# Endoscopic Treatment of Vesicoureteral Reflux with  Dextranomer/Hyaluronic Acid in Children

Authors: Wolfgang H. Cerwinka; Hal C. Scherz; Andrew J. Kirsch
Journal: Advances in Urology
 (2008)

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## Abstract

Purpose. The goal of this review is to present current indications, injectable agents, techniques, success rates, complications, and potential future applications of endoscopic treatment for vesicoureteral reflux (VUR) in children. Materials and Methods. The endoscopic method currently achieving one of the highest success rates is the double hydrodistention-implantation technique (HIT). This method employs dextranomer/hyaluronic acid copolymer, which has been used in pediatric urology for over 10 years and may be at present the first choice injectable agent due to its safety and efficacy. Results. While most contemporary series report cure rates of greater than 85% for primary VUR, success rates of complicated cases of VUR may be, depending on the case, significantly lower. Endoscopic treatment offers major advantages to patients while avoiding potentially complicated open surgery. As the HIT method continues to be applied to complex cases of VUR and more outcome data become available, the indication for endoscopic treatment may exceed the scope of primary VUR. Conclusions. Endoscopic injection is emerging as the treatment of choice for VUR in children.


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## Body

## 1. Introduction

Vesicoureteral reflux (VUR) is diagnosed in approximately 1% of children and promotes pyelonephritis, which may lead to renal scarring and hypertension [1]. VUR is one of many
treatable risk factors (e.g., dysfunctional elimination) in the development of urinary
tract infection (UTI). Treatment intends to prevent pyelonephritis and to
preserve renal function and most children diagnosed with VUR receive
antibiotic prophylaxis regardless of VUR grade [2]. Surgical management is
indicated in cases of break-through UTIs and/or persistence of VUR and
comprises ureteral reimplantation and endoscopic injection. Since the
introduction of endoscopic treatment for VUR in 1981 and its first clinical
application in 1984 as subureteric Teflon injection (STING), injection
techniques, injectable agents, and consequently treatment success rates have considerably
improved [3–6]. Endoscopic treatment not only approaches success rates of open
ureteral reimplantation but offers also significant advantages to patients and
parents such as outpatient surgery, lower morbidity (e.g., pain, scar), fewer
complications, and reduced cost. Consequently, a major shift from
reimplantations toward injection treatments has been observed over the last few
years (Figure 1).Figure 1
Trend of surgical treatment for VUR at Children’s Healthcare of Atlanta from 2000 to 2005.The purpose of
this review is to summarize current indications, injectable agents, techniques,
success rates, complications, and potential future applications of endoscopic
treatment for VUR.


## 2. Materials and Methods

### 2.1. Goals of Treatment

There is little evidence that antireflux surgery of any means decreases the incidence of renal scarring
or end-stage renal disease. Worthwhile goals of treatment are to prevent UTIs,
particularly febrile UTIs, to avoid long-term antibiotic use, and to lessen the
need for distressing voiding cystourethrographies (VCUG) and radiation
exposure. Proponents of the endoscopic approach will argue that decreasing the
incidence of UTI is the main goal of therapy. Recurrence, while possible, may
occur in the absence of symptoms and be viewed as subclinical, similar to an
individual with VUR diagnosed after a sibling screen or for fetal
hydronephrosis. Proponents of the open surgical approach will argue that ureteral
reimplantation provides a permanent cure of VUR and is worth the increased morbidity
to achieve this goal. In terms of reducing the risk of UTI, endoscopic
treatment may achieve this goal as well or better than open surgery [7–9].


### 2.2. Indications

The indications for ureteral
reimplantation and endoscopic treatment are with few exceptions identical and
comprise recurrent UTIs despite antibiotic prophylaxis, persistent VUR after a
period of observation (>2 years), poor
compliance with antibiotic prophylaxis, and new renal scarring. When parents
are counseled regarding surgical options, a significant preference for
endoscopic treatment is apparent [10, 11]. Endoscopic
injection has more frequently been employed for primary rather than for complex
VUR (i.e., VUR associated with functional or anatomical abnormalities such as neurogenic
bladder or ectopic or megaureters). Avoidance of endoscopic treatment for complex
VUR is due to a paucity of supportive clinical data and the current view that bladder
dysfunction and structural defects of the ureterovesical junction necessitate
ureteral reimplantation. Endoscopic treatment is Food and Drug Administration
(FDA)-approved for VUR grades II to IV and for cases of initial endoscopic
treatment failure, however it has been applied to all VUR scenarios. While open
ureteral reimplantation is the treatment of choice for failed injection
therapy, endoscopic treatment has been successfully employed after failed
ureteral reimplantation [12–14]. In general, endoscopic treatment is emerging
as the treatment modality of choice for VUR whereas ureteral reimplantation remains
reserved for cases of failed injection therapy, significant anatomical
abnormalities (e.g., large paraureteral diverticula, ectopic ureters,
megaureters), and surgeon’s or parents’ preference.


### 2.3. Injectable Agents

Numerous injectable
bulking materials have been utilized and abandoned over time in search for the
ideal agent, which should be nonimmunogenic, noncarcinogenic, biocompatible,
and biodegradable. Teflon, the first bulking material used for the treatment of
VUR, was abandoned in pediatric urology in the USA
because of the material’s
propensity to migrate to distant organs and to form granulomas; however, carcinogenesis
of Teflon has not been reported [15–17]. Silicone also demonstrates distant
migration and granuloma formation. Its carcinogenic potential has been
controversial but is most likely unsubstantiated [18, 19]. Glutaraldehyde
cross-linked bovine collagen demonstrates a lower degree of absorption as
compared to native collagen and can cause allergic reactions even in patients with
negative skin test [20]. Several new bulking agents are currently under
investigation, such as inorganic materials and autologous tissue. The latter is
nonimmunogenic, however, cell harvest and/or cell culture are time-consuming
and expensive. Dextranomer/hyaluronic acid copolymer (Deflux, Q-Med Scandinavia Inc., Uppsala, Sweden) is easy to inject, is biodegradable with stable implant
volume, and its relatively large particle size prevents distant migration
[21, 22]. It has been used as injectable material in pediatric urology for over
10 years and is currently the first-choice injectable agent due to its safety
and efficacy. Deflux implants in animal tissue were shown to undergo
time-dependent histopathological changes. The initial phase was dominated by an
ingrowth of granulation tissue, a foreign-body giant-cell reaction, and the formation of a surrounding
capsule. In the later phase, cellular elements were largely replaced by a collagen-rich matrix,
whereas the capsule remained unchanged [21]. These findings were confirmed in
patients who experienced
failed endoscopic injection and proceeded to ureteral reimplantation [22]. In
our experience, explanted Deflux appears essentially unchanged up to 4 years
after implantation. Besides biological properties, cost of bulking agents, and
surgeon’s experience, the choice may ultimately depend on approval by
administrative agencies, such as the European Medicines Agency or the FDA.


### 2.4. Technique

The endoscopic method currently
achieving one of the highest success rates is the double hydrodistention-implantation
technique (HIT). Cystoscopy is performed with a pediatric cystoscope equipped with
an off-set lens. An off-set lens permits direct passage of the needle in line
with the ureter without bending the needle. The bladder is filled to less than
half capacity to permit visualization of the ureter and avoid tension within
the submucosal layer of the ureter secondary to overdistention. Hydrodistention
(HD) is performed with the tip of the cystoscope placed at the ureteral orifice
(UO), a pressured stream achieved by placing the irrigation bag approximately 1
meter above the bladder on full flow. HD of the distal ureter serves two
purposes: it allows visualization of the intraureteral injection site and
assessment of treatment progress (i.e., ureteral coaptation). The needle is
passed into the UO and inserted at the mid ureteral tunnel at the 6 o’clock position. Sufficient
bulking agent is injected to produce a bulge, which initially coapts the
detrusor tunnel, while a second implant within the most distal intramural
tunnel leads to coaptation of the UO (approximately 1–1.5 mL). Rarely,
if the two intraureteric submucosal injections (double-HIT method) fail to coapt the ureter, a
classic STING or a supraureteric injection is needed to achieve coaptation. The
latter two injection sites are used more commonly in complex or redo cases (Figure2). HD is performed after each injection to
monitor treatment progress; when HD ceases to dilate the UO, appropriate
coaptation has been achieved. At our institution, all procedures are
performed on an outpatient basis and all patients receive preoperative
antibiotic prophylaxis, which is continued until resolution of VUR has been
confirmed. Radiographic success is defined as grade 0 VUR on a postoperative
VCUG, from 1 to 3 months after a single treatment. Patients are then followed
clinically on an annual basis to determine clinical success and recurrence.Figure 2
Needle placement algorithm for the endoscopic treatment of VUR. Sites 1 and 2 comprise the double-HIT method, while site 3
(STING) is rarely used.We have shown
that the Deflux bleb size, determined by ultrasound, correlates with treatment
success; a measured volume higher than 25% of the injected volume using the HIT
method will result in a 90% cure and 95% using the double HIT method [23, 24]. Consequently,
as part of a prospective clinical trial we are evaluating bladder ultrasounds from
4 to 6 weeks after endoscopic injection with measurement of the Deflux bleb. If
the retained volume is >25%, antibiotics will be discontinued, no VCUG will
be obtained until 1 year, and the patient will be followed clinically. An earlier VCUG will
be obtained for volumes <25% or if clinically indicated. This protocol
allows for the identification of clinically significant VUR and will evaluate
the longer-term success rate.  If the
long-term VCUGs show favorable results and/or if patients do well clinically,
the postoperative VCUG will be excluded in the future.


## 2.1. Goals of Treatment

There is little evidence that antireflux surgery of any means decreases the incidence of renal scarring
or end-stage renal disease. Worthwhile goals of treatment are to prevent UTIs,
particularly febrile UTIs, to avoid long-term antibiotic use, and to lessen the
need for distressing voiding cystourethrographies (VCUG) and radiation
exposure. Proponents of the endoscopic approach will argue that decreasing the
incidence of UTI is the main goal of therapy. Recurrence, while possible, may
occur in the absence of symptoms and be viewed as subclinical, similar to an
individual with VUR diagnosed after a sibling screen or for fetal
hydronephrosis. Proponents of the open surgical approach will argue that ureteral
reimplantation provides a permanent cure of VUR and is worth the increased morbidity
to achieve this goal. In terms of reducing the risk of UTI, endoscopic
treatment may achieve this goal as well or better than open surgery [7–9].


## 2.2. Indications

The indications for ureteral
reimplantation and endoscopic treatment are with few exceptions identical and
comprise recurrent UTIs despite antibiotic prophylaxis, persistent VUR after a
period of observation (>2 years), poor
compliance with antibiotic prophylaxis, and new renal scarring. When parents
are counseled regarding surgical options, a significant preference for
endoscopic treatment is apparent [10, 11]. Endoscopic
injection has more frequently been employed for primary rather than for complex
VUR (i.e., VUR associated with functional or anatomical abnormalities such as neurogenic
bladder or ectopic or megaureters). Avoidance of endoscopic treatment for complex
VUR is due to a paucity of supportive clinical data and the current view that bladder
dysfunction and structural defects of the ureterovesical junction necessitate
ureteral reimplantation. Endoscopic treatment is Food and Drug Administration
(FDA)-approved for VUR grades II to IV and for cases of initial endoscopic
treatment failure, however it has been applied to all VUR scenarios. While open
ureteral reimplantation is the treatment of choice for failed injection
therapy, endoscopic treatment has been successfully employed after failed
ureteral reimplantation [12–14]. In general, endoscopic treatment is emerging
as the treatment modality of choice for VUR whereas ureteral reimplantation remains
reserved for cases of failed injection therapy, significant anatomical
abnormalities (e.g., large paraureteral diverticula, ectopic ureters,
megaureters), and surgeon’s or parents’ preference.


## 2.3. Injectable Agents

Numerous injectable
bulking materials have been utilized and abandoned over time in search for the
ideal agent, which should be nonimmunogenic, noncarcinogenic, biocompatible,
and biodegradable. Teflon, the first bulking material used for the treatment of
VUR, was abandoned in pediatric urology in the USA
because of the material’s
propensity to migrate to distant organs and to form granulomas; however, carcinogenesis
of Teflon has not been reported [15–17]. Silicone also demonstrates distant
migration and granuloma formation. Its carcinogenic potential has been
controversial but is most likely unsubstantiated [18, 19]. Glutaraldehyde
cross-linked bovine collagen demonstrates a lower degree of absorption as
compared to native collagen and can cause allergic reactions even in patients with
negative skin test [20]. Several new bulking agents are currently under
investigation, such as inorganic materials and autologous tissue. The latter is
nonimmunogenic, however, cell harvest and/or cell culture are time-consuming
and expensive. Dextranomer/hyaluronic acid copolymer (Deflux, Q-Med Scandinavia Inc., Uppsala, Sweden) is easy to inject, is biodegradable with stable implant
volume, and its relatively large particle size prevents distant migration
[21, 22]. It has been used as injectable material in pediatric urology for over
10 years and is currently the first-choice injectable agent due to its safety
and efficacy. Deflux implants in animal tissue were shown to undergo
time-dependent histopathological changes. The initial phase was dominated by an
ingrowth of granulation tissue, a foreign-body giant-cell reaction, and the formation of a surrounding
capsule. In the later phase, cellular elements were largely replaced by a collagen-rich matrix,
whereas the capsule remained unchanged [21]. These findings were confirmed in
patients who experienced
failed endoscopic injection and proceeded to ureteral reimplantation [22]. In
our experience, explanted Deflux appears essentially unchanged up to 4 years
after implantation. Besides biological properties, cost of bulking agents, and
surgeon’s experience, the choice may ultimately depend on approval by
administrative agencies, such as the European Medicines Agency or the FDA.


## 2.4. Technique

The endoscopic method currently
achieving one of the highest success rates is the double hydrodistention-implantation
technique (HIT). Cystoscopy is performed with a pediatric cystoscope equipped with
an off-set lens. An off-set lens permits direct passage of the needle in line
with the ureter without bending the needle. The bladder is filled to less than
half capacity to permit visualization of the ureter and avoid tension within
the submucosal layer of the ureter secondary to overdistention. Hydrodistention
(HD) is performed with the tip of the cystoscope placed at the ureteral orifice
(UO), a pressured stream achieved by placing the irrigation bag approximately 1
meter above the bladder on full flow. HD of the distal ureter serves two
purposes: it allows visualization of the intraureteral injection site and
assessment of treatment progress (i.e., ureteral coaptation). The needle is
passed into the UO and inserted at the mid ureteral tunnel at the 6 o’clock position. Sufficient
bulking agent is injected to produce a bulge, which initially coapts the
detrusor tunnel, while a second implant within the most distal intramural
tunnel leads to coaptation of the UO (approximately 1–1.5 mL). Rarely,
if the two intraureteric submucosal injections (double-HIT method) fail to coapt the ureter, a
classic STING or a supraureteric injection is needed to achieve coaptation. The
latter two injection sites are used more commonly in complex or redo cases (Figure2). HD is performed after each injection to
monitor treatment progress; when HD ceases to dilate the UO, appropriate
coaptation has been achieved. At our institution, all procedures are
performed on an outpatient basis and all patients receive preoperative
antibiotic prophylaxis, which is continued until resolution of VUR has been
confirmed. Radiographic success is defined as grade 0 VUR on a postoperative
VCUG, from 1 to 3 months after a single treatment. Patients are then followed
clinically on an annual basis to determine clinical success and recurrence.Figure 2
Needle placement algorithm for the endoscopic treatment of VUR. Sites 1 and 2 comprise the double-HIT method, while site 3
(STING) is rarely used.We have shown
that the Deflux bleb size, determined by ultrasound, correlates with treatment
success; a measured volume higher than 25% of the injected volume using the HIT
method will result in a 90% cure and 95% using the double HIT method [23, 24]. Consequently,
as part of a prospective clinical trial we are evaluating bladder ultrasounds from
4 to 6 weeks after endoscopic injection with measurement of the Deflux bleb. If
the retained volume is >25%, antibiotics will be discontinued, no VCUG will
be obtained until 1 year, and the patient will be followed clinically. An earlier VCUG will
be obtained for volumes <25% or if clinically indicated. This protocol
allows for the identification of clinically significant VUR and will evaluate
the longer-term success rate.  If the
long-term VCUGs show favorable results and/or if patients do well clinically,
the postoperative VCUG will be excluded in the future.


## 3. Results and Discussion

### 3.1. Success Rates

Outcome of endoscopic
treatment for VUR has been evaluated in several large series (Table1). Most
studies included both, primary and complicated cases of VUR. Interpretation of and
comparison among these studies are confounded by different inclusion criteria (e.g.,
with or without complex VUR, grade I, grade V), varying lengths of follow-up,
definitions of success, and single versus multiple injections. Nevertheless, most
current series report cure rates of greater than 85%. Age, gender, and
bilaterality of VUR have not been shown to predict treatment outcome. While the
STING technique yields lower success rates with higher grades of VUR, the HIT
method achieves similar outcomes across all VUR grades up to grade V [5]. Endoscopic
treatment of complicated VUR has been evaluated in smaller series and success
rates vary significantly depending on the associated pathologies (Table 2). In
general, cure rates for complex cases of VUR are lower than for primary VUR. Treatment
of VUR associated with neurogenic bladder was shown to yield acceptable outcome
whereas voiding dysfunction was a significant predictor of treatment failure
[13, 25]. Endoscopic injection has been successfully employed in patients who either
failed ureteral reimplantation or initial injection [13, 14, 26]. Injection after
failed reimplantion or second injection will be
curative in most instances whereas a third injection has been shown to be far
less successful [27, 28]. Refluxing ureters of transplanted kidneys in
symptomatic patients may be treated endoscopically. Although this approach is
curative in only half the cases, yet it represents an attractive alternative to
open surgery in the setting of immune compromise and reduced wound healing
properties [29]. VUR associated with anatomical abnormalities, previously
thought to be contraindications for endoscopic treatment, was recently shown to
be amenable to injection treatment [30–32].Table 1
Success
rates of endoscopic treatment for primary VUR. Meta-analysis
by Elder JS et al. 2006 summarizes results until 2003. More recent series are listed below. Initial success after one treatment and final success after two or more treatments.
ReferenceBulking agentInjected volumeUretersFollow-upSuccessInitialFinalElder et al. 2006 [27]Various0.2–1.7 mL8101variable76%85%Capozza et al. 2004 [33]Various0.2–2.2 mL169412–204 months77%Kirsch et al. 2004 [5]Dx/HA0.5–1.5 mL1193–12 months92%Kirsch et al. 2006 [34]Dx/HA0.8–2.0 mL1393–18 months93%Van Capelle et al. 2004 [35]PDMS0.2–2 mL3113–110 months75%Kajbafzadeh et al. 2006 [36]Ca hydroxylapatite0.4–0.6 mL3646 months69%Yu and Roth 2006 [6]Dx/HA1 mL1622–26 months87%93%Puri et al. 2006 [37]Dx/HA0.2–1.5 mL11013–46 months87%96%Lorenzo et al. 2006 [38]PDMS35172 months72%Pinto et al. 2006 [39]Dx/HA863 months84%Table 2
Success rates of endoscopic treatment for complex VUR.
ReferencePathologyBulking agentInjected volumeUretersFollow-UpSuccessPerez-Brayfield et al. 2004 [13]Neurogenic bladderDx/HA0.4–2.0 (1.1)93 months78%Capozza et al. 2002 [25]Voiding dysfunctionDx/HA3–6 months49%Elmore et al. 2006 [26]Failed initial injectionDx/HA1.0–1.5533 months89%Perez-Brayfield et al. 2004 [13]Failed reimplantationDx/HA0.4–2.0 (1.1)193 months88%Kitchens et al. 2006 [14]Failed reimplantationDx/HA0.7–3.8 (0.8)2019 months83%Campbell et al. 2006 [29]Renal transplantationDx/HA1155%Molitierno et al. 2007 [30]Duplicated ureterDx/HA0.8–2.8 (1.4)631–3 months85%Cerwinka et al. 2007 [31]Paraureteral diverticulumDx/HA0.8–1.8 (1.2)206.6 months81%Chertin et al. 2007 [32]UreteroceleVarious441–21 months91%There are many factors that may affect the success of the
procedure. Preoperative (i.e., patient selection), intraoperative (i.e.,
injection technique), and postoperative variables have been shown to correlate
with treatment outcome (Table3). Postoperatively, failures may result from
Deflux displacement (implant migration), disruption (mucosal breach), or
dissolution (decrease in implant volume).Table 3
Variables affecting the outcome of endoscopic treatment of VUR with Deflux.
Overall success for patients/ureters.
ReferenceBulking agentPatients/UretersMean ageOverall successPredictors of successNot predictiveLavelle et al. 2005 [40]Dx/HA52/807.6 years71%/80%Volcano: present 87%Voiding dysfunctionabsent 53%VUR gradeInjected volumeYucel et al. 2007 [41]Dx/HA168/2594.2 years82%/86%Volcano: present 87%Voiding dysfunctionabsent 36%LateralityVolume: <0.5 mL success>0.5 mL failureVUR gradeRouth et al. 2007 [42]Dx/HA301/4535.5 years66%/72%VUR gradeSurgeon


### 3.2. Advantages

In comparison to ureteral
reimplantation, endoscopic VUR treatment offers major advantages to patients
and parents. The procedure generally lasts less than 15 minutes and is
performed on an outpatient basis. While cure rates are approaching those of
open ureteral reimplantation, significant complications are rare. Endoscopic
treatment entails greater patient convenience, lower morbidity (e.g., pain,
abdominal scar), and reduced cost [43, 44]. Consequently, a
significant parental preference for endoscopic treatment is evident [10, 11]. A
recent study demonstrated that both, patients and parents viewed injection
therapy as the least bothersome aspect of VUR treatment followed by antibiotic
prophylaxis and VCUG [8].


### 3.3. Complications

The most common
complications following endoscopic treatment of VUR are new contralateral VUR (2.3–17.3%) and
treatment failure [35, 38]. Less than 4% of children complain of flank pain or
emesis several hours after the procedure and all respond to analgesics [5].
Gross hematuria, urinary retention, or febrile UTIs have not been observed. The
most significant potential complication of endoscopic treatment for VUR
includes a 0.6% risk of ureteral obstruction [45]. Our obstruction
rate is 4 ureters (2 patients) in over 1200 ureteral injections, or <0.3%. A
7-month old boy with bilateral grade V VUR and spina bifida developed acute
renal failure and had bilateral ureteral stents placed. A STING technique using
0.7 mL was utilized. A postoperative VCUG after stent removal showed bilateral
grade V VUR and a vesicostomy was performed. Interestingly, no VUR was seen at
the time of bladder augmentation 5 years later. A 6-year old girl developed
bilateral ureteral obstruction after HIT using 1.1 mL and 0.7 mL. Bilateral
nephrostomy tubes were placed and removed 6 weeks later after a normal
antegrade study. The VCUG did not show any evidence of VUR and no further
treatment was required.Factors that may
increase the risk of obstruction include bladder dysfunction and markedly
dilated ureters. Patients with recurrent VUR often remain asymptomatic and
without risk factors for pyelonephritis such as young age, voiding dysfunction,
or significant history of UTIs may be taken off antibiotic prophylaxis [46]. Febrile
UTIs after radiographically successful endoscopic treatment warrant evaluation for
recurrent VUR.


### 3.4. Potential Future Applications

As endoscopic
treatment continues to be applied to more complex cases of VUR and outcome data
become available, the indication for endoscopic treatment may exceed the scope
of primary VUR. In the USA,
for example, duplex ureters are no longer considered a contraindication for
endoscopic treatment with Deflux by the FDA. Outcome analysis of complex cases
of VUR will aid in preoperative counseling and patient selection and paired
with proper technique further improve success rates of endoscopic VUR treatment.
As adults with recurrent pyelonephritis are more consistently evaluated for
VUR, a patient population with distinct requirements and disease
characteristics may emerge. Finally, once more accurate predictors of VUR
resolution/persistence become available, endoscopic treatment may be more
frequently used as the primary treatment in patients with low probability of
VUR resolution.


## 3.1. Success Rates

Outcome of endoscopic
treatment for VUR has been evaluated in several large series (Table1). Most
studies included both, primary and complicated cases of VUR. Interpretation of and
comparison among these studies are confounded by different inclusion criteria (e.g.,
with or without complex VUR, grade I, grade V), varying lengths of follow-up,
definitions of success, and single versus multiple injections. Nevertheless, most
current series report cure rates of greater than 85%. Age, gender, and
bilaterality of VUR have not been shown to predict treatment outcome. While the
STING technique yields lower success rates with higher grades of VUR, the HIT
method achieves similar outcomes across all VUR grades up to grade V [5]. Endoscopic
treatment of complicated VUR has been evaluated in smaller series and success
rates vary significantly depending on the associated pathologies (Table 2). In
general, cure rates for complex cases of VUR are lower than for primary VUR. Treatment
of VUR associated with neurogenic bladder was shown to yield acceptable outcome
whereas voiding dysfunction was a significant predictor of treatment failure
[13, 25]. Endoscopic injection has been successfully employed in patients who either
failed ureteral reimplantation or initial injection [13, 14, 26]. Injection after
failed reimplantion or second injection will be
curative in most instances whereas a third injection has been shown to be far
less successful [27, 28]. Refluxing ureters of transplanted kidneys in
symptomatic patients may be treated endoscopically. Although this approach is
curative in only half the cases, yet it represents an attractive alternative to
open surgery in the setting of immune compromise and reduced wound healing
properties [29]. VUR associated with anatomical abnormalities, previously
thought to be contraindications for endoscopic treatment, was recently shown to
be amenable to injection treatment [30–32].Table 1
Success
rates of endoscopic treatment for primary VUR. Meta-analysis
by Elder JS et al. 2006 summarizes results until 2003. More recent series are listed below. Initial success after one treatment and final success after two or more treatments.
ReferenceBulking agentInjected volumeUretersFollow-upSuccessInitialFinalElder et al. 2006 [27]Various0.2–1.7 mL8101variable76%85%Capozza et al. 2004 [33]Various0.2–2.2 mL169412–204 months77%Kirsch et al. 2004 [5]Dx/HA0.5–1.5 mL1193–12 months92%Kirsch et al. 2006 [34]Dx/HA0.8–2.0 mL1393–18 months93%Van Capelle et al. 2004 [35]PDMS0.2–2 mL3113–110 months75%Kajbafzadeh et al. 2006 [36]Ca hydroxylapatite0.4–0.6 mL3646 months69%Yu and Roth 2006 [6]Dx/HA1 mL1622–26 months87%93%Puri et al. 2006 [37]Dx/HA0.2–1.5 mL11013–46 months87%96%Lorenzo et al. 2006 [38]PDMS35172 months72%Pinto et al. 2006 [39]Dx/HA863 months84%Table 2
Success rates of endoscopic treatment for complex VUR.
ReferencePathologyBulking agentInjected volumeUretersFollow-UpSuccessPerez-Brayfield et al. 2004 [13]Neurogenic bladderDx/HA0.4–2.0 (1.1)93 months78%Capozza et al. 2002 [25]Voiding dysfunctionDx/HA3–6 months49%Elmore et al. 2006 [26]Failed initial injectionDx/HA1.0–1.5533 months89%Perez-Brayfield et al. 2004 [13]Failed reimplantationDx/HA0.4–2.0 (1.1)193 months88%Kitchens et al. 2006 [14]Failed reimplantationDx/HA0.7–3.8 (0.8)2019 months83%Campbell et al. 2006 [29]Renal transplantationDx/HA1155%Molitierno et al. 2007 [30]Duplicated ureterDx/HA0.8–2.8 (1.4)631–3 months85%Cerwinka et al. 2007 [31]Paraureteral diverticulumDx/HA0.8–1.8 (1.2)206.6 months81%Chertin et al. 2007 [32]UreteroceleVarious441–21 months91%There are many factors that may affect the success of the
procedure. Preoperative (i.e., patient selection), intraoperative (i.e.,
injection technique), and postoperative variables have been shown to correlate
with treatment outcome (Table3). Postoperatively, failures may result from
Deflux displacement (implant migration), disruption (mucosal breach), or
dissolution (decrease in implant volume).Table 3
Variables affecting the outcome of endoscopic treatment of VUR with Deflux.
Overall success for patients/ureters.
ReferenceBulking agentPatients/UretersMean ageOverall successPredictors of successNot predictiveLavelle et al. 2005 [40]Dx/HA52/807.6 years71%/80%Volcano: present 87%Voiding dysfunctionabsent 53%VUR gradeInjected volumeYucel et al. 2007 [41]Dx/HA168/2594.2 years82%/86%Volcano: present 87%Voiding dysfunctionabsent 36%LateralityVolume: <0.5 mL success>0.5 mL failureVUR gradeRouth et al. 2007 [42]Dx/HA301/4535.5 years66%/72%VUR gradeSurgeon


## 3.2. Advantages

In comparison to ureteral
reimplantation, endoscopic VUR treatment offers major advantages to patients
and parents. The procedure generally lasts less than 15 minutes and is
performed on an outpatient basis. While cure rates are approaching those of
open ureteral reimplantation, significant complications are rare. Endoscopic
treatment entails greater patient convenience, lower morbidity (e.g., pain,
abdominal scar), and reduced cost [43, 44]. Consequently, a
significant parental preference for endoscopic treatment is evident [10, 11]. A
recent study demonstrated that both, patients and parents viewed injection
therapy as the least bothersome aspect of VUR treatment followed by antibiotic
prophylaxis and VCUG [8].


## 3.3. Complications

The most common
complications following endoscopic treatment of VUR are new contralateral VUR (2.3–17.3%) and
treatment failure [35, 38]. Less than 4% of children complain of flank pain or
emesis several hours after the procedure and all respond to analgesics [5].
Gross hematuria, urinary retention, or febrile UTIs have not been observed. The
most significant potential complication of endoscopic treatment for VUR
includes a 0.6% risk of ureteral obstruction [45]. Our obstruction
rate is 4 ureters (2 patients) in over 1200 ureteral injections, or <0.3%. A
7-month old boy with bilateral grade V VUR and spina bifida developed acute
renal failure and had bilateral ureteral stents placed. A STING technique using
0.7 mL was utilized. A postoperative VCUG after stent removal showed bilateral
grade V VUR and a vesicostomy was performed. Interestingly, no VUR was seen at
the time of bladder augmentation 5 years later. A 6-year old girl developed
bilateral ureteral obstruction after HIT using 1.1 mL and 0.7 mL. Bilateral
nephrostomy tubes were placed and removed 6 weeks later after a normal
antegrade study. The VCUG did not show any evidence of VUR and no further
treatment was required.Factors that may
increase the risk of obstruction include bladder dysfunction and markedly
dilated ureters. Patients with recurrent VUR often remain asymptomatic and
without risk factors for pyelonephritis such as young age, voiding dysfunction,
or significant history of UTIs may be taken off antibiotic prophylaxis [46]. Febrile
UTIs after radiographically successful endoscopic treatment warrant evaluation for
recurrent VUR.


## 3.4. Potential Future Applications

As endoscopic
treatment continues to be applied to more complex cases of VUR and outcome data
become available, the indication for endoscopic treatment may exceed the scope
of primary VUR. In the USA,
for example, duplex ureters are no longer considered a contraindication for
endoscopic treatment with Deflux by the FDA. Outcome analysis of complex cases
of VUR will aid in preoperative counseling and patient selection and paired
with proper technique further improve success rates of endoscopic VUR treatment.
As adults with recurrent pyelonephritis are more consistently evaluated for
VUR, a patient population with distinct requirements and disease
characteristics may emerge. Finally, once more accurate predictors of VUR
resolution/persistence become available, endoscopic treatment may be more
frequently used as the primary treatment in patients with low probability of
VUR resolution.


## 4. Conclusions

Endoscopic
treatment of VUR offers significant advantages to patients and avoids
potentially complicated open surgery. While success of endoscopic treatment for
primary VUR approaches that of ureteral reimplantation, it is acceptable in
complex cases of VUR. Consequently, endoscopic injection
has assumed the role of first-line VUR treatment whereas ureteral
reimplantation remains reserved for cases of failed injection therapy or
significant anatomical abnormalities. The development of new injectable
agents in combination with the improvement of endoscopic techniques will
continue to strengthen the role of endoscopic treatment for VUR.



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*Source: 513854-2008-06-05.xml*