Does Early Treatment of Urinary Tract Infection Prevent Renal Damage?

Dimitrios Doganis, Konstantinos Siafas, Myrsini Mavrikou, George Issaris, Anna

Martirosova, Grigorios Perperidis, Andreas Konstantopoulos and Konstantinos
Sinaniotis
Pediatrics 2007;120;e922-e928; originally published online Sep 17, 2007;
DOI: 10.1542/peds.2006-2417

The online version of this article, along with updated information and services, is
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http://www.pediatrics.org/cgi/content/full/120/4/e922

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ARTICLE

Does Early Treatment of Urinary Tract Infection

Prevent Renal Damage?
Dimitrios Doganis, MDa, Konstantinos Siafas, MDb, Myrsini Mavrikou, MDa, George Issaris, MDb, Anna Martirosova, MDa,
Grigorios Perperidis, MDa, Andreas Konstantopoulos, MDc, Konstantinos Sinaniotis, MDc

aFirst Department of Pediatrics and bThird Department of Pediatrics, P&A Kyriakou Childrens Hospital, Athens, Greece; cSecond Department of Pediatrics, University of
Athens, P&A Kyriakou Childrens Hospital, Athens, Greece

The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. Therapeutic delay has been suggested as the most important factor that is
likely to have an effect on the development of scarring after acute pyelonephritis.
www.pediatrics.org/cgi/doi/10.1542/
However, this opinion has not been supported by prospective studies, so we tested peds.2006-2417
it. doi:10.1542/peds.2006-2417
METHODS. In a prospective clinical study, we evaluated whether the time interval Key Words
urinary tract infection, acute
between the onset of the renal infection and the start of therapy correlates with pyelonephritis, renal scarring,
the development of acute inflammatory changes and the subsequent development vesicoureteral reux
of renal scars, documented by dimercaptosuccinic acid scintigraphy. A total of 278 Abbreviations
infants (153 male and 125 female) aged 0.5 to 12.0 months with their first urinary UTI urinary tract infection
DMSA dimercaptosuccinic acid
tract infection were enrolled in the study. Tc-99mDMSAtechnetium-99m-
dimercaptosuccinic acid
RESULTS. The median time between the onset of infection and the institution of VURvesicoureteral reux
therapy was 2 days (range: 1 8 days). Renal inflammatory changes were docu- CRPC-reactive protein

mented in 57% of the infants. Renal defects were recorded in 41% of the patients Accepted for publication Mar 14, 2007
Address correspondence to Dimitrios Doganis,
treated within the first 24 hours since the onset of fever versus 75% of those MD, 12 Kapetan Petroutsou St, 115 23 Athens,
treated on day 4 and onward. Renal scarring was developed in 51% of the infants Greece. E-mail: doganisd@otenet.gr
with an abnormal scan in the acute phase of infection. The frequency of scarring PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2007 by the
in infants treated early and in those whose treatment was delayed did not differ, American Academy of Pediatrics
suggesting that once acute pyelonephritis has occurred, ultimate renal scarring is
independent of the timing of therapy. Acute inflammatory changes and subse-
quent scarring were more frequent in the presence of vesicoureteral reflux,
especially that which is high grade. However, the difference was not significant,
which suggests that renal damage may be independent of the presence of reflux.
CONCLUSIONS. Early and appropriate treatment of urinary tract infection, especially
during the first 24 hours after the onset of symptoms, diminishes the likelihood of
renal involvement during the acute phase of the infection but does not prevent
scar formation.

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U RINARY TRACT INFECTION (UTI) is among the more
common acute illnesses and the most common
bacterial infection in infants and young children.1 The
infection may be limited to the lower tract or may in-
volve the kidney; it may result in permanent renal dam-
age and scarring, which may lead to development of
hypertension and chronic renal impairment.2
Most cases of the first episode of urinary infection
occur in the first year of life, and it is generally believed
that infants are more susceptible to development of re-
nal parenchymal damage after pyelonephritis than are
older children.35 However, recent data have shown no
difference in age at the time of infection between chil-
dren who develop scars and those who do not,610 and
some studies have even shown that scarring was more
common in children 1 year of age.1113
Technetium-99m-dimercaptosuccinic acid (Tc-99mDMSA)
renal scintigraphy, performed during the acute phase of
infection, is considered the most sensitive test for the diag-
nosis of renal involvement and the subsequent develop-
ment of renal scarring.14 Among several risk factors
likely to have an effect on the development of renal
damage during the acute episode of renal infection, the
time between the onset of symptoms of the infection and
the beginning of the appropriate therapy is considered
by many experts to be 1 of the most significant.3,1520 This
opinion is supported by experimental studies, which
demonstrated a correlation between the duration of in-
fection until the start of treatment and the extent of
renal damage.21,22 On the other hand, this opinion has
not been demonstrated by prospective clinical studies.9
The aim of our prospective study was to correlate the
findings of the Tc-99mDMSA renal scintigraphy with the
time passed since the onset of fever until the commence-
ment of therapy in infants with a first episode of UTI.
METHODS
Enrollment and Eligibility Criteria
We undertook a 5-year (2000 2005) prospective study
in a cohort of 278 children 12 months of age who were
admitted to the hospital with a first documented episode
of UTI. Children were eligible to be included in the study
if they had a temperature of 38C and a positive cul-
ture of urine collected by suprapubic puncture. The
growth of any number of colonies of Gram-negative
bacilli was considered as positive. All of the children
were treated with antibiotics immediately after the urine
and blood samples were obtained. Patients were treated
with intravenous antibiotics given until they had been
afebrile for 24 to 36 hours. An oral antibiotic was pro-
vided to complete a 10- to 14-day course. The time
between the onset of fever and the institution of therapy
was recorded.
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Imaging Studies
Renal ultrasonography and renal scintigraphy with Tc-
99mDMSA were performed within 1 to 18 days (median:
5 days) of admission to determine anatomic abnormali-
ties and the presence or absence of acute pyelonephritis,
respectively. DMSA scan is performed 4 to 6 hours after
intravenous injection of an age-adjusted dose (minimum
dose: 40 MBq; maximum dose: 100 MBq). Posterior,
anterior, and lateral posterior oblique planar views were
collected for 6 minutes each with a camera equipped
with a high-resolution low-energy collimator (computer
matrix: 256 256). Differential renal function was cal-
culated by using the geometric mean method to com-
pensate for differences in the position of each kidney.
Pyelonephritis was defined by the presence of focal or
diffuse areas of decreased uptake of DMSA. A second
cortical scan was performed after 5 to 26 months (me-
dian: 6.5 months) in infants who had a positive DMSA
scan result in the acute phase of infection. An abnormal
second scan was defined by the presence of decreased
uptake of DMSA associated with loss of the contour of
the kidney or by the presence of cortical thinning.
Voiding cystourethrogram was performed in the ma-
jority of cases while the child was in the hospital before
discharge.23,24 Vesicoureteral reflux (VUR) was graded
according to the classification proposed by the Interna-
tional Reflux Study Committee.25 Children who were
found to have VUR were placed on chemoprophylaxis
with trimethoprim-sulfamethoxazole (2 mg/kg for the
trimethoprim component). Infants 2 months of age
were given prophylaxis with cefuroxime-axetil (10 mg/
kg).
Laboratory Tests
The laboratory tests in these patients at the time of
admission included obtaining a white blood cell count
and differential and the C-reactive protein (CRP) level.
Statistics
2 test, Fishers exact test, and the nonparametric Mann-
Whitney test were used for statistical analysis. A P value
of .05 was considered to indicate statistical significance.
RESULTS
Patient Characteristics
A total of 278 children,153 boys and 125 girls, were
enrolled in the study. The median age was 3.5 months
(range: 0.512.0 months). Of the 278 children, 128 (96
boys and 32 girls) were 3 months old, 80 (34 boys and
46 girls) were 3 to 6 months old, and 70 (23 boys and 47
girls) were 6 months old.
Treatment Delay and Timing of Scintigraphy
The median time between the onset of fever and the
institution of treatment was 2 days (range: 1 8 days).
PEDIATRICS Volume 120, Number 4, October 2007 e923
The median time between the onset of fever and renal
scintigraphy was 7 days (range: 4 21 days) and in 266
(96%) of 278 within 14 days or less. Furthermore, the
median time between the onset of treatment and renal
scintigraphy was 5 days (range: 118 days) and in 272
(98%) of 278 within 14 days or less.
DMSA Renal Scan Results
An abnormal renal scan was observed in 158 (57%) of
278 children, and the number of affected kidneys was
179. Twenty-one children (13%) had bilateral involve-
ment and 137 (87%) unilateral. Renal defects were ob-
served in 43 (41%) of the 105 infants treated within the
first 24 hours since the onset of fever, in 43 (59%) of the
73 infants treated during the second day of the infection, in
28 (68%) of the 41 infants treated the third day, and in 44
(75%) of the 59 infants treated on the fourth day and
onward (P .000; Fig 1). Among infants 3 months, renal
defects were observed in 29 (40%) of the 73 treated within
the first day since the onset of fever and in 35 (64%) of the
55 treated on the second day and onward (P .012; Fig 2).
Among infants 3 months of age, renal defects were ob-
served in 14 (44%) of the 32 treated within the first day
since the onset of fever and in 80 (68%) of the 118 treated
on the second day and onward (P .022; Fig 3).
Abnormal DMSA scan was seen more often after the
age of 6 months than in younger infants. A total of 106
infants of the 208 infants (51%) aged 0.5 to 6.0 months
had an abnormal DMSA scan, whereas 52 (74%) of the
70 infants aged 6.0 months showed parenchymal dam-
age (P .001). The frequency of abnormal scans did not
differ between male (87 of 153) and female (71 of 125)
infants.
A second cortical scan was performed 5 to 26 months
(median: 6.5 months) after the infection in 86 of the 158
infants who had a positive DMSA scan result in the acute
phase of infection. en of the 86 infants experienced a
FIGURE 1
DMSA results in the acute phase and day of treatment.
e924 DOGANIS et al
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relapse before the second DMSA scan and were excluded
from the analysis of the results. Among the 76 remaining
infants, there were 44 boys and 32 girls. At the second
scintigraphy, 39 (51%) of 76 children had an abnormal
scan, which showed scar formation in the site of the
initial lesion, and in 5 of them a new scar was developed
in a different site, in addition to the initial lesion.
The frequency of scarring in infants treated early in
the first 24 hours (11 of 24), since the onset of the
infection, and those treated later (28 of 52) did not differ
significantly, but this could be the result of the small
number of patients. No difference in the frequency of
abnormal second scans between male (23 of 44) and
female (16 of 32) infants was documented. Further-
more, no significant differences concerning the fre-
quency of renal scars between infants 6 months of age
(14 of 24) and infants 6 months of age (25 of 52) were
detected.
Voiding Cystourethrogram and Renal Involvement
Voiding cystourethrogram was undertaken in 269
(97%) of 278 infants. In 9 infants, voiding cystourethro-
gram was not performed, because the parents denied it.
VUR was recorded in 66 (24.5%) of 269 children. The
presence of VUR and the relationship between the grade
and the renal involvement on the first DMSA scan are
shown on Table 1. Furthermore, in infants treated dur-
ing the first day since the onset of fever, VUR was
detected in 28 (28%) of 101 infants, during the second
day in 14 (20%) of 70, and on the third day or later in 24
(24%) of the 98 infants. Therefore, the presence of VUR
did not differ according to the time of starting treatment
and did not influence the effect of therapeutic delay on
DMSA results.
The number of infants with scarring and VUR was
greater (18 of 28 [64%]) than in the absence of VUR (21
of 48 [44%]) but the difference did not reach statistical
FIGURE 2
DMSA results in the acute phase and day of treatment in infants
younger than 3 months.

FIGURE 3
DMSA results in the acute phase and day of treatment in infants
older than 3 months.

TABLE 1 The Relationship Between the First DMSA Scan Findings TABLE 2 The Relationship Between the Second DMSA Scan
and the Presence and Grade of VUR Findings and the Presence and Grade of VUR
Variable Patients Without Patients With VUR Total Variable Patients Without Patients With VUR Total
VUR VUR
Grades Grades Grades Grades
I -III IV-V I-III IV-V
Normal DMSA scan result 93 (45.8) 20 (38.5) 2 (14.3) 115 (42.8) Normal DMSA scan result 27 (56.2) 7 (35.0) 3 (37.5) 37 (48.7)
Abnormal DMSA scan result 110 (54.2) 32 (61.5) 12 (85.7) 154 (57.2) Abnormal DMSA scan result 21 (43.8) 13 (65.0) 5 (62.5) 39 (51.3)
Total 203 (100.0) 52 (100.0) 14 (100.0) 269 (100.0) Total 48 (100.0) 20 (100.0) 8 (100.0) 76 (100.0)
Data are number (percentage) of infants. Data are number (percentage) of infants.

significance. The relationship between the presence of
VUR and the results of the follow-up scan are shown on
Table 2.
Clinical and Laboratory Findings and Renal Involvement
Escherichia coli was isolated from the urine of 242 infants,
Proteus mirabilis from 4, Klebsiella spp from 18, Citrobacter
spp from 1, Enterobacter spp from 5, Pseudomonas spp
from 1, Enterococcus spp from 1, other Gram-negative
bacterial pathogens from 1, and 2 Gram-negative bac-
terial pathogens in 5 infants. No correlation between
any type of bacteria and renal involvement was doc-
umented.
Elevated temperature, leucocytosis, increased neutro-
phils, and CRP level were correlated with the presence of
an abnormal scan during the acute infection (Table 3).
On the other hand, no significant differences were noted
comparing maximum temperature, white blood cell
count, neutrophils, CRP level, and development of scar-
ring.

PEDIATRICS Volume 120, Number 4, October 2007 e925

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 TABLE 3 Epidemiologic, Clinical, and Laboratory Findings of Infants
Variable Total Patients (N DMSA SCAN P
278; Boys: n 153;
Girls: n 125)
Median Range Normal Abnormal
(Boys: n 66; Girls: n 54) (Boys: n 87; Girls: n 71)
Age, mo 3.50 0.5012.00 2.65 3.90 .009
WBC count, 103/mm3 15.85 3.8036.20 14.05 17.75 .000
Neutrophils, % 53.90 8.3088.80 52.65 55.35 .03
CRP, mg/L 49 0284 31.5 67 .000
Temperature, C 38.9 3841 38 39 .003
Treatment delay, d 2 18 1 2 .000
Data are median values. WBC indicates white blood cell.

DISCUSSION perts as a clinical factor in determining renal dam-

Scintigraphy with Tc-99mDMSA is considered the im-
aging method of choice for detecting acute renal pa-
renchymal changes, as well as the development of
renal scars after infection. Data from several studies of
acute pyelonephritis using DMSA scintigraphy reveal
that 50% to 90% of children with febrile UTI have
abnormal DMSA renal scan findings.11,14,19,2629 The
DMSA scan in the children of our study showed pa-
renchymal changes in 57% of the patients. Most pre-
vious studies have demonstrated a higher incidence of
abnormal DMSA scintigraphy in acute UTIs.19,27 Sev-
eral reasons may be responsible for the low rate of
abnormal DMSA scan findings in the present study.
First, the young age of the infants studied may have
contributed to it.30 Almost half of them (128 of 278)
were 3 months of age. It has been suggested that the
immature tubular function that characterizes infants 2
to 3 months of age may be responsible for the low rate
of DMSA scan findings in this age group.31 Another
possibility is the timing of the DMSA scintigraphy as
related to the start of antibiotic therapy. Stokland et
al31 have shown that the rate of positive DMSA scin-
tigraphy results rapidly decrease by 50% during the
first 14 days after initiation of antibiotic therapy.
The importance of early treatment of pyelonephritis
has been shown in experimental pyelonephritis in dif-
ferent animals. In these studies, a correlation between
the duration of infection until start of treatment and the
extent of renal damage was detected.22,32,33
Therapeutic delay has been considered by many ex-
age.3,14,1618,34 Unfortunately, data in regard of the bene-
ficial effect of early and aggressive treatment to prevent
renal scarring in children mostly derive from retrospec-
tive analysis,3,1618,34 and this opinion has not been sup-
ported by prospective clinical trials.9
In a retrospective analysis of patients in Goteborg,
Sweden, when treatment was delayed, 4 times as many
of the girls in the study developed a scar as when treat-
ment was prompt and adequate.3 However, it is note-
worthy that no details of what constituted delayed treat-
ment were reported in this study, as well as in other
reports.16,18 The children in our study demonstrating pa-
renchymal changes on the DMSA scan were positively
correlated with the day that they received their first dose
of antibiotic. Forty-three patients (41%) of 105 who
were treated within 24 hours since the onset of fever
showed inflammatory changes, but the incidence in-
creased to 59% (43 of 73) when they were treated the
second day of the infection and to 72% (72 of 100) when
they received therapy between days 3 and 8. Exactly
how long a delay in therapy is harmful is not known.
Hiraka et al35 studied 22 children with first-time UTIs.
They found that renal defects formed only in those chil-
dren who received treatment 24 hours after the onset of
the disease. In agreement with these findings are the
results of a study involving 158 children by Fernandez-
Menendez et al,20 who found that uptake defects in the
acute infection were recorded only when the treatment
delay time was 48 hours. The results of both studies

TABLE 5 Age and Start of Treatment

TABLE 4 The Relationship Between Age and DMSA Scan Findings of
Age, mo Day
Acute Phase of Infection
1 2 3 4
Variable Month
3 73 (69.5) 33 (45.2) 8 (19.5) 14 (23.8)
3 36 69 9 36 23 (21.9) 28 (38.4) 12 (29.3) 17 (28.8)
Normal DMSA scan result 64 (50.0) 38 (47.5) 13 (28.3) 5 (20.8) 69 5 (4.8) 9 (12.3) 15 (36.6) 17 (28.8)
Abnormal DMSA scan result 64 (50.0) 42 (52.5) 33 (71.7) 19 (79.2) 9 4 (3.8) 3 (4.1) 6 (14.6) 11 (18.6)
Total 128 (100.0) 80 (100.0) 46 (100.0) 24 (100.0) Median age, mo 1.9 3.5 6.1 5.9
Data are number (percentage) of infants, with P value of .009. Data are number (percentage) of infants, with P value of .000.

e926 DOGANIS et al
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are in agreement with the findings of our study. Others
have not found a correlation between treatment delay
time and early DMSA findings. In one study, no differ-
ence in the frequency of DMSA abnormalities was noted
between those patients treated within 2 days since the
onset of symptoms of infection and those treated after
2 days.31
The follow-up scan performed 5 to 26 months after
the first in 76 of our patients showed that 39 (51%) of 76
developed scarring. It is of interest that no correlation
between the incidence of scarring and the treatment
delay time was recorded in our patients, suggesting that
renal scars are caused by the infection itself and that if
the kidney is involved, the risk for development of scar-
ring is independent of the timing of therapy.
This observation is in agreement with the findings of
other authors who found no difference in therapy delay
between those with or without scars.8,26,29,36 In a recent
study, Hoberman et al9 reported that scarring was more
common among children who received treatment after
24 hours of fever compared with those treated earlier,
but the difference was not significant.
Among other factors, age has been reported as a risk
factor to develop pyelonephritis and subsequent scarring
and that infants under the age of 1 year are at greater
risk.3,37 These findings have been challenged by other
reports that have recorded a higher incidence of renal
involvement in older children.10,11,28 Renal involvement
in the acute phase of infection was more common with
advancing age in our patients (Tables 3 and 4). The effect
of age in the results of DMSA scintigraphy may be re-
lated to the immature renal function of the very young
infants.31 Another factor is probably the early treatment
that the younger children received. The median age of
those treated on the first, second, and third days was 1.9,
3.5, and 6.1 months, respectively, and of those treated
during the fourth day and onward was 5.9 months (Ta-
ble 5). A reason for the early treatment that the younger
infants received is the fact that parents are more con-
cerned when a young infant is febrile and they ask
sooner for medical advice. In our study, the effect of
early treatment of the infection in the development of
renal changes was found to be independent of the age of
patients (Figs 2 and 3).
Scarring was recorded more often when VUR was
present. Scars were seen in 64% of the children with
VUR and in 44% of those who did not show VUR, but
this difference did not reach a significant level. More-
over, we did not find any correlation between scarring
and grade of reflux. These findings are in accordance
with those of previous reports that showed that VUR is a
poor predictor of renal scarring.6,13,38,39
CONCLUSIONS
In infants with UTI, therapeutic delay for 24 hours is
associated with an increased frequency of renal involve-
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ment but not with permanent renal damage. The pres-
ence of VUR or grade of reflux does not increase the
incidence of renal involvement and scarring.
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 Does Early Treatment of Urinary Tract Infection Prevent Renal Damage?
Dimitrios Doganis, Konstantinos Siafas, Myrsini Mavrikou, George Issaris, Anna
Martirosova, Grigorios Perperidis, Andreas Konstantopoulos and Konstantinos
Sinaniotis
Pediatrics 2007;120;e922-e928; originally published online Sep 17, 2007;
DOI: 10.1542/peds.2006-2417
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/120/4/e922
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