Friedmacher2018 [609081]

Author's Accepted Manuscript
Endoscopic Injection of Dextranomer/Hyaluronic Acid as First-Line Treatment in
851 Consecutive Children with High-Grade Vesicoureteral Reflux: Efficacy and
Long-Term Results
Florian Friedmacher , Eric Colhoun , Prem Puri
PII: S0022-5347(18)42580-3
DOI: 10.1016/j.juro.2018.03.074
Reference: JURO 15509
To appear in: The Journal of Urology
Accepted Date: 9 March 2018
Please cite this article as: Friedmacher F, Colhoun E, Puri P, Endoscopic Injection of Dextranomer/
Hyaluronic Acid as First-Line Treatment in 851 Consecutive Children with High-Grade Vesicoureteral
Reflux: Efficacy and Long-Term Results, The Journal of Urology® (2018), doi: 10.1016/
j.juro.2018.03.074.
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Endoscopic Injection of Dextranomer/Hyaluronic Acid as First-Line Treatment in 851
Consecutive Children with High-Grade Vesicoureteral Reflux: Efficacy and Long-Term
Results

Florian Friedmacher 1,2 *, Eric Colhoun 1, Prem Puri 1,2,3

1The National Children’s Hospital, Tallaght, Dublin, Ireland
2National Children’s Research Centre, Our Lady’s Chi ldren’s Hospital, Crumlin, Dublin,
Ireland
3Conway Institute of Biomolecular and Biomedical Res earch, School of Medicine & Medical
Science, University College Dublin, Dublin, Ireland

*Corresponding Author:
Florian Friedmacher, M.D., M.Sc. (RCSI)
National Children’s Research Centre,
Our Lady’s Children’s Hospital, Crumlin,
Dublin 12,
Ireland
Phone: +353 1 409 6420; Fax: +353 1 455 0201
e-mail address: [anonimizat]

Co-authors’ e-mail: Eric Colhoun: [anonimizat]; Prem Puri: [anonimizat]

Funding: none

Conflict of Interest: The authors declare that this study was conducted in the absence of any
commercial or financial relationships that could be constructed as a potential conflict of
interest.

Word Count: Abstract: 250; Manuscript: 2,475 (excluding abstrac t and references)

Running Head: Endoscopic Dx/HA Injection for High-Grade Vesicour eteral Reflux

Key Words: vesico-ureteral reflux, ureter, endoscopy, dextran omer-hyaluronic acid
copolymer, deflux

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ABSTRACT
Purpose: Endoscopic injection of dextranomer/hyaluronic is widely acknowledged as first-
line treatment of lower grade vesicoureteral reflux . Our objective was to demonstrate its long-
term efficacy and safety in eradicating high-grade reflux.
Materials and Methods: Eight-hundred-fifty-one children (518 girls, 333 b oys), median age
2.3 years (2 months-13.7 years), underwent endoscop ic correction of high-grade
vesicoureteral reflux using dextranomer/hyaluronic acid. Reflux was unilateral in 415 cases
and bilateral in 436, comprising 1,287 refluxing un its: grade IV in 1,153 (89.6%) and grade V
in 134 (10.4%). 99m technetium-dimercaptosuccinic acid imaging identifi ed renal scarring in
317 (37.3%) patients. Follow-up ultrasound and void ing cystourethrogram were performed 3
months post intervention and renal ultrasound annua lly thereafter. Median follow-up was 8.5
years (6 months-16 years).
Results: Overall resolution rate after the first endoscopic injection was 895/1,287 (69.5%):
70.4% in grade IV and 61.9% in grade V, respectivel y. Reflux resolved after a second
injection in 259 (20.1%) and after a third in 133 ( 10.4%). Persistent reflux after initial
treatment was significantly more common in infants <1 year and in cases with renal scarring.
No significant postoperative complications occurred and none required ureteral
reimplantation. Following reflux resolution, 43 (5. 1%) children developed febrile urinary
tract infections: 24 (55.8%) in the first, 15 (34.9 %) in the second and 4 (9.3%) after ≥3 years.
Of these, 6 had reflux recurrence and 8 demonstrate d neocontralateral grade III reflux, which
was successfully treated with single endoscopic inj ection of dextranomer/hyaluronic acid.
Conclusions: Endoscopic injection of dextranomer/hyaluronic aci d is an efficient and safe
long-term treatment for grade IV and V vesicoureter al reflux, which can be easily repeated in
cases of failure with a high subsequent resolution rate.

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INTRODUCTION
Vesicoureteral reflux (VUR) is one of the most comm on urinary tract abnormalities, affecting
approximately 1-2% of the pediatric population and 25-40% of children presenting with
urinary tract infection (UTI) 1,2 . The association of high-grade VUR, febrile UTI (f UTI) and
renal parenchymal damage (RPD) is well established. Up to 89% of patients with grade IV-V
reflux are at risk of renal scarring after the firs t episode of fUTI, which can lead to substantial
morbidity 3. Permanent renal injury associated with VUR result s either from congenital
dysplasia secondary to embryological alterations in bladder dynamics or from acquired
postinfectious damage due to pyelonephritis 4. While congenital reflux nephropathy (RN) is
more common in male infants with high-grade VUR, ac quired renal scarring seems to
develop mostly in girls 5. Despite early diagnosis and prompt treatment of V UR, RN remains
a major cause of childhood hypertension, growth imp airment and end-stage renal disease
(ESRD) 6.
The likelihood of VUR resolution depends on the gra de of reflux. Spontaneous
resolution rates have been shown to be significantl y higher in grade I-III VUR, whereas high-
grade reflux is much less likely to resolve irrespe ctive of prolonged observation and
antibacterial therapy 7. Therefore, timely intervention is essential in ch ildren with grade IV-V
VUR to reduce the risk of RPD and to minimize seque lae of RN. There are various treatment
options available for the management of patients wi th high-grade VUR: surveillance
combined with continuous antibiotic prophylaxis (CA P), ureteral reimplantation and
endoscopic injection of bulking agents into the sub mucosa of the refluxing ureteric orifice.
Open anti-reflux procedures have reported success r ates of 98% 8. However, minimally
invasive endoscopic correction of VUR has become an accepted therapeutic alternative with
resolution rates ranging 50-92% 8. Although most urologists acknowledge that endosco pic
treatment is successful in lower grade VUR, its rol e in grade IV-V disease remains
controversial. Since the copolymer dextranomer/hyal uronic acid (Dx/HA) was approved by
the United States Food and Drug Administration (FDA ) in 2001 as an acceptable tissue
augmenting substance, we have used endoscopic injec tion of Dx/HA as first-line treatment in
the management of high-grade VUR. In this study, we present our long-term results of
prospectively accumulated data demonstrating the ef ficacy and safety of this procedure in
children with grade IV-V reflux.

MATERIALS AND METHODS

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All parents/guardians received detailed information about available treatment options for the
management of high-grade VUR. There were a small nu mber who chose surveillance
combined with CAP or ureteral reimplantation. These patients were subsequently treated by
other clinicians and were excluded from this study. A total of 851 children with high-grade
VUR (grade IV-V) ultimately underwent endoscopic in jection of Dx/HA (September 2001-
March 2017). VUR was diagnosed in all cases by void ing cystourethrography (VCUG) and
graded according to the International Classificatio n System 9. Children with associated
ureteropelvic junction obstruction, solitary kidney and prune-belly syndrome, or reflux
secondary to neuropathic bladder, posterior urethra l valves and ureteroceles were excluded
from this study. Indications for VCUG are shown in Table 1.
Endoscopic treatment was performed on an outpatient basis under general anesthesia. A
9.5-14 Fr cystoscope was inserted into the bladder and a disposable 4 Fr catheter was
introduced through the working channel. The bladder was almost emptied prior to injection of
Dx/HA to keep the ureteric orifice flat. A wide ori fice was found in 1,040 ureters with grade
IV reflux and in all ureters with grade V. In these cases, the needle was introduced directly
into the affected orifice to increase the length of the intravesical ureter. In the remaining 113
refluxing ureters, the needle was inserted 2-3 mm b elow the affected orifice at the 6 o’clock
position into the bladder mucosa and then advanced for 4-5 mm into the submucosal portion
of the distal ureter. Each administration of Dx/HA was accomplished under direct vision and
slowly continued until a volcanic bulge of implant was seen. A correctly placed implant
created the appearance of a nipple, on top of which sat a slit-like ureteric orifice.
Antibiotic prophylaxis was continued until follow-u p ultrasound and VCUG was
carried out 3 months after the procedure. Antibioti cs were stopped if VCUG demonstrated
resolution of reflux (i.e. grade 0-I). Ultrasound w as repeated at 1 year, and thereafter in 2-
year intervals to monitor the appearance of the uri nary tract, and the site and size of the
injected Dx/HA implant. Median follow-up was 8.5 ye ars (range, 6 months-16 years).
Twenty-five (2.9%) cases were followed between 6 mo nths-1 year, 308 (36.2%) between 1-5
years, and 518 (60.9%) >5 years.
Main outcome measures following endoscopic injectio n of Dx/HA were resolution rate
and occurrence of postoperative fUTIs. A fUTI was d efined as a temperature of ≥38.5°C and
growth of ≥10 5 colony-forming units of a single uropathogen from the urine culture.
Parents/guardians were instructed to report if thei r child required medical care for a fUTI
during follow-up. Repeat VCUG was performed in case s that had ≥2 episodes of fUTIs after
successful VUR treatment or pelvicalyceal dilatatio n on ultrasound following the first fUTI.

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RPD was investigated by 99m technetium-dimercaptosuccinic acid (DMSA) scintigra phy
and classified as mild (focal defects in uptake bet ween 40-45%), moderate (uptake of renal
radionuclide between 20-40%) and severe (shrunken k idney with relative uptake of <20%).
In patients that presented with a fUTI, DMSA scanni ng was undertaken 4-6 months after the
initial UTI.
The principles of the Helsinki Declaration were fol lowed in this study and all
parents/guardians provided written informed consent prior to participation.
Statistical analysis was performed with SPSS ® Statistics. A p value of <0.05 was
considered statistically significant.

RESULTS
Patient demographics are shown in Table 2. The over all resolution rate of high-grade VUR
after the first endoscopic injection of Dx/HA was 8 95/1,287 (69.5%) ureters: grade 0 in 849
and residual grade I in 46 [812/1,153 (70.4%) in gr ade IV and 83/134 (61.9%) in grade V,
respectively]. Median volume of injected Dx/HA per ureter was 0.8 mL (range, 0.3-1.2 mL).
Reflux resolved after a second injection in 259/1,2 87 (20.1%) refluxing units and after a third
in 133/1,287 (10.4%). Persistent VUR after the firs t treatment was significantly more
common in infants than in children >1 year [160/418 (38.3%) vs. 77/433 (17.8%); p<0.0001].
The procedure was free of postoperative complicatio ns in 849 (99.8%) children, whereas two
(0.2%) had frank hematuria lasting <8 hours. All pa tients returned to normal activity on the
day of operation and none required ureteral reimpla ntation. Follow-up ultrasound revealed no
evidence of delayed vesicoureteral junction obstruc tion or changes in the sonographic
appearance of the Dx/HA implant.
Of the 33 children with a preoperative diagnosis of BBD, 15 (45.5%) were cured
following endoscopic correction of their high-grade VUR. The remaining 18 (54.5%) cases
had ongoing symptoms and 18 were newly diagnosed wi th BBD after reflux resolution.
Thirteen (36.1%) of these 36 patients with BBD, all girls, subsequently presented with a
fUTI.
A fUTI occurred in 43 (5.1%) children (39 girls, 4 boys) during follow-up. In 24
(55.8%) cases, a fUTI developed in the first year, in 15 (34.9%) in the second and in 4 (9.3%)
≥3 years after VUR resolution. The incidence of post operative fUTIs was significantly higher
in girls than in boys [39/518 (7.5%) vs. 4/333 (1.2%); p<0.0001]. Thirteen girls had BBD an d
3 of the 4 boys were circumcised. The rate of fUTIs following reflux resolution was
significantly higher in cases with persistent or ne wly diagnosed BBD compared to those

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without [13/36 (36.1%) vs. 30/815 (3.7%); p<0.0001]. Thirteen patients presen ted with ≥2
episodes of fUTIs after endoscopic VUR correction a nd one showed pelvicalyceal dilatation
on ultrasound after the first fUTI. All these child ren underwent repeat VCUG. Six
demonstrated recurrence of grade IV reflux and 8 ha d neocontralateral grade III VUR. Reflux
was successfully treated in these cases with a sing le endoscopic injection of Dx/HA. The
incidence of fUTIs/VUR recurrence was not significa ntly higher in patients with residual
grade I reflux compared to those with complete reso lution on initial postoperative VCUG
(Table 3).
DMSA scintigraphy revealed functional abnormalities consistent with RN in 317
(37.3%) patients, including 32 with bilateral scarr ing. RPD was mild in 140 (44.2%) cases,
moderate in 127 (40.0%) and severe in 50 (15.8%). B oys had a significantly higher rate of
moderate-severe defects than girls (Table 4). Child ren >1 year showed renal scarring
significantly more often compared to infants [215/4 33 (49.7%) vs. 102/418 (24.4%);
p<0.0001]. RPD was significantly commoner in cases with grade V VUR in comparison to
those with grade IV VUR [61/84 (72.6%) vs. 256/767 (33.4%); p<0.0001]. Patients with
renal scarring required a repeat injection of Dx/HA after failure of the first treatment
significantly more often compared to those without defects [186/317 (58.7%) vs. 52/534
(9.7%); p<0.0001]. The incidence of fUTIs following successful endoscopic correction of
high-grade reflux was significantly higher in cases that demonstrated RPD in comparison to
those without scarring [28/317 (8.8%) vs. 15/534 (2.8%); p=0.0002].

DISCUSSION
The most dramatic change in the treatment of VUR ha s been the increasing popularity of
endoscopic injection therapy. Since the FDA approva l of Dx/HA in 2001, the procedure has
become widely accepted as an alternative option for managing reflux. Furthermore, parental
preferences play a major role in the selection of e ndoscopic VUR treatment over the
traditional methods of CAP or ureteral reimplantati on 10 . A survey of 100 counseled parents of
children with VUR revealed that 80% opted for endos copic injection therapy rather than
surveillance with CAP or open anti-reflux surgery w hen given the choice 11 .
The spontaneous resolution rate of high-grade VUR h as been reported to be 5% per
year, which could take >15 years on CAP for grade I V-V reflux 12 . However, the success of
antibacterial treatment for VUR has been shown to d epend on patient compliance and
involves the risk of antibiotic resistant uropathog ens accompanied by potential breakthrough
UTIs 13 . According to data from a national health insuranc e database in the USA comprising

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8,415 children <11 years of age with a diagnosis of VUR, compliance with antibacterial
therapy was generally poor. Only 17% of these cases on CAP were compliant with the
therapy and 58% developed an UTI within 1 year of t reatment 14 . In addition, a meta-analysis
of clinical trials including 17,972 patients with p rimary VUR has demonstrated a lack of
efficacy for CAP in terms of decreasing the inciden ce of fUTIs and RPD 8.
Although reimplantation of the ureter has a higher success rate for the correction of
VUR compared to endoscopic therapy (98.1% vs. 83.0%) 8, it remains an invasive procedure
that usually requires uretheral catheterization and overnight hospitalization. The American
Urological Association (AUA) 8 has stated that the likelihood of vesicoureteral o bstruction
requiring reoperation after open anti-reflux surger y was 0.4%. Elder et al. 15 reported that the
rates of VUR persistence following ureteral reimpla ntation for grade IV and V reflux were
1.5% and 19.3%, respectively; however, grade V dise ase resolved in only 32% of ureters
which were endoscopically treated.
Because of differences in study design, patient cha racteristics, injection techniques and
inconsistent definition of “ success ”, published success rates of endoscopic Dx/HA inje ction
in VUR vary widely and make a direct comparison of our results with the literature difficult.
A meta-analysis of endoscopic therapy for VUR, whic h comprised 5 different bulking agents
including Dx/HA, reported a resolution rate of 62.7 % in ureters with grade IV reflux and
50.9% in ureters with grade V reflux after one inje ction 16 . More recently, Routh et al. 17
performed a systematic review of 47 VUR studies and calculated a success rate of 59% for
grade IV and 62% for grade V following Dx/HA inject ion . In our series, the overall
resolution rate after a single injection of Dx/HA w as 69.5% (70.4% in grade IV, 61.9% in
grade V), suggesting that it makes sense to give a child with high-grade VUR at least one
chance of endoscopic treatment before considering m ore invasive procedures. A randomized
controlled trial in 203 Swedish children with grade III-IV reflux has shown that endoscopic
Dx/HA injection resulted in resolution or downgradi ng in most cases 18 . Although 30.5% of
our patients required >1 endoscopic treatment, only 10.4% needed a third injection to cure
their high-grade VUR. Hence, our findings emphasize that endoscopic treatment with
injected Dx/HA provides a high resolution rate in g rade IV-V disease, which obviates the
need for CAP with repeated imaging studies or open anti-reflux surgery. Additionally, it can
easily be repeated in cases of failure with a high subsequent resolution rate. This minimally
invasive procedure has therefore been included as a n option in the 2010 AUA guidelines on
management of primary VUR in children 8. Endoscopic correction of VUR, however, has a
definite learning curve and its success rate appear s to depend on the expertise of the

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performing surgeon. Kirsch et al. 19 suggested that the outcome of endoscopic reflux th erapy
most likely correlates with the location of injecte d material and experience with the
technique.
The risk for a fUTI after successful endoscopic inj ection of Dx/HA has been reported to
be extremely low 20,21 . In our series, 5.1% of the cases with high-grade VUR developed a
fUTI during follow-up. It has previously been indic ated that endoscopic reflux treatment
plays an important role in the reduction of fUTIs a nd was superior compared with cases
receiving CAP 22. In addition, the long follow-up time of our study with a median of 8.5 years
allowed us to draw conclusions regarding long-term implant efficacy. As no significant
alterations in implant size were observed on follow -up ultrasound, this finding supports the
proposed stability of the injected Dx/HA. However, Chertin et al. 23 recommended that all
patients, who had endoscopic correction of VUR but subsequently developed a fUTI, require
prompt revaluation to rule out recurrent or neocont ralateral reflux. Six children in our series
who presented postoperatively with ≥2 fUTIs were found to have recurrence of grade IV-V
reflux on repeat VCUG and 8 had neocontralateral gr ade III reflux. Because untreated
episodes of fUTIs in cases with VUR recurrence are most likely to cause RPD, effective
education of parents and communication with the pri mary care physician are essential to
avoid long-term sequelae of RN. More than one third of our patients with high-grade VUR
already demonstrated renal scarring despite immedia te reflux therapy. A recent study
suggested that early detection and treatment of gra de IV-V VUR may prevent acquired RPD
and limit the progression of renal damage in childr en with congenital RN 24. Indeed, none of
the patients in our series developed hypertension, growth impairment or ESRD during
follow-up.
Apart from lacking cost-utility analysis, we recogn ize that our study has some
limitations. Our resolution criteria also included those cases with residual grade I reflux,
which is not consistent with the majority of publis hed reports. However, Routh et al 17 found
that grade I VUR is not routinely treated by many p ractitioners. In fact, European studies
often considered grade I reflux as part of their de finition of “ success ”. Whether treating those
particular patients is of any clinical benefit is a n open question. As a repeat VCUG was not
performed in all children who presented postoperati vely with a fUTI, it is possible that low-
grade VUR may have been missed in a small number of cases following resolution of grade
IV-V reflux (i.e. in those who had only one single episode of fUTI but no urinary tract
dilatation on follow-up ultrasound). Furthermore, u nreported cases of fUTIs after VUR
resolution could not be completely ruled out, which may have caused a potential result bias.

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Nevertheless, the majority of patients were followe d-up over a long time period and still
remain under continuous surveillance.

CONCLUSIONS
Our results confirm the efficacy and safety of endo scopic injection of Dx/HA in the eradication
of high-grade VUR. We recommend this simple, minima lly invasive outpatient procedure as
the first-line treatment for children with grade IV -V reflux, which can be easily repeated in
cases of failure with a high subsequent resolution rate.

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ACCEPTED MANUSCRIPTTable 1. Indications for VCUG in 851 consecutive children with high-grade VUR
Indications for VCUG Overall ( n = 851)
History of UTI 748 (87.9%)
Screening for sibling VUR 63 (7.4%)
Bladder bowel dysfunction (BBD) * 33 (3.9%)
Prenatal diagnosis of hydronephrosis 7 (0.8%)
*defined as a history of urgency, frequency and/or d aytime incontinence, infrequent voiding and
constipation

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ACCEPTED MANUSCRIPTTable 2. Patient demographics of 851 infants and children w ith high-grade VUR
Patient demographics Overall ( n = 851)
Sex
Female 518 (60.9%)
Male 333 (39.1%)
Median age (range) 2.3 years (2 months – 13.7 years)
Infants (<1 year) 418 (49.1%)
Children (>1 year) 433 (50.9%)
Laterality of high-grade VUR
Unilateral 415 (48.8%)
Bilateral 436 (51.2%)
Total refluxing units
(with high-grade VUR) 1,287 (100%)
Grade IV 1,153 (89.6%)
Grade V 134 (10.4%)
Unilateral cases associated with
contralateral grade II VUR 240 (57.8%)
Duplex system (per refluxing unit) * 92 (7.1%)
*with VUR in one or both moieties

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ACCEPTED MANUSCRIPTTable 3. Initial postoperative VCUG findings in 851 patient s with
or without fUTI after endoscopic treatment of high- grade VUR
Postoperative VCUG No fUTI ( n=808) fUTI ( n=43) *
Complete reflux resolution 765 (94.7%) 40 (93.0%)
Residual grade I reflux 43 (5.3%) 3 (7.0%)
*included 6 patients with recurrence of grade IV ref lux on repeat VCUG
[p=0.5007 (Fisher's exact test)]

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ACCEPTED MANUSCRIPTTable 4. Classification of renal parenchymal damage
in 317 patients with high-grade VUR
Renal scarring Girls ( n=185) Boys ( n=132)
Mild 98 (53.0%) 42 (31.8%)
Moderate * 76 (41.1%) 51 (38.6%)
Severe * 11 (5.9%) 39 (29.6%)
*p=0.0002 vs. Mild (Chi-square test)

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ACCEPTED MANUSCRIPTKey of Definitions for Abbreviations
AUA = American Urological Association
BBD = bladder bowel dysfunction
CAP = continuous antibiotic prophylaxis
DMSA = 99m technetium-dimercaptosuccinic acid
Dx/HA = dextranomer/hyaluronic acid
ESRD = end-stage renal disease
FDA = Food and Drug Administration
fUTI = febrile urinary tract infection
RN = reflux nephropathy
RPD = renal parenchymal damage
UTI = urinary tract infection
VCUG = voiding cystourethrogram
VUR = vesicoureteral reflux