Learning from history or the rationale for considering surgical correction of vesicoureteral reflux.
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ABSTRACT: To review the current literature regarding the outcome of endoscopic treatment of vesicoureteric reflux (VUR) using different tissue-augmenting substances, with special emphasis on long-term efficacy. The current literature, including our own experience, on long-term results after endoscopic treatment was reviewed by MEDLINE/PubMed search. The short-term results are similar in the majority of series to those of open surgery, but there is a high recurrence rate with use of dextranomer/hyaluronic acid (Deflux) as a tissue-augmenting material. There is a significant shortage of evidence-based literature on long-term follow-up after endoscopic correction of VUR utilizing dextranomer/hyaluronic acid. The high recurrence rate that has been reported after Deflux injection highlights a need for close observation beyond routine protocols and appropriate parental counseling upon endoscopic correction, and also the need to search further for alternative tissue-augmenting substances. The algorithm for treating VUR is yet to be finally determined.Journal of pediatric urology 11/2009; 6(3):251-6. · 1.38 Impact Factor
- New England Journal of Medicine 10/2009; 361(18):1804-6. · 51.66 Impact Factor
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ABSTRACT: Dextranomer/hyaluronic acid injection of ureteral orifices is a popular option in the treatment of vesicoureteral reflux, with success rates ranging from 69% to 89%. We found only 1 study that followed patients beyond the initial postoperative voiding cystourethrogram, which describes a 96% success rate at 2 to 5 years but defines success as "nondilating" reflux. We examined our dextranomer/hyaluronic acid series to evaluate the long-term (1-year) outcome in children who had resolution of reflux on initial postoperative voiding cystourethrography. We retrospectively reviewed our dextranomer/hyaluronic acid experience from February of 2002 to December of 2005. We determined initial success on early (6 to 12-week) postoperative voiding cystourethrogram. We then evaluated long-term success by obtaining a voiding cystourethrogram at 1 year postoperatively in patients who were initially cured of reflux. In addition, success rates between the first and second halves of our experience were evaluated to account for surgeon experience and modification of technique. Our total success rate at initial voiding cystourethrogram was 73% (246 of 337 total ureters). The success rate in the first half of our experience was 65.9% (112 of 170 ureters) and in the second half was 80.2% (134 of 167). A total of 150 ureteral units with initial successful dextranomer/hyaluronic acid treatment were evaluated at 1 year by voiding cystourethrogram. Of these ureters 111 had continued resolution of vesicoureteral reflux, for a long-term success rate of 74%. Including initial postoperative failures, the complete 1-year total success rate was 46.1% (111 of 241 ureters). Although the reflux resolution rates at initial postoperative voiding cystourethrogram approach those of open surgery, there is a significant failure rate at 1 year, which warrants long-term followup.The Journal of urology 03/2009; 181(4):1869-74; discussion 1874-5. · 4.02 Impact Factor
CUAJ • August 2010 • Volume 4, Issue 4
© 2010 Canadian Urological Association
Original research POint/cOunterPOint
Can Urol Assoc J 2010;4(4):280-3
ably over the past 50 years, owing in various degrees to more
rapid detection of urinary tract infection (UTI) in infants and
children, improved medical therapy and timely surgical inter-
vention. Reflux nephropathy once accounted for 22% of all
pediatric renal transplantations, and now accounts for less
than 6%.1 Despite this improvement, 8.5% of chronic renal
disease in North American children is still due to RN.2 In
some series, there is a history of childhood pyelonephritis with
subsequent renal scarring in up to 15% of adult renal trans-
plantation.3 Therefore, the modern day debate on the optimal
management of VUR has significant merit in terms of prevent-
ing RN, and its impact on pediatric and adult populations.
During the 1950s, Hutch was the first to suggest a link
between VUR, pyelonephritis and renal scars based on his
work on adult paraplegics, and the benefits of ureteral reim-
plantation.4 Politano, Leadbetter, Paquin and others improved
upon the concept of an adequate length, detrusor-backed
submucosal tunnel, cementing ureteral reimplant as a time-
tested cornerstone in the management of VUR. 5,6 Reported
contemporary success rates of antireflux surgery range from
96% to 98%.7
The VUR treatment paradigm shifted from surgery towards
medical management during the late 1970s. Lenaghan and
colleagues showed a natural tendency for most VUR to resolve
spontaneously. 8 This work, coupled with the work of Smellie
and colleagues,9,10 which showed a low rate of new scar for-
mation on daily low dose antimicrobial prophylaxis, provided
the rationale for the expectant VUR treatment we have seen
for the past 3 decades. The rationale of preventing UTIs and
pyelonephritis, while the refluxing kidney is at risk, formed
the basis of the 1997 American Urological Association expert
panel on VUR,11 where surgery is reserved for patients who
failed on antibiotic prophylaxis and with high-grade reflux.
istory reminds us of valuable lessons learned in
the treatment of vesicoureteral reflux (VUR). Rates
of reflux nephropathy (RN) have decreased remark-
Issues with medical management
Several recent publications have questioned the efficacy of
daily antimicrobial prophylaxis in terms of preventing UTI
and new renal scarring (Table 1).12-15 Breakthrough UTIs of
up to 25% have been reported. This challenges the current
assumption that daily antibiotic prophylaxis “prevents” UTIs,
pyelonephritis and subsequent scar formation in affected
renal units. Criticisms over the methodology of the afore-
mentioned studies have led to great anticipation for the
results of the Randomized lntervention for children with
VesicoUreteral Reflux (RIVUR) study (Fig. 1).16
Adequately designed and powered, this study will hope-
fully answer the question of whether prophylaxis prevents UTI
and scarring in VUR patients (and thus potentially validate
VUR management for the past 3 decades). Post-RIVUR, lin-
gering concerns will still remain about antimicrobial prophy-
laxis. These include (1) increased bacterial resistance;17 (2)
the inconvenience and risk associated with serial radiologic
investigations; (3) decreased cost-effectiveness;18 (4) the clini-
cal versus statistical significance of any result;19 and (5) the fate
of those refluxers who do not resolve over time, in that we are
shifting the progression of chronic renal disease into adulthood
given the known, slow progression of reflux nephropathy.
Some proponents of medical therapy have proposed that
early treatment of early pyelonephritis can decrease the risk
or lessen scar formation.20 Two recent studies refute this
idea. 21,22 Hoberman and colleagues, in a large prospective
trial of oral versus intravenous therapy for UTIs in young
children, found no significant difference in scarring among
children who presented after 24 hours of fever compared
with those who presented sooner.21 Hewitt and colleagues
used data from 2 multicentre, prospective, randomized con-
trolled trials to demonstrate a 30.7% scar rate on dimercap-
tosuccinic acid (DMSA) 12 months after an acute pyelo-
nephritis.22 Progressive delay in antibiotic treatment from
<1 day to >5 days after onset of fever was not associated
with increased scarring. In other words, prompt treatment
of febrile UTI does not prevent associated scarring and/or
the potential for RN.
Advances in surgical technique
While the debate over the efficacy of medical management
continues, there must be an overt acknowledgement in
any VUR debate that ureteral reimplantation cures reflux.
With published minimal acceptable success rates of 95%
Jonathan Riddell, MD, FRCSC; Julie Franc-Guimond, MD, FRCSC
Learning from history or the rationale for considering surgical
correction of vesicoureteral reflux
CUAJVolume4No.4August10.indd 280 7/22/10 9:53 PM
CUAJ • August 2010 • Volume 4, Issue 4
and reproducible results reported as high as 99%, pediatric
urologists have essentially perfected the art of the ureteral
reimplant. At our institution, unilateral reimplantation is gen-
erally performed extravesically. Bilateral reimplantation is
performed by an intravesical, cross-trigonal fashion to avoid
the risk of transient postoperatively urinary retention observed
with bilateral extravesical reimplantation (4% to 15%). Other
reported complications of ureteral reimplantation include
mild transient hydronephrosis in 6% to 7%, and an overall
rate of ureteral obstruction requiring revision in <1%.
The perioperative management of the child undergoing
ureteral reimplantation has changed dramatically. Two-week
hospital stays in the early series have evolved into outpatient
or overnight stays. Routine placement of suprapubic catheters,
ureteral stents and surgical drains have been abandoned, and
most patients with uncomplicated ureteral reimplants are dis-
charged on postoperative day 1 with no tubes in place.
Pediatric anesthesia has also improved greatly. Judicious
use of anti-inflammatories and anticholinergics decrease
narcotic requirements and relieve bladder spasms. Regional
blocks and/or continuous epidural infusions help children
recover quickly by providing pre-emptive and better pain
control; these are the standard at our centre.
Finally, as laparoscopic, vesicoscopic and robotic
approaches gain acceptance as equivalent or superior in
terms of success, morbidity from ureteral reimplantation will
be further reduced.
Role of endoscopic bulking agents
Endoscopic bulking agents represent an extension of the sur-
gical armamentarium. Originally pioneered over 30 years
ago as an alternative to ureteral reimplantation,23 endoscopic
injection for VUR has undergone several modifications of
technique, and injection material (polytetrafluoroethylene,
silicone paste, collagen, dextranomer/hyaluronic acid copo-
lymer). Currently, dextranomer/hyaluronic acid copolymer is
the dominant injectable in part due to its biocompatibility
(both contents are biodegradeable polysaccharides) and lack
of migration (due to infiltration with endogenous connective
tissue). Controversy exists as to the exact mechanism by which
reflux is prevented, and success rates are highly variable (60%
to 90%). At our institution, endoscopic injection has evolved
into a common surgical intervention performed for VUR, espe-
cially for lower grade reflux. As with any emerging technol-
ogy, long-term, prospective studies are needed to better define
short- and long-term success and complications and to further
clarify the role of endoscopic injection in treating VUR.
From the original animal work of Ransley and Risdon,24
we know that reflux in and of itself is not a disease. Add,
however, UTI to VUR, with the appropriate confluence of
bacterial virulence and host factors, and renal scarring can
ensue. Although the exact pathogenesis of renal scarring is
not well-understood, the end result, reflux nephropathy, is
understood, and could be entirely preventable.
Given that most reflux is self-limited, the key to any man-
agement strategy is selecting out the small minority of patients
who are at risk for future deterioration. To avoid overtreatment,
some authors are advocating a “top-down” approach to inves-
tigation of first febrile UTI.25 Rather than starting with voiding
cystourethrography and identifying mainly “benign VUR,”
ultrasound and DMSA has become the first-line investiga-
tion. Recurrent UTI, and/or renal scars motivate cystography,
which then contributes to stratification into low- and high-risk
groups in terms of the potential for progressive renal damage.
The presence of renal scars and reflux at initial presentation is
associated with a 17-fold risk of progressive renal damage over
the presence of reflux alone. Though we applaud the efforts to
characterize at-risk populations, we do not condone an algo-
rithm that waits for the disease process to become macroscopic
before initiating therapy. Further prospective studies are neces-
sary to better identify and characterize high-risk populations
with VUR, as well as to validate surgical efficacy and other
Table 1. Randomized lntervention for children with Vesico-
Ureteral Reflux (RIVUR) study design
Table 2. Vesicoureteral risk assessment
CUAJVolume4No.4August10.indd 2817/22/10 9:53 PM
CUAJ • August 2010 • Volume 4, Issue 4
riddell and Franc-guimond
de novo strategies at preventing renal deterioration in these
groups. A search at the molecular level for either a genetic or
protein marker of susceptibility could be the eventual Rosetta
stone for VUR management.
Until then, we believe every patient must be managed on
a case-by-case basis. Multiple variables must be taken into
account (Fig. 2).26 These variables can then be incorporated
into evidence-based constructs, such as recently published
nomograms,27 quantifying the likelihood of reflux resolu-
tion. A move from experience-based to evidenced-based
medicine is essential in moving forward.
Until the role of antimicrobial prophylaxis is clarified,
surgical intervention in the form of ureteral reimplanta-
tion remains the gold standard for the prevention of reflux
nephropathy in susceptible renal units.
Université de Montréal, CHU Sainte-Justine, Department of Surgery, Division of Pediatric Urology,
Competing Interests: None declared.
This paper has been peer-reviewed.
1. Cendron M. Reflux nephropathy. J Pediatr Urol 2008;4:414-21.
2. Novak TE, Mathews R, Martz K, et al. Progression of chronic kidney disease in children with vesi-
coureteral reflux: the North American Pediatric Renal Trials Collaborative Studies Database. J Urol
3. Coulthard MG. Vesicoureteric reflux is not a benign condition. Pediatr Nephrol 2009;24:227-32.
4. Hutch JA. Vesico-ureteral reflux in the paraplegic: cause and correction. J Urol 1952;68:457-69.
5. Politano VA, Leadbetter WF. An operative technique for the correction of vesicoureteral reflux. J Urol
6. Paquin AJ. Ureterovesical anastomosis: The description and evaluation of a technique. J Urol 1959;82:573.
7. Austin JC, CS Cooper. Vesicoureteral reflux: surgical approaches. Urol Clin N Am 2004;31:543-57.
8. Lenaghan D, Whitaker JG, Jensen F, et al. The natural history of reflux and long-term effects of reflux on
the kidney. J Urol 1976;115:728-30.
9. Smellie JM, Normand IC. Bacteriuria, reflux, and renal scarring. Arch Dis Child 1975;50:581-5.
10. Smellie JM, Katz G, Gruneberg RN. Controlled trial of prophylactic treatment in childhood urinary tract
infection. Lancet 1978;2:175-8.
11. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report
on the management of primary vesicoureteral reflux in children. J Urol 1991;157:1846-51.
12. Conway PH, Cnaan A, Zaoutis T, et al. Recurrent urinary tract infections in children: risk factors and
association with prophylactic antimicrobials. JAMA 2007;298:179-86.
13. Roussey-Kesler G, Gadjos V, Idres N, et al. Antibiotic prophylaxis for the prevention of recurrent urinary
tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized
study. J Urol 2008;179:674-9.
14. Montini G, Rigon L, Zucchetta P, et al. Prophylaxis after first febrile urinary tract infection in children? A
multicenter, randomized, controlled, noninferiority trial. Pediatrics 2008;122:1064-71.
15. Garin EH, Olavarria F, Garcia Nieto V, et al. Clinical significance of primary vesicoureteral reflux and urinary
antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics
16. Mathews R, Carpenter M, Chesney R, et al. Controversies in the management of vesicoureteral reflux:
the rationale for the RIVUR study. J Pediatr Urol 2009;5:336-41.
17. Chung A, Perera R, Brueggemann AB, et al. Effect of antibiotic prescribing on antibiotic resistance in
individual children in primary care: prospective cohort study. BMJ 2007;335:429.
18. Hsieh MH, Swana HS, Baskin LS, et al. Cost-utility analysis of treatment algorithms for moderate grade
vesicoureteral reflux using Markov models. J Urol 2007;177:703-9; discussion 709.
19. Diaz M. Editorial comment. J Urol 2009;182:2445.
20. Coulthard MG, Verber I, Jani JC, et al. Can prompt treatment of childhood UTI prevent kidney scarring?
Pediatr Nephrol 2009;24:2059-63.
21. Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy for urinary tract infections
in young febrile children. Pediatrics 1999;104:79-86.
22. Hewitt IK, Zucchetta P, Rigon L, et al. Early treatment of acute pyelonephritis in children fails to reduce
renal scarring: data from the Italian renal infection study trials. Pediatrics 2008;122:486-90.
23. Läckgren G, Kirsch AJ. Surgery Illustrated - Surgical Atlas Endoscopic treatment of vesicoureteral reflux.
BJU Int 2010;105:1332-47.
24. Ransley PG, Risdon RA. Reflux and renal scarring. Br J Radiol 1978;14(Suppl):1-35.
Table 3. Recent publications addressing antimicrobial prophylaxis
Subjects Age; reflux status
(J Urol 2008)
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CUAJ • August 2010 • Volume 4, Issue 4
25. Merrick MV, Notghi A, Chalmers N, et al. Long term follow up to determine the prognostic value of imaging
after urinary tract infection. Part 1: reflux. Arch Dis Child 1995;72:388-92.
26. Caldamone AA. Commentary to “Controversies in the management of vesicoureteral reflux - the rationale
for the RIVUR study”: Urinary tract infections and vesicoureteral reflux in childen: What have we learned?
J Pediatr Urol 2009;5:342-3.
27. Estrada CR Jr, Passerotti CC, Graham DA, et al. Nomograms for predicting annual resolution rate of primary
vesicoureteral reflux: results from 2,462 children. J Urol 2009;182:1535-41.
Correspondence: Dr. Julie Franc-Guimond, Associate Professor, Université de Montréal, CHU Sainte-
Justine, Department of Surgery, Division of Pediatric Urology, A-4, 3175 Côte Sainte-Catherine,
Montréal, QC H3T 1C5; email@example.com
ureteral reflux.1 It is particularly reassuring that we see eye-
to-eye on important points, most notably the role of patient
selection. Nevertheless, the main question that remains to
be answered is not so much if we can surgically correct
vesicoureteral reflux, but in whom should it be corrected.
After all, let us consider that the elegantly portrayed his-
torical evidence reflects overall improvements in medical
care, with increased awareness, better diagnostic tools and
advances in medical therapy, along with the surgical innova-
tions described. Moreover, the idea that surgical interven-
tion has played a major role in decreasing the incidence of
end-stage renal disease secondary to reflux is debatable;
published data (adjusting for changes in diagnostic practices)
refute the contention that our treatment efforts have had a
strong impact on this outcome.2
Adding to the debate is the somewhat heterogeneous
group of interventions that “anti-reflux surgery” includes.
This has to be well-defined, considering that the popular
dextranomer/hyaluronic acid endoscopic injection has
been reported to have unexpectedly high recurrence rates
on longer-term follow-up.3-6 Recently published data from
the Swedish Reflux Trial in Children have not shown a dif-
ference in infection rates comparing antibiotic prophylaxis
and endoscopic treatment groups;7 there was no evidence of
new renal damage reported in the medical therapy group.8
Thus, confirmation that surgery is significantly better is hard
to find; this unfortunately weakens our colleagues’ stand
and ultimate conclusion that surgery is the “gold standard”
(particularly in terms of preventing long-term problems such
as reflux nephropathy). Furthermore, statements challenging
the potential benefits of medical therapy can also be called
into question. For example, consider the studies listed in the
provided table.1 Missing from this list of seminal publica-
tions is perhaps one of the best trials recently conducted on
the topic,9 a randomized-controlled trial that showed benefit
for those patients who received prophylaxis over placebo.
Indeed, important criticisms of many of the studies that have
shown lack of benefit from medical therapy include the prob-
lem with inadequate power of the trials.10 In addition, some
r. Riddell and Dr. Franc-Guimond present a strong,
thorough and thoughtful argument in favour of sur-
gical intervention for the management of vesico-
of the arguments about the lack of benefit in early treatment
of pyelonephritis are based on data that may have significant
shortcomings (such as the reliance on sub-group analyses11).
What can we make out of this debate? As indicated in the
point/counterpoint article, my personal impression is that the
controversy is sometimes erroneously approached.12 I firmly
believe that one of the main problems with our manage-
ment originates in the idea that there is an overall “superior
approach,” disregarding the principles of individualization.
Patients are different in many underlying factors, some of
which may be far more important than the mere presence of
reflux or time-honoured descriptive characteristics (such as
grade). At the end of the day, we should at least agree that
better data are needed, that individualized patient care will
play an increasingly important role in management and that
long-term endpoints will trump the potentially meaningless
early outcomes that we have often focused on until now.
1. Riddell J, Franc-Guimond J. Learning from history or the rationale for considering surgical correction of
vesicoureteral reflux. Can Urol Assoc J 2010;4:280-3.
2. Craig JC, Irwig LM, Knight JF, et al. Does treatment of vesicoureteric reflux in childhood prevent end-stage
renal disease attributable to reflux nephropathy? Pediatrics 2000;105:1236-41.
3. Chertin B, Kocherov S. Long-term results of endoscopic treatment of vesicoureteric reflux with different
tissue-augmenting substances. J Pediatr Urol Epub 2009 Nov 5.
4. Holmdahl G, Brandstrom P, Lackgren G, et al. The Swedish reflux trial in children: II. Vesicoureteral reflux
outcome. J Urol 2010;184:280-5.
5. Sedberry-Ross S, Rice DC, Pohl HG, et al. Febrile urinary tract infections in children with an early negative
voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid. J Urol
2008;180:1605-9; discussion 1610.
6. Lee EK, Gatti JM, Demarco RT, et al. Long-term followup of dextranomer/hyaluronic acid injection for
vesicoureteral reflux: late failure warrants continued followup. J Urol 2009;181:1869-74; discussion
7. Brandstrom P, Esbjorner E, Herthelius M, et al. The Swedish reflux trial in children: III. Urinary tract
infection pattern. J Urol 2010;184:286-91.
8. Brandstrom P, Neveus T, Sixt R, et al. The Swedish reflux trial in children: IV. Renal damage. J Urol
9. Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in
children. N Engl J Med 2009;361:1748-59.
10. Hoberman A, Keren R. Antimicrobial prophylaxis for urinary tract infection in children. N Engl J Med
11. Edmonson MB, Wald ER. Treatment of pyelonephritis and risk of renal scarring. Pediatrics 2009;123:e544-
545; author reply 545.
12. Lorenzo AJ. Medical versus surgical management for vesicoureteral reflux: the case for medical manage-
ment. Can Urol Assoc J 2010;4:276-8.
Armando J. Lorenzo, MD, MSc, FRCSC, FAAP
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