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62 Urinary Tract Infection
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Table 5.5 Strengths and weaknesses (“pros and cons”) of the different imaging modalities available
for the investigation of UTI in children
Investigation Pros Cons
Renal ultrasound with
postvoid bladder
views
DMSA Most sensitive test for renal scarring and
Indirect cystogram
(MAG3)
Contrast micturating
cystourethrogram
(MCUG)
Detects dilatation and allows
measurement of renal size
Detects major scarring
Provides information on bladder
dysfunction
Visualises calculi and well tolerated
differential function
Detects reux during normal voiding
Provides differential renal function
Avoids the need for urethral
catheterization
Most reliable test for detection of reux
Excludes urethral and other bladder
pathology
Poor at detecting scarring or
reux
Operator dependent
Relatively expensive and time
consuming
Requires IV cannulation
Child must be cooperative
and toilet trained
Poor sensitivity for detecting
low-grade reux
Requires IV cannulation
Requires urethral
catheterisation and incurs
exposure to radiation
25–50% for the detection of grade III VUR and
fails to identify renal scarring in 15–45% of cases.
e most controversial aspects of newer
guidelines therefore relate to the role of further
diagnostic imaging in children with normal
ultrasound ndings.
Indications for Further Imaging
Although, there are dierences in the recommendations contained in current published
guidelines they all advocate a far more limited
use of DMSA and MCUG than in the past. Even
in infants under 6 months of age these invasive
investigations may not be routinely indicated
following a single UTI which responds well
to treatment within 48 hours. For children in
the age range 6 months to 3 years with normal
ultrasound ndings the NICE guidelines recommend that DMSA should be reserved for those
with recurrent UTIs or those with the type of
clinical features listed in Table 5.6. However,
this approach is arguable because, in practice,
it is oen dicult to establish retrospectively
whether a UTI which was initially treated with
antibiotics in a community setting was accompanied by fever or not. Likewise, there may be
insucient information to determine whether
a UTI responded well to treatment within 48
hours. e justication for DMSA as an early
investigation is based on the argument that
because ultrasonography is not a sensitive test for
detecting renal scarring in young children, there
is a signicant risk that scarring and underlying
VUR will be missed if it is not used fairly widely
in this age group. ere is broad agreement in the
various guidelines that an MCUG may be indicated if there is upper tract dilatation on ultrasound. Where the guidelines dier is on the role
of MCUG in children with normal ultrasound
ndings. Controversially, the NICE guidelines
make no provision for MCUG in children aged
3 years and upwards (even those with recurrent
or “atypical” UTIs) if the ultrasound ndings
are normal. It can be reasonably assumed that
strict implementation of these guidelines would
result in many cases of mild to moderate VUR
in older children remaining undetected. It has
been argued that this may not matter because the
risk of new scarring is low aer 3 years of age.
However, the critics of the NICE guidelines point
Management / Initial Management 63
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Table 5.6 Clinical features which merit further investigation
•
Severe infection with systemic symptoms indicating upper tract infection (pyelonephritis)
•
Family history of VUR and/or renal scarring
•
Poor urinary stream
•
Palpable bladder or other abdominal mass (although these will generally be evident as
abnormalities on ultrasound)
•
Raised creatinine
•
Failure to respond to treatment with suitable antibiotics within 48 hours
•
Infection with organisms other than E. coli
•
Age – although this is a weak discriminator, it is a factor when considering further investigation in
view of the greater susceptibility of infants and young children to renal scarring. Most paediatric
urologists continue to recommend further investigation in boys presenting with UTI in the rst
6 months of life. However this is aimed more at detecting vesico ureteric reux (VUR) than
urethral obstruction, which usually gives rise to detectable abnormalities on ultrasound.
•
Recurrent infection. This can be variously dened as:
– two or more episodes of UTI with acute pyelonephritis/upper urinary tract infection, or
– one episode of UTI with acute pyelonephritis plus one or more episodes of UTI with cystitis or
–three or more episodes of UTI with cystitis
out that whilst new scarring may be uncommon it can undoubtedly occur aer this age.
Moreover, even if older children with VUR may
be at a lower low risk of renal scarring they may
still suer from recurrent symptomatic UTIs and
bouts of ill health which interfere with schooling
and create considerable anxiety within the family. In such circumstances the results of a MCUG
may be of considerable relevance to clinical
management – for example by identifying those
children who might benet from endoscopic
correction of their VUR. e relative merits of
MCUG and IRC are considered in Chapter 3.
Some suggested imaging protocols are illustrated in Figures 5.2a, 5.2b and 5.2c. ese are
based on UK guidelines and can be compared
with the imaging protocol recommended from the
European A ssociation of Urology (EAU) Guidelines
(Figure 5.2d) and the American Academy of
Pediatrics (AAP) guidelines (Figure5.2e).
“Top-Down ”versus “Bottom-Up”
Approach to Imaging after a UTI
Normal ultrasound appearances of the urinary tract in a child with a history of presumed
upper tract infection pose a potential dilemma
to the clinician. Is the urinary tract genuinely
entirely normal or has the scan simply failed to
identify VUR in a child who may be at risk of
developing further UTI s and possible renal scarring? is question can be resolved by either a
“top-down” or “bottom-up” approach. e “topdown” approach relies on a DMSA scan in the
rst instance. If this is normal it is assumed that
even if the child does have VUR it is not clinically signicant and a MCUG is not warranted.
Alternatively, in the “bottom-up” approach a
MCUG is performed as the rst investigation. If
this is negative (no evidence of VUR) no DMSA
scan is performed. See also Chapter 6.
MANAGEMENT
Initial Management
Older children and those with mild to moderate
UTI are usually treated in a community setting in
the rst instance and then referred for outpatient
investigation. However, infants under 3 months
and older children with clinical features of
pyelonephritis should be referred promptly to
64 Urinary Tract Infection
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Figure 5.2 (a) Imaging protocol based on UK guidelines for infants aged 0–6 months.
Figure 5.2 (b) Imaging protocol incorporating modied UK guidelines for young children aged
6months to 3 years.
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Figure 5.2 (c) Imaging protocol incorporating modied UK guidelines for children aged 3 years
and upwards.
Figure 5.2 (d) European Association of Urology guidelines for assessment and treatment of febrile
UTI. BBD, bladder bowel dysfunction.
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Figure 5.2 (e) Imaging recommendations taken from American Academy of Pediatrics guidelines
for investigation and management of a child presenting with a UTI at 2–24 months of age.
a paediatric specialist at the outset. For infants
under 3 months and for older children with presumed pyelonephritis (the groups at particular risk
of renal scarring) treatment usually consists of an
intravenous antibiotic such as cefotaxime or ceftriaxone. is typically comprises treatment with
an intravenous antibiotic for 2–4 days followed
by an oral antibiotic for a total duration of 10 days.
If an aminoglycoside such as gentamicin is used, it
is important to monitor blood levels. Depending
upon the severity of the child’s condition, oral
rather than intravenous antibiotics may be considered (e.g. a 7–10 days course of cephalosporin
or coamoxiclav). An ultrasound scan should be
performed soon aer admission in case there is a
need for urgent intervention to bring the infection
under control. Such interventions may include
percutaneous nephrostomy in cases of upper tract
obstruction complicated by infection (pyonephrosis) and percutaneous insertion of a suprapubic
catheter in cases of bladder outow obstruction.
Oral antibiotics are the rst-line treatment
for afebrile, lower UTI in children aged over
3 months. Although many clinicians now favour
a short (3-day) course of treatment with an agent
such as trimethoprim, cephalosporin, nitrofurantoin or amoxicillin there are others who still
prefer to prescribe a longer course. e antibiotic
should be switched to a more appropriate alternative if this is indicated by the results of sensitivities obtained from the MSU.
Longer-Term Management
Only a relatively small proportion of children
require surgical intervention or ongoing management for abnormalities identied during the
course of investigation. e majority of do not
require urological intervention or follow-up.
Nevertheless, some children, predominantly
girls, suer from recurrent UTIs despite having
no underlying urological abnormality. In these
children it is essential to identify and treat any
predisposing factors – of which dysfunctional
voiding is by far the most important. e role of
constipation is more dicult to establish but there
is a well-recognised association between these
two “elimination disorders”. Treatment is aimed
at establishing a routine of regular and complete
voiding coupled with measures designed to break
the cycle of “holding back” – particularly in chil-
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dren who also experience habitual constipation.
Even in the absence of VUR, a period of antibiotic
prophylaxis may be helpful in some children by
breaking the cycle of infection and allowing the
bladder to settle down.
Other Conservative Measures
Cranberry juice has become increasingly popular
as a prophylactic measure and although evidence
of its eectiveness in children is lacking, some
benet has been shown in adult women. Probiotic
yoghurts have also increased in popularity and,
anecdotally, do seem to be benecial in some
children. However it is important that parents
who do opt for alternative therapies should not
disregard the three most important measures –
increased uid intake, treatment of constipation
and, most importantly, treatment of voiding dysfunction to improve the frequency and eectiveness of bladder emptying.
Management / Other Conservative Measures 67
choice of further imaging is guided
largely by the ultrasound ndings.
●
Further imaging (to look primarily
for vesicoureteric reux and/or renal
scarring) may also be justied despite
normal ultrasound ndings. e
indications for further investigation
and the choice of imaging are determined by the age of the child, severity
of infection and factors such as family
history.
●
Dysfunctional voiding is the most
important factor predisposing to lower
tract urinary infection in girls with
normal urinary tracts. Management
should be directed towards improving
voiding function and treating constipation when present.
FURTHER READING
KEY POINTS
●
Urinary tract infection is one of the
commonest disorders of childhood.
Many more children with relatively
asymptomatic lower tract urinary
infections are being referred for investigation than in the past.
●
Care is needed to obtain an uncontaminated urine sample for reagent
dipstick testing and microscopy and
culture whenever possible.
●
It is important to conrm the diagnosis
of urinary infection before submitting
a child to any investigation which is
more invasive than ultrasonography.
●
Ultrasonography is the investigation of
rst choice but it is not a sensitive test
for detecting vesicoureteric reux and/
or scarring.
●
Further investigation is indicated if
the initial ultrasound scan reveals an
abnormality of the urinary tract. e
Christian MT, McColl JH, MacKenzie JR, Beattie
TJ. Risk assessment of renal cortical scarring
with urinary tract infection by clinical features and ultrasonography. Arch Dis Child.
2000;82(5):376–380.
National Institute for Health and Clinical
Excellence. Guidelines on urinary tract
infection in children. 2007. www.nice.org.uk/
CG054
Newman TB. The new American Academy of
Pediatrics urinary tract infection guideline.
Paediatrics. 2011;128(3):572–575.
Singh-Grewal D, Macdessi J, Craig J.
Circumcision for the prevention of urinary
tract infection in boys: a systematic review of
clinical trials and observation studies. Arch
Dis Child. 2005;90(8):853–858.
Stein R, Dogan HS, Hoebeke P, Kocvara R,
Nijman RJM, Radmayr C, et al. Urinary tract
infections in children: EAU/ESPU Guidelines.
Eur Urol. 2015;67(3):546–558.
Williams G, Craig JC. Long-term antibiotics for
preventing recurrent urinary tract infection
in children. Cochrane Database Syst Rev.
2019;4:CD001534.
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Vesicoureteral Reux
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ROHIT TEJWANI and JONATHAN C ROUTH
Topics covered
6
Etiology and genetic basis of VUR
CAKUT and reux nephropathy
Clinical features
Investigation and diagnostic Imaging
Diagnosis of VUR in children with UTI’s
Screening for VUR in siblings
Screening for VUR in prenatally detected
hydronephrosis
INTRODUCTION
Vesicoureteral reux (VUR) is dened as the retrograde ow of urine from the bladder into the
upper urinary tract. It can be classied as primary or secondary. Primary VUR is due to an
intrinsic failure of the valve mechanism at the
ureterovesical junction whereas secondary VUR
results from sustained exposure of the valve
mechanism to the eects of elevated intravesical
pressure. Secondary VUR is a feature of bladder
outow obstruction such as posterior urethral
valves or functional abnormalities such as neurogenic bladder or severe dysfunctional voiding.
is chapter is largely devoted to primary VUR
because secondary VUR is covered in more detail
in the other relevant chapters (9 and 13).
Treatment options for children with
VUR
Nonoperative management with continuous
antibiotic prophylaxis
Endoscopic correction
Ureteroneocystostomy
Other surgical options
It has long been recognized that urinary tract
infection (UTI) and pyelonephritis are important causes of morbidity in childhood. By the
mid- to late-20th century, VUR was known to
play a central role in linking UTI, pyelonephritis, renal parenchymal scarring, and end-stage
renal disease (ESRD). As a result of better understanding of the natural history of VUR and the
availability of safe and eective prophylactic
antibiotics, continuous antibiotic prophylaxis
(CAP) became adopted as the mainstay of the
initial management of children with VUR in
the 1970s. However, surgical management by
ureteroneocystostomy (ureteric reimplantation)
remained the treatment of choice for children
experiencing recurrent/breakthrough UTIs
or unresolved VUR. In the 1980s, endoscopic
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correction by injection of biocompatible materials (STING procedure) was introduced as a
less invasive alternative to open surgery. More
recently, robotic and laparoscopic ureteroneocystostomy have been added to the range of surgical options.
Numerous studies and controlled trials have
been undertaken to compare the eectiveness of
conservative and surgical management in preventing UTIs and renal scarring. However, these studies
oen yielded conicting or inconclusive ndings
which failed to demonstrate any convincing advantage of one form of treatment over another. is
probably reects the diculty in designing and
conducting studies to take account of the many
dierent variables in study populations. Metaanalyses have demonstrated a denite benet from
CAP in reducing the frequency of recurrent UTIs.
However, the incidence of de novo renal scarring
is relatively low in both medically and surgically
treated patients and successful surgical correction
of VUR has also been demonstrated to reduce the
risk of recurrent UTIs.
Against this background of uncertainty, numerous professional organizations and national bodies have published guidelines for the diagnosis and
management of UTI and VUR.
by aberrant interaction with the metanephric
mesenchyme leading to congenital renal dysplasia or hypoplasia. Attempts to identify a single
“reux gene” have been unrewarding and there
have been very few studies with sucient power
to dene the genetic basis of this condition. e
available evidence indicates that nonsyndromic
VUR has a polygenetic basis characterized by
an autosomal dominant pattern of transmission with variable penetrance and expression.
Amongst the genes expressed in the ureteric bud
which have been have been implicated in VUR
are RET, PA X2, EYA1, SALL1, SIX1, SIX2, BMP4,
TNXB, and GATA3. Similarly, genes expressed
in the metanephric tissue (SLIT2, ROBO2, and
SOX17), have been linked to congenital renal
malformations associated with VUR as have
other genes expressed in the developing kidney
such as WNT4, FGF20, AGT, REN, ACE, AGTR1,
and UMOD.
It is hoped that ongoing and future genetic
research may yield valuable insights into the
genetic basis of VUR which could contribute to
advances in diagnosis and management.
ETIOLOGY AND GENETIC BASIS
OF VUR
e true incidence of VUR in children is dicult to ascertain with accuracy but the available
evidence indicates that it can be found in 1–2%
of younger children, decreasing in the older age
groups. ere is ample evidence that VUR has
a strong genetic basis – with the incidence of
VUR in infant siblings of aected children being
approximately 30%, rising to 50% in the ospring
of aected parents. Primary VUR is thought to
represent the outcome of a developmental anomaly of the ureteral bud which typically results
in a laterally placed ureteral orice and defective valve mechanism caused by an abnormally
short intramural/submucosal tunnel. Severe
ureteral bud anomalies may be accompanied
CAKUT (CONGENITAL
ANOMALY OF THE KIDNEYS
AND URINARY TRACT) AND
REFLUX NEPHROPATHY
VUR is the commonest congenital anomaly of
the kidneys and urinary tract (CAKUT). It is a
major risk factor in the etiology of UTI and an
important factor in bladder/bowel dysfunction
(BBD). VUR is frequently identied as a causative
or contributory factor in children with end-stage
renal disease (ESRD). e presence of VUR is
associated with a threefold increase in the incidence of acute pyelonephritis and pyelonephritic
parenchymal scarring. However, the presence
of VUR is not an essential prerequisite because
both pyelonephritis and scarring can occur in the
absence of VUR.
e term “reux nephropathy” encompasses patterns of renal damage which may be
the outcome of congenial dysplasia, acquired
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pyelonephritic scarring or, frequently, a combination of both mechanisms. However, the weight of
experimental and clinical evidence indicates that
the reux of sterile urine at physiological voiding pressures does not cause renal scarring or
impairment of renal growth. Reux nephropathy accounts for more than 20% of children on
end-stage renal failure programs and also poses
a signicant long-term risk of less severe forms of
chronic kidney disease.
Severe congenital renal damage (renal dysplasia) is seen mainly in conjunction with high
grade (IV–V) VUR (Figure 6.1). Histological
studies of nephrectomy specimens in adults
with severe reux nephropathy have shown that
whereas congenital renal damage is seen more
commonly in males, pyelonephritic scarring is
a far more important cause of long-term renal
damage in females. Although, renal morphology is usually normal at the time of birth in
children with low to moderate grades of VUR
a small proportion may have renal hypoplasia –
a variant in which the normal renal outline is
preserved but the kidney is reduced in size and
contains fewer nephrons than a normal kidney.
Pyelonephritic scarring can occur at any age
but the kidneys of infants and young children
under the age of four are considerably more
susceptible. In addition to gender-related dierences there is considerable geographic, racial,
and ethnic variation in rates of reux nephropathy worldwide. Which of the dierent forms of
medical and surgical management is most eective in protecting the kidney against acquired
reux nephropathy remains the subject of considerable controversy.
Presentation
Symptomatic presentation
Urinary tract infection (UTI) is the commonest form of clinical presentation. e incidence of
VUR identied during the investigation of children with symptomatic UTIs has been historica lly
quoted to be as high 30%. However, this gure
is almost certainly lower in children with mild,
predominantly lower tract UTIs. VUR is strongly
associated with Bladder and Bowel Dysfunction
(BBD) – a clinical syndrome dened by the
coexistence of functional constipation and lower
urinary tract symptoms (LUTS). Comorbid conditions associated with BBD include psychiatric/
developmental disorders, and obesity.
Loin pain can occur as a symptom of pyelone-
phritis and pain may rarely denote the presence
of secondary pelvi-ureteric junction obstruc-
tion. However, pain is not generally considered
to be a feature of uncomplicated primary VUR.
VUR sometimes comes to light for the rst time
in patients presenting with renal insuciency
and/or hypertension who may have little if any,
history of documented symptomatic UTIs. In
such cases the reux nephropathy may be congenital in etiology or the late consequence of
undiagnosed pyelonephritis in early childhood.
Figure 6.1 DMSA scan in a one month old infant
with prenatally detected unilateral grade V VUR;
9% differential function in the affected kidney.
No urinary tract infection prior to the DMSA.
Findings demonstrate severe loss of function
due to congenital dysplasia.
Asymptomatic Presentation
is includes VUR detected during screening of
asymptomatic siblings and the ospring of parents with VUR and VUR identied during the
investigation of infants with prenatally detected
urinary tract dilatation (prenatal hydronephrosis
[PNH]).
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