Pediatr Nephrol

DOI 10.1007/s00467-015-3195-2

ORIGINAL ARTICLE

Plasma levels of oxidative stress in children with steroid-sensitive

nephrotic syndrome and their predictive value
for relapse frequency
Aiwen Fan 1 & Xiaoyun Jiang 2 & Ying Mo 2 &
Huizhen Tan 1 & Mengjie Jiang 2 & Jinhua Li 3

Received: 10 March 2015 / Revised: 4 August 2015 / Accepted: 13 August 2015

# IPNA 2015

Abstract treatment were positively correlated with the relapse frequency in

Background Oxidative stress has been reported to play an
important role in children with primary nephrotic syndrome
(PNS). However, the results of previous studies are
controversial.
Methods Forty children with steroid-sensitive nephrotic syn-
drome (SSNS) and 20 age- and sex-matched healthy controls
were enrolled. Patients were followed-up for 12-18 months
and divided into three subgroups: frequent relapse (n=10),
non-frequent relapse (n=12), and non-relapse (n=18). The
plasma levels of advanced oxidation protein products
(AOPP), malondialdehyde (MDA), and superoxide dismutase
(SOD) were tested in controls and patient group at first pre-
sentation and after 4 weeks of steroid treatment.
Results Patients had higher AOPP and MDA levels but lower
SOD compared with controls. AOPP levels were significantly
higher in the frequent relapse subgroup compared with the non-
frequent relapse and non-relapse subgroups, respectively. No sig-
nificant differences were found in the plasma levels of MDA and
SOD among the three subgroups. AOPP >87.55 μmol/l before
steroid treatment and AOPP >78.5 μmol/l after 4-week steroid
* Xiaoyun Jiang
jiangxiaoyun2015@126.com
patients with SSNS.
Conclusions Children with SSNS have oxidative stress. The
plasma levels of AOPP before and after 4-week steroid treat-
ment may predict whether patients with SSNS will relapse
frequently.
Keywords Children . Steroid-sensitive nephrotic syndrome .
Oxidative stress . Relapse
Introduction
Oxidative stress is defined as an imbalance between the oxi-
dation and antioxidation systems, which results in excessive
production and/or reduced clearance of highly reactive mole-
cules including mainly reactive oxygen species (ROS).
Studies suggest that oxidative stress exists in children with
nephrotic syndrome (NS) [1]. However, it is not clear how
oxidative stress changes in patients with steroid-sensitive
nephrotic syndrome (SSNS) in response to steroid treatment.
Furthermore, the relationship between the tendency for
relapse and the level of oxidative stress remains to be revealed.
Therefore, this study was designed to assess plasma levels of
oxidative stress in children with SSNS and their correlation
with the relapse frequency.

1
Department of Pediatrics, Eastern District of the First Affiliated
Hospital, Sun Yet-sen University, NO. 183, Huangpu East Road,
Patients and methods
Huangpu District Guangzhou 510070, China
2
Department of Pediatrics, the First Affiliated Hospital, Sun Yet-sen
Patients
University, NO. 58, Zhongshan Road 2, Yuexiu District
Guangzhou 510080, China This was a prospective study conducted on 53 children (38
3
Department of Anatomy and Developmental Biology, Monash males/15 females) aged 1–13 years old (median, 5 years old)
University, Clayton, Victoria 3800, Australia newly diagnosed with PNS, and on 20 age- and sex-matched

healthy volunteers as the control group. The patients were
admitted to the Department of Pediatric Nephrology, the First
Affiliated Hospital of Sun Yat-sen University from January
2012 to May 2013. The timing of entry of patients into the study
was the period immediately following a diagnosis of PNS in all
patients. Patients were diagnosed as PNS when the following
criteria were met: 1. heavy proteinuria (dipstick+++~++++, a
random or morning urine protein/creatinine ratio (mg/mg) ≥2.0,
or 24-h urinary protein ≥50 mg/kg, repeated three times in one
week); 2. hypoalbuminemia (serum albumin <25 g/l); 3. hyper-
lipidemia (serum cholesterol >5.7 mmol/l); 4. edema; 5. exclu-
sion of secondary and congenital nephrotic syndrome. Children
were excluded if they had acute infection or systemic diseases,
or had received treatment of albumin, blood or nonsteroidal anti-
inflammatory drugs within 2 weeks prior to the study. All pa-
tients received standard oral prednisone [2 mg/(kg.day) or
60 mg/(m2.day)] for 4 weeks as induction therapy [2]. SSNS
(n=40) was defined as negative protein on urine dipstick testing
after induction therapy. If patients achieved remission, steroids
were tapered and withdrawn over a 2-month period. The
steroid-resistant nephrotic syndrome (SRNS) group (n=13)
comprised patients who did not respond to induction therapy.
The patients with SSNS were followed-up for a median of
14 months (range, 12-18 months) and retrospectively classified
into three subgroups according to the criteria of PNS relapse:
frequent relapse (n=10), non-frequent relapse (n=12), and non-
relapse (n=18) subgroups. A relapse was defined as proteinuria
(+++) or (++++), or 24-h urinary protein ≥50 mg/kg, or urine
protein/creatinine ratio (mg/mg) ≥2.0 for 3 consecutive days,
having been in remission previously. Frequent relapse refers to
two or more relapses in the first 6 months or three or more
relapses in a 1-year period [2], while non-frequent relapsers
relapsed less than that. The patients who did not relapse during
the follow-up period were non-relapsers.
The average time spent on steroid therapy was 15 months in
the frequent relapse subgroup, 11 months in the non-frequent
relapse subgroup, and 7 months in the non-relapse subgroup.
When patients in the non-frequent relapsers subgroup relapsed,
they required induction therapy again. Immunosuppressants
were added when patients relapsed frequently.
Sample collection and preparation
All blood samples were collected at the time patients first pre-
sented (prior to induction therapy), and at the end of the 4-week
steroid treatment. Measurements of AOPP, MDA, and SOD
concentrations were obtained from the patients and controls
after overnight fast, measured in plasma samples (collected in
tubes containing 16 IU/ml heparin), centrifuged at 4 °C for
15 min (3000 r/min) and immediately frozen, stored at -80 °C
(for no longer than 3 months) until analysis. AOPP was detect-
ed via spectrophotometric assay as described by Witko-
Sarsat et al. [3]. Plasma MDA was estimated by the
Pediatr Nephrol
thiobarbituric acid test [4]. Plasma SOD was measured accord-
ing to the methods described by Marklund et al. [5]. Serum
albumin, creatinine, and cholesterol, as well as 24-h urinary
protein and urinalysis were tested by standard methods.
Statistical analysis
SPSS 17 software was used to analyze the data. Quantitative
data of normal distribution is presented as mean ± SD.
Student’s t test was applied to the parameters with normal
(Gaussian) distribution, and the Mann–Whitney U test was
used to for parameters with non-normal distribution. One-
way analysis of variance (ANOVA) was applied to compare
different variables among different groups. Receiver operator
characteristic (ROC) curve analysis was done by plotting sen-
sitivity on the y-axis and 1-specificity on the x-axis for differ-
ent parameters to determine the cutoff levels. p values ≤0.05
were considered to be significant.
Results
Characteristics of the study cohort
The data presented in Table 1 reveals that there were no
significant differences in age or gender among the con-
trols, the SSNS groups and the SRNS groups enrolled in
the study. As shown in Table 2, no significant differences
were revealed in gender, age, mean arterial pressure, cre-
atinine clearance rate, albumin, and cholesterol among the
three subgroups of frequent relapse, non-frequent relapse,
and non-relapse.
Plasma levels of oxidative stress in children with SSNS
As Table 3 displays, the plasma levels of AOPP and MAD in
patients with SSNS before steroid treatment were significantly
higher compared with the control group (84.19±16.71 μmol/l
vs. 66.41±12.18 μmol/l, p<0.01; 13.34±3.90 nmol/l vs. 7.43±
1.95 nmol/l, p<0.01). However, the plasma level of SOD was
significantly lower in patients with SSNS compared with the
control group (78.50±17.30 μ/ml vs. 95.05±14.90 μ/ml,
p<0.01).
Table 1 Clinical and demographic characteristics of the patients and
controls
Parameter Controls (n=20) SSNS (n=40) SRNS (n=13)
Gender (male/female) 14/6 29/11 9/4
Median age (years) 4.3 (3.5-7.0) 4.9 (3.0-6.8) 6.0 (3.5-8.0)
SSNS steroid-sensitive nephrotic syndrome; SRNS steroid-resistant ne-
phrotic syndrome
Pediatr Nephrol

Table 2 Clinical and demographic characteristics of the patients among the frequent relapse, non-frequent relapse, and non-relapse groups

Parameter Frequent relapse (n=10) Non-frequent relapse (n=12) Non-relapse (n=18) F/χ2/H p value

Gender (male/female) 6/4 9/3 14/4 1.073 0.585

Median age (years) 4.3(2.8-5.0) 6.5(4.3-8.0) 5.7(3.0-9.0) 2.830 0.243
MAP (mmHg) 77.40±7.01 78.25±8.57 77.83±7.07 0.035 0.966
ALB (g/l) 19.80±1.62 19.75±2.83 19.83±2.33 0.005 0.996
CHOL (mmol/l) 9.61±1.23 9.52±1.66 9.21±1.36 0.319 0.729
Ccr (ml/kg.1.73 m2.min) 137.6±16.98 143.00±11.72 137.9±14.61 0.541 0.587

ALB albumin; Ccr creatinine clearance rate; CHOL Cholesterol; MAP mean arterial pressure
Data are presented as mean±standard deviation (SD)

Plasma levels of oxidative stress in the frequent relapse,
non-frequent relapse, and non-relapse subgroups
As shown in Fig. 1 and Table 3, plasma AOPP levels in
the frequent relapse subgroup (100.4±16.34 μmol/l) were
higher than those in the non-frequent relapse (80.73 ±
12.85 μmol/l) and non-relapse (77.48±13.46 μmol/) sub-
groups before steroid treatment, and the difference was
statistically significant (p<0.01). There were no signifi-
cant differences in the plasma levels of MDA (14.52 ±
1.72 nmol/l vs. 13.88±3.10 nmol/l vs. 12.32±5.00 nmol/
l, p>0.05) and SOD (76.30±14.44 μ/ml vs. 83.11±20.93
μ/ml vs. 76.64±16.47 μ/ml, p>0.05) among these three
subgroups before steroid treatment.
After 4 weeks of steroid treatment, the plasma levels
of AOPP in the frequent relapse subgroup (91.10 ±
12.45 μmol/l) were higher than those in the non-
frequent relapse (73.42±13.94 μmol/l) and non-relapse
(67.11 ± 13.86 μmol/l) subgroups, and the differences
were statistically significant (p< 0.05, p < 0.01, respec-
tively). No significant difference was observed in
AOPP levels between the non-frequent relapse subgroup
and non-relapse subgroup (p>0.05). However, there was
no statistical difference in plasma levels of MDA among
the frequent relapse subgroup, non-frequent relapse sub-
group and non-relapse subgroup (13.70 ± 1.49 nmol/l
versus 12.59 ± 2.01 nmol/l vs. 12.93 ± 2.93 nmol/l,
p > 0.05). The plasma levels of SOD in the frequent
relapse subgroup were significantly lower than those in
the non-frequent relapse subgroup (64.30±9.17 μ/ml vs.
79.54±9.19 μ/ml, p<0.05); but there was no significant
difference in the plasma levels of SOD between the
frequent relapse subgroup and non-relapse subgroup
(64.30 ± 9.17 μ/ml vs. 73.97 ± 13.91 μ/ml, p > 0.05;
Table 4).
As shown in Fig. 1, there was no significant change in
AOPP levels in each subgroup after 4-week steroid treatment.
Likewise, the levels of MDA and SOD did not change signif-
icantly after 4-week steroid treatment.
The value of plasma levels of AOPP in prediction
of relapse frequency in patients with SSNS
According to the results that plasma levels of AOPP in the
frequent relapse subgroup were significantly higher than
those in the non-frequent relapse and non-relapse sub-
groups (p < 0.01), we combined these data of plasma
AOPP levels in the latter two subgroups and drew a ROC
curve. As shown in Fig. 2, the ROC curve may predict that
patients with SSNS would relapse frequently by using a
cut-off level of >87.55 μmol/l AOPP before steroid treat-
ment (sensitivity 90 %, specificity 76.7 %, AUC 0.8683,
SD 0.079, p< 0.01). Alternatively, an AOPP level after 4-
week steroid treatment at a cut-off level >78.5 μmol/l
could be applied to predict the relapse frequency in pa-
tients with SSNS (sensitivity 80 %, specificity 76.7 %,
AUC 0.8733, SD 0.059, p<0.01), as presented in Fig. 3.

Table 3 Comparison of plasma levels of oxidative stress between controls and the patients before steroid treatment

Controls (n=20) SSNS (n=40) Frequent relapse (n=10) Non-frequent relapse (n=12) Non-relapse (n=18)

AOPP (μmol/l) 66.41±12.18 84.19±16.71** 100.4±16.34 80.73±12.85**△ 77.48±13.46**△

MDA (nmol/l) 7.43±1.95 13.34±3.90** 14.52±1.72 13.88±3.10 12.32±5.00
SOD (u/ml) 95.05±14.90 78.50±17.30** 76.30±14.44 83.11±20.93 76.64±16.47

SSNS steroid-sensitive nephrotic syndrome; AOPP advanced oxidation protein products; MDA malondialdehyde; SOD superoxide dismutase
Data are presented as mean±standard deviation (SD)
** SSNS vs. control, p<0.01; **△ compared to frequent relapse group, p<0.01
 Pediatr Nephrol

Fig. 1 Serial changes in plasma (A)

oxidative stress levels in the AOPP frequent relapse
150
frequent relapse, non-frequent
relapse, and non-relapse groups at non-frequent relapse
different stages of steroid- **
sensitive nephrotic syndrome 100 ** * non-relapse
** △

mol/l
(SSNS) Stage 1: before steroid
treatment; Stage 2: after 4-week
steroid treatment; **, before 50
steroid treatment, compared to
frequent relapse group, p<0.01;
*, after 4-week steroid treatment, 0
non-frequent relapse group vs. Stage1 Stage2
frequent relapse group, p<0.05;
**△, after 4-week steroid (B) (C)
treatment, non-relapse group vs.
MDA 150 SOD
frequently relapse group, p<0.01 20

15 100 *

u/ml
nmol/l

10
50
5

0 0
Stage1 Stage2 Stage1 Stage2

Discussion positively correlated with deterioration of renal function [10].

PNS is a common kidney disease in childhood and its con-
ventional treatment is glucocorticoids. PNS is most common-
ly caused by minimal-change nephrotic syndrome (MCNS)
and 80~90 % of the patients with this type are sensitive to
glucocorticoid therapy [6]. However, the pathogenesis of
SSNS remains unclear. Growing evidence has shown that a
relative deficiency in antioxidants and subsequent oxidative
stress occur during the acute phase of PNS, resulting in an
imbalance between antioxidant and oxidant systems [7, 8].
ROS are difficult to detect since they are metabolized rapidly
in vivo [9]. Therefore, molecular markers of oxidative stress,
including AOPP, MDA, and SOD, are often used to evaluate
the level of oxidative stress in vivo. AOPP, first discovered in
patients with renal failure [3], are the end products of ROS and
amino acid residues in protein oxidation caused by
hypochlorous acid and chlorine oxides. AOPP level has been
Descamps et al. [11] assessed the risk factors of declined renal
function in 120 adult patients with IgA nephropathy (IgAN)
and found that AOPP was an independent risk factor of poor
prognosis in patients with IgAN. Increased plasma levels of
MDA reveal increased activity of lipid peroxidation [12]. As a
strong oxidant, MDA can enhance ROS release from glomer-
ular cells through a variety of mechanisms, such as promoting
cell damage, increasing glomerular permeability, impairing
the integrity of renal tubular epithelial cells, and modulating
glomerular hemodynamics [13]. SOD is one of the main an-
tioxidant enzymes and is considered as the first line of defense
system against ROS in vivo [14].
Our study revealed that the plasma levels of oxidative in-
dicators AOPP and MDA were elevated, while the plasma
levels of SOD, an antioxidant indicator, were decreased sig-
nificantly in children with SSNS compared with normal con-
trols. These results suggest that the overwhelming oxidative

Table 4 Comparison of plasma levels of oxidative stress in each subgroup of steroid sensitive nephrotic syndrome (SSNS) after 4-week steroid treatment

Frequent relapse (n=10) Non-frequent relapse (n=12) Non-relapse (n=18) p value

AOPP (μmol/l) 91.10±12.45 73.42±13.94* 67.11±13.86** <0.001

MDA (nmol/l) 13.70±1.49 12.59±2.01 12.93±2.93 0.547
SOD (μ/ml) 64.30±9.17 79.54±9.19* 73.97±13.91 0.014

AOPP advanced oxidation protein products; MDA malondialdehyde; SOD superoxide dismutase
Data are presented as mean±standard deviation (SD)
*, compared to frequent relapse group, p<0.05; **, compared to frequent relapse group, p<0.01
Pediatr Nephrol
Fig. 2 Receiver operator characteristic (ROC) curve to differentiate be-
tween the frequent relapse group and non-frequent/non-relapse group
using the plasma level of advanced oxidation protein products (AOPP)
before corticosteroid treatment
stress in children with SSNS may be manifested as increased
levels of oxidants and decreased antioxidant capacity or an
exhausted antioxidant system, which is consistent with the
study by Bakr et al. [1].
Tarshish et al. reported that 76~93 % of patients with PNS
relapsed, and 45~50 % relapsed frequently or depended on
steroid treatment [15]. Jiang et al. [16] reviewed hospitalized
children with PNS between 2008 and 2011 in China and
found that PNS with non-frequent relapse, frequent relapse,
and steroid dependence accounted for 28.2, 20.1, and 5.9 %,
respectively. The recurrence of PNS may require induction
therapy with full-dose steroids, which would increase the
probability of side effects associated with steroid treatment,
such as obesity, hypertension, diabetes, growth inhibition, os-
teoporosis, and cataracts. In addition, prolonged steroid treat-
ment would make patients lose confidence in the therapy and
prognosis, or even stop following the prescription. In this
scenario, immunosuppressants are often added due to the side
effects caused by long-term and repeated use of glucocorti-
coids. However, immunosuppressants may also cause some
serious side effects. Hence, it is necessary to identify risk
Fig. 3 Receiver operator characteristic (ROC) curve to differentiate be-
tween the frequent relapse group and non-frequent/non relapse group
using the plasma level of advanced oxidation protein products (AOPP)
after 4-week corticosteroid treatment
factors involved in the relapse of PNS. Infection is the most
common cause of relapse in PNS. A number of experiments
have shown that there is a strong correlation between infection
and oxidative stress, which can induce nephropathy [17, 18].
During the steroid-maintaining phase of treatment, patients
with infection were more likely to relapse [19]. Also, de-
creased antioxidant capacity and increased ROS levels were
observed in patients with acute kidney injury caused by sepsis
[20]. Though the mechanism of PNS relapse is not very clear,
growing evidence shows that dysfunction of the immune sys-
tem, including both cellular and humoral immunity, might
play a critical role. Some research has demonstrated that
Th1/Th2 cytokine imbalance (Th2 cell hyperfunction) might
be one of the major causes for relapse of SSNS [21]. The
relationship between immune disorders and PNS relapse-
associated oxidative stress requires further investigation.
Oxidative stress plays a critical role in the relapse of
SSNS, and its correlation with steroid treatment remains
unclear. This present study revealed that plasma levels of
AOPP in the frequent relapse subgroup were significantly
higher than those in the non-frequent relapse or non-
relapse subgroups before steroid treatment, suggesting that
oxidative capacity in the frequent relapse subgroup was sig-
nificantly increased. However, there was no significant dif-
ference observed in MDA and SOD levels among the three
subgroups. Chronic conditions such as nephrotic syndrome
differ much from acute damage and diseases. We speculate
that as NS is a chronic disease, AOPP might be a chronic
bio-maker while MDA and SOD differ more obviously in
acute illness. However, further research is needed to confirm
this hypothesis. These results suggest that AOPP might be
more appropriate to predict the frequency of SSNS relapse
compared with MDA and SOD. Consistently, ROC curve
analysis showed that plasma levels of AOPP higher than
87.6 μmol/l before steroid treatment, or higher than
78.5 μmol/l after 4-week steroid treatment, could predict
frequent relapse (sensitivity 0.900 and 0.800 respectively;
specificity 0.767). Due to the small sample size of this study,
further prospective studies on larger numbers of patients are
still needed to validate these results. MDA levels did not
change significantly in any of the three subgroups after 4-
week steroid treatment, though they were significantly
higher than that in the normal controls. However, Bakr
et al. [1] demonstrated that MDA levels were significantly
lower in both relapsers and non-relapsers after steroid treat-
ment and reached similar levels found in controls. This dif-
ference may be attributed to the small number of patients in
both studies. Since some patients in remission in our study
were lost to follow-up and some refused to return to have
plasma oxidation levels detected, future studies are required
to have a larger sample size to clarify this discrepancy.
In conclusion, an oxidative stress exists in children with
SSNS. This oxidative stress is more significant in the patients

who suffer frequent relapse after steroid treatment. The plasma
levels of AOPP may be presented as a suitable prognostic bio-
marker for the relapse frequency in children with SSNS.
Acknowledgments This study was supported by the Science and Tech-
nology Program of Guangzhou, China grant (No 2014A020212140) and
the Traditional Chinese Medicine Bureau of Guangdong Province grant
(No 20151161).
Conflict of interest The authors have no conflict of interest to declare.
Ethical disclosure The study protocol was approved by the Affiliated
Hospital of Sun Yat-sen University Ethics Committee. Informed consent
was obtained from patients aged over 8 and the parents of all patients.
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