Deflux® clinical update
List of key references (1)
Safety
•
•
•
Stenberg et al. Injectable dextranomer-based implant: histopathology, volume changes and DNA-analysis.
Scand J Urol Nephrol 1999; 33: 355–61
Stenberg et al. Endoscopic treatment with dextranomer-hyaluronic acid for vesicoureteral reflux:
histological findings. J Urol 2003; 169: 1109–13
Stenberg et al. Lack of distant migration after injection of a 125iodine labelled dextranomer based
implant into rabbit bladder. J Urol 1997; 158: 1937–41
Efficacy
•
•
Kirsch et al. The modified STING procedure to correct vesicoureteral reflux: improved results with submucosal
implantation within the intramural ureter. J Urol 2004; 171: 2413–6
Yu and Roth. Treatment of vesicoureteral reflux using endoscopic injection of nonanimal stabilized hyaluronic
acid/dextranomer gel: initial experience in pediatric patients by a single surgeon. Pediatrics 2006; 118: 698–703
Efficacy: long term
•
•
Läckgren et al. Long-term followup of children treated with dextranomer/hyaluronic acid copolymer
for vesicoureteral reflux. J Urol 2001; 166: 1887–92
Stenberg and Läckgren. Treatment of vesicoureteral reflux in children using stabilized non-animal hyaluronic
acid/dextranomer gel (NASH/Dx): a long-term observational study. J Pediatr Urol 2007; 3: 80–85
List of key references (2)
Antibiotics vs endoscopic injection
•
•
Capozza and Caione. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral
reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr 2002; 140(2): 230–4
Koyle et al. Critical appraisal: antibiotic prophylaxis and endoscopic injection for VUR.
Issues in Urology 2006; 18(3): 123–30
Complicated cases
•
•
•
Läckgren et al. Endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is
effective in either double ureters or a small kidney. J Urol 2003; 170: 1551–5
Perez-Brayfield et al. Endoscopic treatment with dextranomer/hyaluronic acid for complex cases of
vesicoureteral reflux. J Urol 2004; 172: 1614–6.
Läckgren et al. Endoscopic treatment with stabilized nonanimal hyaluronic acid/dextranomer gel is effective in
vesicoureteral reflux associated with bladder dysfunction. J Urol 2007; 177:1124–8.
Parental preference
•
Capozza et al. Treatment of vesico-ureteral reflux: a new algorithm based on parental preference.
BJU Int 2003; 92: 285–8
Resolution
•
Schwab et al. Spontaneous resolution of vesicoureteral reflux: a 15 year perspective. J Urol 2002; 168: 2594–9
Safety
Stenberg et al. 1999, histopathology, volume, DNA
– introduction
Article type
• Original research – Deflux safety study
Objective
• Monitor any changes in the tissues (histopathology), implant volume and
DNA profile of invading cells after Deflux injection into pigs and rats
Methods
• Preclinical (animal)
• Pigs: n=9, follow-up 2 weeks to 3.5 months; rats: n=34, follow-up
3 weeks to 16 months
• Deflux injection into the bladder (pigs) or subcutaneous tissue (rats)
• Histopathological analysis: 16 pig, 63 rat implants
• DNA profile: 31 rat implants
• Changes in implant volume over time: 51 rat implants analysed for up to
12 months after implantation
Stenberg et al. 1999, histopathology, volume, DNA
– results
Histopathology
• A mild inflammatory response of the foreign body type (identification of
giant cells, macrophages and lymphocytes) was observed
• No cell death was identified in the tissues surrounding the implant
Volume change
• Implant volume decreased by 23% at 12 months post-injection
DNA profile
• No changes in the cells that would indicate tumour formation were seen
and no change in the DNA profile was observed
Stenberg et al. 1999, histopathology, volume, DNA
– conclusions
• Deflux does not induce any major tissue changes in and
around the implant
• Deflux treatment is associated with a foreign body reaction,
as expected
• The volume of the implant remained stable over 12 months
• Deflux is not associated with any signs of malignant
transformation (risk of cancer) or tissue necrosis
“After injection of DiHA [Deflux] into the experimental
animals no unexpected adverse events were noted
and no safety concerns were raised”
Stenberg et al. 2003, histological findings
– introduction
Article type
• Original research – Deflux histological study
Objective
• Evaluate any changes in the tissues (histology) associated with Deflux
injection in children with VUR
Methods
• Retrospective
• Children (n=13) aged 0–7 years at diagnosis of VUR
• Persistent reflux grades III–V following treatment with Deflux
• Deflux implant and surrounding tissue removed during surgical
treatment (ureteral reimplantation) for VUR and fixed for analysis
• Patients (n=10) with similar grade VUR, but no previous endoscopic
treatment included as controls
VUR, vesicoureteral reflux
Stenberg et al. 2003, histological findings
– results
Location of implant
• The implant remained in situ for 13–39 months (mean 22 months)
• The implant was located at the site of injection in 12/13 patients (92%)
Distal ureter
• A mild inflammatory reaction (presence of multinucleated giant cells)
was observed at the implantation site
− the degree of fibrosis and mast cell infiltration was similar in
treatment and control groups
Implantation site
• Implant pseudo-encapsulation (development of a capsule of fibrous
material surrounding the implant) and calcification was present in 9
implants
Stenberg et al. 2003, histological findings
– conclusions
• A long duration of implant persistence after Deflux treatment
is consistent with the clinical findings (long-term resolution
of reflux)
• As expected, Deflux treatment is associated with a mild
inflammatory reaction at the implantation site
• The histological findings are typical following implantation of
a foreign material
“Dextranomer-hyaluronic acid co-polymer was well
tolerated and remains a safe and effective bulking
agent for vesicoureteral reflux”
Stenberg et al. 1997, lack of migration
– introduction
Article type
• Original research – Deflux safety study
Objective
• Investigate any possible migration of dextranomer particles after implantation of
a radioactive Deflux implant
Methods
• Preclinical (animal)
• 125Iodine-labelled dextranomer particles were mixed with a nonradioactive
Deflux solution
• Labelled detranomer microspheres injected into rabbit bladder wall (n=6)
• Samples of blood and various tissues were examined for radioactivity over 28
days
• The whole body was examined on day 1 and weeks 1 and 4
post-injection
Stenberg et al. 1997, lack of migration
– results
Injection of radioactively labelled
dextranomer into the bladder wall
Leakage in urine
Bladder wall
– 45% remaining
Blood, brain, spleen, lung, liver
– background levels
Stenberg et al. 1997, lack of migration
– conclusions
• Almost half of the injected dose of radioactivity remained in
the bladder wall after 28 days
• Levels of radioactivity in the blood and other organs were
very low
• These findings confirm the lack of migration of dextranomer
particles from the injection site
“Judging by the findings of only background levels of
radioactivity in organs and the circulation, there was no
migration of particles from the implant in our study”
Efficacy
Kirsch et al. 2004, modified STING procedure
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Assess the efficacy of Deflux injection using two implantation techniques:
STING and HIT
Methods
• Prospective comparison of surgical methods
• STING, n=52 patients; HIT, n=70
• Children aged 7 months to 15 years
• Reflux grades II–IV (and grade I contralateral reflux)
• One treatment with Deflux
• Follow-up VCUG at 3 months post-treatment
STING, subureteric transurethral injection; HIT, hydrodistention implantation
technique; VCUG, voiding cystourethrogram
Kirsch et al. 2004, modified STING procedure
– results
Cure rate (patients, %)
p<0.05
100
80
89
76
71
60
40
20
0
Overall
STING, subureteric transurethral injection;
HIT, hydrodistention implantation technique
STING
HIT
Kirsch et al. 2004, modified STING procedure
– conclusions
• The majority of children can expect to be cured following a
single injection of Deflux
• Improvements in cure rate can be achieved using a
modified implantation technique, the HIT
• Both implantation techniques are well tolerated
(no significant short-term adverse events)
“The modified STING [HIT] is our preferred method of
implant injection for the correction of VUR and in our
hands produces a resolution rate of 89%”
STING, subureteric transurethral injection; HIT, hydrodistention
implantation technique; VUR, vesicoureteral reflux
Yu and Roth 2006, experience by a single surgeon
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Assess the efficacy and safety of Deflux injection during the centre’s first
18 months of using the treatment
Methods
• Open, prospective
• Children (n=107) aged 6 months to 15 years
• Primary reflux grades I–V (unilateral or bilateral)
• One or two treatments with Deflux; STING or HIT injection
• Follow-up VCUG ≥2 weeks post-treatment
STING, subureteric transurethral injection; HIT, hydrodistention implantation
technique; VCUG, voiding cystourethrogram
Yu and Roth 2006, experience by a single surgeon
– results
No. of Deflux injections
Resolution rate
First injection
Patients (n=107)
Ureters (n=162)
Second injection
82.2%
86.9%
Patients (n=14)
64.3%
Ureters (n=20)
64.3%
Overall (1–2 injections)
Patients (n=107)
90.7%
Ureters (n=162)
92.6%
Yu and Roth 2006, experience by a single surgeon
– conclusions
• Deflux treatment can be successfully administered to
children with VUR by a surgeon without previous
experience of the technique
• VUR can be cured using Deflux in the majority of children
• Repeat injection of Deflux is viable and effective
“Endoscopic treatment with NASHA/Dx gel [Deflux]…
should be considered as a first-line treatment in place of
antibiotic prophylaxis”
VUR, vesicoureteral reflux
Efficacy: long term
Läckgren et al. 2001, long-term follow-up
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Assess the long-term efficacy and safety of Deflux treatment in children
with VUR
Methods
• Open, prospective
• Children (n=221) aged 1–15 years
• Reflux grades III–V (unilateral or bilateral)
• 1–3 Deflux treatments; STING injection
• Follow-up VCUG at 3 months and 1 year post-treatment
• Mean follow-up 5 years; range, 2.0–7.5 years
• Late VCUG at 2–5 years in select patients (n=49)
STING, subureteric transurethral injection; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
Läckgren et al. 2001, long-term follow-up
– results
Ureteral response (%)
100
Cured
Improved
Unchanged
90
80
70
60
50
40
30
20
10
0
III (n=208)
IV (n=80)
V (n=6)
Baseline reflux grade
96% of ureters
free from reflux
at 3–12 months
remained free
from dilating
reflux (grade ≥III)
at 2–5 years.
Läckgren et al. 2001, long-term follow-up
– conclusions
• The response to Deflux treatment is sustained long-term
• Many children only require a single Deflux treatment,
though retreatment is a viable option
• Deflux is well tolerated and there are no long-term safety
concerns
“We would recommend endoscopic therapy with
dextranomer/hyaluronic acid copolymer [Deflux] as
first-line treatment for children with long-term VUR”
VUR, vesicoureteral reflux
Stenberg and Läckgren 2007, observational study
– introduction
Article type
• Original research – a long-term observational study of Deflux treatment
Objective
• Investigate long-term outcomes and experiences of Deflux
Methods
• Retrospective
• Questionnaire sent to children (n=231) 7–12 years following Deflux treatment
• Questionnaire assessed clinical outcome and patient/parental attitudes to
treatment
• Children aged 6 months to 23 years at the time of treatment
• Reflux grades III–V before treatment, 0–II after treatment
• Endoscopic injection; one (72%), two (20%) or three (4%) Deflux treatments
Stenberg and Läckgren 2007, observational study
– results
Response rate
• Questionnaire returned by 179 patients (77.5%)
UTIs post-treatment
• UTI without fever: 21.8% (n=39)
• UTI with fever: 3.4% (n=6)
Worst aspect of VUR treatment
• Deflux treatment: patients, 9%; parents, 19%
• Medication: patients, 19%; parents, 24%
• VCUG: patients, 72%; parents, 57%
UTI, urinary tract infection; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
Stenberg and Läckgren 2007, observational study
– conclusions
• Incidence of febrile UTI is low after Deflux
• Prevention of febrile UTIs is a primary goal of VUR
treatment to reduce the risk of renal damage and long-term
consequences
• Children view endoscopic injection of Deflux as less
bothersome than medication or VCUG
“…there is an excellent long-term success rate in
patients initially treated successfully with NASHA/Dx
gel [Deflux], with up to 96.6% of patients experiencing
no febrile UTIs in the 7–12 years since treatment.”
UTI, urinary tract infection; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
Antibiotics vs endoscopic injection
Capozza and Caione 2002, comparison with antibiotics
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Compare the efficacy and safety of Deflux with antibiotic prophylaxis in
children with VUR
Methods
• Open, randomised, prospective
• 1–2 Deflux treatments (STING procedure; n=39) or antibiotic
prophylaxis for 12 months (n=21)
• Children >1 year of age
• Reflux grades II–IV
• Follow-up VCUG at 3 and 12 months post-treatment
STING, subureteric transurethral injection; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
Capozza and Caione 2002, comparison with antibiotics
– results
Deflux (n=39)
95
Response rate at
month 12 (%)
100
80
Antibiotic prophylaxis (n=21)
71
69
60
40
38
37
43
33
20
0
0
Overall
response
(patients)
Reflux grade II Reflux grade III Reflux grade IV
(ureters)
(ureters)
(ureters)
Capozza and Caione 2002, comparison with antibiotics
– conclusions
• Deflux is more effective than antibiotic prophylaxis for the
treatment of childhood VUR
• Response to Deflux is sustained for at least
12 months
• The benefits of Deflux suggest that it is a useful option for
children with VUR
“Patients undergoing successful endoscopic treatment
receive immediate protection against further refluxassociated damage”
VUR, vesicoureteral reflux
Koyle et al. 2006, critical appraisal: antibiotics
– introduction
Article type
• Review – VUR treatment
Objective
• Compare antibiotic prophylaxis (long-term use of antibiotics) and
endoscopic injection for the treatment of VUR
Points discussed
• Clinical efficacy of antibiotic prophylaxis
• Implications of long-term antibiotic prophylaxis
• Antibiotic resistance
• Treatment alternatives for VUR
− open surgery
− endoscopic injection
VUR, vesicoureteral reflux
Koyle et al. 2006, critical appraisal: antibiotics
– results
Efficacy of antibiotic prophylaxis
• Data supporting the clinical value of antibiotic prophylaxis are limited
• Long-term therapy offers no benefit for VUR that fails to respond spontaneously
Implications of long-term antibiotic prophylaxis
• Treatment requires serial VCUGs and may still result in surgery or endoscopic
intervention
• Poor compliance leaves patients vulnerable to infection
• Low antibiotic doses used for prophylaxis may promote resistance
Treatment alternatives
• Surgery and endoscopic injection are potentially curative
• Endoscopic therapy avoids the morbidity and costs associated with surgery
• Parents prefer endoscopic treatment over antibiotic prophylaxis or open surgery
VCUG, voiding cystourethrogram; VUR, vesicoureteral reflux
Koyle et al. 2006, critical appraisal: antibiotics
– conclusions
• Poor compliance and bacterial resistance are concerns with
antibiotic prophylaxis for VUR
• Endoscopic treatment is a valuable alternative to antibiotic
prophylaxis
• Endoscopic therapy reduces the need for VCUGs and is
associated with minimal morbidity
“The minimally invasive nature of endoscopic therapy
offers a viable alternative in the management of VUR”
VCUG, voiding cystourethrogram; VUR, vesicoureteral reflux
Complicated cases
Läckgren et al. 2003, double ureters/a small kidney
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Assess the efficacy of Deflux for the treatment of primary VUR associated with
either double ureters or a small kidney
Methods
• Open, retrospective
• Children (n=108) aged 7 months to 12.5 years
• Primary reflux grade III–V (unilateral or bilateral) associated with either:
− double ureter: duplication of a ureter (complete or incomplete separation)
− small kidney: one kidney contributing 10–35% of renal function
• 1–3 Deflux treatments; STING injection
• Follow-up VCUG at 3 and 12 months post-treatment
STING, subureteric transurethral injection; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
Läckgren et al. 2003, double ureters/a small kidney
– results
Double ureters (n=68)
Patients (%)
80
63
Small kidney (n=40)
70
60
41
40
38
25
23
20
0
Response rate
Retreated
Referred for
surgery
Läckgren et al. 2003, double ureters/a small kidney
– conclusions
• Deflux is effective for VUR associated with either double
ureters or a small kidney
• Results with either double ureters or a small kidney are
similar to those observed in patients free from complications
• Deflux is a valuable alternative to open surgery for patients
with complicated cases of VUR
“Endoscopic Dx/HA copolymer [Deflux] appears to be
effective and well tolerated for the treatment of VUR
associated with either double ureters or a small kidney”
VUR, vesicoureteral reflux
Perez-Brayfield et al. 2004, complex cases
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Assess the efficacy of Deflux for the treatment of complex VUR cases
Methods
• Open, prospective
• Children (n=72) aged 9 months to 31 years
• Mean maximum reflux grade IV/V
• 1 Deflux treatment using the HIT
• Follow-up VCUG at 3 months post-treatment
HIT, hydrodistention implantation technique; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
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Response rate (patients, %)
Perez-Brayfield et al. 2004, complex cases
– results
100
80
60
40
20
0
Complicating factors
Perez-Brayfield et al. 2004, complex cases
– conclusions
• Deflux can be effective in patients with complex VUR
• Deflux is well tolerated in children with VUR associated with
a range of complications
• Deflux provides an alternative to open surgical correction of
VUR in patients with complications
“This minimally invasive approach is warranted as an
initial step in the management of complex cases of
vesicoureteral reflux”
VUR, vesicoureteral reflux
Läckgren et al. 2007, VUR and bladder dysfunction
– introduction
Article type
• Original research – Deflux clinical study
Objective
• Assess the efficacy of Deflux for VUR with bladder dysfunction
Methods
• Open, retrospective
• Children with VUR and bladder dysfunction (n=54) aged 2–15 years
• Reflux grade II–V
• 1–3 Deflux treatments using STING
• Follow-up VCUG at 3 and 12 months post-treatment
• Long-term follow-up for 7–12 years
STING, subureteric transurethral injection; VCUG, voiding cystourethrogram;
VUR, vesicoureteral reflux
Läckgren et al. 2007, VUR and bladder dysfunction
– results
Resolution rate after last
Deflux treatment
(patients, %)
VUR
83
Bladder dysfunction
59
UTIs
83
No VUR, bladder
dysfunction or UTIs
56
UTI, urinary tract infection
Läckgren et al. 2007, VUR and bladder dysfunction
– conclusions
• Deflux appears to be effective and well tolerated in children
with VUR and bladder dysfunction
• Success rates and number of post-treatment UTIs are
comparable in patients with and without bladder dysfunction
• These findings suggest that bladder dysfunction should not
be considered a contraindication to Deflux treatment
“This study supports treating patients with concurrent
bladder dysfunction and VUR with endoscopic
injection……”
UTI, urinary tract infection; VUR, vesicoureteral reflux
Parental preference
Capozza et al. 2003, parental preference
– introduction
Article type
• Original research – parental preference study
Objective
• Assess informed parental preference when choosing between antibiotic
prophylaxis, open surgery and endoscopic treatment for VUR
Methods
• Cross-sectional
• Parents of children (n=100; mean age 4 years) with reflux grade III
• Detailed information provided on antibiotic prophylaxis, open surgery
and endoscopic treatment (efficacy, mode of action, potential
complications)
• Questionnaire circulated asking which treatment they would choose
VUR, vesicoureteral reflux
Capozza et al. 2003, parental preference
– results
Undecided 13%
Endoscopic
injection 80%
Antibiotics 5%
Open surgery 2%
Capozza et al. 2003, parental preference
– conclusions
• The majority of parents would choose endoscopic injection
over open surgery or antibiotic prophylaxis to treat VUR in
their children
• Endoscopic treatment should be considered as first-line
therapy for persistent VUR
“We propose a new treatment algorithm for VUR, with
endoscopic treatment as first-line therapy for most
patients with persistent reflux.”
VUR, vesicoureteral reflux
Resolution
Schwab et al. 2002, spontaneous resolution
– introduction
Article type
• Original research – review of patient records
Objective
• Determine the spontaneous resolution rate of VUR
Methods
• Retrospective review of 179 girls and 35 boys with VUR during
1981–1984
− bilateral reflux n=109; dysfunctional voiding n=60
− mean age: 4.2 years (3 months to 15.8 years)
− median follow-up: 3 years
• Patients categorised by worst grade of reflux and maintained on antibiotic
prophylaxis
• VCUG undertaken annually until reflux resolved
• Spontaneous resolutions rates per reflux grade were calculated using KaplanMeier curves
VCUG, voiding cystourethrogram; VUR, vesicoureteral reflux
Schwab et al. 2002, spontaneous resolution
– results
100
83.3
76.8
Resolution rate
(patients, %)
80
68.4
60
35.5
40
20
0
Years to resolution:
Grade I
Grade II
Grade III
Grade IV
2.7
3.1
4.5
9.5
Schwab et al. 2002, spontaneous resolution
– conclusions
• VUR can take a number of years to resolve, particularly in
severe cases
• Various factors influence the likelihood of spontaneous
resolution of VUR, including:
− initial reflux grade (grades I–III tend to resolve more quickly)
− unilateral vs bilateral reflux (bilateral reflux can be expected to
take longer to resolve)
− gender (tendency for VUR to resolve more rapidly in boys)
“While resolution can occur at any time, the more
important decision is whether a patient remains at risk
for morbidity due to renal scarring or pyelonephritis”
VUR, vesicoureteral reflux