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Acute pyelonephritis in children

Article  in  Pediatric Nephrology · August 2015

DOI: 10.1007/s00467-015-3168-5 · Source: PubMed

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Pediatr Nephrol
DOI 10.1007/s00467-015-3168-5

EDUCATIONAL REVIEW

Acute pyelonephritis in children

William Morello 1 & Claudio La Scola 1 & Irene Alberici 1 & Giovanni Montini 2

Received: 12 November 2014 / Revised: 22 June 2015 / Accepted: 30 June 2015

# IPNA 2015

Abstract Acute pyelonephritis is one of the most serious
bacterial illnesses during childhood. Escherichia coli is re-
sponsible in most cases, however other organisms including
Klebsiella, Enterococcus, Enterobacter, Proteus, and
Pseudomonas species are being more frequently isolated. In
infants, who are at major risk of complications such as sepsis
and meningitis, symptoms are ambiguous and fever is not
always useful in identifying those at high risk. A diagnosis
of acute pyelonephritis is initially made on the basis of urinal-
ysis; dipstick tests for nitrites and/or leukocyte esterase are the
most accurate indicators of infection. Collecting a viable urine
sample for urine culture using clean voided methods is feasi-
ble, even in young children. No gold standard antibiotic treat-
ment exists. In children appearing well, oral therapy and out-
patient care is possible. New guidelines suggest less aggres-
sive imaging strategies after a first infection, reducing radia-
tion exposure and costs. The efficacy of antibiotic prophylaxis
in preventing recurrence is still a matter of debate and the risk
of antibiotic resistance is a warning against its widespread use.
Well-performed randomized controlled trials are required in
order to better define both the imaging strategies and medical
options aimed at preserving long-term renal function.

Keywords Urinary tract infections . Acute pyelonephritis .

Key summary points (1) Very young children with acute pyelonephritis
have ambiguous symptoms and are at major risk of complications. The Vesicoureteral reflux . Guidelines . Antibiotic prophylaxis .
presence of fever is not helpful in identifying high-risk infants. Antibiotic resistance
(2) Collecting a correct urine sample for urine culture using clean voided
methods is reliable and effective, even in infants.
(3) Oral antibiotic treatment is recommended in well-appearing children,
while hospital admission and intravenous therapy are suggested for chil- Abbreviations
dren in bad clinical condition and for newborns. AAP American Academy of Pediatrics
(4) The usefulness of a full imaging work-up after a first fUTI is AP Acute pyelonephritis
questioned. The new guidelines suggest less aggressive imaging strate-
CKD Chronic kidney disease
gies, to reduce radiation exposure and costs.
(5) The efficacy of antibiotic prophylaxis in preventing recurrence is still DMSA Dimercaptosuccinic acid
a matter of debate, even in patients with VUR. It seems to reduce the rate E. coli Escherichia coli
of recurrence, but with no influence on the appearance of kidney scarring. fUTI Febrile urinary tract infections
The risk of antibiotic resistance is a warning against its routine use.
ISPN Italian Society of Pediatric Nephrology
LUTI Lower urinary tract infections
* Giovanni Montini
giovanni.montini@unimi.it
NICE National Institute for Clinical Excellence
PCT Procalcitonin
RCT Randomized controlled trial
1
Nephrology and Dialysis Unit, Department of Pediatrics, Azienda SPA Suprapubic bladder aspiration
Ospedaliero Universitaria Sant’Orsola-Malpighi, Via Massarenti 11,
40138 Bologna, Italy
TDA Top-down approach
2
U-CATH Urethral catheterization
Pediatric Nephrology and Dialysis Unit, Department of Clinical
Sciences and Community Health, University of Milan Fondazione
UPEC Uropathogenic E. coli
IRCCS Cà Granda -Ospedale Maggiore Policlinico Via della US Ultrasound
Commenda, 9 20122 Milano, Italy UTI Urinary tract infections

VCUG Voiding cystourethrography
VUR Vesicoureteral reflux
Introduction
Acute pyelonephritis (AP) is an infection involving the renal
parenchyma, which is generally associated with systemic
signs of inflammation. As the presence of fever is usually an
indicator of renal involvement, the terms febrile urinary tract
infection (fUTI) and AP are often used interchangeably and
will be used synonymously in this paper.
AP is considered to be one of the most serious bacterial
illnesses during childhood. These concerns are warranted by
the high risk of sepsis in young children in the acute phase [1]
and the potential risk of renal scarring with possible long-term
morbidity. In the past, a great effort was made to try to mini-
mize these consequences through the aggressive treatment of
the acute infection, an intensive imaging work-up in order to
discover possible anatomical defects, and the use of antibiotic
prophylaxis to prevent recurrences. Over the last three de-
cades, however, it has become apparent that congenital bilat-
eral renal hypodysplasia is the main reason for renal damage
in the children who progress towards the need for dialysis and
kidney transplantation [2], even in the absence of a history of
AP and/or vesicoureteral reflux (VUR). Therefore, a less in-
tensive approach in the management of children following a
AP has been suggested by the most recent guidelines. How-
ever, a number of major concerns still remain, especially re-
garding diagnosis, the need to perform imaging in order to
diagnose reflux and scarring, and the role of antibiotic pro-
phylaxis. Here we summarize the state of the art, focusing on
the most controversial topics.
Etiology/physiopathology
The kidneys and urinary tract are usually germ-free. Most
cases of AP result from the ascension of fecally derived or-
ganisms through the urethra and periurethral tissues into the
bladder, with subsequent invasion of the kidney. Usually,
urine flow prevents infection, washing out the bacteria pene-
trating into the urinary tract [3]. When bacteria colonize the
urinary tract, some children will develop asymptomatic bac-
teriuria or lower urinary tract infections (LUTIs), while only a
minority will experience AP, with systemic symptoms second-
ary to immune system activation. A variety of host factors or
germ characteristics contribute to the risk of AP in early
childhood.
Regarding the host, the most important condition associat-
ed with AP is the presence of anatomical, renal, and urinary
tract abnormalities, such as VUR, obstructive megaureter, or
neurogenic bladder, in relation to urine stasis. Other host
Pediatr Nephrol
factors could include dysfunctional bladder emptying [4],
detrusor instability [5], constipation, and fecal soiling.
On the other hand, germ virulence also plays a central role
in the pathogenesis of AP. Escherichia coli (E. coli) is the
most frequent bacteria, with a prevalence of about 80–90 %
[6–8]. The primary reservoir of E. coli is the human gut, where
this germ is a normal commensal. The anatomical proximity
to the urethral orifice increases the risk of colonization of the
urinary tract. The isolate responsible for AP in a given indi-
vidual often matches rectal isolates from that same person [9].
Among the different strains of E. coli, uropathogenic E. coli
(UPEC) are characterized both by additional virulence mech-
anisms that facilitate their invasion of the urinary tract and
kidneys and their resistance to innate immune responses.
UPECs are equipped with fimbriae (or pili) that facilitate
uroepithelial adherence, even in the presence of adequate
urine flow. Their ability to bind to host tissues is essential
for the colonization of the urinary tract, against the flow of
urine. Type 1 and type P pili are the two best-known types,
type P being more frequently associated with AP than LUTI
[10]. Other types of pili have also been described. The switch
in the expression of different types of pili seems to be influ-
enced by the environment (a process known as phase varia-
tion) [11]. These processes increase the likelihood of adher-
ence to host tissue [10]. Other UPEC characteristics that con-
fer a survival advantage are virulent capsule antigens, iron
acquisition systems, and toxin secretion [10, 12]. Moreover,
the presence of plasmids can contribute to antibiotic resistance
[13].
UPECs act as opportunistic intracellular pathogens. Once
UPECs invade the uroepithelium, the formation of an intra-
cellular biofilm, containing thousands of rapidly multiplying
organisms, can protect themselves from the host immune sys-
tem. From the bladder, bacteria ascend to the kidney, especial-
ly in the presence of anatomical factors such as VUR or major
dilation with obstruction. The host’s inflammatory response to
colonization by UPECs is characterized by cytokine produc-
tion, neutrophil influx, exfoliation of infected bladder epithe-
lial cells, and the generation of reactive nitrogen and oxygen
species [14]. A prolonged inflammatory state could result in
scarring, although the exact underlying mechanisms are still
unknown (Fig. 1).
The remaining 10–20 % cases of AP are caused by a vari-
ety of other organisms including Klebsiella, Enterococcus,
Enterobacter, Proteus, and Pseudomonas species. A recent
report by pediatric nephrologists from 18 units in ten Europe-
an countries focused on the causative organisms detected in
4745 positive urine cultures between July 2010 and June 2012
from both hospitalized and non-hospitalized infants under
24 months of age. E. coli was the most frequent bacterium
isolated from the urine cultures. However, in 10/16 hospitals
and in 6/15 community settings, E. coli was isolated in less
than 50 % of the total positive urine cultures. Other isolated
Pediatr Nephrol

Fig. 1 Pathogenesis of acute

pyelonephritis: E. coli invades
uroepithelium, facilitated by the
presence of fimbriae. The
lipopolysaccharide binds CD14
and activate Toll-like receptors
(TLR). As a consequence, nuclear
factor κB (NF-κB) migrates into
the cell nucleus, stimulating the
transcription of inflammatory
factors that will mediate fever,
neutrophil recruitment, and
vascular permeability. The same
mechanism can also be
responsible for kidney scarring
(modified from Montini et al. [4]
with permission from
Massachusetts Medical Society)

bacterial strains were Klebsiella, Enterococcus, Proteus, and
Pseudomonas, not only from hospital settings. This underlines
the fact that E. coli is the most common organism causing
UTIs in infants, however other bacterial strains are now being
isolated more frequently than in the past [15].
Clinical manifestations
Symptomatology of AP in pediatric patients is variable and
influenced by the age of the child, the virulence of the organ-
ism, and the inflammatory immune response. Fever (38.5 °C
and over) is commonly considered a marker of renal paren-
chyma involvement, while localized symptoms such as dys-
uria, frequency, malodorous urine, and urinary incontinence
are associated with urethra and bladder involvement. Howev-
er, symptoms are often non-specific in very young children
(<2–3 months): labile temperature, slow feeding and poor
weight gain, irritability, lethargy, hypotony, abdominal pain,
nausea, and vomiting. These children with ambiguous symp-
toms have been reported to be at higher risk of complications,
such as sepsis and meningitis [1]. The identification of the
children at higher risk for complications represents a clinical
challenge: in a recent report by Averbuch et al. involving 81
infants with UTI aged 0–2 months, the risk of bacteremia was
associated with a blood creatinine level above the 50th per-
centile for age, however, this risk was not associated with the
presence of fever [16]. Furthermore, a recent retrospective
study conducted on 350 infants between 29 and 90 days of
age with UTI showed a similar rate of bacteraemia in afebrile
and febrile infants, while well-appearing young infants with a
procalcitonin (PCT) value <0.7 ng/ml were at very low risk of
bacteremia [17]. In a large, multicenter, retrospective study of
1895 patients aged 29–60 days with culture-proven fUTI, in-
fants not clinically ill on emergency department examination
and without a high-risk past medical history were at very low
risk for adverse events such as death, shock, bacterial menin-
gitis, intensive care unit admission, or need for ventilator

support. In the same study, the presence of bacteremia was
associated with a higher frequency of complications [18].
Similar data has also been reported in a smaller cohort of
140 children [19].
The emission of malodorous urine can be reported by par-
ents or caregivers, but as shown in a recent study by Gauthier
et al. [20], its presence is neither specific nor sensitive enough
to rule in or rule out a diagnosis of AP. Macroscopic analysis
may also reveal cloudy urine. In older children, recurrent AP
may result from voiding disturbances, including hyperactivity
and dysfunctional bladder emptying. A precise history of
voiding modality including incontinence, enuresis, frequency
of micturition, urgency and bowel habits are useful in this
setting.
In conclusion, a diagnosis of AP has to be taken in consid-
eration in all infants with fever and no signs of localization.
Diagnosis
The diagnosis of AP is initially made on the basis of urinalysis
results and the presence of clinical symptoms due to the fact
that urine culture results take 24–48 h to obtain. If AP is
strongly suspected, particularly in the case of clinically ill
young children, empirical antibiotic treatment should be
started, always in consideration of local drug-sensitivity pat-
terns. While waiting for urine culture results, the diagnosis of
AP can be supported by the presence of white blood cells or
bacteria on microscopic examination of an uncentrifuged
urine sample. Manual microscopy is accurate, but can be time
consuming, while automated urine microscopy is faster and
less costly. In a recent prospective study, both techniques gave
comparable results in terms of the detection of pyuria, while
automated analysis is less sensitive and specific for bacteriuria
than Gram-stained smears [21]. A urine dipstick, a chemically
sensitive strip of paper that can identify one or more constit-
uents of urine by immersion, provides a rapid, easy and cost-
effective way of guiding initial diagnosis and management.
When more abnormalities are found together, this increases
the likelihood of AP. A positive leukocyte esterase test results
from the presence of white blood cells, but it may be related to
infections other than AP or to non-steroidal anti-inflammatory
Table 1 Practical approach for urinary tract infection (UTI) diagnosis on the base of urinalysis (modified from Ammenti et al. [23] with permission
from John Wiley and Sons)
Nitrite Leucocyte esterase Likelihood of urinary tract infection (UTI)
Positive Positive UTI very likely
Positive Negative UTI very likely
Negative Positive UTI likely
Negative Negative UTI unlikely
Pediatr Nephrol
agents as well. Leukocyte esterase is also present when lysed
leucocytes are not visible on microscopy. A positive nitrite test
indicates bacteriuria; most uropathogens can indeed convert
nitrate to nitrite. Generating sufficient nitrite for a positive test
can take up to 4 h, so in the case of urine frequency (infants),
the possibility of false negatives should be considered. There-
fore, leukocyte esterase has a good sensitivity but a lower
specificity than nitrite; a combination of both tests can be
helpful in guiding interpretation [22, 23].
A systematic review published by Whiting et al. in 2006
[24] showed that the combination of results of leukocyte ester-
ase and nitrite on a urine dipstick is a reliable test both for
ruling in or out UTI. A subsequent meta-analysis carried out
in 2010 evaluated the effect of age on the performance of
dipstick and compared this test to microscopy [25]. Of the
six studies included in the analysis, only two compared the
performance of dipstick in younger and older children. When
both nitrites and leukocyte esterase are considered, the ability
of dipstick to rule bacteriuria both in and out was good in
children over 2 years, but the performance was significantly
less reliable in younger children. However, in a recent retro-
spective study [26] comparing the performance of urine dip-
stick and urine microscopy as screening tests for AP in 6394
febrile infants aged 1 to 90 days, the dipstick had a greater
positive predictive value (PPV) than combined urinalysis
(66.8 vs. 51.2 %; p<0.001) or microscopic urinalysis (66.8
vs. 58.6 %; p<0.001) and a negative predictive value (NPV)
of 98.7 %. The addition of microscopy would slightly increase
the NPV to 99.2 %, but resulting in eight false-positives for
every missed AP. More recently, Velasco et al. [27] focusing on
the leukocyte esterase test only showed that dipstick use has
the same accuracy in young febrile infants as in older children.
In conclusion, we believe that urine dipstick represents a
useful and rapid screening tool for AP. A practical approach
for the interpretation of results is summarized in Table 1.
Diagnosis of renal parenchymal involvement
The differentiation of AP from LUTIs can be a challenge,
especially in younger children. However, the confirmation of
renal parenchymal involvement can be useful for the
Action
Perform urine culture and start antibiotic on an empiric basis
Perform urine culture and start antibiotic on an empiric basis
Perform urine culture and start antibiotic on an empiric basis
Search for alternative diagnosis
Repeat urine dipstick if fever persists
Pediatr Nephrol
identification of children at major risk for complications, renal
scarring, and long-term sequelae. Technetium-99 m–
dimercaptosuccinic acid (DMSA) scanning is considered the
reference standard for the confirmation of AP [28, 29], but its
routine use is not generally recommended due to the radiation
dose and several practical issues related to the availability of
the test. Therefore, clinical signs, laboratory tests, and other
imaging techniques have been considered as surrogates for the
diagnosis of AP. Ultrasound (US) has been found to be a poor
test for the localization of UTI [24]. Fever higher than 38.5 °C
is commonly considered as a marker of renal parenchymal
involvement even if specificity and sensitivity are low [24,
30, 31] . Moreover, as mentioned previously, fever can be
absent in infants under 90 days. Regarding laboratory
markers, the elevation of C-reactive protein levels and white
blood cell count can suggest the presence of renal involve-
ment, but sensitivity and specificity are low [32]. PCT, a pre-
cursor of calcitonin, produced by the thyroid gland and re-
leased during bacterial infections, is a new promising marker
of renal parenchymal involvement [33], and also in very
young children [34].
A meta-analysis of 18 studies involving 1011 patients eval-
uated the role of PCT as a predictor of both AP and scarring in
children with UTI [32]. PCT was associated with AP and
scarring and demonstrated a significantly higher area under
the curve than either C-reactive protein or white blood cell
count. A value ≥0.5 ng/ml predicted early and late (scar) renal
parenchymal involvement [32]. This cut-off provided an odds
ratio of 7.9 for the identification of AP with a sensitivity of
71 % and specificity of 72 %. Sensitivity was 79 % for late
scarring with a lower specificity of 50 %. Even if PCT cannot
replace the DMSA scan as the gold standard for parenchymal
involvement, it can be used as an available biomarker to dis-
criminate between LUTIs and AP and identify children who
would benefit from a late DMSA scan [32, 34]. This has been
confirmed by a recent Cochrane review [35].
We believe that in well-appearing children with AP blood
tests and DMSA scans are not necessary in the majority of
cases; in selective cases or in hospitalized children, PCT rep-
resents a useful marker of renal parenchymal involvement.
Collection of urine samples for microbiological
diagnosis
The diagnosis of AP is confirmed by the culture of a single
strain of bacteria in significant numbers from an appropriately
collected urine specimen. Particular efforts have been made to
better understand how to avoid false-positive tests due to con-
tamination during collection. Whether the child can control
his/her bladder must be taken into account when selecting
the appropriate method of collection, and the best method
for urine sample collection is still a matter of debate in non-
toilet trained children. Methods can be either invasive or non-
invasive. The cut-off point necessary for the positivity of a
urine culture test differs according to the collection technique;
the decreased risk of contamination associated with invasive
methods allows for a lower cut-off of positivity. Invasive tech-
niques are suprapubic bladder aspiration (SPA) and urethral
catheterization (U-CATH), while non-invasive methods in-
clude mainly the clean-voided method (mid-stream and
clean catch) and the sterile bag.
There is some concern regarding the low specificity of non-
invasive techniques due to the contamination rate. Sensitivity
can be lower in very young infants (<90 days) with both
methods [36]. Some authors suggest that every bag-obtained
positive-result urinalysis should be confirmed with a more
reliable method before therapy [37].
However, even invasive methods can fail to collect a viable
urine sample for culture; the success rate of invasive methods
varies from 20 to 90 % for SPA, while it is reported to be
between 72 and 100 % for U-CATH [31, 38, 39]. Moreover,
both methods are associated with pain and discomfort for both
the child and caregivers [40].
The clean voided mid-stream method is the best for toilet-
trained children. Performing a thorough perineal/genital
cleaning with soap before collection significantly reduces
the rate of contamination, which is described as around
20 % [41]. Collecting a clean sample from non toilet-trained
children can be more difficult.
Fernández et al. [42] recently described a technique for
successfully obtaining clean-catch specimens from very young
infants. It consists of three steps: (1) feed the baby and clean
the genitals 25 min after feeding; (2) stimulate the bladder by
tapping the suprapubic area at a frequency of 100 taps per
minute for 30 s, while someone holds the baby under their
armpits with their legs dangling; (3) massage the paravertebral
lumbar area with light circular movements for 30 s.
More recently, this method was validated as safe, quick,
and effective in a randomized controlled trial (RCT) involving
127 term newborns performed by Altuntas et al. [43]. The
success rate of midstream urine sample collection was 78 %
for children assigned to the experimental group (bladder stim-
ulation and lumbar massage) and 33 % for the control group
(p<0.001) with a median time of 60 s versus 300 s in the
control group.
Presently, there is no consensus regarding the best method
to use in non-toilet-trained children and different guidelines
recommend different approaches (Table 2). The American
Academy of Pediatrics (AAP) guidelines [31] recommend
the use of invasive methods only. The National Institute for
Clinical Excellence (NICE) [30] and the Italian Society of
Pediatric Nephrology (ISPN) guidelines [23] recommend a
less aggressive approach, using invasive techniques only in
specific clinical situations, for example, for a febrile child in
poor general health or severely ill in appearance.

Table 2 Urine collection methods in non-toilet-trained children according to the most recent guidelines
Guidelines Suprapubic bladder aspiration (SPA)
National Institute for Clinical Second option*
Excellence (NICE) [30]
American Academy of First choice
Pediatrics (AAP) [31]
Italian Society of Pediatric Not considered
Nephrology (ISPN) [23]
*If other non-invasive methods are not possible
**If clean catch is not possible, other non-invasive methods (pads) are recommended
***In case of good clinical condition
A recent survey [44] on current practice in primary care of
children aged 1–36 months, performed in 26 European coun-
tries, identified bag as the most frequently used method in
Europe, with a significant difference being seen in children
<3 months vs. older. The study showed major differences
among countries: in Poland, the bag is hardly ever used, while
in Germany, the bag is preferred even for children under
3 months old. Similar data emerged from a survey of general
practitioners in the West of Ireland aimed at evaluating the
implementation of the NICE UTI guidelines in children. Eighty
percent of responders stated a preference for the use of a bag to
collect a urine sample from a child older than 1 year of age
while only 20 % would use the clean-catch method [45].
In conclusion, contamination by bacteria not present in the
bladder is possible for all urine collection methods. In our
opinion, clean voided methods should be the first choice as
they are relatively easy to perform, reliable, cost-effective and
acceptable to children, parents, and caregivers. The use of
invasive methods should be reserved for children in poor gen-
eral health.
The sterile bag, one of the most widely used methods,
especially in primary care, is often preferred by parents for
home collection. This method should be used for a dipstick
only. In the case of positivity for leucocyte esterase or nitrites,
a urine culture should be collected using a different method.
Treatment and hospitalization
Historically, children with AP have been managed with hos-
pitalization and intravenous therapy. Nevertheless, short
courses of intravenous antibiotics (up to 4 days) followed by
oral therapy are as effective as longer courses of intravenous
treatment (7–14 days) [46–50]. Recent evidence [6, 7, 51–53],
moreover, suggests that oral antibiotic treatment alone is as
effective as initial parenteral treatment followed by oral
antibiotics.
A Cochrane review update on antibiotic treatment for AP
performed in 2014 [51] found four studies [6, 7, 52, 53] in-
volving 1131 children comparing oral antibiotics for 10 to
Pediatr Nephrol
Urethral catheterization (U-CATH) Clean catch Sterile bag
First choice Not recommended**
Not considered No
In case of bad clinical conditions First choice Second choice***
14 days with intravenous followed by oral antibiotics. Time
to resolution of fever and the number of children with persis-
tent AP at 72 h after the start of therapy did not differ signif-
icantly between groups. No significant difference in the mean
levels of laboratory biomarkers were found in one study [6].
The number of children with kidney parenchymal damage on
DMSA scan at follow-up did not differ significantly between
groups. On the basis of these data, the most recent guidelines
[23, 30, 31] for the treatment of childhood AP, recommend
oral antibiotics for the treatment of children >2 months of age,
unless the child is seriously ill and/or unable to tolerate oral
antibiotics. To date, no data from RCTs are available to deter-
mine the optimal total duration of antibiotic therapy for AP.
Oral antibiotic administration is therefore recommended in
the outpatient setting. Hospital admission for intravenous ther-
apy is suggested for children in bad clinical condition, if they
are vomiting, or if poor compliance is suspected [23, 30].
There is no gold standard empirical antibiotic treatment;
resistance patterns can be very different between countries,
as demonstrated by the above-mentioned recent European sur-
vey [15], which evaluated the resistance patterns of E. coli. A
high rate of resistance to amoxicillin was reported by almost
all the centers. Data on co-amoxiclavulanate and oral cepha-
losporin showed a large geographic variability, while a high
prevalence of trimethoprim-resistant E. coli was found, prob-
ably due to its widespread use as a prophylactic antibiotic.
Nitrofurantoin showed a good rate of efficacy, with some iso-
lated but important exceptions. Therefore, pediatricians
should be aware of the local resistance patterns in order to
better define the initial therapy; the antibiotic can be subse-
quently modified according to antibiogram results.
Regarding the prompt initiation of therapy after the onset of
symptoms, a retrospective analysis involving 287 children
with AP did not show an increased risk of scarring related to
the delay in antibiotic treatment [54]. Further evidence is
needed to confirm this initial observation. However, as men-
tioned above, empirical antibiotic treatment should be started
soon after AP is suspected (urinalysis and symptoms), partic-
ularly in young children. The association of steroid therapy,
during the acute phase, has been proposed for the prevention
Pediatr Nephrol

of subsequent scarring. A randomized trial of oral methylpred-
nisolone compared with placebo in 84 children with a first
episode of AP on DMSA scan, demonstrated a significant
reduction in scarring at 6 months (33 vs. 60 %; p < 0.05) in
those given steroids [55].
As mentioned above, a subgroup of children that require
special attention and rapid hospitalization are newborns who
present unwell with unstable temperature. These children need
intravenous antibiotics after appropriate cultures, including
blood and urine cultures.
Imaging
In the past, children were subjected to extensive diagnostic
imaging procedures after a first AP, which involved US,
voiding cystourethrography (VCUG), and DMSA scanning
[56]. This approach was aimed at detecting scarring and iden-
tifying VUR of any grade, with the intention of preventing
“reflux nephropathy” and its long-term sequelae (hyperten-
sion and renal failure) [57]. It was believed that early detection
of VUR and scars would permit the prompt initiation of anti-
biotic prophylaxis and/or surgical correction of the reflux,
with the intent of reducing AP recurrence and the appearance
of renal scarring. The true benefit of this approach has been
reconsidered over time [23, 31, 58]. Data from pediatric reg-
istries for chronic kidney disease (CKD) together with the
improvement and diffusion of antenatal US has shown that
renal damage, which was previously associated with acquired
pyelonephritic scarring, is very often congenital in nature,
caused by alterations in kidney development, particularly
hypodysplasia [59, 60], and can be associated with urinary
tract anomalies, such as obstruction or high-grade VUR. In
effect, distinguishing between congenital damage and AP-
related renal scarring is quite impossible with the available
diagnostic tools (renal US and DMSA scan).
Furthermore, recent publications have highlighted a low
correlation between AP and its long-term sequelae. In a sys-
tematic review by Toffolo et al. it was observed that of the
1029 children evaluated in prospective studies with normal
renal function at the time of the fUTI, only 0.4 % showed a
deterioration in renal function during the follow-up period
[61]. Salo et al. reported that the etiologic fraction of recurrent
childhood fUTIs as a main cause of CKD was, at most, 0.3 %
in the absence of structural kidney abnormalities evident in
imaging studies after the first childhood fUTI [62]. The use-
fulness of a complete imaging work-up in children with con-
firmed AP has never been proved, while a systematic review
showed no evidence of a reduction in the recurrence of infec-
tion or renal scarring [63]. The role of surgery [58, 64, 65] and
antibiotic prophylaxis [65–70] in children with VUR has also
been recently reevaluated.
In light of these new emerging data, the current guidelines
for the management of a first fUTI in children have been
modified, favoring less aggressive imaging strategies
(Table 3). However, there is no agreement regarding the best
screening test, the nature of malformations or the degree of
reflux or damage that merits detection [2].
The AAP guidelines suggest performing a routine renal and
bladder US after a first fUTI, while VCUG is recommended
only if hydronephrosis, scarring, or other anomalies are de-
tected at US [31] or in the presence of “other atypical or
complex clinical circumstances”, not specified in detail.
DMSA scanning is not recommended. NICE [30] and ISPN
[23] integrate the results of US with the presence of risk fac-
tors for the identification of children in need of further

Table 3 Imaging strategies after a first febrile urinary tract infection (fUTI) according to the different guidelines

National Institute for American Academy of Italian Society of Top-down approach

Clinical Excellence Pediatrics (AAP) [31] Pediatric Nephrology (TDA) [28]
(NICE) [30] (ISPN) [23]

<6 months >6 months

US Yes If atypical UTIa Yes Yes No

VCUG If abnormal US If risk factorsb If abnormal US If abnormal US and/or If positive acute
and/or atypical UTIa risk factorsc DMSA
Acute DMSA No No No No Yes
Late DMSA If atypical UTIa If atypical UTIa No If abnormal US If positive acute
and/or VUR DMSA

UTI urinary tract infection, US ultrasound, VCUG voiding cystourethrography, DMSA dimercaptosuccinic acid
a
Seriously ill, poor urine flow, abdominal or bladder mass, raised creatinine, septicemia, failure to respond to correct antibiotic treatment within 48 h,
infection with non-E. coli organisms
b
Dilatation on US, poor urine flow, non-E. coli infection, family history of VUR
c
Abnormal prenatal US of the urinary tract, family history of VUR, septicemia, renal failure, age<6 months in a male infant, likely non-compliance of
the family, abnormal bladder emptying, no clinical response to correct antibiotic treatment within 72 h, non-E. coli infection

imaging (VCUG and/or DMSA scan). However, in clinical
practice, it is common to perform an initial DMSA scan in
children with a first fUTI, during the acute phase, only
performing VCUG in those with a renal involvement (top-
down approach, TDA) [28].
Recently, Nelson et al. [71] analyzed data from 2259 patients
under 60 months of age who underwent VCUG and US for a
history of UTI in order to assess the sensitivity, specificity, and
predictive values of US for VCUG abnormalities. The authors
concluded that in children with a history of UTI, US is a poor
screening test for genitourinary abnormalities, with low sensi-
tivity and specificity and that sonography and cystography
should be considered complimentary. However, in the same
paper, among the 1203 children aged 2 to 24 months who
underwent imaging after a first fUTI, the negative predictive
value was 72–74 % for VUR grade II and 95–96 % for VUR
grade>III, even though the likelihood ratio is not available for
the interpretation of the data. This interesting finding suggests
that with a normal renal and bladder US we can confidently
exclude those refluxes at higher risk of recurrent fUTIs and
therefore possible renal damage. Further diagnostic procedures
should be limited to those children who have recurrent febrile
infections or documented renal developmental anomalies (e.g.,
hypodysplasia) that represent an independent risk factor for the
development of chronic kidney disease.
In a recent study [72], the authors retrospectively simulated
the application of these different guidelines to a cohort of 304
children aged 2 to 36 months enrolled in the Italian Renal
Infection Study 1 [6], comparing the efficacy of exclusive oral
with initial parenteral antibiotic treatment, after a first fUTI.
The results of US, VCUG, acute and late DMSA scans were
available for all the recruited children. The missed rate of
reflux grades III–V was 27 % for ISPN, 50 % for NICE,
61 % for AAP and 15 % for the TDA, while the rate of missed
scars was 53 % for ISPN, 62 % for NICE and 100 % for AAP.
Clearly, the TDA would have detected the presence of all
scars. All the above-mentioned imaging approaches, apart
from the TDA, showed low sensitivity and failed to identify
a good proportion of patients with VUR and scars. Conse-
quently, all three diagnostic algorithms are unable to rule chil-
dren with high-grade VUR or scarring either in or out. On the
other hand, a less aggressive imaging work-up allows for a
substantial reduction in economic costs and radiation expo-
sure. A recent study associated the exposure to diagnostic
radiography in early infancy with an increased risk of lympho-
ma (odds ratio, 5.14; 95 % CI, 1.27–20.78) [73]. Although the
results referred to a small number and must be confirmed by
means of further studies, the radiation risks connected to ra-
diographic and scintigraphic imaging should not be
underestimated.
Moreover, the clinical significance of missing some chil-
dren with VUR or scars is still unclear regarding the long-term
consequences.
Pediatr Nephrol
Another interesting approach is reported in a recent meta-
analysis in which Shaik et al. [8] evaluated data from published
studies of children (0–18 years old) with a first UTI who
underwent a DMSA scan at least 5 months after the index epi-
sode and tested three prediction models to identify children at
major risk of scarring. The authors identified nine studies that
met the criteria and for which data was available, six were ob-
servational and three were RCTs. Data on the primary outcome
was available for a total of 1280 children. Renal scarring was
present in 199 children (15.5 %) and 100 of these (50.3 %) had
VUR. The presence of scars was associated, in decreasing order,
with: grade IV–V VUR; abnormal US findings; grade III VUR;
C-reactive protein level; temperature; organism other than
E. coli; polymorphonuclear cell count; grade I–II VUR. Age,
sex, and duration of fever did not influence the presence of scars
at late DMSA scan. They also developed a prediction model that
combines US finding + clinical information (temperature + or-
ganism other than E. coli) that can identify children at higher risk
of scarring. The other two models studied, which included in-
flammatory markers (model 2) and presence and grade of VUR
(model 3), appeared less robust in terms of sensitivity, specific-
ity, PPV, NPV, positive and negative likelihood ratios.
Screening all children after a first fUTI would reveal a low
prevalence of VUR (20–30 %), above all for grades IV–V (1–
4 %) [6, 8, 31]. Furthermore, only 15 % of children present
scarring at late DMSA scan after a first fUTI [8]. As children
with recurrent infections have an increased risk of VUR and
scars [8], a complete imaging work-up is usually required for
recurrent infections, therefore VUR or scars would be correct-
ly identified at this point.
In conclusion, we believe that, in light of current knowl-
edge, a less aggressive diagnostic approach should be adopted
after a first fUTI. Therefore, we suggest performing an US,
conversely we discourage the routine execution of VCUG and
DMSA scans, considering the high rate of spontaneous reso-
lution of VUR with age and the good renal outcome for pa-
tients with scarring but without major congenital renal abnor-
malities. Identifying the high risk population for which a full
imaging work-up is necessary allows for a reduction in the
number of unnecessary imaging tests, psychological stress
and economic and radiation costs.
Outcome
With the improvement of antibiotic therapies, acute infections
usually resolve without sequelae. The long-term outcome of
fUTIs is mostly related to the appearance of renal scarring.
However, the frequency and severity of scarring as a conse-
quence of AP, the time point at which it occurs and the long-
term sequelae, such as the risk of consequent CKD, hyperten-
sion and pre-eclampsia, have been recently questioned. The
diffusion of routine prenatal US over the past 20–30 years has
Pediatr Nephrol
demonstrated that much of the renal damage previously attrib-
uted to AP is related to the congenital mal-development of the
kidneys and is often associated with urinary tract abnormali-
ties (high-grade VUR or obstruction). As a consequence, the
role AP plays in renal scarring and its subsequent adverse
outcome has been reconsidered [74]. Just a small minority of
children (0.4 %) enrolled in prospective studies showed a
deterioration of renal function to CKD after a fUTI on
follow-up [61]. Conversely, virtually all the children with de-
creased renal function at the conclusion of studies had scarring
or renal dysplasia at enrolment. The risk of hypertension is
low [61]. The rate of hypertension only increased from 2.4 to
4.6 % in 713 children enrolled in five studies where blood
pressure was measured at the beginning and end of follow-
up (from 5 to 20 years). In the studies reporting a higher
incidence of hypertension, up to 35 %, scarring and renal
damage were almost always present at enrolment [61]. In con-
trast, one study [75] that followed two groups of children after
a first UTI for 16 to 26 years found no significant differences
in ambulatory blood pressure monitoring between the 53 in-
dividuals with scars when compared with 51 controls without
scars. Childhood UTI has not been seen to influence growth or
cause complications during pregnancy [61]. We believe that
the long-term outcome of children following a single AP, in
the absence of pre-existent renal damage, has to be considered
good.
Risk of recurrence and prevention
While the prognosis of a single episode of AP is good, there
are many concerns regarding the effect of recurrent fUTIs on
scarring [76], renal function, and quality of life for children
and caregivers. Identifying children at major risk could there-
fore allow for the implementation of preventive measures to
reduce the risk of recurrences and preserve the final renal
outcome in these children.
There is a lack of solid evidence and some controversy
regarding the risk factors predisposing recurrence. A major
role for AP recurrence is played by dilating reflux, while
grades I and II are not associated with frequent relapses, unless
bladder dysfunction is also present.
Panaretto et al., in a cohort of 290 children (aged up to
5 years) after a first fUTI, who developed 46 relapses, identi-
fied an age of less than 6 months at the time of the first UTI
(OR 2.9) and grade III–V VUR (OR: 3.5) as independent risk
factors for recurrence [76].
Conway et al. evaluated a cohort of 611 children under
6 years of age, recruited from a network of 27 pediatric pri-
mary care centers, 83 of whom developed recurrent UTI [77].
Factors associated with recurrences in multivariate analysis
were white race, age between 3 and 4 years, age between 4
and 5 years, and grade IV and V VUR. Sex, grade I–III VUR,
and no circumcision did not influence the risk of recurrence.
The role of circumcision in preventing AP in male infants
is still a matter of debate. Two systematic reviews analyzed the
role it plays with different conclusions; the first one performed
by Sing-Grewal et al. [78] demonstrated that circumcision
reduces the risk of UTI, but 111 circumcisions are required
to prevent one infection in boys with no other risk factors. A
lower number-needed-to-treat is necessary in case of recurrent
UTI or high-grade VUR (11 and 4, respectively). Instead, a
more recent meta-analysis by Morris et al. [79] reported lack
of circumcision as an important risk factor for UTI during
lifetime, irrespective of other risk factors. Moreover, a
Cochrane review [80] failed to identify any randomized con-
trolled study on the use of routine neonatal circumcision for
the prevention of UTI in male infants. We believe that circum-
cision could be helpful in children with high-grade VUR and
recurrent UTIs while on antibiotic prophylaxis.
Other described risk factors relating to AP recurrence were
family history of UTI, dysfunctional voiding syndrome, poor
fluid intake, and functional stool retention.
While some of the identified risk factors are not modifiable
(age, white race, familiarity), others (presence of reflux,
voiding habits, phimosis, bladder function, constipation, and
fluid intake) can be modified through behavioral changes and/
or medical interventions.
Historically, antibiotic prophylaxis has been used to pre-
vent recurrence in children after fUTI, especially when VUR
was detected. Antibiotic prophylaxis is the only preventive
measure considered by the most recent guidelines, but none
of these recommend its routine use [23, 31].
In a recent meta-analysis on the efficacy of antibiotic pro-
phylaxis in children with VUR carried out by Wang et al. [81],
the results of the eight RCTs that met the criteria were ana-
lyzed, and while the pooled results showed a reduced risk of
recurrence in children undergoing antibiotic prophylaxis
(pooled OR=0.63, 95 % CI=0.42–0.96), no differences were
found in the appearance of new renal scars between the two
groups. Furthermore, the number of renal scars was low in all
the RCTs included. Antibiotic prophylaxis was associated
with an increased risk of resistant bacteria (pooled OR 8.75,
95 % CI=3.52–21.73, p<0.0001). The most recent of the
RCTs included in this review is the recently published Ran-
domized Intervention for Children with Vesicoureteral Reflux
(RIVUR) trial [82]. The study involved 607 children with
grade I to IV VUR, diagnosed after a first or second fUTI.
They were randomized into two groups, either prophylaxis
with trimethoprim-sulphamethoxazole or placebo, for 2 years;
520/607 children were eligible for evaluation at the end of
study. Hoberman et al. showed a reduction in the risk of re-
currences by 50 % in children receiving prophylaxis (39/302
vs. 72/305). The authors concluded that antibiotic prophylaxis
is useful in children with VUR, but no differences were found

in the risk of renal scarring, with about an 8 % incidence of
new scars occurring in both groups. Furthermore, 16 patient-
years of antibiotics were required to prevent one UTI and 22
patient-years of antibiotics were needed to prevent one fUTI.
The treatment group received 600 years of prophylaxis in
excess. Moreover, an increased risk of antibiotic resistance
was found in the antibiotic group; among the 87 children with
a first recurrence caused by E. coli, the proportion of isolates
that were resistant to trimethoprim-sulfamethoxazole was
63 % in the prophylaxis group and 19 % in the placebo group.
Furthermore, some biases have to be considered in the inter-
pretation of the results. Around 92 % of children enrolled in
the trial were female. This distribution is different from other
similar published studies and from real-life settings. The chil-
dren enrolled were aged up to 71 months, 126 patients were
already toilet-trained and about 30 % of recurrences were
afebrile. In addition, 92 % of patients had grade I–III VUR.
In conclusion, the lack of difference in scarring and the
increased risk of resistance at present do not justify, in our
opinion, the routine use of prophylaxis. As stated by the edi-
torial accompanying the RIVUR trial in the New England
Journal of Medicine [83]: “Sadly, the decision to use antibiotic
prophylaxis in children with reflux remains a clinical dilem-
ma, despite this well-done study. In the face of the emergence
of antibiotic resistance, the lack of a significant between-
group difference in renal parenchymal scarring, and questions
about generalizability, the RIVUR study results would imply
that the general recommendation of prophylactic antibiotics
for vesicoureteral reflux in young children awaits more evi-
dence before universal adoption.”
Multiple-choice questions (answers are provided
following the reference list)
1) Which children are at major risk of UTIs and
pyelonephritis?
a) Children undergoing immunosuppressive therapy
b) No risk factors can be associated with fUTI in
children
c) Children with urinary tract abnormalities
d) Neonates
2) Which are the best predictors of complications in infants
(<90 days) with AP?
a) The presence of fever
b) High fever and normal C-reactive protein value
c) No markers
d) Bad clinical condition, an increase in C-reactive pro-
tein, creatinine, and procalcitonin levels but no fever
3) Which diagnostic approach do the recent guidelines sug-
gest after a first fUTI?
Pediatr Nephrol
a) Top-down approach
b) Performing a US, while VCUG and DMSA scanning
for selected at-risk children
c) Complete imaging work-up (US, DMSA scan, and
VCUG) in all children
d) No imaging
4) What is the risk of chronic kidney damage in children
following a fUTI?
a) < 0.5 %.
b) 5 %
c) 10 %
d) >20 %
5) What is the best treatment of a well-appearing infant
>2 months of age with AP, according to the most recent
guidelines?
a) Parental antibiotic treatment and hospitalization
b) Oral antibiotic treatment for 10–14 days
c) Initial oral antibiotic followed by parenteral treatment
d) Initial parenteral antibiotic followed by oral treatment
Conflict of interest The authors declare that they have no conflict of
interest.
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Answers
1. C
2. D
3. B
4. A
5. B