The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical therapeutics

Endoscopic Treatment of Primary

Vesicoureteral Reflux
David A. Diamond, M.D., and Tej K. Mattoo, M.D., D.C.H.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the authors clinical recommendations.

From the Department of Urology, Childrens Hospital Boston, Boston (D.A.D.);

and the Division of Pediatric Nephrology,
Childrens Hospital of Michigan, Wayne
State University School of Medicine, Detroit (T.K.M.). Address reprint requests
to Dr. Diamond at the Department of
Urology, Childrens Hospital Boston, 300
Longwood Ave., Boston, MA 02115, or at
david.diamond@childrens.harvard.edu.
N Engl J Med 2012;366:1218-26.
Copyright 2012 Massachusetts Medical Society.

A 7-year-old girl with a history of recurrent urinary tract infection since the age of
3 years is known to have bilateral, moderately severe (grade III) vesicoureteral reflux.
Renal scintigraphy with technetium-99labeled dimercaptosuccinic acid has revealed
bilateral scarring in the upper poles of her kidneys, with more severe scarring on the
left kidney than on the right. Despite ongoing antimicrobial prophylaxis, she has recently had another febrile urinary tract infection, which responded well to antibiotic
treatment. Radionuclide cystography reveals persistent bilateral, moderately severe
vesicoureteral reflux. The patient has no history of constipation or dysfunctional
voiding. She is referred to a pediatric urologist, who discusses with the patient and
her parents the various treatment options, including endoscopic correction.

The Cl inic a l Probl em

Primary vesicoureteral reflux is one of the most common urologic abnormalities in
children. The overall prevalence of the disorder is typically estimated to be about
1%.1 However, it has been suggested that the actual prevalence may be substantially
higher.2,3 The frequency with which it is detected depends on the indication for
testing that leads to the diagnosis. For example, vesicoureteral reflux is diagnosed in
about one third of children (mostly girls) who are evaluated after urinary tract infection2,4,5 and in about 10% of infants (mostly boys) with antenatal hydronephrosis.
Vesicoureteral reflux is much less common in black children than in whites.5,6 The
natural course of the disorder is spontaneous resolution, which has been reported to
occur in anywhere from 25 to 80% of patients.7-9 Resolution may be delayed by voiding dysfunction (the inability to release urine with a coordinated bladder contraction and sphincter relaxation), which increases the risk of recurrent urinary tract
infection.10-12
Vesicoureteral reflux in a child with urinary tract infection may predispose that
child to pyelonephritis and renal scarring, termed reflux nephropathy.13 The renal
scarring may be congenital or acquired in origin. The former appears to be a result
of segmental renal dysplasia and is seen mostly in boys with high-grade vesicoureteral reflux with no history of urinary tract infection. The latter is a result of renal
injury caused by acute pyelonephritis and is seen mostly in girls. Patients with reflux
nephropathy may be completely asymptomatic. The known complications of reflux
nephropathy include hypertension and proteinuria.14 In addition, pregnancy-related
complications and chronic kidney disease with end-stage renal failure may occur in
some patients.14
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clinical Ther apeutics

Pathoph ysiol o gy a nd Effec t

of Ther a py
The normal ureterovesical junction prevents retrograde flow of urine to the kidneys by means of a
flap-valve mechanism. This mechanism does not
include a typical anatomical valve but instead relies on the length of the ureter in the bladder wall
and submucosa (the tunnel), its oblique insertion, and the support of the detrusor muscle behind the ureter (Fig. 1). A rise in intravesical pressure causes compression of the ureter with no
backflow of urine.
Primary vesicoureteral reflux results from failed
development of the ureterovesical junction, which
produces an abnormally short tunnel. Normally,
the ratio of the intramural tunnel length to the
ureteral diameter is 5:1,15,16 whereas the ratio is
1.4:1 in refluxing ureters.16,17 Secondary vesicoureteral reflux, which is much less common, results from urinary tract disease associated with
increased intravesical pressure, which may occur
with neurogenic bladder, posterior urethral valves,
or dysfunctional voiding.18 Congenital anomalies
involving the ureterovesical junction, such as paraureteral bladder diverticula or complete ureteral
duplication, also predispose to reflux.
The standard diagnostic test for vesicoureteral
reflux is voiding cystourethrography. This study is
typically performed by filling the bladder with a
radiocontrast agent through a urethral catheter
and then using fluoroscopy to observe the distribution of the dye. Retrograde filling of the upper
urinary tract is diagnostic of vesicoureteral reflux,
which is graded from I to V, with grade V being the
most severe (Fig. 2).19
The presence of vesicoureteral reflux provides a
mechanism by which bacteria in the bladder can
reach the kidney and produce pyelonephritis and
reflux nephropathy. The scarring may occur after
a single episode of pyelonephritis, especially in
young children.20 There is a significant correlation
between the grade of reflux and the development
of abnormalities on renal scintigraphy 1 to 2 years
later.21 The mechanism for renal scarring is unknown and has been attributed to immunologic
mechanisms, macromolecules that are released
owing to cell injury and mesangial dysfunction,
vascular alterations, hypertension, and hemodynamic alterations.22
Long-term antimicrobial prophylaxis and surgical correction of vesicoureteral reflux have both

been used in an attempt to lower the risks of recurrent urinary tract infection and reflux nephropathy. The standard surgical correction is ureteral
reimplantation through an open or laparoscopic
procedure. In this procedure, a long submucosal
tunnel is created for the ureter to achieve a ratio of
tunnel length to ureteral diameter of 4:1 or 5:1.23
An alternative to reimplantation is endoscopic
injection of a biocompatible bulking agent at the
ureterovesical junction (Fig. 3). This procedure is
believed to prevent reflux by buttressing the distal
ureter and narrowing the ureterovesical junction
without impeding the normal flow of urine from
kidneys to bladder. The bulking agent in current
use for this purpose is a copolymer gel that consists of dextranomer microspheres suspended in
hyaluronic acid (Deflux, Salix Pharmaceuticals).
After injection, the hyaluronic acid undergoes
gradual absorption over time and is replaced by
a collagen matrix, resulting in the formation of a
persistent tissue implant at the site of injection.24

Cl inic a l E v idence
Relatively few trials have compared endoscopic correction of vesicoureteral reflux with other therapeutic options. The largest such trial, the Swedish
Reflux Trial in Children, enrolled 128 girls and
75 boys who were between the ages of 1 and
2 years and who had grade III or IV vesicoureteral
reflux. Study subjects were randomly assigned to
receive antibiotic prophylaxis, endoscopic treatment, or surveillance alone. At 2 years, on the
basis of repeat voiding cystourethrography, reflux
had resolved or diminished to grade I or II in
39% of subjects receiving antibiotic prophylaxis,
71% of those receiving endoscopic treatment, and
47% of those undergoing surveillance alone25;
recurrent febrile urinary tract infection occurred
in 14%, 21%, and 37%, respectively,26 with recurrences more common in girls than in boys. New
parenchymal damage was detected by renal scintigraphy in 0%, 9%, and 13%, respectively, and
was again more frequent in girls than in boys.27
In another smaller randomized trial, 61 children
who were older than 1 year of age and had grade
II to IV vesicoureteral reflux were assigned in a
2:1 ratio to receive either endoscopic treatment or
antibiotic therapy. At 1 year, reflux had resolved
or diminished to grade I in 69% of subjects receiving endoscopic treatment and 38% of those
receiving antibiotic therapy.28

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Ureter

Intramural ureter

Submucosal ureter

Reflux

Possible reflux

No reflux

Figure 1. Anatomy of the Ureterovesical Junction.

Primary vesicoureteral reflux results from the failure of development of the ureterovesical junction, producing a short,
inadequate intramural tunnel. The likelihood of vesicoureteral reflux is related to the length of the ureteral tunnel in the
bladder. In this figure, A denotes a tunnel of normal length, and no reflux is present; B, a shorter tunnel, which could be
associated with reflux; C, a short tunnel, which could be associated with reflux. Normally, the ratio of the length of the
intramural tunnel to the ureteral diameter is 5:1, whereas the ratio is 1.4:1 in patients with vesicoureteral reflux.

No randomized clinical trials have compared

endoscopic correction of vesicoureteral reflux with
ureteral reimplantation. However, resolution of
reflux is expected to be nearly 100% with open
reimplantation. In comparison, a recent systematic review of the endoscopic procedure with the
use of dextranomer and hyaluronic acid copolymer
gel showed a success rate of 77% at 3 months
after a single injection. Efficacy ranged from 81%
for grade I reflux to 62% for grade V reflux.29

Cl inic a l Use
The optimal management of vesicoureteral reflux
remains a subject of debate.14,30-32 Although it is
clear that surgical intervention can eliminate or reduce the severity of reflux itself, the clinical trials
do not provide convincing evidence that either surgery or antibiotic prophylaxis can reduce the incidence of recurrent urinary tract infection or, more
important, the incidence of renal damage, as compared with surveillance alone. In addition, it is important to recognize that vesicoureteral reflux has
1220

n engl j med 366;13

a tendency to resolve in many patients with conservative management.7-9 However, the currently
available data do not answer the question of whether more selective intervention may be helpful for
the subgroup of patients at greatest risk for complications, and enrollment in clinical trials has
typically not been restricted to such patients. We
recommend consideration of surgical treatment for
patients with higher-grade reflux (grade III, IV, or
V), for those in whom antimicrobial prophylaxis
has proved to be ineffective (as shown by recurrent
urinary tract infections while receiving such therapy), for those who cannot or do not consistently
use antimicrobial therapy, and for those with progressive renal scarring.14 We also consider surgical
repair in girls with vesicoureteral reflux that persists as puberty approaches.
Voiding dysfunction is a relative contraindication to surgical correction of reflux because the
likelihood of treatment failure and recurrent urinary tract infection is substantially increased.33-35
It is generally recommended that patients with
bowel and bladder dysfunction undergo treatment

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clinical Ther apeutics

Kidney
Renal
pelvis

Ureter

Vesicoureteral
reflux

Bladder

Grade I

Grade II

Grade III

Grade IV

Grade V

Reflux into a ureter

without dilatation

Reflux into the

renal pelvis and
calyces without
dilatation

Mild-to-moderate
dilatation of the
ureter, renal pelvis,
and calyces with
minimal blunting
of the fornices

Moderate ureteral
tortuosity and
dilatation of the
renal pelvis and
calyces

Gross dilatation of
the ureter, pelvis,
and calyces; loss of
papillary impressions; and ureteral
tortuosity

Figure 2. International Classification of Vesicoureteral Reflux.

During voiding cystourethrography, the bladder is filled with a radiocontrast agent through a urethral catheter and
the distribution of the contrast material is observed on fluoroscopy. Retrograde filling of the upper urinary tract is
diagnostic of vesicoureteral reflux, which is graded in severity from I to V as indicated.

for this condition before surgical intervention.

Although optimal treatment of bowel and bladder
dysfunction is not well defined, options include
behavioral therapy, biofeedback, the use of anticholinergic medications or alpha-blockers, and
treatment of constipation.12
Open ureteral reimplantation has a 98% success rate in the definitive elimination of vesicoureteral reflux and remains the standard procedure.
However, the endoscopic procedure, in spite of a
lower success rate (70 to 80%), has become a viable
alternative because it is less invasive than ureteral
reimplantation. The indications for endoscopic
correction are similar to those for reimplantation,
but there are a number of relative contraindications to its use. These include anatomic variants
of the ureterovesical junction and severe vesicoureteral reflux (grade IV or V), for which endoscopic
surgery is less successful. In addition, the Food
and Drug Administration (FDA) has listed the
association of vesicoureteral reflux with nonfunctioning kidneys, paraureteral bladder diverticula,
duplicated ureters, active voiding dysfunction,

and ongoing urinary tract infection as contraindications for the endoscopic procedure.
Endoscopic correction of vesicoureteral reflux
was first described in 1984.36 The first procedures
involved cystoscopic injection of polytetrafluoroethylene (Teflon, DuPont) at the ureterovesical
junction immediately beneath the ureteral orifice.
The treatment was given the acronym STING (for
subureteral Teflon injection). This approach was
subsequently modified to include submucosal injection in the distal ureter, which may require
distention of the ureter with irrigating fluid and
is designated HIT (hydrodistention implantation
technique).37 Because of safety concerns related
to the migration of Teflon particles into the systemic circulation, alternative substances were developed. In 1995, the use of dextranomerhyalVersion 4
03/13/12
uronic acid (Deflux) was first described.24 Deflux
Author
Diamond
obtained FDA approval in 2001 and remains
the
Fig #
2
Title
Vesicoureteral Reflux
only approved substance for endoscopic correction
ME
MP
of grade II, III, or IV vesicoureteral reflux.
There
Jarcho
DE
LAM
was insufficient evidence for the FDA toArtist
approve
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
its use in grade V reflux.
Please check carefully
COLOR FIGURE

Issue date

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03/29/12

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STING Technique

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m e dic i n e

HIT Technique

Figure 3. Endoscopic Correction of Vesicoureteral Reflux.

In Panel A, a gel consisting of dextranomer microspheres suspended in hyaluronic acid (Deflux) is injected at the ureterovesical junction
just below the ureteral orifice, a procedure that was given the acronym STING (for subureteral Teflon injection, because of the material
that was originally used). In Panel B, the injection of the gel results in the buttressing of the distal ureter and narrowing of the ureterovesical junction. The ureteral orifice may have a volcano-like appearance after completion of the procedure. In Panel C, in a modification
of the STING procedure that is termed HIT (hydrodistention implantation technique), cystoscopic irrigation is performed in order to hydrodistend the ureter so that the injection needle can enter the tunnel. In Panel D, the injection needle is positioned within the distal ureter,
resulting in protrusion of the ureteral mucosa to create a mound. In a further elaboration of this approach, two injections are performed,
one more proximally and one more distally within the ureter (the double-HIT technique).

Children undergoing endoscopic treatment for

vesicoureteral reflux should have results from recent voiding cystourethrography for delineation of
anatomy (e.g., paraureteral diverticulum, occult
duplication) available for review. Depending on the
clinical presentation and severity of renal scarring,
preprocedural laboratory testing may include a
complete blood count; measurement of electrolyte,
blood urea nitrogen, and creatinine levels; urinalysis; and urine culture. Patients with fever or other
signs of acute infection should not undergo the
procedure until the infection has been treated and
resolved.
Endoscopic treatment is carried out under general anesthesia in an operating room with the pa1222

n engl j med 366;13

tient in the lithotomy position. Prophylactic intravenous antibiotics (cefazolin at a dose of 50 mg

per kilogram of body weight) are administered.
The procedure is performed through a cystoscope
under direct visualization of the ureterovesical
junction. The dextranomerhyaluronic acid copolymer gel is injected with the use of a 23-gauge
needle attached to a syringe through an injection
catheter. For the STING technique, the needle is
positioned immediately beneath the ureteral orifice at the 6 oclock position. With injection, a
localized mound is created, causing the orifice to
become volcano-shaped (Fig. 3A and 3B). In the
HIT technique, the needle is placed within the
ureteral orifice beneath the mucosa at the

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clinical Ther apeutics

6 oclock position. In some cases, the HIT technique requires hydrodistention of the ureter with
cystoscopic irrigation. With injection, the ureteral mucosa protrudes toward the ureteral orifice, producing a moundlike elevation with ureteral narrowing (Fig. 3C). In a further elaboration
of this approach, two injections are performed,
one proximally and one more distally, within the
ureter (the double-HIT technique). The volume of
dextranomerhyaluronic acid (available in 1-ml
vials) that is injected varies according to the
procedure, the severity of reflux, and the surgeons preference but may range from 0.5 to 2.0 ml
per ureter.37-39 Some, but not all, investigators
have found a correlation between greater injection volume and procedural success.37,40
After the procedure, patients are maintained
on antibiotic prophylaxis (trimethoprimsulfamethoxazole or nitrofurantoin) until correction
of the reflux has been confirmed on follow-up
radionuclide cystography or voiding cystourethrography 3 months after the procedure. Some centers recommend confirmatory radionuclide cystography at 1 year. In the event of a failed first
injection, a second injection may be considered,
but the success rate decreases to 50 to 60%. The
success rate with a third injection is approximately 30% and is therefore not advised.41
In a U.S. analysis conducted in 2002, the average cost of endoscopic correction of vesicoureteral
reflux with dextranomerhyaluronic acid was estimated at $6,530 per patient, with the assumption
that 40% of procedures were bilateral and that
postinjection follow-up was included.42 In another U.S. study of data from 2002 to 2007, the average actual reimbursement for endoscopic treatment of unilateral reflux was estimated at $4,259
per patient.43 An important variable in the cost
of the procedure is the cost of the dextranomer
hyaluronic acid, which is currently approximately
$1,900 per single-use vial. A study examining procedures that were performed between 2003 and
2008 noted a 33% increase in the number of vials
of dextranomerhyaluronic acid used per patient,
from 1.67 to 2.22.44

A dv er se Effec t s
The most common adverse effects of endoscopic
treatment for vesicoureteral reflux include transient
hydronephrosis, febrile urinary tract infection,
hematuria, flank pain, and emesis. These com-

plications, which are typically short-lived and

without long-term sequelae, have been reported
in fewer than 10% of patients in several large
series.25,34,37,45,46
The most serious complication of any antireflux
procedure is persistent obstruction of the ureterovesical junction. Such obstruction may cause severe hydronephrosis and irreversible damage to
the kidney. Oliguria or anuria with renal failure
may occur if bilateral obstruction occurs. The 1997
guidelines of the American Urological Association
reported a 2% rate of obstruction requiring reoperation after ureteral reimplantation. For endoscopic correction with dextranomerhyaluronic
acid, the incidence of significant postoperative
obstruction is reported to be 0.7%.47 Such obstruction may require either ureteral stenting for up to
6 weeks or open reoperation.48
An unexpected outcome of subureteric injection
with dextranomerhyaluronic acid is calcification
of the submucosal mound, which has been observed as early as 3 years after injection.49 Because
of its location at the ureterovesical junction, the
calcified mound can mimic a distal ureteral calculus in some patients and require diagnostic clarification to avoid unnecessary intervention.49-51

A r e a s of Uncer ta in t y
As noted above, results of clinical trials suggest that
endoscopic correction of vesicoureteral reflux is not
appropriate for all patients with the disorder, since
antimicrobial prophylaxis or even surveillance
alone may have similar outcomes for many children.25-27 Selecting the right patient for the procedure remains an area of uncertainty. Intervention
may not be necessary for children with milder
grades of reflux, yet the procedure is typically more
effective in such patients.39,52,53 Failure of anti
biotic prophylaxis is an indication for corrective
surgery even though the frequency of urinary infections may not decrease after the procedure.35
Coexisting voiding dysfunction is not uncommon
with vesicoureteral reflux but is a predictor of treatment failure and recurrent infection.33-35 Parental
preferences can influence the decision to perform
corrective surgery, but such preferences are substantially affected by the guidance and information that the parents receive.54
The long-term durability of the endoscopic procedure has not been well studied. Most series have
reported success rates at 3 months, with few pre-

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senting more long-term data. Reported rates of

recurrence of vesicoureteral reflux range from 11
to 26% at 1 year after negative 3-month postoperative cystography24,55 to 13% at 2 to 5 years after
negative cystography at both 3 and 12 months.45
These values suggest the need for adjustment of
long-term success rates to more accurately represent clinical outcomes to patients and their
families. Approximately half of failures are attributed to anatomic shifting of the submucosal
mound.33,56 It is possible that the HIT technique,
by creating a larger mound that extends further
into the ureteral orifice, might achieve more durable success, although very limited long-term
follow-up data are available regarding this procedure.57

of

m e dic i n e

receiving continuous antimicrobial prophylaxis,

consideration of surgical intervention for curative
therapy is a recommendation, whereas it is an
option in patients with a single febrile breakthrough urinary tract infection and no evidence
of preexisting or new renal cortical abnormalities;
the other option in such cases is to change the
prophylactic agent. The guidelines recommend
treatment of bowel and bladder dysfunction, if
present, before any surgical intervention. The
panel acknowledges that the choice between open
and endoscopic surgery reflects a balance between
morbidity and efficacy, quoting a 98% success rate
for open reimplantation versus 83% for endoscopic
therapy after one injection.

R ec om mendat ions

Guidel ine s
In 2007, the National Institute for Health and Clinical Excellence (NICE) of Great Britain published
guidelines for the management of urinary tract infection in children.58 These guidelines note that
current indications for surgery in the UK are
symptomatic breakthrough urinary tract infections
despite medical management and/or increased renal parenchymal defects, but they conclude that
surgical management of vesicoureteral reflux is
not routinely recommended. The NICE guidelines
were published before the completion of the Swedish Reflux Trial in Children, and they mention the
need for randomized trials to evaluate the efficacy
of endoscopic correction.
In 2010, the American Urological Association
published its guidelines on management of primary vesicoureteral reflux in children.12 The recommendations are stratified into three categories
(standard, recommendation, and option) on the
basis of the current available evidence, with standard being the most rigid statement policy. Accordingly, in these guidelines, among patients with
breakthrough febrile urinary tract infections while

The patient described in the vignette is a good candidate for surgical intervention because of her age,
sex, breakthrough febrile urinary tract infection
while receiving antimicrobial prophylaxis, grade
of vesicoureteral reflux, and the presence of renal
scarring. The age and sex are important because
the vesicoureteral reflux has not improved during
several years of conservative management and because reflux nephropathy will place this patient at
higher risk for pregnancy-related complications in
adult life. We would therefore recommend intervention at this stage. It is important that the pediatric urologist have unbiased discussions with the
patient and her family about the relative merits and
risks of each surgical approach and the follow-up
management, with a clear understanding that in
selecting the endoscopic approach, morbidity is
minimized at the cost of a reduced likelihood of
success and indeterminate durability, as compared
with the open surgical technique.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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