# Has the Data Efflux Regarding the Promising Outcome Following Injection of Deflux Changed the Management of Adult Vesicoureteral Reflux?

Authors: D. E. Zilberman; Y. Mor
Journal: Advances in Urology
 (2008)

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## Abstract

Primary vesicoureteral reflux (VUR), traditionally considered a problem of childhood, can also be detected during adulthood. However, while the concept regarding the therapeutic management of VUR in children has undergone revolutionary changes, moving from surgical to conservative approach, the optimal therapeutic approach in adult reflux is poorly addressed   and is still unknown. Herein, we review clinical and therapeutic approaches of VUR in pediatric population as published throughout the years. With the introduction of Deflux injection as a minimally invasive procedure, we identify a beginning of a new trend that further extends the indications for endoscopic injections, including its introduction to adult patients as well.


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## Body

## 1. Introduction

Primary vesicoureteral
reflux (VUR), traditionally considered a problem of childhood, can also be
detected during adulthood [1]. However, while the concept regarding the
therapeutic management of VUR in children has undergone revolutionary changes,
moving from surgical to conservative approach, based upon solid prospective
data, the optimal therapeutic approach in adult reflux is poorly addressed in
the literature and is still unknown. The current therapeutic strategy for
management of reflux has drawn its inspiration from three important large
prospective studies dealing with the management of VUR [2–4]. The most
comprehensive was the International Reflux Study (IRS), where 452 patients in Europe and USA were randomly allocated to
medical and surgical arms. In 5 years follow-up,
the same incidence of urinary tract infection (UTI) was seen in both arms
(38%), though surgery was more effective in preventing pyelonephritis (PN) (21%
versus 10%). However, in 10 years follow-up, clinical findings did not support
the surgical attitude as there was no significant difference in renal growth comparing
both arms, and there was no support to the view that the outcome of renal
function is improved by surgical correction of VUR in children with bilateral
disease. These studies had led to the publication of the clinical guidelines
for the management of VUR in children, both by the American Urological
Association (AUA) [5] and the European Association of Urology (EAU) [6].In general,
conservative attitude is currently the mainstay, and surgical intervention
takes its place in the more severe conditions. While those observations are
extremly important in children, they are irrelevant for adults as factors such
as the natural history of the disease, the associated risks such as infections
or scars are completely different. Unfortunately, with regard to VUR in adults,
review of the literature reveals only few retrospective studies, some of them
biased with conflicting results.


## 2. Prevalence of VUR in Adults

In the general pediatric
population, the prevalence of VUR is around 1-2% with higher
rates in siblings (30%) and in children with acute PN (25–40%) [5].As the rates of
disappearance of VUR in children are as high as 71% and can occur at any age,
in infancy or at puberty [7], the actual prevalence in adults is still unclear.
Baker and coworkers [8] found an incidence of 26.4% of VUR in children but only
5.2% in adults, each group suspected of “having infravesical
obstruction”.Similarly, Choi et al.
[9] studied 86 adult women suffering from uncomplicated PN with voiding
cystourethrogram (VCUG) performed on the 3rd and the 7th days of antibiotic
treatment, and only in 2 cases (2.3%), VUR was demonstrated.Pinthus et al. [10]
explored the same situation in 47 women who presented with acute PN. Early indirect
cystography revealed VUR in 28%, while VCUG performed later found VUR in only 3
patients (9%). In accordance, while the resolution rates of reflux in children are rather predicted, it
seems that the possibility of resolution even past puberty still exists, yet
the chance for resolution is probably much less than in infants [11].


## 3. Presentation

The most common
initial symptoms and findings that can lead to the diagnosis of VUR are UTI,
asymptomatic bacteriuria, proteinuria, renal failure, and hypertension [12]. Köhler et al. followed after 115 adult
patients and found UTIs in 87%, hypertension in 34%, renal calculi in 18%, and
back pain in 42% [12]. Vice versa, reflux nephropathy may be clinically latent
as the prevalence of reflux in patients with incidentally diagnosed adult
hypertension exceeds to 19%, without any apparent renal parenchymal or renovascular
involvement [13]. However, the correlation between presence of VUR and various
clinical presentations cannot be made that easily as different, and somehow
confounding observations were published in other studies and in some patients
the reflux may be even completely asymptomatic [11].


## 4. The Current Approach for Management of Adult VUR

So far, although no
evidence-based recommendations are available in the literature, the last AUA update (1998) [11]
for the treatment of VUR in adolescents and adults recommends the following.
(i)
No medical management is needed in VUR grade 1-2 and no history of UTI.(ii)
Medical management with lifelong antibacterial prophylaxis should be considered in the cases
of low-grade VUR, shortened life expectancy, and poor surgical risk.(iii)
Surgery is indicated in VUR grade 3 or
higher, history of recurrent PN, and evidence of nephron loss. When conservative
treatment is the mainstay, progressive renal damage and caliceal scarring
should be expected [14]. Reimplantation, when performed, does not improve
hypertension or renal failure, but it rather stops the anticipated progressive
deterioration [10, 15].Similar conclusions
were coming up from Köhler and Guthman's studies
[16, 17]. In the first study [16],
surgical treatment (e.g., ureteral reimplantation) did not alter the frequency
of lower UTI, though it significantly decreased the frequency of PN. Yet, the
surgical option according to the author should be considered only when
conservative treatment failed and not with the aim of arresting renal functional
deterioration. However, the second study [17] had expanded the indications for
surgical treatment also for asymptomatic women in childbearing age “in
whom pyelonephritis of pregnancy would pose a major risk to the fetus and
mother”, without supporting evidences. Ever since, most clinicians
recommend that surgical correction of VUR should be accomplished before
pregnancy in women at childbearing age or even earlier in girls with reflux
that persists beyond puberty.This recommendation is
based upon the fact that history of VUR is known to increase morbidity during
pregnancy including the risk of preeclampsia, obstetric interventions, and
fetal loss. Women with hypertension and an element of renal failure are particularly
at risk, though surgical correction does not prevent complications but rather
decreases their frequency [18]. It should be also remembered that reimplantation
in adults is more difficult with lower success rates compared to infants. This
can be attributed to difficult bladder exposition, increased vascularity around
the ureter and in the retrovesical space, and increased body mass [11].Altogether, VUR in
adults is still a very controversial subject, and throughout the years, the
pendulum had moved from surgical to a more conservative treatment and again to
surgical treatment in certain and severe cases.


## 5. Endoscopic Correction of VUR

During the last seven
years, we are witnessing an increasing number of studies published in the
English literature, discussing the safety and efficacy of endoscopic injection
of bulking materials for the correction of ureteric reflux. The need for alternative
treatment aroused as a result of the significant disadvantages of both reimplantation
and antibiotic prophylaxis.
Reimplantation in the pediatric population carries significant cost, morbidity,
and inpatient hospital stay, while antibiotic prophylaxis requires annual
imaging which is expensive, invasive, and often requires sedation [19].The first report on endoscopic
injection of polytetrafluoroethylene (Teflon) in pigs came from Puri and O'Donnell in 1984 [20].
Later on, long-term results were published covering 8332 children and 12251
refluxing ureters [21], and the final conclusion was that “polytetrafluoroethylene injection is a
simple, safe and effective outpatient procedure for treating all grades of
vesicoureteral reflux.” Chertin and Puri [22] supported
their own conclusion by reporting long-term (e.g., six years) follow-up among
258 patients with primary VUR who were treated by polytetrafluoroethylene
injection. They reported overall success rates of 77% following one injection,
13.5% success rate following two injections, 2.6% following three injections,
and 0.5% following four injections. Yet, the initial enthusiasm from PTFE has
disappeared following the observation that small particles can be injected
directly into capillaries and embolize to distant organs, causing the FDA to
withdraw PTFE from the United States market [23]. Remaining with the
impressive results of the endoscopic injection for treating vesicoureteric
reflux, alternative materials took the PTFE place in order to keep its momentum
of success, while keeping complication rates as low as possible. At present, the
most popular injectable material is dextranomer/hyaluronic acid (Dx/HA)
copolymer (Deflux) which is FDA approved. This is an organic substance
comprising 80–250 μm microspheres which are nonallergic, nonimmunogenic, and have no potential for malignant
transformation [24, 25]. The large size of the microspheres prevents them from migrating outside the urinary
bladder and they do not tend to form granulomas or induce calcifications [24].Injection procedure consists of injecting the bulking material through direct inspection and under general
anesthesia. Approximately, 1 mL of Deflux is submucosally injected through a
special needle, which is inserted 2-3 mm below the
affected ureteral orifice at the 6 o'clock position [25, 26]. The needle
is slowly withdrawn as a “volcanic bulge” starts to create [25].
Overall procedure length does not exceed 30 minutes [26, 27], and the
patient is discharged home the same day [19, 23, 27, 28] or the
following day [24].Overall complication
rate is very low, and the procedure is considered very safe and effective. UTI,
flank pain, postoperative ureteral obstruction, retrograde tracking of Deflux, intravesical
extravasation of Deflux, and new contralateral VUR were reported in only few
percents (0.6–4.5%) [23, 28, 29].Success rates, on the
other hand, are high and reported in various series with regard to the number
of injections required to cure VUR and to the original reflux grade. Following a
single injection, the reported success rates in pediatric population vary
between 72–86%, following two injections—between 12-13% and following
three injections—between 1-2% [23, 25, 27, 28]. Overall,
cure rates reached 82–100% for grade 1
reflux, 82–88% for grade 2, 73–87% for grade 3, 64–73% for grade 4, and
50% for grade 5 [19, 23, 28]. Kirsch et al. [23] describe the lowest success
rates (60%) in the first twenty cases, meaning that a reasonable learning curve
exists for this certain procedure.


## 6. The Evolvement of the Therapeutic Approach in Adults

All the advantages
mentioned with regard to endoscopic treatment for VUR in children can
definitely change the concept regarding the treatment of VUR in adults. Arguments
such as high success rates, very short hospital stay, absence of significant
postoperative complications, safety of injectable materials, and low cost
compared to the cost of long-term antibiotic prophylactic treatment which have been raised in
discussions regarding children [30–32], are also
valid concerning adults. Understandably, this can widen the circle of patients
treated with bulking agents to include also adults. However, in oppose to
increasing reports regarding using this technique in the pediatric age group,
the reported experience in adults with Deflux is very limited [19, 29, 33]. Those
reports usually describe the outcome of injection of various substances in
series composed of mixed populations, including children and adults. Although
there is usually no specific reference to the adult subgroup, it is obvious
that there has been some experience with injection of cross-linked bovine collagen [34] or STING [35, 36] in adults,
with cure rates as high as 86% following the injection of polymethylsiloxan in
adult women or 70% following the first injection of Teflon in adults [36].Nowadays, in the “Deflux era”, review of the literature as well as presentations in urological conferences
can identify the beginning of a new trend that further extends the indications
for endoscopic injections, including its introduction to adult patients as
well. Some current pediatric reports [19, 29] include in their series some
adult patients as old as 22 years. Unfortunately, they do not specify this
unique population in terms of number of individuals, sex, indications for
Deflux injection, age at injection, follow-up length, complications, and
success rates. However, we can assume that both groups were stunned by their
impressive success rates, and taking into consideration that endoscopic
treatment for VUR is “self and efficacious with low-complication
rate” [19], they decided to offer it to certain individuals that
traditionally were excluded from any definitive treatment. Enthusiasm from the
introduction of Deflux injection for adult population was also expressed by
Kirsch [37] who achieved success rates of 90 and 95% after one or two
treatments in 22 patients ranging in age between 13–71 years.In summary, the efflux
of data regarding the safety and the promising results of Deflux endoscopic
correction of VUR in children will certainly change the management of VUR in
adults which unfortunately has been poorly addressed and controversial till
recently. In similar with the shifting therapeutic policy of adult
ureteropelvic junction obstruction following the arrival of the endourological
era [38], one can likewise anticipate that “it would be unethical to refrain
from treating” [30] adult patients diagnosed with VUR. Furthermore, as the
procedure is safe, less invasive, highly successful, and can be repeated, we
foresee that a more active strategy, namely, early endoscopic correction, will
become the new gold standard of treatment of adult VUR, and we hope that this shift
of policy will be clearly reflected in the coming updated clinical urological guidelines
for management of VUR.



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*Source: 361324-2009-03-10.xml*