# The “Top-Down” Approach to the Evaluation of Children with Febrile Urinary Tract Infection

Authors: Hans G. Pohl; A. Barry Belman
Journal: Advances in Urology
 (2009)

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## Abstract

The evaluation of children presenting with urinary tract infection (UTI) has long entailed sonography and cystography to identify all urological abnormalities that might contribute to morbidity. The identification of vesicoureteral reflux (VUR) has been of primary concern since retrospective studies from the 1930s to 1960s established a strong association between VUR, recurrent UTI, and renal cortical scarring. It has been proposed that all VUR carries a risk for renal scarring and, therefore, all VUR should be identified and treated. We will not discuss the controversies surrounding VUR treatment in this review focusing instead on a new paradigm for the evaluation of the child with UTI that is predicated on identifying those at risk for scarring who are most deserving of further evaluation by cystography.


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## Body

## 1. Introduction

Concern for the influence of vesicoureteral reflux (VUR) on renal cortical scarring began with the recognition
that VUR transmits bacteria to the upper urinary tract and the observation that
APN, VUR, and renal scarring frequently coexisted in the same patient. Although
APN was considered to be an ascending infection, it was mistakenly considered to always
result from VUR [1, 2]. With these relationships established, the American Academy
of Pediatrics Subcommittee on Urinary Tract Infection published a practice
parameter that recommends renal-bladder sonography (RBUS) and voiding
cystourethrography (VCUG) for the evaluation of urinary tract infection in
febrile infants and young children [3].Sonography is appealing as a method of
evaluation following UTI; however, its ability to detect upper urinary tract
abnormalities is limited. Although RBUS is noninvasive and sufficiently
sensitive to evaluate collecting system dilatation, controlled trials have
found it to be less sensitive than contrast cystography and
99m-Tc-dimercaptosuccinic acid (DMSA) renal scintigraphy in detecting VUR or
parenchymal lesions.  As much as 60% of
reflux and 50% of renal scan abnormalities noted on DMSA are routinely missed
by sonography [4–6]. Given the
prevalence of prenatal sonography, few RBUSs performed for the evaluation of febrile UTI
demonstrate clinically significant abnormalities [7]. Alternatively, VCUG is
the gold standard for the detection of VUR; however, it is invasive, requiring
catheterization, generally of the nonsedated child. Despite the liabilities of
this evaluation paradigm, it remains the recommended guideline, although there
is a tendency for children not to undergo recommended testing, particularly
when treated as outpatients for their UTI [8]. These limitations combined with an increasing clinical
experience with DMSA renal scans has led some to advocate a novel paradigm for
the evaluation of children with UTI, termed the “top-down approach” which
focuses on identifying children at risk for renal scarring, whether or not VUR
is present, as compared with the recommended scheme which proposes to identify
all VUR.  Both approaches employ ionizing
radiation to image the urinary tract, but a direct comparison of effective
doses cannot be made reliably because the radiation is focused in the one case
(cystography) and diffused
throughout the body in the other (DMSA renal scan).  Gonadal dosimetry is lower for continuous
fluoroscopic cystography (effective dose, 0.45 mSv) as compared with DMSA renal
scans (effective dose, 1.8 mSV; ovary, 85 mrads; testis 45 mrads) but as we will
demonstrate, the “top-down” approach offers significant advantages that
outweigh this potential liability.


## 2. Renal Scintigraphy in the Evaluation of UTI, VUR, and Acquired Renal Cortical Abnormalities

Experimental studies in the refluxing
piglet model of ascending acute pyelonephritis were conducted using strict
histopathologic criteria as the standard of reference to evaluate the true
sensitivity and specificity of renal cortical scintigraphy [9, 10]. These
experimental studies, as well as clinical observations, have facilitated our
ability to discriminate between lesions consistent with acute inflammation and
those that represent congenital or acquired abnormalities of the renal cortex.  Acute inflammation results in relative
photopenia of the renal cortex without loss of the renal contour.  Over time, inflammation can lead to scarring
of the renal cortex that produces loss of volume as renal tissue contracts.
This volume loss is represented as disruption of the renal contour with
photopenia.  Renographically, congenital
abnormalities of the renal cortex can look similar to those that are acquired
following infection, the ability to distinguish between the two depends on whether the
child had no UTI prior to the abnormality being discovered (congenital) or
whether a DMSA scan previously demonstrated no cortical lesion or only those
consistent with inflammation (acquired).
In the absence of acute inflammation, the presence of congenital
abnormalities of the renal cortex, such as hypoplasia or volume loss, suggests
VUR and warrants cystography.
Identification of developmental renal parenchymal abnormalities is most
accurately made in the newborn in whom one knows UTI did not play a role.  Beyond that, it may be difficult to
differentiate acquired from congenital defects regardless of UTI history.The DMSA scan was determined to be
highly sensitive and reliable for the detection and localization of
experimental acute pyelonephritis, with a sensitivity of 87 to 89 percent and
specificity of 100 percent for both. When individual pyelonephritic lesions
were analyzed, DMSA scan findings correlated with histopathological changes with an overall
agreement rate of 89 to 94 percent. Those lesions not detected were microscopic
foci of inflammation not evident on gross examination and not associated with
significant parenchymal damage.  DMSA nuclear
renography has been shown to be the most accurate (96%) for the detection of
APN as compared with gadolinium-enhanced MRI (91%), contrast CT scan (90%), and
power Doppler sonography (69%) [11].The clinical diagnosis of acute
pyelonephritis traditionally has been made on the basis of the classic signs
and symptoms of fever and flank pain or tenderness associated with pyuria and
positive urine culture. However, accurate diagnosis based solely on these
parameters is often incorrect, particularly in neonates and infants [12]. Despite the fact that the
majority of patients (50 to 80 percent) with fever and systemic clinical
findings consistent with acute pyelonephritis have abnormal DMSA scan findings,
there is still a high false-positive and/or negative rate based on routine
clinical and laboratory parameters, including fever, elevated WBC, elevated
c-reactive protein (CRP), elevated erythrocyte sedimentation rate (ESR), and
the presence of VUR [13].
Not only is DMSA scintigraphy highly sensitive and specific for the
diagnosis of acute pyelonephritis, but it also provides important information
regarding renal function and the extent of renal parenchymal inflammation.
Documentation of renal parenchymal damage associated with acute pyelonephritis
is fundamental to understanding the roles of infection and vesicoureteral
reflux in the etiology of pyelonephritis and renal scarring.The critical role that infection plays
in the pathogenesis of renal scarring associated with VUR was clarified by
Ransley and Risdon’s experimental studies on the refluxing piglet model, by
which—in the face of
VUR and normal voiding pressures—they showed
that renal scarring occurs only when UTI is present [14]. While a single episode of APN can lead
to significant renal damage, a clear association between the number of APN
attacks and the incidence of renal scarring has been reported [15–19]. Renal
scarring can be prevented or diminished, whether or not APN occurred in the
face of VUR, by the appropriate administration of antibiotics [15, 20–22]. Based on all of the above, it is clear that
infection, not reflux alone, is a prerequisite for acquired renal scarring.


## 3. Evolution of Acute Inflammation to Postinfection Scars

Several investigators have now
evaluated the evolution of the acute inflammatory changes associated with
pyelonephritis using serial DMSA renal scans [23–27]. Acute DMSA
renal scan defects persisted as renal scars in 36 to 52 percent of kidneys. The
sites of new renal scarring corresponded exactly to those sites of acute
pyelonephritis seen on the initial DMSA renal scans, confirming the primary
role of the acute inflammatory response to infection in the etiology of acquired renal
scarring. Contralateral normal kidneys and initially uninvolved areas of
abnormal kidneys have almost always remained normal on follow-up DMSA renal
scans.Surprisingly, reflux has been identified in only 25 to 50 percent of
kidneys that developed new renal scarring. This is attributable in part
to the fact that the majority of patients (63 to 75 percent) with acute
inflammatory changes on the initial DMSA renal scans did not have VUR. In one
prospective study of 38 kidneys with initially abnormal DMSA scans, scarring
developed in 6 of 15 (40 percent) kidneys with associated VUR and in 10 of 23
(42 percent) kidneys without demonstrable reflux [25]. Others have observed
similar findings [28]. These
observations provide convincing clinical evidence that renal parenchymal
infection, rather than vesicoureteral reflux, is the prerequisite for acquired
(postnatal) renal scarring and that the incidence of VUR in children with acute
pyelonephritis is lower than commonly appreciated.Despite these findings, the importance
of VUR (particularly grades III or higher) as a risk factor for renal scarring
should not be discounted. Clearly, patients with moderate and severe reflux are
much more likely to develop acute pyelonephritic damage than children with mild
or no reflux [12, 29]. Furthermore, although 62 percent of the kidneys with
postpyelonephritic renal scarring in one study were drained by nonrefluxing
ureters, renal scarring was still significantly more common in those kidneys
with grade III or higher VUR compared with kidneys with mild or no reflux [29].
Thus, the increased propensity for
scarring in patients with higher grades of VUR is attributable in part to
the increased risk of these kidneys for acute inflammatory damage at the time
of the initial infection [12, 28, 30].


## 4. The “Top-Down” Approach

The DMSA renal scan could supplant the
standard evaluation scheme since it can better discriminate which child is at
risk for renal scarring irrespective of the presence of VUR.  In this novel algorithm, a child who presents
with clinical signs and symptoms suggestive of pyelonephritis first undergoes a
DMSA renal scan to detect renal inflammation. Once radiographic evidence of
renal involvement is demonstrated, the child then undergoes cystography to
search for VUR. This approach is supported by the following two studies.Hansson et al. retrospectively reviewed 303 children under 2
years of age who presented with a first UTI (82% of whom had fever on
presentation) [31]. VUR was found in 26% of the children (80/303), 66% of whom
had abnormal DMSA scans, while no abnormalities were detected in the remaining
27 patients.  An approach based on
identifying renal cortical abnormalities prior to obtaining a VCUG would have
identified not only the 66% of children with VUR presumably at risk for further
scarring, but it would also have identified the 46% of the children without VUR
who were also at renal risk, and most importantly, it would have excluded 120
children (40%) without VUR from a VCUG. One obvious criticism might be this
approach inability to detect 34% (27/80) of VUR without renal involvement. However,
74% of these were low grade while the remaining seven cases of VUR—all grade III—either resolved or improved
significantly during a two-year period follow-up period with no episodes of
recurrent UTI and no new renal scars documented.In a follow-up study, Preda et al. prospectively evaluated
290 children less than 1 year of age with UTI (79% of whom had fever on
presentation) with VCUG and DMSA renal scans [32]. Fifty-one percent of the
patients had positive scans, including 85% (44/52) of the children later found
to have VUR.  Among the eight cases of
VUR that were “missed” by DMSA scans, 7 were of low grade, the remaining boy has grade III VUR with no
acquired renal scars in follow-up despite an episode of breakthrough UTI.This algorithm is further supported by
the observations that while clinically significant acute lesions may occur in
the presence or absence of VUR, significant renal scarring is most likely to
occur in those with grades
III and IV VUR [33]. Taken together, these studies suggest that the “top-down approach”
is able to identify all children at risk for upper tract damage following UTI,
whether or not they have VUR, and excludes children who may not be at risk,
again irrespective of the presence of VUR. The sensitivity of this approach is
improved by performing the DMSA renal scan as close to the time of the febrile
UTI as possible.  In the absence of acute
inflammatory changes, the presence of congenital abnormalities of the renal
cortex such as hypoplasia or focal volume loss typical of scarring is highly
suggestive of VUR and warrants cystography.


## 5. Cost Savings of the “Top-Down” Approach

The “top-down” approach also serves to
reduce the overall charges for the evaluation of children with UTIs. How great
a reduction depends on what estimates are used for the prevalence of patients
with VUR among children with febrile UTI, and among those with positive DMSA
renal scans as well as the timing of evaluation. DMSA scans performed at a
longer interval following the acute episode are less likely to demonstrate
pyelonephritis, as many as half of those lesions having resolved.  In Table1, we present charge data for Children's
National Medical Center and the assumptions used to calculate the cost per
diagnosis of VUR by the traditional “bottom-up” approach ($3368–$8420) versus
the “top-down” approach ($2630–$3033). This should not be surprising since
almost half of the charge associated with the standard “bottom-up” approach is
associated with sonography, a study that rarely identifies significant
abnormalities in children with UTIs in contemporary series. If one routinely obtains DMSA
renal scans on children with moderate to severe VUR, then the cost of
this additional examination would further increase the charges
associated with the bottom up approach in up to 25% of the children with
VUR.Table 1CPT codeChargeTotal chargeU/S, renal bladder76770*$651$83276770.26*$181VCUG74455$779$85274455.26$73DMSA78700$781$96878700.26$187Assumptions used in calculations:Positive DMSA renal scans among children with febrile UTI50–80%Presence of VUR among children with febrile UTI25–50%Presence of VUR among children with positive DMSA scan66%Charge per case of VUR diagnosedBottom-up$3368–$8420Top-down$2630–$3033*The first CPT code and charge relates to the technical fee for performing the examination, while the second code (.26 modified) relates to the professional component.


## 6. Recommendations

In our effort to identify those children who are
most at risk, we might be tempted to apply certain demographic facts to further
minimize studies. Patient age is recognized as being a risk factor for renal
scarring; younger individuals are thought to be more susceptible. Gender may
also play a role as younger males, particularly those who are not circumcised,
tend to be at greater risk for UTI as well as high grade reflux. Reflux in
blacks is also less common; however the renal effects are the same as in other
groups in those who have reflux [34]. Finally, older children may be less
susceptible to renal scarring following pyelonephritis.Therefore, a negative evaluation by any
means, whether by the traditional approach or by the “top-down” approach, may
not be sufficient to exclude all children at risk. Therefore, those who present
with recurrent febrile UTI deserve further attention.  We, therefore, recommend that a prudent
approach includes DMSA renal scans for all children with febrile UTI, ideally
as close to the acute episode as possible. Those with positive scans should
undergo cystography. If VUR is identified, the clinician should then formulate
an appropriate treatment plan depending on various factors such as likelihood
of VUR resolution, likelihood of renal scarring, taking into consideration
parental concerns regarding various treatments, and their outcomes. Children
with a negative DMSA scan require no further evaluation unless recurrent
febrile UTI occurs, in which case cystography should be performed. The use of
antimicrobial prophylaxis should be recommended based on known risks for
recurrent UTI and for renal scarring should UTI occur regardless of the
presence of absence of reflux.


## 7. Summary

The “top-down” evaluation provides an
assessment of risk for renal scarring that strongly correlates with the
presence of clinically relevant VUR.  In
addition to being a more cost-effective means of evaluating children with
febrile UTIs, it is also predicted to lessen medical care costs by reducing the
number of children on antibiotic prophylaxis and of children undergoing surgery
for reflux that is unlikely to result in renal scarring.



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