Coverage Policy Manual
Policy #: 2006041
Category: Surgery
Initiated: August 2017
Last Review: October 2018
  Periureteral Bulking Agents as a Treatment of Vesicoureteral Reflux (VUR)

Description:
Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder upward toward the kidney, most commonly seen in children. Severe reflux may damage the kidney through mechanical or immunological mechanisms. VUR also predisposes an individual to renal infection (pyelonephritis) by facilitating the transport of bacteria from the bladder to the upper urinary tract. Pyelonephritis causes renal scarring in as many as 40% of children, and extensive scarring may lead to renal insufficiency and hypertension. The central management strategy of children with VUR has been the reduction of reflux and prevention of renal damage induced by urinary tract infection (UTI).
 
In most cases, VUR is diagnosed during evaluation of UTI. About one third of children with UTIs are found to have VUR.  The average age for the onset of UTI is 2–3 years, corresponding to the age when toilet training occurs. There also appears to be a genetic predisposition to VUR, and siblings may also be examined. The gold standard for diagnosis is voiding cystourography, a procedure that involves catheterization of the bladder. The severity of reflux is described by a grade, typically with the International Reflux Study Group grading system, which grades severity from I (reflux partway up the ureter) to V (massive reflux of urine up the ureter with marked tortuosity and dilation of the ureter and calyces). Determination of VUR grade is not exact, however, due to factors such as bladder pressure, which may vary at the time of measurement. In general, more severe reflux is associated with higher rates of renal injury. Spontaneous resolution and treatment success also varies with reflux grade.
 
Treatment strategies include bladder training, antibiotic prophylaxis, and surgical modification of the ureters to correct the underlying reflux. VUR is likely to resolve spontaneously over a period of 1–5 years; lower grades of reflux (i.e., grades I and II) are associated with a higher probability of spontaneous resolution.  The decision to administer prophylactic antibiotic treatment depends both on the probability of spontaneous resolution and the level of parental concern for potential adverse effects of long-term antibiotic treatment, which can include allergic reactions and development of treatment-resistant bacteria resulting in breakthrough UTIs.
 
Open surgical treatment is typically reserved for patients with high-grade reflux (grades III and IV) or as salvage therapy for those who are noncompliant with antibiotic therapy or have breakthrough UTIs while receiving prophylactic therapy. Surgical management involves lengthening the intramural ureter by modification of the ureterovesical attachment with reimplantation of the ureters. Success rates for open surgery are reported to be above 98% for reflux grades III and IV; and about 80% for reflux grade V. In addition to surgery-associated morbidity, obstruction and reoperation rates have been reported to be as high as 9%.
 
The use of bulking agents in the treatment of VUR has been reported for over 20 years and has been suggested as an alternative to either antibiotic or surgical therapy. Bulking agents can be injected into tissue around the ureteral orifices to minimize reflux. The STING procedure (suburethral trans-urethral injection) involves the endoscopic injection of a bulking agent into the submucosal bladder wall just below the ureteral opening. In the more recently used modified STING procedure, the needle is placed in the ureteral tunnel and the bulking agent is injected into the submucosal intraureteral space. When successfully injected the compound tracks along the length of the detrusor tunnel and establishes a coapted ureteral tunnel. This endoscopic procedure can be performed in an outpatient setting.
 
A variety of bulking agents have been tested for biocompatibility and absence of migration. Some of the compounds used in clinical studies are collagen (Contigen, Zyderm, Zyplast), polytetrafluoroethylene paste (Teflon), polydimethylsiloxane (Macroplastique®), calcium hydroxyapatite (Coaptite®), and dextranomer/hyaluronic acid copolymer (Deflux® or Dx/HA). In 2001, Deflux® received pre-market approval from the U.S. Food and Drug Administration (FDA) for the “treatment of children with vesicoureteral reflux (VUR) grades II-IV.” Contraindications include patients with non-functioning kidney(s), duplicated ureters, active voiding dysfunction, and ongoing urinary tract infection.
 
Note: Polytetrafluoroethylene may migrate, causing serious adverse events; this agent is not FDA-approved. Coaptite®, Macroplastique®, and Tegress® are categorized by the FDA as “Agent, Bulking, Injectable for Gastro-Urology Use.” These are currently indicated for the treatment of stress urinary incontinence.

Policy/
Coverage:
Periureteral bulking agents as a treatment of vesicoureteral reflux grades II–IV when surgical intervention is otherwise indicated meets member certificate primary coverage criteria.
 
For Member Benefit Contracts or Plans with Primary Coverage Criteria, the use of bulking agents as a treatment of vesicoureteral reflux in other clinical situations is not covered because it fails to meet the Primary Coverage Criteria (“The Criteria”) of the applicable benefit certificate or health plan (The Criteria require, among other things, that there be scientific evidence of effectiveness, as defined in The Criteria).  The use of bulking agents as a treatment of vesicoureteral reflux in other clinical situations fails to meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For Member Benefit contracts or Plans with explicit exclusion language for experimental or investigational services, the use of bulking agents as a treatment of vesicoureteral reflux in other clinical situations is not covered because it is considered experimental or investigational treatment, as defined in the applicable benefit contract or health plan, which excludes coverage of experimental or investigational treatment or services.

Rationale:
Treatment of vesicoureteral reflux is based on the following assumptions:
    1. VUR predisposes patients to URI.
    2. VUR predisposes patients to pyelonephritis.
    3. VUR predisposes patients to reflux nephropathy and renal scarring, potentially leading to morbidity- related renal disease (i.e., hypertension, end-stage disease).
 
Critical reviews of the natural history and treatment of VUR point out that these 3 assumptions, entrenched in pediatric practice, have never been proven.  In 1997, the American Urological Association (AUA) published practice guidelines for the treatment of childhood VUR. These guidelines included literature published until 1994.  This review noted that there was little information regarding health outcomes related to reflux, for example the extent to which reflux increases the risk of renal scarring related to UTIs. These gaps in the understanding of the natural history and health outcomes of VUR underscore the importance of including final health outcomes (not just resolution of reflux itself) in studies of the treatment of VUR. Indeed, the AUA guidelines noted that only a few recommendations could be derived purely from scientific evidence of a beneficial effect on health outcomes, therefore, the guidelines were primarily based on expert opinion.
 
A 2004 Cochrane review focused on treatment of primary VUR.  This review analyzed the published randomized studies of surgery (including open surgery or endoscopic use of bulking agents), antibiotic prophylaxis of any duration, and non-invasive techniques, such as bladder training. Outcome measures included final health outcomes, such as incidence of UTI, renal parenchymal abnormalities, development of hypertension, or renal function impairment. Correction of VUR and obstruction following VUR correction were also evaluated. Eleven randomized controlled trials were identified, 2 of which involved Deflux. (These 2 trials are reviewed in greater detail below.) Overall, the authors concluded that no significant differences in the risk for UTI or renal parenchymal injury were found in a meta-analysis of 7 trials with 847 evaluable patients combining antibiotic prophylaxis with combined surgery and antibiotics. This finding challenges the assumptions underlying the treatment of VUR, since one would expect a reduction in UTI if the hypothesis is correct that VUR is a modifiable risk factor for UTI and renal parenchymal damage. No differences between treatment groups were demonstrated for the endpoints of hypertension and chronic renal failure, but the trials were not powered to detect these endpoints and follow-up time was too short. Furthermore, data from available randomized trials did not provide evidence as to whether the current practice of diagnosing and treating children with VUR confers important health benefits, since no adequately powered trials have included a no treatment arm. The only positive finding from the meta-analysis was a reduction in the incidence of febrile UTI in children surgically treated; however, the clinical significance of this finding is uncertain. For example, if one assumes a relatively high baseline 20% risk of a UTI, about 9 children would need to be treated with combined reimplantation surgery and antibiotics compared with antibiotics alone to prevent 1 febrile UTI during the ensuing 5 years.
 
Randomized Studies of Dextranomer/Hyaluronic Acid Copolymer (Deflux)
 
Capozza and colleagues reported on the results of a study of 61children with VUR (grades II to IV) who were randomized to receive an endoscopic subureteral implantation (n=40) of Deflux or 12 months of antibiotic prophylaxis (n=21).  The 2001 FDA approval of Deflux was also based in part on this study. Entry criteria included grades II to IV reflux present for at least 6 months. The antibiotic therapy was not specified and presumably was variable. It was not reported whether patients had been receiving antibiotic therapy during the preceding 6 months and experienced breakthrough UTIs, were noncompliant, or showed no evidence of spontaneous resolution of VUR. Therefore it is unknown whether the Deflux treatment was primarily considered an alternative to medical therapy or to surgical therapy. In part due to the small numbers in the antibiotic control group, the distribution of the different grades of VUR were different in the 2 groups. Outcomes included improvement in reflux grade and measures of renal function; incidence of UTIs was not reported. The only significant outcome reported was the improvement in reflux grade, with 69% of those in the Deflux group reporting a reflux grade of <=1, compared to only 38% in the antibiotic group. However, these results are not surprising, since antibiotic therapy in and of itself is not intended to improve reflux grade, but simply to sterilize the urine while awaiting the spontaneous resolution of VUR. Therefore, the only conclusion is that Deflux results in a higher incidence of VUR resolution compared to spontaneous resolution.
 
The second identified randomized study was reported by Oswald and colleagues, which randomized 72 children with VUR to receive either Deflux or Macroplastique in addition to antibiotic prophylaxis.  Entry criteria included grades II to IV reflux. Since all patients continued to receive antibiotic therapy, presumably the bulking procedure was primarily considered an alternative to surgical reimplantation of ureters. However, the patient selection criteria do not indicate whether patients had failed prior antibiotic therapy or had unresolved VUR. Correction of underlying VUR was similar in the 2 groups.
 
There were no randomized studies comparing bulking procedures with surgical reimplantation. The Cochrane review states that bulking agents offer an alternative method of correcting VUR, although the rates of correction are lower than those reported with surgical reimplantation techniques. However, the Cochrane review also points out that the benefit of any type of correction of VUR is unproven at this point.
 
Additional Studies
Since the 2004 Cochrane report, no additional randomized studies have been reported. Additional case series of bulking agents including Deflux have been published and continue to report success rates of elimination of reflux in the 70% range, although the rates are higher in those with low-grade reflux and lower in those with high-grade reflux.  The fact that these case series include patients with grades I and II reflux, typically treated with prophylactic antibiotics, and patients with grades III and IV reflux, for whom surgery might be considered an initial therapy, suggests that bulking agents continue to be considered an alternative to either medical or surgical therapy. Many of the reports of the use of bulking agents are published in international journals, and it may be that this treatment option has been integrated into clinical practice primarily outside the United States.
 
2006-2007 Update
A search of the MEDLINE database was performed for the period of March 2005 through November 2006. As indicated above, one can consider use of periureteral bulking agents as either an alternative to antiobiotic prophylaxis or as an alternative to open surgical intervention for VUR. While questions may exist about the role of surgical treatment of VUR, some patients with high-grade VUR who have recurrent UTIs resulting from antibiotic resistance or noncompliance with antibiotic prophylaxis are currently treated with open surgery. Thus, it is important to compare VUR with surgery for this group of patients.
 
As previously described, a 2004 Cochrane review assessed the published randomized studies of surgery (including open surgery or endoscopic use of bulking agents), antibiotic prophylaxis of any duration, and non-invasive techniques such as bladder training.  Eleven randomized controlled trials (RCTs) were identified, 2 of which involved Deflux. This meta-analysis found a reduction in the incidence of febrile UTI with surgical treatment and concluded that although the rates of correction may be lower than those reported with surgical reimplantation techniques, bulking agents offer an alternative method of correcting VUR.
 
A number of recent publications, mostly retrospective, have been published on the use of periureteral bulking agents for the treatment of VUR. A 2006 meta-analysis included 63 studies (3 randomized prospective, 7 prospective, 52 retrospective, and 1 study of unknown design) with a total of 5,527 patients.  Interpretation of this meta-analysis is limited by the inclusion of a variety of bulking agents, some of which have since been abandoned due to low success rates, and by the large proportion of retrospective studies in which concerns exist about enrollment criteria and adequacy of follow-up.
 
An important factor in success rates appears to be the injection technique (including the use of multiple injections), which has evolved over the last several years. A European group described their experience treating 692 children with the STING procedure.  They reported that of 1,101 (mostly grade III or IV) refluxing ureters treated between 2001 and 2004, 96% had completely resolved (grade 0) and the rest had downgraded to grade I after 1 (86%), 2 (12%), or 3 (2%) injections. Patients with neurogenic bladder, bladder diverticulum, ureterocele, and urethral valves were excluded from analysis. The FDA-listed contraindications are non-functioning kidney(s), hutch diverticuli, duplicated ureters, and active voiding dysfunction, and Dx/HA has only been shown to be effective in children without these conditions.
 
Another study from the same European group assessed outcomes of their treatment experience in consecutive infants with a total of 209 ureters (about 125 infants).  One injection of Dx/HA was reported to adequately resolve VUR (complete resolution to grade 0 or improvement to grade I–II) in 80% of ureters, and the remaining 20% required multiple injections. There were no recurrences of symptomatic bacteriuria during the study period (median follow-up of 7 years; ranging from 6 months to 20 years). Other studies have shown stability of implant size by ultrasound for up to 3 years 10 months, with over 96% of patients remaining free of VUR as measured by voiding cystourography for 2–5 years after treatment.  Since VUR can resolve spontaneously over a period of 5 years in greater than 60% of young children, a treatment lasting only a few years could provide protection from UTI-associated renal damage until VUR resolves spontaneously with normal growth and development.
 
Overall, the literature indicates that one or more periureteral injections of Dx/HA can effectively resolve reflux in as many as 90%–96% of cases, depending on technical experience and patient selection. These resolution rates approach those of open surgical intervention. Procedural morbidity is lower with the endoscopic procedure compared with open surgical intervention.  Injection of a bulking agent is less invasive than open surgical techniques and can be performed as an outpatient procedure with use of general anesthesia. Temporary postoperative ureteral obstruction may occur in less than 0.7% of patients following injection of bulking agents; this can be treated with ureteral stenting until the problem resolves.  In comparison, an average 2% (range of 0% to 9%) ureteral obstruction and reoperation rate has been reported following ureteral reimplantation.  Because of the differing benefits and risks of treatment with bulking agents in comparison with surgical reimplantation of the ureters, parents should make an informed choice between the procedures.
 
Use of a periureteral bulking agent is considered to be a medically appropriate alternative to open surgical treatment of VUR when a decision for surgical intervention has been made.
 
Randomized studies assessing long-term health outcomes (incidence of UTI, renal parenchymal abnormalities, development of hypertension, or renal function impairment) of various treatment procedures are lacking. Until these studies are done, evidence will remain insufficient to compare periureteral injection of bulking agents with antibiotic prophylaxis for VUR.
 
Use of the biocompatible compound calcium hydroxyapatite to treat VUR has been reported in a multi-center prospective study from the United States. (18) This compound is FDA approved for gastro-urology use, but has not received FDA approval for the treatment of VUR.
 
2008 Update
A search of the MEDLINE database was performed for the period of December 2006 through February 2008. The effect of treatment of VUR on the risk of future renal damage remains controversial. A Cochrane review evaluated 11 studies (1,148 children) that compared the correction of VUR by surgery, endoscopy, and/or antibiotics.  The review found that the risk of UTI by 2, 5, and 10 years was not significantly different between surgical and medical groups. Combined treatment resulted in a 50% reduction in febrile UTI by 10 years, but there was no concomitant reduction in risk of renal damage by 10 years. Retrospective reviews were published on the use of periureteral bulking agents in cases of Grade V VUR (n=132) and Hutch diverticuli (n=17).  As discussed above, VUR may resolve spontaneously without intervention; therefore, the absence of a comparator group limits interpretation of these case series. Evidence is insufficient to extend the use of periureteral bulking agents beyond VUR grades II, III, or IV when open surgical reimplantation is indicated. Thus, the policy statements remain unchanged.
 
2009 Update
A 2009 comparison of 2 cohorts of children treated at a single institution compared success rates with Deflux and “mini-ureteroneocystostomy” (mini-UNC), a modified extravesical ureteroneocystostomy performed through a 2 cm. groin incision (Ashley, 2008).  A total of 99 children were treated with one of these procedures, 57 had a mini-UNC and 42 had Deflux injections. The groups were similar at baseline, except that children in the mini-UNC group had higher-grade VUR (all grades were included, most children had grade II or III disease), and 5 had a solitary kidney. About 80% of each cohort returned for the 3-month follow-up and received a voiding cystourethrogram (VCUG) examination. All 47 of the patients in the mini-UNC group, and 26 of the 33 in the Deflux group (78%) demonstrated surgical cure; 4 children in the mini-UNC group later experienced complications that required urological intervention or rehospitalization. The authors concluded that mini-UNC has a better success rate than Deflux injection, with a low complication given the higher-grade VUR of the patients in this group. Due to lack of randomization and differences in VUR grade, outcomes cannot be directly compared.
 
A number of case series of bulking agents have been published and they generally report higher rates of successful elimination of reflux with low-grade reflux and lower in those with high-grade reflux (Lavelle, 2005) (Capozza, 2004). One of the larger case series was by a European group and reported on 692 children (1,101 ureters) treated with the STING procedure (Puri, 2006).  Ninety-six percent of the 1,101 ureters treated (mostly grade III or IV) had completely resolved (grade 0) and the rest had downgraded to grade I after 1 (86%), 2 (12%), or 3 (2%) injections. Patients with neurogenic bladder, bladder diverticulum, ureterocele, and urethral valves were excluded from analysis. Among the studies reporting longer term success rates, most but not all have had high rates of treatment success. Another study by the European research group assessed outcomes in 209 ureters (about 125 consecutively treated infants) (Dawrant, 2006).  One injection of Dx/HA was reported to adequately resolve VUR (complete resolution to grade 0 or improvement to grade I–II) in 80% of ureters, and the remaining 20% required multiple injections. There were no recurrences of symptomatic bacteriuria during the study period (median follow-up of 7 years; ranging from 6 months to 20 years). Other studies have shown stability of implant size by ultrasound for up to 3 years 10 months, with over 96% of patients remaining free of VUR as measured by voiding cystourography for 2–5 years after treatment (Puri, 2006) (Lackgren, 2001). On the other hand, a retrospective series published in 2009 reported a 73% (246/337 ureters in 219 patients) success rate at post-operative voiding cystourecystourethregram (Lee, 2009).  A total of 150 ureters were reevaluated at 1 year with another VCUG. Seventy-four percent (111 of 150 ureters) had long-term success. Including the initial treatment failures, the overall one-year success rate was 46.1% (111 of 241 ureters). Data were missing at 1 year on 74 patients (96 ureters). If all 96 had lasting success at 1 year, the overall success rate would be 61.4% (207 of 337 ureters). As discussed above, VUR may resolve spontaneously without intervention; therefore, the absence of a comparator group limits interpretation of these case series.
 
According to case series data, there are low morbidity rates associated with injection of periureteral bulking agents. Temporary postoperative ureteral obstruction may occur in less than 0.7% of patients following injection of bulking agents; this can be treated with ureteral stenting until the problem resolves (Vandersteen, 2006).  In comparison, an average 2% (range of 0% to 9%) ureteral obstruction and reoperation rate has been reported following ureteral reimplantation (Elder, 1997).
 
Summary
There are no head-to-head randomized controlled trials comparing periurethral bulking agents to other types of surgery. The available evidence suggests that rates of reflux resolution are reasonably high with bulking agent injection. Morbidity rates tend to be lower than with other surgeries, although surgical methods have improved recently, leading to a reduction in adverse effects. There is insufficient evidence to evaluate outcomes from treating VUR with periureteral bulking agents compared to outcomes obtained when using antibiotic prophylaxis or other non-surgical treatments. Based on the assessment of reasonably similar outcomes with lower morbidity, periureteral bulking agents may be considered medically necessary for patients otherwise eligible for surgical intervention. The use of bulking agents to treat VUR, other than as an alternative to other surgical methods, is investigational.
 
Technology Assessments, Guidelines and Position Statements
The American Urological Association (AUA) issued a guideline on management of VUR in children in 1997; this guideline is currently being updated. Due to a lack of evidence, it is primarily an expert opinion guideline. In 2007, the AUA issued a position statement on use of Deflux® stating that it is a valid option to open surgery.  The statement acknowledges that evidence is still insufficient to guide treatment decisions and the Deflux recommendation is based largely on the lower morbidity of this procedure compared to open surgery.
 
2012 Update
The Cochrane Library conducted a review of randomized controlled trials (RCTs) on treatments for VUR (Nagler, 2011).  The review was available at the time the policy was developed and it was updated most recently in 2011. It addressed a variety of interventions including long-term antibiotic prophylaxis, open surgery, and use of bulking agents. The Cochrane review had limited ability to evaluate the efficacy of bulking agents because it combined studies on open surgery and bulking agents in the analysis. The review, however, is useful for examining the assumption that VUR increases the risk of complications.
 
Findings from the Swedish Reflux trial in children were published in 2010 (Brandstrom, 2010) (Holmdahl, 2010) (Brandstrom, 2010) (Brandstrom, 2010).  This non-blinded multicenter study included 203 children (128 girls and 75 boys) between the ages of 1 and 2 years with grade III to IV reflux. Most of the participants (194, 96%) were identified after a symptomatic UTI. Recruitment was more difficult than expected, and enrollment was stopped after 6 years. Participants were randomly assigned to 1 of 3 groups: antibiotic prophylaxis (n=69), endoscopic treatment with Deflux (n=66), or surveillance only (n=68). Participants were not required to have failed antibiotic prophylaxis; thus the trial evaluated injection of a bulking agent as an alternative to antibiotic therapy. The study aimed to simulate clinical practice, i.e., prophylactic antibiotics were prescribed without monitoring compliance, rather than ensuring that study participants took a known dose of antibiotics. Primary study outcomes included VUR status, and rates of febrile UTI and kidney damage after 2 years. Sixty-four of 66 patients randomly assigned to endoscopy received treatment. Fourteen of 19 patients with still dilating VUR after 1 injection received a second injection; 2 patients received a third injection. The investigators reported that complications occurred in 6 of the 64 (9%) individuals who received endoscopic treatment. Overall, 187 participants (92%) completed at least 6 of the 8 follow-up visits; analysis was intention to treat.
 
Two-year cystourethrography was done in 185 of the 203 (91%) patients. Findings from voiding cystourethrography were that VUR had resolved in 9 of 68 (13%) patients in the prophylaxis group, 20 of 52 (38%) in the endoscopy group, and 10 of 65 (15%) in the surveillance group. The proportion of patients in the 3 groups whose VUR was downgraded to grade I or II was 18 of 68 (26%), 17 of 52 (33%) and 21 of 65 (32%), respectively. There was a significantly greater proportion of patients whose VUR had resolved or had been downgraded in the endoscopy group compared to the prophylaxis (p=0.0002) and surveillance groups (p=0.003), but no statistically significant differences were found between the prophylaxis and surveillance groups. Thirteen patients (20% of the 66 patients randomly assigned to endoscopy) whose VUR had initially resolved or been downgraded experienced recurrences and had stage III or IV VUR at 2 years. Rates of febrile UTI recurrence during follow-up were dramatically higher in girls (42 of 128, 33%) than boys (7 of 75, 9%). Febrile UTI rates by treatment group in girls were 8 of 43 (19%), 10 of 43 (23%), and 24 of 42 (57%), respectively, in the prophylaxis, endoscopic, and surveillance groups. Rates were significantly higher in the surveillance group than either the prophylaxis group (p=0.002) or the endoscopic group (p=0.14); rates did not differ significantly in the prophylaxis versus the endoscopic groups. Rates of febrile UTIs in boys were 2 of 26 (8%) in the prophylaxis group, 4 of 23 (17%) in the endoscopic group, and 1 of 26 (4%) in the surveillance group; there were no statistically significant differences between groups. A total of 24 patients were found to have new renal damage in a previously unscarred area, 4 of 68 (6%) on prophylaxis, 8 of 65 (12%) in the endoscopy group, and 12 of 68 (18%) in the surveillance group. (Two children were not evaluated for this outcome.) The rate of new renal damage did not differ significantly among groups. After stratifying findings by gender, the sample sizes in reported analyses were relatively small. There may have been insufficient power to evaluate some of the outcomes of interest, e.g., kidney damage and febrile UTIs. Moreover, findings might not be applicable to children outside of the restricted age range included in the study and to those with lower-grade VUR. Larger studies with a more representative sample of children with VUR are needed to further evaluate the effectiveness of this treatment.
 
A systematic review published in 2010 identified randomized trials and observational studies evaluating dextranomer/hyaluronic acid (Dx/HA) treatment for pediatric VUR (Routh, 2010).  A total of 47 studies, mainly retrospective case series, met eligibility criteria. A key inclusion was that studies report the postoperative success rate after a single injection of Dx/HA. Success was defined as resolution of VUR and could also include downgrading to grade 1 VUR. Of 7,303 ureters injected with Dx/HA, 5,633 (77%) were considered treatment successes. There were higher rates of success in children with lower-grade reflux compared to those with high-grade reflux. For example, the 164 children whose preoperative VUR was grade 1 had an 89% success rate compared to a 59% success rate among the 1,109 children with initial grade IV VUR.
 
Practice Guidelines and Position Statements
In 2010, the American Urological Association (AUA) published an updated guideline on management of primary VUR in children (Peters, 2010).  They recommend that patients older than 1 year who have a febrile breakthrough UTI while receiving continuous antibiotic prophylaxis be considered for either open surgery or endoscopic injection of bulking agents. Specific bulking agents mentioned were Deflux and Macroplastique. The guideline was based on a review of the evidence, but the authors acknowledged the lack of robust randomized controlled trials.
 
Based on this literature review, no additional information was identified that would prompt a change in the coverage statement.
 
2013 Update
This policy is being updated with a literature review through January 2013. There was no new information that would prompt a change in the coverage statement.
  
2014 Update
A literature search conducted through January 2013 did not reveal any new literature that would prompt a change in the coverage statement. One RCT was published in 2013. Garcia-Aparicio and colleagues in Spain randomized 41 children older than 1 year of age with VUR grades I-IV to receive endoscopic treatment with Dx/HA (n=22) or UR (n=19) (Garcia-Aparicio, 2013).   Indications for surgery included recurrent UTIs, persistent VUR after 2 years of antibiotic prophylaxis, impairment of renal function or another type of impairment due to VUR. A total of 35 refluxing ureters were treated with bulking agents, and 32 refluxing ureters were treated with UR. One year after treatment, 32 of 35 ureters (91.4%) in the Dx/HA group and 32 of 32 ureters (100%) in the surgical reimplantation group were cured; the difference between groups was not statistically significant, p=0.23. Findings were similar at final follow-up. At 5 years, 30 of 35 ureters (85.7%) in the Dx/HA group and 100% in the UR group were free of VUR; p=0.48. One patient in the Dx/HA group and 2 patients in the UR group experienced complications associated with the treatment. Two patients in the Dx/HA group and none in the UR group experienced fevers posttreatment. Rates of complications and adverse events did not differ significantly between groups. The results of this trial support that there are no large differences between the two treatments, but the study was not powered to detect smaller differences in outcomes and was also likely too small to detect differences in complications and adverse events.
 
Children With Duplicated Ureters
No controlled studies have been published that compare bulking agents to other treatments in children with duplicated ureters. However, several case series are available, and these uncontrolled studies suggest reasonable response rates and do not report high complication rates in this population of patients. The largest series to date was published in 2013 by Hunziker and colleagues in Ireland (Hunziker, 2013). The study included 123 children with complete duplex systems who were treated with Dx/HA for grade II-V VUR. The mean age of participants was 3 years (range: 1 month to 12 years). Complete duplicated ureters were unilateral in 100 patients (81%) and bilateral in the remaining 13. A total of 136 refluxing units were treated with endoscopic injections of Dx/HA. Three months after treatment, children were evaluated with voiding cystourethrography and bladder ultrasound. The rate of VUR resolution after 1 injection was 68.4% (93 of 136 ureters). VUR resolved in an additional 35 ureters (25.7%) after a second injection and in the remaining 8 ureters (5.9%) after a third injection. There was only 1 complication associated with the endoscopic injections, which was a case of frank hematuria. No patients needed ureteral reimplantation, and there was no evidence on ultrasound of delayed vesicoureteral junction obstruction. Five patients (4%) developed febrile UTIs during follow-up.
 
Other smaller case series have also evaluated bulking agents as a treatment of VUR in patients with duplicated ureters. For example, Molitierno and colleagues included 52 children with duplex ureters who had VUR grade II-V (Molitierno, 2008). Overall, VUR was cured in 44 of 52 patients (85%) after 1 or 2 treatments with Dx/HA. Moreover, Lackgren and colleagues evaluated 68 children with duplex ureters and VUR (Lackgren, 2003). Forty-three children (63%) had a positive response to treatment, defined as having their reflux resolve to grade 0 or I. There were no complications associated with treatment. Seventeen (25%) children required open surgery.
 
2014 Update
 
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2014 RCT by Moore and Bolduc in Canada randomized 275 children (median age: 50 months) with Grade I-V VUR to endoscopic treatment with Macroplastique or Deflux (Moore, 2014). Unlike previous trials, the study included patients with Grade 1 VUR (9% of ureters) as well as higher-grade disease; results were not stratified by VUR grade. Previous endoscopic treatment of VUR was an exclusion criterion but previous use of antibiotics was not reported. Three months after a single injection of bulking agents, VUR was corrected in104 (85%) of 122 patients in the Macroplastique group and 101 (76%) of 133 patients in the Deflux group. As in the Kim et al study, the difference between groups was statistically significant, favoring Macroplastique (p<0.05).
 
2015 Update
A literature search conducted using the MEDLINE database through September 2015 did not reveal any new information that would prompt a change in the coverage statement.   
 
2017 Update
A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
52327Cystourethroscopy (including ureteral catheterization); with subureteric injection of implant material
L8603Injectable bulking agent, collagen implant, urinary tract, 2.5 ml syringe, includes shipping and necessary supplies
L8604Injectable bulking agent, dextranomer/hyaluronic acid copolymer implant, urinary tract, 1 ml, includes shipping and necessary supplies
L8606Injectable bulking agent, synthetic implant, urinary tract, 1 ml syringe, includes shipping and necessary supplies

References: Arant BS.(1992) Medical management of mild and moderate vesicoureteral reflux: follow up studies of infants and young children. A preliminary report of the Southwest Pediatic Nephrology Study Group. J Urol, 1992; 148(5 pt 2):1683-7.

Ashley R, Vandersteen D.(2008) Outcome analysis of mini-ureteroneocystostomy versus dextranomer/hyaluronic acid copolymer injection for unilateral vesicoureteral reflux. J Urol 2008; 180(4 suppl):1611-4.

Brandstrom P, Esbjorner E, Herthelius M et al.(2010) The Swedish Reflux Trial in children: I. Study design and study population characteristics. J Urol 2010 184(1):274-9.

Brandstrom P, Neveus T, Sixt R et al.(2010) The Swedish reflux trial in children: IV. Renal damage. J Urol. 2010; 184(1):292-7.

Capozza N, Caione P.(2002) Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr, 2002; 140:230-4.

Capozza N, Lais A, et al.(2004) The role of endoscopic treatment of vesicoureteral reflux. J Urol, 2004; 172 (4 pt 2):1626-9.

Cerwinka WH, Scherz HC, Kirsch AJ.(2007) Endoscopic treatment of vesicoureteral reflux associated with paraureteral diverticula in children. J Urol 2007; 178(4 pt 1):1469-73.

Cooper CS.(2009) Diagnosis and management of vesicoureteral reflux in children. Nat Rev Urol 2009; 6(9):481-9.

Dawrant MJ, Mohanan N, Puri P.(2006) Endoscopic treatment for high grade vesicoureteral reflux in infants. J Urol 2006; 176(4 pt 2):1847-50.

Dwyer ME, Husmann DA, Rathbun SR et al.(2013) Febrile urinary tract infections after ureteroneocystostomy and subureteral injection of dextranomer/hyaluronic acid for vesicoureteral reflux--do choice of procedure and success matter? J Urol 2013; 189(1):275-82.

Elder JS, Diaz M, Caldamone AA, et al.(2006) Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175(2):716-22.

Elder JS, Peters CA, et al.(1997) Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol, 1997; 157:1846-51.

Garcia-Aparicio L, Rovira J, Blazquez-Gomez E et al.(2013) Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen's ureteral reimplantation for vesicoureteral reflux: long-term results. J Pediatr Urol 2013; 9(4):483-7.

Garin EH, Orta-Sibu N, Campos A.(2002) Primary vesicoureteral reflux in childhood. Adv Pediatr, 2002; 49:341-57.

Hayn MH, Smaldone MC, Ost MC et al.(2008) Minimally invasive treatment of vesicoureteral reflux. Urol Clin North Am 2008; 35(3):477-88.

Hodson EM, Wheeler DM, Vimalchandra D et al.(2007) Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2007; (3):CD001532.

Holmdahl G, Brandstrom P, Lackgren G et al.(2010) The Swedish Reflux Trial in children: II. Vesicoureteral reflux outcome. J Urol 2010; 184(1):280-5.

Hunziker M, Mohanan N, Puri P.(2013) Dextranomer/hyaluronic acid endoscopic injection is effective in the treatment of intermediate and high grade vesicoureteral reflux in patients with complete duplex systems. J Urol 2013; 189(5):1876-81.

J Urol 2010; 184(1):286-91.(2010) The Swedish reflux trial in children: III. Urinary tract infection pattern. Brandstrom P, Esbjorner E, Herthelius M et al.

Jodal U, Smellie JM, et al.(2006) Ten-year results of randomized treatment of children with severe vesicoureteral reflux. Final report of the International Reflux Study in Children. Pediatr Nephrol, 2006; 21:785-92.

Keating MA.(2005) Role of periureteral injections in children with vesicoureteral reflux. Curr Opin Urol, 2005; 15:369-73.

Lackgren G, Wahlin N, Skoldenberg E et al.(2003) Endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is effective in either double ureters or a small kidney. J Urol 2003; 170(4 Pt 2):1551-5; discussion 55.

Lackgren G, Wahlin N, Skoldenberg E, et al.(2001) Long-term follow-up of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2001; 166(5):1887-92.

Lavelle MT, Conlin MJ, Skoog SJ.(2005) Subureteral injection of Deflux for correction of reflux: analysis of factors predicting success. Urol, 2005; 65:564-7.

Lee EK, Gatti JM, DeMarco RT et al.(2009) Long-term followup of dextranomer/hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. J Urol 2009; 181(4):1869-75.

McMillan ZM, Austin JC, Knudson MJ et al.(2006) Bladder volume at onset of reflux on initial cystogram predicts spontaneous resolution. J Urol 2006; 176(4 pt 2):1838-41.

Menezes MN, Puri P.(2007) The role of endoscopic treatment in the management of grade V primary vesicoureteral reflux. Eur Urol 2007; 52(5):1505-9.

Mevorach RA, Hulbert WC, Rabinowitz R, et al.(2006) Results of a 2-year multicenter trial of endoscopic treatment of vesicoureteral reflux with synthetic calcium hydroxyapatite. J Urol 2006; 175(1):288-91.

Molitierno JA, Jr., Scherz HC, Kirsch AJ.(2008) Endoscopic injection of dextranomer hyaluronic acid copolymer for the treatment of vesicoureteral reflux in duplex ureters. J Pediatr Urol 2008; 4(5):372-6.

Moore K, Bolduc S.(2014) Prospective Study of Polydimethylsiloxane vs Dextranomer/Hyaluronic Acid Injection for Treatment of Vesicoureteral Reflux J Urol. Jun 10 2014. PMID 24928269

Nagler EVT, Williams G, Hodson EM et al.(2011) nterventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2011; (6):CD001532.

Oswald J, Riccabona M, et al.(2002) Prospective comparison and 1-year follow-up of a single endoscopic subureteral polydimethylsiloxane versus dextranomer/hyaluronic acid copolymer injection for treatment of vesicoureteral reflux in children. Urol, 2002; 60:894-8.

Peters CA, Skoog SJ, Arant BS et al.(2010) Summary of the AUA guidelines on the management of primary vesicoureteral reflux in children. J Urol 2010; 184(3):1134-44.

Puri P, Pirker M, Mohanan N et al.(2006) Subureteral dextranomer/hyaluronic acid injection as first line treatment in the management of high grade vesicoureteral reflux. J Urol 2006; 176(4 pt 2):1856-9.

Routh JC, Inman BA, Reinberg Y.(2010) Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics 2010; 125(5):1010-9.

Smellie JM, Poulton A, Prescod NP.(1994) Retrospective study of children with renal scarring associated with reflux and urinary retention. Br Med J, 1994; 308:1193-6.

Tamminen-Mobus T, Brunier E, et al.(1992) Cessation of vesicoureteral reflux for 5 years in infants and children allocated to medical treatment. The International Reflux Study in Children. J Urol, 1992; 148(5 pt 2):1662-6.

Vandersteen DR, Routh JC, Kirsch AJ, et al.(2006) Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. J Urol 2006; 176(4 pt 1):1593-5.

Wheeler DM, Vimalachandra D, et al.(2004) Interventions for primary vesicoureteric reflux. The Cochrane Database Syst Rev, 2004;3:CD001532.


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