LDL (U/L)
sVCAM-1 (ng/mL)
sCD36 (ng/mL)
NOx (mM)

INS vitamins C and E

INS

107.8
1072.0
55.8
8.2






66.1
454.7
51.70
3.4

Remission (n Z 9)
45.5
943.9
68.2
7.0






39.2*
342.3
69.4
3.1

Nonremission (n Z 8)
128.4
1060.3
85.8
8.2






59.3
199.2
150.0
5.6

Remission (n Z 10)
58.3
714.8
153.7
8.7






50.36**
109.8**
205.2
6.4

*p < 0.05, in comparison with the nonremission-INS group.

**p < 0.05, in comparison with the nonremission-INS vitamins C and E group.
INS Z idiopathic nephrotic syndrome; NOx Z nitrite/nitrate oxide; ox-LDL Z oxidized low-density lipoprotein; sCD36 Z soluble cluster
of differentiation 36; sVCAM Z soluble vascular cells adhesion molecule.

group (p < 0.05). This finding shows that the level of ox-LDL
will decrease with or without combined vitamin treatment.
Macrophage CD36 is surface molecule that is able to bind
and internalize LDL for the formation of foam cells.28,29
Elevated plasma sCD36 levels have been proposed to be a
marker of insulin resistance and atherosclerosis risk. In this
study, we found that the sCD36 level increased in both
groups, but this was not significantly different (p > 0.05).
We hypothesize that this increase might have been due to
the increased number of platelets and monocytes. A previous report showed that the circulating form of the sCD36
receptor is associated with MPs coming from platelets,
leukocytes, and endothelial cells upon receiving stimuli or
apoptosis signal.8 Besides, low-grade inflammation also induces the production of MPs.30e32
Asymmetric dimethylarginine (ADMA) is an endogenous
inhibitor of NO synthase. The inhibition of NO synthesis is
known to be associated with an increase in the expression
of endothelial adhesion molecule (sVCAM-1).33e36 In this
study, there was no significant difference in the levels of
NOx and sVCAM-1 between the two study groups (p > 0.05).
In a previous study of 15 teenage children with familial
hypercholesterolemia and familial combined hyperlipidemia, treatment with vitamins C (500 mg/d) and E (400 IU/
d) for 6 weeks did not have an effect on ADMA.26 In other
words, our study shows that the combined supplementation
of vitamins C and E cannot modulate the endothelial
dysfunction in patients with NS. Interestingly, the level of
sVCAM-1 was significantly decreased in the remissiontreated group, compared with the nonremission-treated
group (p < 0.05). This finding shows that the combined
supplementation of vitamins C and E modulates the endothelial dysfunction in patients with remission of NS.
In conclusion, the combined supplementation of vitamins C and E cannot modify the ox-LDL, sCD36, sVCAM-1,

and NOx levels in children with INS. In remission cases, the

combined supplementation of vitamins C and E reduces the
ox-LDL and sVCAM-1 levels.

Conflicts of interest
The authors declare that there are no conflicts of interest
regarding the publication of this article.

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