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Vitamin E as Adjuvant Treatment for Urinary Tract Infection in Girls with

Acute Pyelonephritis

Article  in  Iranian Journal of Kidney Diseases · March 2015

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 KIDNEY DISEASES

Vitamin E as Adjuvant Treatment for Urinary Tract Infection

in Girls with Acute Pyelonephritis
Parsa Yousefichaijan,1 Manigeh Kahbazi,2 Sara Rasti,2
Mohammad Rafeie,3 Mojtaba Sharafkhah4

1Division of Pediatric Introduction. Vitamin E is a fat-soluble vitamin that functions as

Nephrology, Department of an antioxidant. The aim of this study was to investigate the effects
Pediatrics, Arak University of
Medical Sciences, Arak, Iran
of vitamins E supplementation in combination with antibiotics for
the treatment of girls with acute pyelonephritis.

Original Paper
2Department of Pediatrics, Arak
University of Medical Sciences, Materials and Methods. This double-blinded randomized
Arak, Iran controlled trial was conducted on 152 girls aged 5 to 12 years with
3Department of Biostatistics
a first acute pyelonephritis episode based on technetium Tc 99m
and Epidemiology, Arak
dimercaptosuccinic acid (99mTc-DMSA). They were randomized to
university of Medical Sciences,
Arak, Iran
receive a 14-day treatment with only antibiotics (control group;
4Students Research n  =  76) and 14-day treatment with supplements of vitamin E
Committee, School of Medicine, (intervention group; n  =  76) in addition to the antibiotics. Patients’
Arak University of Medical clinical symptoms were monitored for 14 days and urine culture
Sciences, Arak, Iran was performed 3 to 4 days and 7 to 10 days after the start of the
Keywords. urinary tract
treatment and its completion, respectively. All of the girls once
infection, vitamin E, child underwent DMSA scan 4 to 6 months after the treatment.
Results. During the follow-up days, the mean frequency of fever
(P = .01), urinary frequency (P = .001), urgency (P = .003), dribbling
(P = .001), and urinary incontinence (P = .006) were significantly
lower in the intervention group compared to the control group.
There was no significant difference in the results of urine culture 3
to 4 days after the start of treatment (P = .16) and 7 to 10 days after
its termination (P = .37). There was also no significant difference
between the results of DMSA scan 4 to 6 months after the start of
treatment (P = .31).
Conclusions. Vitamin E supplementation has a significant effect in
ameliorating sign and symptoms of UTI. However, further studies
are recommended to confirm these findings.

IJKD 2015;9:97-104
www.ijkd.org

INTRODUCTION or flank pain; malaise; nausea and vomiting; and

Urinary tract infections (UTIs) are common in occasionally, diarrhea.4-6 Pyelonephritis is the most
childhood, affecting up to 3.5% of children in the common serious bacterial infection in infants who
United States annually.1 Urinary tract infection is have fever without an obvious focus. 4 Overall,
a serious bacterial infection because of its potential involvement of the renal parenchyma is termed
to produce renal scarring. 2 The 3 basic forms of acute pyelonephritis. 4 Only up to two-thirds of
UTI are pyelonephritis, cystitis, and asymptomatic children with a UTI accompanied by fever have
bacteriuria.3 Clinical pyelonephritis is characterized acute parenchymal infection, with acute lesions
by any or all of the following: abdominal, back, on technetium Tc 99m dimercaptosuccinic acid

Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015 97

Vitamin E in Urinary Tract Infection—Yousefichaijan et al

( 99m Tc-DMSA) scintigraphy, 7-11 which is the and phagocytosis. 26,27,29 Tengerdy and Brown 26
definitive diagnosis of acute pyelonephritis. 11-13 demonstrated that production of prostaglandin
In girls, 75% to 90% of all acute pyelonephritis in bursa homogenates of E coli-infected chickens
episodes are caused by Escherichia coli, followed by was reduced by supplementation of vitamin E.
Klebsiella and Proteus.4,14 It has been suggested that This was corroborated by Likoff and colleagues.30
bacterial characteristics and the host defense play On the basis of these observations, a hypothesis is
significant roles in the development of the scars proposed that the disease protective effect of vitamin
in pyelonephritis. 14,15 It has also been proposed E is connected with its antioxidant inhibitory effect
that oxygen-free radicals play a role in renal scar on prostaglandin modulation caused by vitamin
formation after an acute pyelonephritis model in that may counteract prostaglandin modulation
monkeys and mice.11,12 caused by the infectious process, thereby triggering
Recent experimental studies demonstrate that host defense mechanisms. All these may lead to
oxygen-free radical scavengers and antioxidants increased resistance to infection. Given the limited
can reduce tissue damage and renal scaring during information regarding the supplementary effect of
acute and chronic pyelonephritis.13-16 Antioxidant vitamin E in children with acute pyelonephritis,
vitamins A, E, and C increase tissue protection we decided to conduct a study in this area. Since
from oxidative stress. 16,17 Recently, it has been UTI is more common in girls due to their shorter
shown that both vitamins E and C decrease lipid urethras,31 and boys suffering from UTI usually have
peroxidation and augment the activity of antioxidant underlying anatomical or functional abnormalities of
enzymes in the kidneys of diabetic rats.18 Vitamin the genitourinary tract that confound the study, we
E acts as a chain-breaking antioxidant and is an restricted our research to girls with pyelonephritis.
efficient pyroxyl radical scavenger, which protects
low-density lipoproteins and polyunsaturated MATERIALS AND METHODS
fats in membranes from oxidation.16 In addition Participants
to the cases mentioned regarding the role of This double-blind randomized controlled trial
oxidative stress in the pathophysiology of kidney study was conducted from 22 April, 2012 to 21
diseases such as pyelonephritis and the effect of November, 2013 on the patients admitted to the
antioxidant vitamins on it, it has been reported Department of Pediatrics of Amir Kabir Hospital
that the pathology of the infectious process and and Vali Asr Hospital, in Arak, Iran. Participants
host defenses against infection are apparently included 5- to 12-year-old girls who had developed
connected with a modulation of prostaglandin a form of acute pyelonephritis, for the first time and
biosynthesis in the host.19 Infection, and especially had indications of hospitalization due to UTI. With
the antigenic stimulus represented by the infection, respect to the study conditions, these indications
may dramatically increase prostaglandin and were defined as mild to moderate dehydration
cyclic nucleotide levels within minutes after a requiring rehydration and intravenous antibiotic
challenge. 19,20 There is growing evidence that therapy. Girls with repeated vomiting, severe
prostaglandin may regulate immune responses, UTI-induced dehydration, or bacteremia were not
and at elevated levels, prostaglandin may be included in the study. The study was approved by
immunosuppressive.21,22 the Ethics Committee of Arak University of Medical
Vitamin E is an effective inhibitor of prostaglandin Sciences and a written consent was obtained from
synthetize in certain tissues,23,24 and as an antioxidant all patients’ parents or guardians. The patients
it may prevent the oxidation of arachidonic could also withdraw liberally from the study at
acid in the biosynthetic pathway leading to any time. The researchers were committed to the
prostaglandin. It is conceivable then that some Declaration of Helsinki throughout the research.
of the biological functions of vitamin E may be The children and their parents were interviewed
connected with its modulation of prostaglandin and underwent laboratory examinations in order
synthesis. 25 Several reports demonstrated that to assess the inclusion criteria. These examinations
vitamin E is effective in protecting human from included medical history of UTI symptoms (fever,
bacterial infection. 26,27 This protection has been frequency, urgency, dribbling, dysuria, urinary
associated with increased antibody titer, 26,28,29 incontinence, and abdominal pain) urinalysis and

98 Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015

 Vitamin E in Urinary Tract Infection—Yousefichaijan et al

urine culture, ultrasonography of the abdomen cortical loss, and renal scar was defined as areas
and pelvis, voiding cystourethrography, computed of negative DMSA uptake.2,35
tomography, and 99mTc-DMSA scintigraphy. The
midstream catch method was used for urine culture.2 Inclusion and Exclusion Criteria
The genital area was washed from front to back The children were included if they were female,
with soap and water 3 times and intermediate aged 5 to 12 years old, had a medical history
urine samples were collected in sterile bags and and symptoms of UTI and diagnosed with acute
transferred to the hospital laboratory. In order to pyelonephritis based on fever (without any source
perform the urine culture and confirm the result, other than UTI) and evidence of renal inflammation
urine samples with infected medium were excluded on DMSA scan, and had positive urinalysis and
from the study and urine samples prepared using culture results only for E coli sensitive to ceftriaxone
the sterile method underwent analysis and culture and cefixime. Informed consent from the parents was
for the second time.2 Contamination of the culture obtained for participating in the study and proper
medium was defined as a positive urine culture adherence to the study protocol after discharge
without pyuria. from hospital was ensured. Patients with any of the
If the urine culture showed more than 10 000 following were excluded from the study: a diagnosis
colonies of a single pathogen and the child was of renal scarring based on the results of DMSA
symptomatic (including fever, urinary frequency, scan; history of any form of UTI; vesicoureteral
urgency, dribbling, dysuria, urinary incontinence, reflux, symptoms of renal abscess, renal and
and abdominal pain), the child was considered to urinary tract calculus, urinary tract obstruction,
have UTI.32,33 Since E coli is the most common cause emphysematous pyelonephritis, renal hypoplasia,
of UTI and for easier cloning of the subjects for ectopic kidney, and any unilateral or bilateral renal
UTI factor organism, only the patients with UTI anomaly based on ultrasonography, CT scan, and
resulted by E coli were included in the study. Since voiding cystourethrography findings; neurogenic
this study aimed at analyzing urine samples with bladder; history of voiding dysfunctions; anatomical
E coli sensitive to ceftriaxone and cefixime, E coli problems of the genitalia such as labial adhesion,
isolated from urine cultures underwent sensitivity due to trauma, surgery, and congenital anomalies;
test for evaluating their resistance or sensitivity to history of allergy to vitamin E or its intolerance;
ceftriaxone and cefixime antibiotics. The evaluation history of diabetes mellitus, immunodeficiency,
was performed using the disk diffusion method. and organ transplantation; administration of
For this purpose, E coli was isolated from culture antibiotics or vitamin E at least 5 days before the
samples and underwent disk diffusion sensitivity start of the study; severe sepsis and bacteremia;
test with the Kirby-Bauer method based on the and severe dehydration.
CLSI M100-S22 (Clinical Laboratory Standards
Institute M100-S20) protocol on 2010.34 Antibiotic Study Protocol
susceptibility disks were provided by Padtan Teb Considering the prevalence of UTI, sample size
Company (Tehran, Iran). was determined at 152 (α = 0.05, β = 0.2). After
assessment of the girls and their parents, they were
Renal Dimercaptosuccinic Acid Scintigraphy randomly assigned into the intervention or control
Since DMSA scintigraphy is the gold standard groups each with 76 participants. Medications were
method for the diagnosis and localization of acute administered for 14 days in a way that all girls
pediatric pyelonephritis,2 all the girls qualified for underwent routine UTI treatment. The treatment
the study’s initial assessments underwent this scan included 50 mg/kg/d to 75 mg/kg/d of intravenous
for the evaluation of acute pyelonephritis. Girls ceftriaxone in 2 divided doses during hospitalization
with diagnosed renal scarring after DMSA scan and 8 mg/kg/d of oral cefixime in 2 divided doses
were not included in the study. Renal scintigraphy after discharge. Other than the routine treatment,
was performed 3 to 4 hours after injection of a the intervention group was administered 100 IU
weight-scaled dose of DMSA. Acute scintigraphic of oral vitamin E on a daily basis, 1 daily tablet,
pyelonephritis was defined as focal or diffuse areas and the control group was administered placebo.
of decreased DMSA uptake without evidence of Placebos were similar to vitamin E regarding their

Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015 99

Vitamin E in Urinary Tract Infection—Yousefichaijan et al

shape, color, and size. Antibiotics were made by staff. After the girls were discharged, the parents
Jaber Ibn Hayyan (Tehran, Iran) and vitamin E and were provided with the necessary training for
its placebo were made by Raazak (Tehran, Iran). administering medicine to their children. They were
Vitamin E and the placebo were administered in also told to refer 7 to 10 days and 4 to 6 months
unnamed capped containers with a label containing after the treatment for repeated urine culture and
the code of each medicine by a group other than DMSA scan, respectively.
the groups who examined and followed up the All of the patient information was recorded in
patients. The participants were unaware of the their clinical information forms. The forms included
type of administered medicine. their demographic information, the results of urine
The assessment of clinical response and the culture 3 to 4 days after the start of the treatment
follow-up of patients were conducted by research and 7 to 10 days after its termination, the results
assistant who was unaware of the type of medicine of DMSA scan 4 to 6 months after the treatment,
administered to patients for 14 days. As long as and the presence or absence of clinical symptoms
the girls were hospitalized, medications were (fever, frequency, urgency, dribbling, dysuria,
administered by the rendering physician and urinary incontinence, and abdominal pain) during

Random allocation and interventions flowchart.

100 Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015

 Vitamin E in Urinary Tract Infection—Yousefichaijan et al

14 days of their follow-up.

.001
P
Antibiotic susceptibility test was also carried
out using the disk diffusion method along with

Vitamin E

12.1 ± 17.7
urine culture to prove the possible existence of

49 (64.4)
44 (57.8)
34 (44.7)
22 (28.9)
10 (13.1)
5 (6.5)
1 (1.3)
1 (1.3)
1 (1.3)
1 (1.3)

1 (1.3)
only 1 type of disease-causing organism and also

0
0
measure the sensitivity of E coli to administered

Dribbling
antibiotics. It was aimed to exclude participants
from the study in the case of recurrence of UTI

20.1 ± 17.4
52 (68.4)
37 (48.6)
29 (38.1)
23 (30.2)
21 (27.6)
16 (21.0)
14 (18.4)
12 (15.7)
11 (14.4)
Control

5 (6.5)
4 (5.2)
2 (2.6)
1 (1.3)
with another bacterium, multiple bacteria, or E

54 (71)
coli resistant to antibiotic treatment.
Fever was defined as a body temperature increase
(oral temperature) above 38.5°C without a source

.003
except for UTI; frequency was defined as increased

P
frequency of urination twice as before; urinary
incontinence was defined as urination outside

8.2 ± 13.1
Table 1. Girls and With Fever, Frequency, Urgency, and Dribbling During the 14-Day Follow-up in the Control and Vitamin E Groups

Vitamin E
37 (48.6)
32 (42.1)
22 (28.9)
15 (19.7)
8 (10.5)

1 (1.3)
the control of patient; dribbling was defined as

0
0
0
0
0
0
0
0
involuntary urinary cessation and its restoration;

Urgency
dysuria was defined as feeling pain or burning when
urinating; urgency was described as immediate

20.9 ± 21.6
63 (82.8)
58 (76.3)
44 (57.8)
34 (44.7)
28 (36.8)
21 (27.6)
17 (22.3)
14 (18.4)
Control

7 (9.2)
6 (7.8)
1 (1.3)
need to urinate; and abdominal pain was defined
as pain and discomfort in the abdominal cavity.4

0
0
0
The results of urine culture and DMSA were
recorded in patients’ clinical information forms at

.001
specific times and 4 to 6 months after the treatment,
P

respectively. All the renal scans were reviewed

secondarily by 2 independent nuclear medicine

6.4 ± 10.0
Vitamin E
32 (42.1)
21 (27.6)
18 (23.6)
7 (9.2)
4 (5.2)
3 (3.9)
1 (1.3)

2 (2.6)

1 (1.3)
experts who were unaware of the treatment that
0
0
0

0
had been assigned to the patients.
Frequency

Exclusion criteria during follow-up were

as follows: (1) the absence of cooperation or

24.1 ± 22.6
64 (84.2)
62 (81.5)
52 (68.4)
44 (57.8)
29 (38.1)
22 (28.9)
21 (27.6)
16 (21.0)
10 (13.1)
Control

5 (6.5)
4 (5.2)
4 (5.2)
2 (2.6)
2 (2.6)
satisfaction for continuing the participation; (2)
the recurrence of UTI according to the results of
urine culture during follow-up with more than 1
type of bacterium, an organism other than E coli or
.01

with an E coli resistant to administered antibiotics;

P

(3) intolerance of oral vitamin E; (4) irregular use

Vitamin E

12.4 ± 24.8
61 (80.2)
24 (31.5)
8 (10.5)

of medication; (5) comorbidity of febrile diseases

76 (100)

3 (3.9)

1 (1.3)

1 (1.3)

other than UTI during the follow-up requiring the

0
0

0
0
0
0

consumption of any other antibiotics, especially

Fever

those used in this study; and (6) re-infection

with any type of UTI between the second urine
21.6 ± 25.5
62 (81.5)
54 (71.0)
36 (47.3)
25 (32.8)
18 (23.6)
11 (14.4)
76 (100)
Control

4 (5.2)
3 (3.9)
3 (3.9)
3 (3.9)
4 (5.2)
2 (2.6)
1 (1.3)

culture and repeated DMSA scan. When a child

was excluded from the study for any reason, she
was randomly replaced with another matching
participant eligible according to the terms of the
study and inclusion and exclusion criteria. The
Mean frequency

Figure illustrates the study recruitment process.

Days

The collected data were analyzed using the

SPSS software (Statistical Package for the Social
10

12
13
14

Sciences, version 18.0, SPSS Inc, Chicago, Ill, USA),

11
1
2
3
4
5
6
7
8
9

Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015 101

Vitamin E in Urinary Tract Infection—Yousefichaijan et al

and the chi-square test or the Fisher exact test and Table 3. Result of Urine Culture and Dimercaptosuccinic Acid
Scintigraphy (DMSA) in the Control and Vitamin E Groups
the Student t test were used for comparisons. P
values less than .05 were considered significant. Vitamin
Test Control P
E
Urine culture
RESULTS
3 to 4 days after start of 2 (2.7) 0 .16
In this 18-month study, 307 girls with UTIs were treatment
assessed against the inclusion and exclusion criteria. 7 to 10 days after end of 1 (1.3) 0 .37
Sixty-eight of the girls were excluded and were treatment
replaced with other qualified participants. Overall, DMSA
Before treatment 76 (100) 76 (100) > .99
93 girls with UTI were randomly analyzed based
4 to 6 months after start of 1 (1.3) 0 .31
on the inclusion and exclusion criteria. Among 62 treatment
girls who were excluded during the follow-up, 38
(55.8%), 9 (13.2%), and 21 (30.8%) were excluded
due to parental dissatisfaction for continuing of treatment and 7 to 10 days after its termination
participation, development of a febrile infection (Table 3). Analysis of the results of DMSA scan 4 to
other than UTI requiring antibiotic treatment, and 6 months after the start of the treatment indicated
recurrence of UTI discordant with the conditions that the inflammation of the renal parenchyma
for continuing the participation, respectively. completely subsided in 76 (100%) and 75 (98.6%)
The mean age of the participants was 5.8 ± 2.2 of the girls in the intervention and control groups,
years old. This figure was 6.1 ± 2.5 years and respectively (Table 3).
5.5 ± 2.0 years for the intervention and control
groups, respectively (P = .14). The frequencies of DISCUSSION
symptoms in the intervention and control group are According to our study, although there was no
presented in Tables 1 and 2. The average frequencies significant difference in the results of urine culture
of fever, urinary frequency, urgency, dribbling, and DMSA scan of girls receiving vitamin E and
and urinary incontinence was significantly lower antibiotic and those receiving only antibiotic, it
in the intervention group than the control group was indicated that vitamin E could be significantly
during the 14 days of follow-up, while no significant effective in the treatment of the majority of common
difference was observed in dysuria and abdominal clinical symptoms in girls with acute pyelonephritis,
pain between the groups. such as fever, frequency, urgency, dribbling, and
There was no significant difference in the urinary incontinence. Sobouti and colleagues 36
results of urine culture 3 to 4 days after the start conducted a study on 61 children with the age of

Table 2. Girls and With Abdominal Pain, Dysuria, and Incontinency During the 14-Day Follow-up in the Control and Vitamin E Groups

Abdominal Pain Dysuria Incontinency

Days Control Vitamin E P Control Vitamin E P Control Vitamin E P
1 42 (55.2) 66 (86.8) 38 (50.0) 71 (93.4) 57 (75.0) 40 (52.6)
2 32 (42.1) 60 (78.9) 19 (25.0) 63 (82.8) 54 (71.0) 32 (42.1)
3 22 (28.9) 42 (55.2) 15 (19.7) 48 (63.1) 41 (53.9) 26 (34.2)
4 20 (26.3) 31 (40.7) 9 (11.8) 32 (42.1) 38 (50.0) 17 (22.3)
5 13 (17.1) 21 (27.6) 4 (5.2) 28 (36.8) 30 (39.4) 11 (14.4)
6 10 (13.1) 18 (23.6) 5 (6.5) 24 (31.5) 19 (25.0) 8 (10.5)
7 5 (6.5) 15 (19.7) 3 (3.9) 17 (22.3) 15 (19.7) 2 (2.6)
8 3 (3.9) 11 (14.4) 2 (2.6) 12 (15.7) 12 (15.7) 3 (3.9)
9 2 (2.6) 6 (7.8) 2 (2.6) 9 (11.8) 10 (13.1) 2 (2.6)
10 1 (1.3) 4 (5.2) 1 (1.3) 5 (6.5) 8 (10.5) 1 (1.3)
11 3 (3.9) 1 (1.3) 1 (1.3) 3 (3.9) 5 (6.5) 0
12 0 0 1 (1.3) 0 1 (1.3) 0
13 0 0 1 (1.3) 0 1 (1.3) 0
14 0 0 1 (1.3) 0 0 0
Mean frequency 10.92 ± 13.35 19.64 ± 22.26 .27 7.28 ± 10.49 22.28 ± 23.68 .44 20.78 ± 19.73 10.14 ± 13.44 .006

102 Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015

 Vitamin E in Urinary Tract Infection—Yousefichaijan et al

1 month to 10 years with acute pyelonephritis to is recommended from the start of the treatment to
investigate the effect of vitamins A and E on the decrease clinical symptoms in infected girls because
improvement of renal scarring in Iran from 2004 of its significant effect on the improvement of clinical
to 2006. In this clinical trial, the children were symptoms in the acute phase of UTI. However,
randomized into 3 treatment groups of 10-day future study is recommended in this area due to
treatment with only antibiotics (control group; the lack of clinical evidence regarding the effect
n  =  25) and 10-day treatment with supplements of of vitamin E supplement on the treatment of UTI
vitamin A (n  =  17) or vitamin E (n  =  18) in addition patients’ clinical symptoms, renal inflammation,
to antibiotics during the acute phase of infection. and scarring and more importantly, recurrent
Based on this study, a worsening of lesions, UTI cases.
based on the second DMSA scan, was observed
in 42.5%, none, and 23.3 % of the control, vitamin ACKNOWLEDGMENTS
E, and vitamin A patients, respectively (likelihood The research team wishes to thank the vice
ratio, 26.3; P  <  .001). In another study, Sadeghi and chancellor of research for their financial support
colleagues37 investigated the effect of vitamin E on and also children and their parents who contributed
mouse models with acute pyelonephritis by E coli to this research project.
in 2008. The results indicated that inflammation
and fibrosis scores in the group undergoing CONFLICT OF INTERETST
treatment with only intraperitoneal ceftriaxone None declared.
was significantly higher than the group undergoing
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104 Iranian Journal of Kidney Diseases | Volume 9 | Number 2 | March 2015

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