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Pacharn et al.
Preeyacha Pacharn, M.D., Benjapa Khiewvan, M.D., Utarat Kaewumporn, M.D.
Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Relationship Between Vesicoureteral Reux and
Renal Scarring in Children with Urinary Tract
Infection
ABSTRACT
Objective: To evaluate the association of vesicoureteral reux (VUR) in comparison with the development of renal
scarring in child patients with urinary tract infection (UTI).
Methods: is study involved a retrospective review. Patients under 14 years old with a diagnosis of UTI with a
positive urine culture and who had a voiding cystourethrogram (VCUG) and technetium 99 m dimercaptosuccinic
acid (Tc-99m_DMSA) renal scintigraphy performed within 4-6 months aer acute UTI were included in the study.
e VCUG results were classied as positive or negative for vesicoureteral reux (VUR). If reux was present, the
severity was graded according to the recommendation of the International Reux Study in children.
1
e Tc-99m
DMSA results were interpreted as positive or negative for renal scarring. Statistical analysis was performed using
the χ2 test or Fisher’s exact test and Mann–Whitney test to compare the presence of VUR and renal scarring as
well as the grading of the VUR and renal scarring. Positive and negative likelihood ratios (LR) were calculated.
Results: In total, 185 patients (74 girls and 111 boys; mean age, 3.5 years old) were included in the study. ere
were ve children with only a single kidney, resulting in 365 kidneys for analysis. Vesicoureteral reux was found
in 203 (55.6%) kidneys, classied as grades 1, 2, 3, 4, and 5 in 19, 31, 81, 38, and 34 kidneys, respectively. Scarring
was found in 110 of 203 kidneys (54.2%) with VUR and in 18 of 162 kidneys (11.1%) without VUR (p < 0.0001).
e LR positive was 2.2 (95%CI, 1.9-2.5) and LR negative was 0.23 (95% CI, 0.1-0.4).
Conclusion: ere was a signicant correlation between positive VUR and the development of renal scarring.
Patients with positive VUR should be considered for a Tc99m-DMSA scan to evaluate them for the development
of renal scarring.
Keywords: Vesicoureteral reux; VUR; renal scar; urinary tract infection; UTI (Siriraj Med J 2021; 73: 26-31)
Corresponding author: Preeyacha Pacharn
E-mail: ppacharn@gmail.com
Received 18 May 2020 Revised 23 June 2020 Accepted 22 July 2020
ORCID ID: http://orcid.org/0000-0003-3696-9107
http://dx.doi.org/10.33192/Smj.2021.04
INTRODUCTION
Urinary tract infection (UTI) is a common cause
of acute illness in infants and children. e infection
may involve the upper part of the urinary tract (kidneys
and ureters) or the lower urinary tract (bladder and
urethra). Patients with renal infection or pyelonephritis
may develop renal scarring, hypertension, and end-stage
renal dysfunction later in life. It is mandatory to identify
these patients with acute pyelonephritis to prevent further
renal damage. Clinically, urinary tract infection with
the presence of fever increases the probability of renal
involvement. Moreover, there is an increased risk of
underlying urologic abnormalities as well as a greater
risk of consequent renal scarring.
2
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Renal scarring is considered a cause of long-term morbidity.
e prevalence has been reported to be about 10-40%.
3
Young age, delayed treatment, the presence of vesicoureteral
reux (VUR), and recurrent episodes of pyelonephritis
are associated with an increased risk of renal damage.
In children with UTI, the most important reason for
performing an investigation is to identify abnormalities
of the genitourinary tract that may require additional
evaluation and management.
Renal and bladder ultrasonography is a noninvasive
procedure and is always the rst line of investigation. e
size and shape of the kidneys, dilatation of the ureters,
and the presence of gross anatomic abnormalities can
be demonstrated with this technique. However, it is not
reliable in diagnosing renal scarring.
4
Technetium-99m dimercaptosuccinic acid (Tc-99m
DMSA) renal scintigraphy can be used to detect acute
pyelonephritis and renal scarring in acute and chronic
settings. However, using DMSA as the initial test is more
expensive and involves radiation exposure. According to
the American Academy of Pediatrics guidance, DMSA
is not recommended as a routine evaluation for children
with a rst UTI.
5
Voiding cystourethrogram (VCUG) is the study of
choice to establish the presence and degree of vesicoureteral
reux (VUR). A prior study reported an approximately
25% to 30% incidence of VUR in children (0 to 18 years
old) with a rst UTI.
6
Even though VUR is a signicant
risk factor for the development of renal scarring, the
exact relationship between VUR and scarring is still
undetermined.
7
erefore, VCUG cannot directly diagnosis
renal scarring.
e purpose of this study was to determine if the
presence and severity of VUR can predict the development
of renal scarring in children with febrile UTI.
MATERIALS AND METHODS
e study was approved by the Institutional Ethics
Committee of Siriraj Hospital (Si 283/2019). is study
was a retrospective single-center study. Medical records
were searched using the keywords “febrile UTI” in patients
less than 14 years old from January 2016 to July 2018.
Only patients with a positive urine culture and who had
both VCUG and a DMSA scan done within 4-6 months
of each other were included in this study.
Demographic data and blood urea nitrogen (BUN)
as well as creatinine result were recorded. e VCUG
results were reviewed by a pediatric radiologist and a
radiology resident who were unaware of the patients’
test results. e results were classied as positive or
negative for VUR. e degree of vesicoureteral reux
was graded according to the recommendations of the
International Reux study in children
1
:
Grade 1: Reux into a non-dilated ureter.
Grade 2: Reux into the upper collecting system
but non-dilated.
Grade 3: Mild or moderate dilatation and/or tortuosity
of the ureter and mild or moderate dilatation of the renal
pelvis.
Grade 4: Moderate dilatation and/or tortuosity of
the ureter and moderate dilatation of the renal pelvis
and calyces.
Grade 5: Gross dilatation and tortuosity of the
ureter. Gross dilatation of the renal pelvis and calyces
and the loss of papillary impressions.
Dimercaptosuccinic acid renal scintigraphy was
performed using a standard procedure. e patients
were injected with DMSA 0.1 mCi/kg (minimum dosage
of 0.3 mCi and maximum dosage of 3 mCi). Data were
acquired on a dual-head, large eld of view, gamma
camera equipped with a low-energy high-resolution
collimator in 256 × 256 matrices.
Relative tracer uptake (RU) was calculated as the mean
value of uptake in the anterior and posterior projections,
corrected for background activity. e presence of focal
defects in the renal cortex with distortion or indentation
of the normal renal outline, renal volume loss, and cortical
thinning were classied as renal scarring. If the result
was undetermined, DMSA was repeated in the next six
months, and the nal result was used for interpretation.
Statistical analysis
e Mann–Whitney test and chi-square test were
used for statistical analysis between the groups of children
with VUR and without VUR, and between the dierent
grades of VUR, considering a p-value of less than 0.01
as statistically signicant.
Positive and negative likelihood ratios (LR) along
with 95% condence intervals (CI) were calculated for
VCUG using DMSA as the gold standard for permanent
renal damage.
RESULTS
Overall, there were 598 children aged 0-14 years
old with febrile UTI. Of those, 185 children (74 girls and
111 boys; mean age, 3.5 years old) met all the criteria
with a positive urine culture and had had both diagnostic
studies performed (Table 1). ere were ve children
with only a single kidney each, resulting in 365 kidneys
for analysis.
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Pacharn et al.
Vesicoureteral reux was found in 203 kidneys
(55.6%). Reuxes were classied as grades 1, 2, 3, 4, and
5 in 19, 31, 81, 38, and 34 kidneys, respectively
DMSA scintigraphy showed normal renal uptake
in 237 kidneys (65%) and renal scarring in 128 kidneys
(35%). In 6 kidneys, the result was equivocal in the rst
study, but subsequently demonstrated renal scarring on
the following examination.
Scarring was shown in 110 of 203 (54.2%) kidneys
with VUR and in 18 of 162 (11.1%) kidneys without VUR
(Table 2). e incidence of DMSA renal scarring was
signicantly associated with the presence of a reuxing
kidney (p < 0.001). e sensitivity of VCUG in the prediction
of renal scarring was 85.94% (95% CI, 78.7-91.4), and
the specicity was 60.76% (95%CI, 54.2-67.0).
e number of kidneys with renal scarring compared
with the dierent grades of VUR was calculated (Table 3).
e positive and negative likelihood ratios (LR) of VUR
in detecting renal scarring was calculated according to
VUR grading. e cumulative data for the presence of
VUR from grades 1-5 caused a positive LR of 2.2 (95%
CI, 1.9-2.5), and a negative LR negative of 0.23, (95%,
CI 0.1-0.4) (Table 4).
One hundred and sixty-six patients had BUN and
creatinine in medical records. Five in 166 patients (9
in 365 kidneys) had high creatinine levels indicating
impaired renal function. Four kidneys in these patients
were associated with vesicoureteral reux, grade 2 in 1
kidney, grade 3 in 1 kidney and grade 4 in two kidneys.
ere were 5 kidneys in patients with abnormal renal
function that were not associated with vesicoureteral
reux.
TABLE 1. Demographic data of the study patients with UTI.
TABLE 2. Comparison of the VUR results with renal scarring.
Age (year) Sex Total
Male Female
0-5 88 55 143 (77.3%)
>5-10 20 14 34 (18.4%)
>10-15 3 5 8 (4.3%)
Total 111 74 185 (100%)
Scar No scar Total
VUR 110 93 203
Non-VUR 18 144 162
Total 128 237 365
Sensitivity 85.9% (95% CI: 78.7-91.4), Specicity 60.8% (95%CI 54.2-67.0)
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TABLE 3. Comparison of the kidneys with negative and positive VUR in dierent grades for testing for renal scarring.
VUR Scar No scar Total kidneys % of kidneys
with a scar
No VUR 18 144 162 11.1
Grade 1 9 10 19 47.4
Grade 2 12 19 31 38.7
Grade 3 45 36 81 55.6
Grade 4 21 17 38 55.3
Grade 5 23 11 34 67.6
Total 128 237 365
TABLE 4. Likelihood ratio (LR) for renal scarring in dierent grades from VUR.
+LR -LR
Grade 1-5 2.2 (95%CI 1.9-2.5) 0.2 (95%CI 0.1-0.4)
Grade 2-5 2.3 (95%CI 2.0-2.6) 0.3 (95%CI 0.2-0.5)
Grade 3-5 2.6 (95%CI 2.2-3.0) 0.4 (95%CI 0.3-0.6)
Grade 4-5 2.9 (95%CI 2.3-3.7) 0.7 (95%CI 0.5-1.1)
Grade 5 3.9 (95%CI 2.7-5.6) 0.9 (95%CI 0.5-1.5)
DISCUSSION
Urinary tract infection is one of the most common
causes of bacterial infections in childhood. e diagnosis
and management of UTI continue to be controversial
with many challenges in clinical practice.
In terms of imaging investigations in patients with
UTI, there is no consensus on a single guideline in the
pediatric population. e method and timing of imaging
to evaluate for urinary tract anatomical abnormalities and
renal scarring aer a febrile UTI vary between institutions.
Technetium-99m DMSA seems to be the most
reliable method for the diagnosis of chronic cortical renal
scarring. Prior studies suggested that DMSA may obviate
VCUG in the evaluation of febrile UTI.
8,9
However, this
method requires nuclear medicine specialists and may
not be available in all institutions. VUCG is an optimal
method to diagnose VUR as well as for assessing the degree
of VUR and the anatomy of the male urethra. However,
VCUG cannot detect renal scarring or pyelonephritis.
In our study, we wanted to assess if the presence
and severity of VUR could predict the development
of renal scarring in children with UTI. We found that
the incidence of DMSA renal scarring was signicantly
associated with the presence of vesicoureteral reux.
Renal scars were found in 54.2% of kidneys with VUR
and 11.1% of kidneys with no VUR.
Our study ndings concurred with prior research.
For instance, Canoe et al. found renal damage in 67% of
kidneys with VUR and in 16% of kidneys with no VUR,
and concluded that the presence of VUR was associated
with renal damage.
10
However, some prior studies do not concur with our
results.
11,12
For instance, Moorthy et al. found that only
16% of children with VUR had an abnormal kidney on
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Pacharn et al.
DMSA scan. e heterogeneity of the published results
may depend on several factors, such as the ages and types
of patients, the timing between UTI and investigation,
and the antibiotic treatments applied.
Our study also compared the incidence of renal
scarring with the VUR results according to the severity
of VUR using VUR grading. We found that there was
a slight increase in the percentages of the kidneys with
renal scars as the grade of the VUR increased; from 47.4%
with VUR grade 1 to 67.6% in VUR grade 5. However,
from our results, the percentage of renal scarring in
grade 2 reux was less than in grade 1.
Prior studies also reported VUR as a risk factor for
developing a renal scar and increased renal scarring in
patients with a higher grading of VUR.
13,14
Other risk
factors of renal scarring included recurrent UTI, bladder-
bowel dysfunction, and delayed treatment.
15
Interestingly, we also observed BUN and creatinine
levels in comparison with VUR and scarring. We found
that most patients (161 of 166) had normal BUN and
creatinine levels. ere were 5 patients with 9 kidneys
with impaired renal function. In these patients, less
than 50% of kidneys had reux on VCUG in dierent
grades from 2 to 4. We suggested that there was no direct
correlation between VUR and renal function, which can
be explained by the fact that patients have two kidneys.
Severe VUR or scarring in one kidney will not lead to
abnormal renal function with high BUN and creatine
levels. It could be dierent if the patient had a single
kidney. In fact, we had one patient with a single kidney
with VUR grade4 and had renal failure.
To evaluate the signicance of VUR, we also looked
at the likelihood ratio with the dierent VUR grades.
We found that the positive likelihood ratio was slightly
increased if we included only higher grades of VUR.
However, the ranges of positive LR were between 2.2 and
3.9. A low number positive LR presumes that VCUG may
not be a useful diagnostic test to detect renal scarring.
From our study, 11.1% of scarred kidneys would have
been missed if Tc-99m DMSA was not performed in
patients with no VUR and 14.9% would have been missed
if we had avoided Tc-99m DMSA in patients with no
VUR and VUR grade 1 (Figs 1 A, B, and C).
A B
C
Fig 1. A 3 year-old boy with a history of myelomeningocele
S/P surgery presented with UTI.
Anterior (A) and posterior (B) projections of the
Tc-99m DMSA scan showed a renal cortical scar at
the upper pole of the right kidney (arrows). VCUG
(C) showed no evidence of vesicoureteral reux. ere
was an irregular wall of the urinary bladder with
diverticula, consistent with a neurogenic bladder.
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Our study has several limitations. First, this was a
retrospective study. ere was a diversity of patients in
terms of VCUG techniques. Some patients might have
a cyclic lling of the contrast medium. e dierent
kinds and durations of the antibiotic treatments might
also have aected the results. A large prospective result
would be useful for the homogeneity of the population.
CONCLUSION
From our study, we found that there was a signicant
correlation between positive VUR and the development
of renal scarring. e number of scarred kidneys also
slightly increased as the grade of VUR increased. Moreover,
the presence of low-grade VUR cannot exclude renal
scarring and these cases should be considered for further
evaluation and a follow up with Tc99m- DMSA.
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