<title>1. INTRODUCTION</title> <p>Urinary tract infection (UTI) is one of the
most common serious bacterial infections in children. Cumulative incidence is
1–2% among boys and 3–7% among girls, and between 70 000 to 180 000 of the
annual US birth cohort will have a UTI by the age of 6 [##REF##9112544##1##]. Roughly 30–50% of children
with UTI are found to have vesicoureteral reflux (VUR, the retrograde flow of
urine from the bladder into the ureter and/or kidney). Because VUR (particularly
when coexistent with UTI) has been associated with increased risk of renal
scarring, proteinuria, hypertension, eclampsia, and end-stage renal disease
(ESRD) [##REF##8180534##2##], children with UTI typically undergo diagnostic evaluation for and
treatment of VUR.</p> <p>In addition to its
association with UTI, VUR is also a highly genetic condition, displaying an
autosomal dominant transmission pattern, with variable penetrance. VUR may
occur in up to 66% of the offspring of VUR patients [##REF##1433624##3##], and the prevalence of
VUR among siblings of index VUR patients is approximately 32% [##REF##12394743##4##].</p> <p>It has long been
appreciated that there is an association between recurrent UTI, VUR and renal
parenchymal scarring [##REF##1104981##5##]. The traditional paradigm holds that once pathogenic
bacteria establish infection in the bladder, the presence of VUR allows these
bacteria to gain access to the upper tracts, invading the renal parenchyma and
producing clinical acute pyelonephritis [##REF##7038262##6##]. The resulting inflammatory cascade
is presumed to result in tissue damage, fibrosis, and scarring in susceptible
individuals.</p> <p>In general, most
management strategies for VUR have sought to address and defeat this process at
various points along the pathogenic sequence. Medical management with
antimicrobial prophylaxis seeks to maintain sterile urine, rendering the VUR
itself relatively harmless, since there are no bacteria present to reach and
invade the kidney. Antireflux surgery (ARS), in contrast, reconfigures the ureterovesical
junction anatomy to block access to the upper tracts, so that any episodes of cystitis
that do occur cannot progress to pyelonephritis.</p> <p>However, this model
has been called into question in recent years by data that challenges many of
the assumptions of the VUR paradigm. Long-term studies show that renal scarring
can occur in children without VUR, and that renal scarring is not common in
children with even high degrees of reflux [##REF##16240156##7##, ##REF##12876164##8##]. 
Rushton et al. noted that new
renal scars are formed
less frequently after acute pyelonephritis in kidneys with VUR than those without
VUR [##REF##1314912##9##], and other studies have supported these findings to some extent [##UREF##0##10##]. End-stage
renal disease and transplant registries maintained since the 1960's have not
demonstrated the reduction in the proportion of cases attributable to VUR that
one would expect, if the management strategies instituted since that time were
having a significant impact on rates of renal scarring and renal insufficiency
[##REF##16240156##7##, ##UREF##1##11##].</p> <p>As we will see
below, it has been difficult to demonstrate that current management strategies for
VUR result in measurably improved outcomes. Since these management strategies are
based on assumptions about the pathophysiology of UTI, VUR, and renal scarring,
if such assumptions are incorrect then it should not surprise us that our
interventions seem to have little or no effect.</p>
<p>Recommended by Hiep Nguyen</p> <p>Evaluation of the relative merits of medical versus surgical management of vesicoureteral reflux (VUR) has been limited by the few prospective studies comparing these strategies. Among those trials that have been reported, the only consistent positive finding has been that incidence of febrile UTI is lower among children undergoing surgical treatment in comparison with medical treatment. Studies have not found significant differences in overall incidence of UTI, or in rates of new renal scarring or progression of existing scarring. It is likely that there is a subset of children with VUR who do benefit from aggressive treatment of their VUR, but we are not yet able to fully determine which children these are. It is hoped that future research will further clarify which treatments are useful in which children. </p>
<title>2. MEDICAL MANAGEMENT</title> <p>The use of antimicrobials to reduce
recurrent and/or chronic UTI's dates back to the 1940's and 50's, and is the mainstay of initial management in children diagnosed
with VUR. Based on the perception that antimicrobial prophylaxis is safe, effective,
and easily tolerated, generations of children with VUR have spent years
undergoing this treatment while awaiting the spontaneous resolution of their
VUR. The classic studies of Smellie et al. form much of the basis for prophylaxis as a management tool 
[##REF##8180534##2##, ##REF##1104981##5##, ##REF##974492##12##]. In their numerous series, the Smellie group made seminal observations
regarding the associations between VUR, UTI, and negative renal outcomes
including scarring and decreased renal growth, and developed hypotheses
regarding the apparent benefits of antimicrobial prophylaxis in children with
VUR. They noted that children on continuous antimicrobial prophylaxis seemed to
have fewer recurrent UTI than those on intermittent antibiotics, that children
who stopped antibiotics seemed to be prone to recurrence shortly thereafter,
and that increasing number of infections was associated with increased risk of
renal scarring. Although groundbreaking, these data were based on
nonrandomized, retrospective reviews, and thus do not adequately control for
confounding factors and bias.</p> <p>As a consequence,
antimicrobial prophylaxis lacks basic evidence of efficacy in prevention of
either UTI or renal scarring. Three randomized controlled trials comparing
antimicrobial prophylaxis with no treatment (surveillance only) have been
reported [##REF##16510640##13##–##REF##18490378##15##], and one of these was published in conference proceedings
only [##UREF##2##14##]. None of the trials found significant differences in rates of UTI
or renal scarring in treatment versus nontreatment groups. In the most recent
study [##REF##18490378##15##], subjects were kept on antimicrobial prophylaxis or no treatment for
2 years, and then were followed off medication for an additional 2 years. There
were no differences in UTI rates either at the 2-year or 4-year mark. A recent
population-based study using administrative data in a group of 611 children with
UTI (27% of whom had VUR) found that the use of antimicrobial prophylaxis was
not associated with decrease in risk of recurrent UTI [##REF##17622599##16##]. Although each of
these studies has methodological
problems, the failure of any of them to find any effect of antimicrobial
prophylaxis in preventing UTI suggests that the effect, if any, is likely to be
very small. This, in turn, suggests that large number of children need to be
treated for any single child to experience the benefits of prophylaxis.</p> <title>3. SURGICAL MANAGEMENT</title> <p>Since the initial report of surgical correction
of VUR by Hutch in 1952 [##REF##14955874##17##], numerous techniques have been developed to
accomplish the basic goals of ARS, that is, prevention of retrograde flow of
urine into the ureter and kidney. In fact, many of the leading figures in the development
of the specialty of pediatric urology made their names largely through their
accomplishments in perfecting ARS techniques. Today, in expert hands, the
success rate of straightforward ARS approaches 100%, such that some surgeons no longer
bother with post-ARS cystography to confirm VUR resolution [##REF##11272679##18##–##REF##11744485##20##].</p> <p>The extraordinary
success of modern ARS might lead one to assume that there is little room left
for technical innovation in this field. However, investigators have long sought
a less invasive way to correct VUR. In 1981, the first injection technique was
reported by Matouschek using polytetrafluoroethylene (PTFE; Teflon) paste [##REF##7197421##21##].
Concern over migration of PTFE particles to distant body sites [##REF##8508896##22##] limited the
popularity of this bulking agent in the United States, but in 1995, a Swedish
group reported development of a dextranomer copolymer/hyaluronic acid gel for
use as an injectable bulking agent (DX/HA; Deflux) [##REF##7541869##23##]. The FDA approved
Deflux for correction of VUR in 2001, and since then its use has increased
significantly in many parts of the US [##REF##16945675##24##]
, with reported VUR
resolution rates of 68–89% [##REF##14501655##25##–##REF##11586255##28##].</p> <p>To our knowledge,
there have not been any prospective trials of surgical management compared with
observation in children with VUR. Therefore, we simply do not know if ARS is
superior to surveillance alone in prevention of UTI or renal scarring. Because
active management of VUR (either with antibiotics or surgery) is considered
standard of care, it is difficult to find patients who have truly been given no
treatment for their VUR, even in a retrospective review.</p> <title>4. COMPARISON OF SURGICAL VERSUS
MEDICAL MANAGEMENT</title> <p>Comparison of medical treatment with
surgical treatment for VUR is challenging because the different studies have
used various outcome measures, and even studies using similar outcome measures
may be difficult to compare due to differing definitions of similar outcomes.
Reported outcomes in many studies include postoperative incidence of any UTI, incidence
of febrile UTI (presumed in most cases to be equivalent to pyelonephritis), and
renal cortical abnormalities (scarring).</p> <p>In a recent
metaanalysis of clinical trials, Hodson et al. identified seven randomized
controlled trials comparing surgical and medical management 
[##REF##6981165##29##–##REF##11865276##35##], and summarized their results 
[##UREF##5##36##]:</p> <title>4.1. Any
UTI</title> <p>There was no difference in incidence of any UTI between treatment groups, with
incidence of 29–42% in antibiotic
only group and 25–40% in the
surgical group [##REF##6981165##29##–##REF##11865276##35##]. Thus, surgical treatment of VUR
does not seem to reduce the rate of UTI overall.</p> <title>4.2. Febrile
UTI</title> <p>Reported in only 2 studies, this is the only outcome where significant
differences in outcomes have been observed between treatments [##REF##1433585##31##, ##REF##1433581##37##]. The
surgical group had significantly fewer febrile UTI's in short-term and
long-term followup
[##REF##16565873##32##], with relative risk of febrile UTI during the first 5 years of 0.43 (95%
CI: 0.27–0.70).</p> <title>4.3. Renal
scarring</title> <p>In the five studies that assessed renal parenchymal abnormalities using
IVP criteria [##REF##6981165##29##–##REF##1433585##31##, ##REF##2888509##33##, ##REF##1433582##38##], there were no significant differences noted
between surgical and medical groups. The majority of these studies assessed
renal abnormalities using IVP. In the two studies that reported DMSA renal
scintigraphy [##REF##11865276##35##, ##REF##9776536##39##], there was no difference in either progression of
existing scars or development of new scars.</p> <title>4.4. Future
directions</title> <p>
There is little strong evidence supporting the hypothesis that early
detection and treatment of VUR is of any benefit, primarily because it has been
so difficult to demonstrate any benefit from the available therapies. Perhaps
the one firm conclusion we can draw from the literature described above is
that, among children with VUR who have had breakthrough febrile UTI's while on
antimicrobial prophylaxis, ARS is an appropriate therapy that can be expected
to reduce the incidence of such febrile episodes. However, neither prophylaxis
nor ARS can be reliably stated to reduce the risk of new or progressive renal
scarring, although it is prevention of this outcome that is widely assumed to
be the most important benefit of VUR treatment.</p> <p>It is plausible
that, while treatment of VUR may reduce the risk of negative outcomes in a
small subset of VUR patients, the number needed to be treated (in order to realize
those benefits); it may be so high as to make the intervention unjustified for the
overall VUR population. For this reason, ongoing research into biomarkers that
will indicate those at highest risk for recurrent infection and progressive
renal damage is crucial; such biomarkers would allow us to narrow the field of
candidates for medical or surgical treatment to those most likely to benefit,
and allow the larger VUR population to escape the morbidity and bother associated
with these treatments.</p> <p>Finally, there has
been much recent discussion about whether the availability of endoscopic ARS
should alter the indications for ARS. Suggestions have begun to appear in the
literature and at national meetings that endoscopic treatment should be
utilized as initial therapy for patients diagnosed with VUR. Advocates argue
that immediate endoscopic therapy is preferable to antimicrobial prophylaxis in
children just diagnosed with VUR [##REF##16945670##40##]. Current standards of care do not yet
embrace such early treatment: Khoury and Bagli state in their textbook chapter
that “the indications for correction of reflux should remain unchanged
regardless” of technique [##UREF##6##41##]. Furthermore, the data shown above make it clear
that immediate ARS (using any method) makes little sense: the only demonstrated
benefit of ARS is the reduction in incidence of recurrent febrile UTI, and a
majority of newly diagnosed patients with VUR (except those with high-grade
VUR) will never experience a recurrent febrile UTI, regardless of treatment
choice [##REF##16510640##13##, ##REF##17622599##16##]. Therefore, an algorithm that directs all newly diagnosed VUR
patients into immediate surgical treatment (even if it is the “low morbidity”
of endoscopic ARS) is destined to overtreat large numbers of children for whom
there will not be measurable benefits.</p> <p>Ongoing clinical
studies will hopefully clarify some of the glaring shortcomings in our evidence
base. The NIDDK-funded RIVUR study is a randomized trial of antimicrobial
prophylaxis versus placebo in children with VUR and UTI [##REF##18076937##42##]. Each subject is
followed for 2 years during which incidence of UTI and renal scarring by DMSA
criteria will be tracked. DMSA scans will be obtained at study entry, 1 year,
and 2 years. Weaknesses of the study will include the broad range of subjects
(intended to increase generalizability), including boys and girls, VUR Grade
I-IV, ages 2 months to 5 years, and inclusion of trained and nontoilet trained
children, with or without voiding dysfunction. Although the 2-year time frame is short, this large
study (target sample <italic>n</italic> = 600) will provide us with superb data regarding risk of
UTI and renal scarring in children with VUR in the short term, as well as
demonstrate whether antimicrobial prophylaxis is effective in preventing either
UTI or scarring. Other studies assessing the utility of ARS in various clinical
scenarios are desperately needed. Until such studies are complete, clinicians
who treat children with VUR will continue to rely on clinical judgment,
experience, and intuition to manage their young patients.</p>
[{"label": ["10"], "surname": ["Hodson", "Wheeler", "Vimalachandra", "Smith", "Craig"], "given-names": ["EM", "DM", "D", "GH", "JC"], "article-title": ["Interventions for primary vesicoureteric reflux"], "italic": ["Cochrane Database of Systematic Reviews"], "year": ["2004"], "issue": ["3, CD001532"]}, {"label": ["11"], "surname": ["Fanos", "Cataldi"], "given-names": ["V", "L"], "article-title": ["Antibiotics or surgery for vesicoureteric reflux in children"], "italic": ["The Lancet"], "year": ["2004"], "volume": ["364"], "issue": ["9446"], "fpage": ["1720"], "lpage": ["1722"]}, {"label": ["14"], "surname": ["Reddy", "Evans", "Hughes"], "given-names": ["PP", "MT", "PA"], "article-title": ["Antimicrobial prophylaxis in children with vesico-ureteral reflux: a randomized prospective study of continuous therapy vs intermittent therapy vs surveillance"], "italic": ["Pediatrics"], "year": ["1997"], "volume": ["100"], "issue": ["3S"], "fpage": ["555"], "lpage": ["556"]}, {"label": ["30"], "surname": ["Smellie", "Barratt", "Chantler"], "given-names": ["JM", "TM", "C"], "article-title": ["Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial"], "italic": ["The Lancet"], "year": ["2001"], "volume": ["357"], "issue": ["9265"], "fpage": ["1329"], "lpage": ["1333"]}, {"label": ["34"], "surname": ["Morris", "Rothwell", "Paykel"], "given-names": ["MC", "DL", "AD"], "article-title": ["A prospective study of vesicoureteric reflux and renal function in children"], "conf-name": ["In: Proceedings of the 2nd CJ Hodson Symposium on Reflux Nephropathy"], "conf-date": ["February 1991"], "conf-loc": ["Christchurch, New Zealand"]}, {"label": ["36"], "surname": ["Hodson", "Wheeler", "Vimalchandra", "Smith", "Craig"], "given-names": ["EM", "DM", "D", "GH", "JC"], "article-title": ["Interventions for primary vesicoureteric reflux"], "italic": ["Cochrane Database of Systematic Reviews"], "year": ["2007"], "issue": ["3, CD001532"]}, {"label": ["41"], "surname": ["Khoury", "Bagli", "Wein"], "given-names": ["AE", "DJ", "AJ"], "article-title": ["Reflux and megaureter"], "italic": ["Campbell-Walsh Urology"], "year": ["2007"], "publisher-loc": ["Philadelphia, Pa, USA"], "publisher-name": ["Saunders"], "fpage": ["3423"], "lpage": ["3481"], "comment": ["chapter 117."]}]
Adv Urol. 2008 Jul 21; 2008:437560