Periureteral Bulking Agents for the Treatment of Vesicoureteral Reflux (VUR) - CAM 701102

Description
Most commonly seen in children, vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder upward toward the kidney. The primary management strategies have been prophylactic antibiotics to reduce urinary tract infections and, for higher grade disease, surgical correction of the underlying reflux. Injection of periureteral bulking agents is proposed as an alternative to surgical intervention.

For individuals who have VUR who have failed medical therapy and are eligible for surgery who receive endoscopic treatment with periureteral bulking agents, the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are symptoms, morbid events, and treatment-related morbidity. Overall, studies have reported similar rates of reflux resolution compared with ureteral reimplantation surgery and the body of evidence would suggest that morbidity rates are similar or lower with bulking agents. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have VUR who have not failed medical therapy and may be ineligible for surgery who receive endoscopic treatment with periureteral bulking agents, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, and treatment-related morbidity. The RCTs, which had relatively small sample sizes in each arm, compared periureteral bulking agents with antibiotic prophylaxis and/or surveillance only and reported mixed findings. Additional, larger studies are needed before conclusions can be drawn about the efficacy of periureteral bulking agents as first-line treatment for patients with VUR. The evidence is insufficient to determine the effects of the technology on health outcomes. 

BACKGROUND
VESICOURETERAL REFLUX
Treatment of vesicoureteral reflux (VUR) is based on the assumption that VUR predisposes patients to urinary tract infections (UTIs) and 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 period between first renal scarring from pyelonephritis and the development of hypertension or end-stage renal disease can be 30 to 40 years.1 

Diagnosis
In most cases, VUR is diagnosed during evaluation of UTIs. Approximately one third of children with UTIs are found to have VUR.2 The average age for UTI onset is 2 to 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 criterion 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, and less severe reflux (ie, grade I and II) is associated with higher rates of spontaneous resolution and treatment success.3,4 Other factors found to be associated with the likelihood of spontaneous resolution of VUR and/or renal injury include age, sex, laterality, presence of renal scars, presence of voiding dysfunction, and history of UTI.

Treatment
Treatment strategies for VUR include bladder training, antibiotic prophylaxis, and surgical modification of the ureter to correct the underlying reflux. VUR is likely to resolve spontaneously over 1 to 5 years; lower grades of reflux (i.e., grades I and II) are associated with a higher probability of spontaneous resolution.3,4 The decision to administer prophylactic antibiotic treatment includes consideration of potential adverse events 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 ureter. Success rates for open surgery are reported to be greater than 95% and nearly 100% for patients with lower grades of reflux. In recent years, there have been advances in surgical technique, including use of a lower abdominal transverse incision that leaves a smaller scar. Combined with a reduction in the use of ureteral stents and prolonged catheterization, the changes have led to shorter hospital stays and reduced surgery-related morbidity. Moreover, surgeries can now be done on an outpatient basis. Surgery, however, still involves risks associated with anesthesia and potential complications, such as ureteral obstruction, infection, and bleeding.1 Some centers have reported using laparoscopic antireflux surgery, but this is technically difficult and has not become widespread. Robotic-assisted laparoscopic methods are being developed to overcome some of the technical difficulties.5 

Treatment of VUR remains controversial. There is a lack of good evidence that VUR actually increases the risk of pyelonephritis and renal scarring, and the long period of time before renal scarring, hypertension, and end-stage renal disease makes these serious conditions difficult to study. Moreover, VUR has a relatively high rate of spontaneous resolution, more than 60% over 5 years, so many children may not benefit from treatment.6 An important challenge is to identify the subset of children most likely to benefit from VUR treatment. At present, in the absence of definitive answers on the utility of treating VUR or the best treatment option, antibiotic prophylaxis to prevent recurrent UTIs and surgery to treat the underlying reflux remain accepted management strategies. 

Bulking Agents
The use of bulking agents in the treatment of VUR has been reported for more than 20 years and has been suggested as an alternative to antibiotic and surgical therapy. Bulking agents can be injected into tissue around the ureteral orifices to minimize reflux. The STING procedure (subureteral transurethral 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® [Allergan, Coolock, Ireland; note: this product is no longer commercially available], Zyderm®, Zyplast® [Caollagen Corp., Palo Alto, CA]), polytetrafluoroethylene paste (Teflon), polydimethylsiloxane (Macroplastique® [Cogentix Medical, Minnetonka, MN]), calcium hydroxyapatite (Coaptite®), dextranomer/hyaluronic acid copolymer (Deflux® or Dx/HA), and polyacrylamide hydrogel (Bulkamid® [Contura International A/S]).

Adverse Events
According to case series data, injection of periureteral bulking agents is associated with low morbidity rates. 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.7 In comparison, on average, a 2% (range, 0%-9%) ureteral obstruction and reoperation rate has been reported following ureteral reimplantation.8 A large series published by Puri et al. (2012) retrospectively reported on 1551 children injected with Dx/HA for high-grade VUR.9 The only reported procedure-related complication was hematuria lasting up to 12 hours in 3 patients. There was no evidence of delayed vesicoureteral junction obstruction. Febrile UTIs occurred in 69 (5%) patients during follow-up; median follow-up was 5.6 years. Dwyer et al. (2013) compared the rate of febrile UTIs in 2 cohorts of patients with VUR.10 The incidence of febrile UTI did not differ significantly between patients who had ureter reimplantation (8% [16/210 cases]) and those who had endoscopic injections of Dx/HA (4% [4/106 patients]) (p=0.24).

Regulatory Status
In 2001, Deflux® was approved by the U.S. Food and Drug Administration (FDA) through the premarket application process for the “treatment of children with vesicoureteral reflux (VUR) grades II-IV.” Contraindications include patients with nonfunctioning kidney(s), active voiding dysfunction, and ongoing UTI. Duplicated ureters were initially considered a contraindication to Deflux® treatment, but this was changed to a precaution in 2007.

Note: Polytetrafluoroethylene may migrate, causing serious adverse events; this agent is not FDA- approved. Coaptite® (Merz Aesthetics), Macroplastique® (Cogentix Medical), and Tegress™ (CR Bard) are categorized by FDA as “Agent, Bulking, Injectable for Gastro-Urology Use.” Tegress™ was voluntarily withdrawn from the market by CR Bard in January 2007.

FDA product code: LNM.

Related Policies
70119  Periuretheral Bulking Agents for the Treatment of Urinary Incontinence

Policy:
Periureteral bulking agents may be considered MEDICALLY NECESSARY as a treatment of vesicoureteral reflux grades II-IV when medical therapy has failed and surgical intervention is otherwise indicated.

The use of bulking agents as a treatment of vesicoureteral reflux in other clinical situations is investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines  
The use of bulking agents is contraindicated in patients with nonfunctioning kidney(s), Hutch diverticuli, active voiding dysfunction, and ongoing urinary tract infection.

Coding
Please see the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Efficacy of Bulking Agents for Vesicoureteral Reflux
Treatment of vesicoureteral reflux (VUR) with periurethral bulking agents is proposed for 2 indications: (1) an alternative to other types of surgery for patients with high-grade VUR (predominantly grades III and IV) who have failed or are noncompliant with prophylactic antibiotics; and (2) an alternative to prophylactic antibiotics for patients with low-grade or high-grade VUR (ie, those who have not failed medical treatment and may be ineligible for surgery).

Clinical Context and Therapy Purpose
The purpose of endoscopic treatment with periureteral bulking agents in patients with VUR who have either failed medical therapy and are eligible for surgery or not failed medical therapy and may be ineligible for surgery is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of endoscopic treatment with periureteral bulking agents improve the net health outcome in patients with VUR who may or may not have failed medical therapy and, consequently, are eligible or ineligible for surgery?

The following PICO was used to select literature to inform this review.

Populations
The relevant populations of interest are patients with VUR who have either failed medical therapy and are eligible for surgery or have not failed medical therapy and may be ineligible for surgery. Primary VUR is the most common type of VUR and occurs as a result of a congenitally incompetent ureterovesical junction. Children younger than 2 years of age, white ethnicity, and female sex are risk factors for VUR. Children with partial or complete duplicated ureters are also at an increased risk of VUR.

Interventions
The therapy being considered is endoscopic treatment with periureteral bulking agents.

Comparators
The following therapies and practices are currently being used to make decisions about VUR: ureteral reimplantation surgery for patients who have either failed medical therapy and are eligible for surgery or antibiotic prophylaxis, ureteral reimplantation surgery, and surveillance only for those who have not failed medical therapy and may be ineligible for surgery.

Outcomes
The general outcomes of interest are a reduction in urinary tract infections (UTIs), reduction in the incidence of pyelonephritis, and treatment-related adverse events.

Appropriate outcomes for the comparison of bulking agents and other types of surgery are the resolution of reflux and reduction in the rate of UTIs and pyelonephritis. Because prophylactic antibiotic use does not treat the underlying reflux, reduction in the rate of UTIs and pyelonephritis are reasonable outcomes for studies comparing antibiotics with bulking agents. Differences in morbidity are also important outcomes for both proposed uses. Bulking agents may or may not be curative, and follow-up injection may be necessary within 6 months. Beneficial effects may last between 3 and 12 months.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A Cochrane review by Williams et al. (2019) included RCTs evaluating treatments for VUR.18 Reviewers addressed a variety of interventions including long-term antibiotic prophylaxis, open surgery, and the use of bulking agents. The reviewers' decision to combine studies on open surgery and bulking agents limited the ability to analyze the efficacy of bulking agents. This Cochrane review selected 34 trials (N=4001 children). Four studies compared endoscopic injection with antibiotics alone and 3 studies assessed the outcome of febrile UTI. There was little or no difference in the risk of febrile UTI with endoscopic injection as compared to antibiotic therapy (relative risk [RR], 0.74; 95% CI, 0.31 to 1.78; low certainty evidence). Four studies comparing 2 different materials for endoscopic injection (n=425 children) reported VUR resolution rates and the 2 studies that compared Macroplastique to Deflux found Macroplastique to be probably superior to Deflux (3 months: RR, 0.50; 95% CI, 0.33 to 0.78; 12 months: RR, 0.54; 95% CI, 0.35 to 0.83; low certainty evidence).

In a systematic review and network meta-analysis, Mina-Riascos et al. (2021) evaluated the effectiveness and safety of endoscopic management versus ureteral reimplantation in pediatric patients (1 month to 15 years of age) with primary high-grade VUR.19 The authors evaluated clinical experiments, quasi-experiments, and cohort studies for this review; bulking agents used in the studies included polytetrafluoroethylene, hyaluronic acid, collagen, dextranomer/hyaluronic acid (Dx/HA), and polyacrylate-polyalcohol copolymer. Overall 9 studies met the inclusion criteria - 7 observational and 2 clinical experiments. The primary outcome was the occurrence of post-treatment UTI. When comparing endoscopic management (Dx/HA and polyacrylate-polyalcohol copolymer) to ureteral reimplantation, no significant differences were found in mixed comparisons. Only 3 studies assessed complications with no statistically significant differences observed. Limitations of this systematic review include a lack of stratification by grade and patient age. Only 3 studies reported UTI diagnostic criteria, which may potentially lead to information bias.

A systematic review by Routh et al. (2010) identified randomized trials and observational studies evaluating Dx/HA copolymer treatment for pediatric VUR.20 A total of 47 studies, mainly retrospective case series, met eligibility criteria. A key inclusion criterion 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 I VUR. Of 7303 ureters injected with Dx/HA, 5,633 (77%) were considered treatment successes. There were higher rates of success in children with low-grade reflux than in those with high-grade reflux. For example, the 164 children whose preoperative VUR was grade I had an 89% success rate compared with a 59% success rate among the 1,109 children with initial grade IV VUR.

Randomized Controlled Trials
Periureteral Bulking Agents versus Surgery
The first RCT comparing periureteral bulking agents with UR was published by Garcia-Aparicio et al. (2013). The authors randomized 41 children older than 1 year of age with VUR grades I to IV to endoscopic treatment with Dx/HA (n=22) or ureteral reimplantation (n=19).21 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. Thirty-five refluxing ureters were treated with bulking agents, and 32 refluxing ureters were treated with ureteral reimplantation. One year after treatment, 32 (91.4%) of 35 ureters in the Dx/HA group and 32 (100%) of 32 ureters in the surgical reimplantation group were cured; the difference between groups was not statistically significant (p=.23). Findings were similar at final follow-up. At 5 years, 30 (85.7%) of 35 ureters in the Dx/HA group and 100% in the ureteral reimplantation group were free of VUR (p=.48). One patient in the Dx/HA group and 2 patients in the ureteral reimplantation group experienced treatment complications. Two patients in the Dx/HA group and none in the ureteral reimplantation group experienced fevers posttreatment. Rates of complications and adverse events did not differ significantly between groups. Trial results supported a finding of no large differences between the 2 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.

Salih et al. (2021) randomly assigned 60 pediatric patients older than 1 year of age with primary VUR grades III and IV to endoscopic injection of Dx/HA (n=30) or extravesical ureteral reimplantation utilizing an open Lich-Gregoir technique (n=30).22 Indications for the intervention included recurrent UTI, impairment of renal function due to reflux, persistence of reflux after continuous antibiotic prophylaxis, and renal scarring, with the majority of cases operated on for breakthrough infections. Endoscopic Dx/HA was performed in 45 refluxing ureters and open ureteral reimplantation was conducted in 48 refluxing ureters. The mean follow-up for all patients was 17.7 ± 7.1 months. Overall reflux resolution was 80% (36/45) of the ureters in the Dx/HA group after a single injection and 93.75% (45/48) of the ureters in the ureteral reimplantation group (p=.007). Endoscopic injection failed in 9 ureters; therefore, another Dx/HA injection was given with improvement in 4 cases. The failed 5 cases after the second injection underwent salvage ureteral reimplantation. The mean operative time was longer for the ureteral reimplantation group versus the endoscopic group (110.3 ± 18.9 minutes vs. 28.6 ± 7.4 minutes; p<.001) and the median hospital stay was significantly shorter in the endoscopic injection group (1 vs. 4 days; p<.001). Trial results supported a finding of an increased success rate with ureteral reimplantation in comparison to endoscopic injection of Dx/HA; however, the minimally invasive endoscopic injection was superior in terms of operative time and hospital stay.

Periureteral Bulking Agents versus Antibiotic Prophylaxis
Findings from the Swedish Reflux Trial in children were published by Brandstrom et al. (2010).23-26 This nonblinded multicenter study included 203 children (128 girls, 75 boys) between the ages of 1 and 2 years with grade II, III, or IV reflux. Participants were not required to have failed antibiotic prophylaxis; thus, the trial evaluated injection of a bulking agent as an alternative to antibiotic therapy. Most participants (194 [96%]) were identified after a symptomatic UTI. Recruitment was more difficult than expected, and enrollment was stopped after 6 years. Participants were randomized to 1 of 3 groups: antibiotic prophylaxis (n=69), endoscopic treatment with Deflux (n=66), or surveillance only (n=68).

The trial aimed to simulate clinical practice (ie, 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 randomized to endoscopy received treatment. Fourteen of 19 patients with ongoing dilating VUR after 1 injection received a second injection; 2 patients received a third injection. Complications occurred in 6 (9%) of the 64 individuals who received endoscopic treatment. Overall, 187 (92%) participants completed at least 6 of the 8 follow-up visits; analysis was intention to treat. Two-year cystourethrography was done in 185 (91%) of the 203 patients. Voiding cystourethrography findings indicated that VUR had resolved in 9 (13%) of 68 patients in the prophylaxis group, in 20 (38%) of 52 in the endoscopy group, and in 10 (15%) of 65 in the surveillance group. The proportion of patients in the 3 groups whose VUR was downgraded to grade I or II was 18 (26%) of 68, 17 (33%) of 52, and 21 (32%) of 65, respectively. There was a significantly greater proportion of patients whose VUR had resolved or had been downgraded in the endoscopy group than in the prophylaxis (p<.001) and the surveillance groups (p=.003). Thirteen (20%) of the 66 patients randomized to endoscopy whose VUR had initially resolved or been downgraded experienced recurrences and had stage III or IV VUR at 2 years.

Febrile UTI rates by treatment group in girls were 8 (19%) of 43, 10 (23%) of 43, and 24 (57%) of 42, respectively, in the prophylaxis, endoscopic, and surveillance groups. Rates were significantly higher in the surveillance group than either the prophylaxis group (p=.002) or the endoscopic group (p=.14); rates did not differ significantly between the prophylaxis and endoscopic groups. Rates of febrile UTI recurrence during follow-up were dramatically higher in girls (42/128 [33%]) than in boys (7/75 [9%]). The rate of new renal damage did not differ significantly among groups.

After stratifying findings by sex, the sample sizes in reported analyses were relatively small. For this reason, the study might have been insufficiently powered to evaluate some of the outcomes of interest (e.g., kidney damage, febrile UTIs). Moreover, findings might not be applicable to children outside of the restricted age range evaluated or to those with lower grade VUR. Larger studies with a more representative sample of children with VUR are needed to evaluate the effectiveness of this treatment further.

Capozza and Caione (2002) reported on the results of 61 children with VUR (grades II-IV) who were randomized to an endoscopic subureteral implantation (n=40) of Deflux or 12 months of antibiotic prophylaxis (n=21).27 Entry criteria included grades II, III, or IV reflux present for at least 6 months. The antibiotic therapy was not specified and presumably varied. 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. Partly due to the small numbers in the antibiotic control group, the distribution of the different grades of VUR differed between groups. Outcomes included improvement in reflux grade and measures of renal function; incidence of UTIs was not reported. The only statistically significant outcome reported was an improvement in reflux grade at month 12, with 69% of those in the Deflux group reporting a reflux grade of I or less compared with only 38% in the antibiotic group. However, these results should not be surprising, because antibiotic therapy 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 than spontaneous resolution.

Comparison Among Bulking Agents
Three RCTs have compared Deflux with Macroplastique for treatment of VUR in children. An early study by Oswald et al. (2002) found similar rates of reflux correction in the 2 groups28; however, more recent RCTs have found higher success rates with Macroplastique than with Deflux.29;30. Studies varied in their eligibility criteria (eg, grade of VUR, previous use of antibiotics).

Moore and Bolduc (2014) randomized 275 children (median age, 50 months) with grade I, II, III, IV, or V VUR to endoscopic treatment with Macroplastique or Deflux.29 Unlike previous trials, the trial included patients with grade I 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 in 104 (85%) of 122 patients in the Macroplastique group and in 101 (76%) of 133 patients in the Deflux group. The difference between groups was statistically significant, favoring Macroplastique (p<.05).

Kim et al. (2011) randomized 85 children ages 2 to 15 years with VUR (grades II-V) to subureteral injections of Macroplastique (n=42) or Deflux (n=43).30 Eligibility included breakthrough UTI and persistent VUR; most patients (exact number not reported) started immediately on antibiotic prophylaxis after diagnosis. Seventy-three (86%) of 85 children were available for the 3-month follow-up. The cure rate, defined as no evidence of reflux, was 69% in the Macroplastique group and 55% in the Deflux group. The difference between groups was statistically significant, favoring Macroplastique (p<.05).

Oswald et al. (2002) randomized 72 children with VUR to Deflux or Macroplastique in addition to antibiotic prophylaxis.28 Eligible children had grade II, III, or IV reflux (International Reflux Study Group grading system). Because all patients continued to receive antibiotic therapy, the bulking procedure would have been primarily considered an alternative to surgical reimplantation of the ureter; however, patient selection criteria do not indicate whether patients had failed prior antibiotic therapy or had unresolved VUR. Three months postinjection, VUR was corrected in 50 (86%) of 58 ureters in the Macroplastique group and in 40 (71%) of 56 ureters in the Deflux group; the difference between groups was not statistically significant. Rates of maintaining reflux correction at 1 year were also similar in both groups.

Bele and colleague (2019) compared Dx/HA and polyacrylate-polyalcohol copolymer for the endoscopic treatment of VUR in 125 patients (89 girls; 36 boys) with grades I-V disease, comprising a total of 174 refluxing ureters.31 Treatment success (defined as complete VUR resolution) was assessed with voiding cystourethrography at 3 and 12 months post-procedure. Results revealed that complete resolution was similar with polyacrylate-polyalcohol copolymer (80%) versus Dx/HA (68.7%) after a single injection (p=.094). An additional injection resulted in healing of another 10 refluxing ureters in the polyacrylate-polyalcohol copolymer group and 16 refluxing ureters in the Dx/HA group. At the 12 month evaluation, the total resolution rate was 94.7% with polyacrylate-polyalcohol copolymer and 87.9% with Dx/HA (p=.125). Limitations included the relatively short 1 year follow-up and the retrospective nature of data collection.

Children With Duplicated Ureters
No controlled studies have been published comparing bulking agents with other treatments in children with duplicated ureters. However, several case series are available, and these uncontrolled studies suggest reasonable response rates without high complication rates in this population. Hunziker et al. (2013) published a case series of 123 children with complete duplex systems who were treated with Dx/HA for grade II, III, IV, or V VUR.32 The mean age of participants was 3 years (range, 1 month to 12 years). Complete duplicated ureters were unilateral in 100 (81%) patients and bilateral in the remaining 13. A total of 136 refluxing ureteral units were treated with endoscopic injections of Dx/HA. Three months after treatment, children were evaluated using voiding cystourethrography and bladder ultrasound. The rate of VUR resolution after 1 injection was 68.4% (93/136 ureters). Vesicoureteral reflux resolved in an additional 35 (25.7%) ureters after a second injection and in the remaining 8 (5.9%) ureters after a third injection. There was 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 (4%) patients developed febrile UTIs during follow-up.

Molitierno et al. (2008) included 52 children with duplex ureters who had grade II, III, IV, or V VUR.33 Overall, VUR was cured in 44 (85%) of 52 patients after 1 or 2 treatments with Dx/HA. Lackgren et al. (2003) evaluated 68 children with duplex ureters and VUR.34 Forty-three (63%) children 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.

Summary of Evidence
For individuals who have VUR who have failed medical therapy and are eligible for surgery who receive endoscopic treatment with periureteral bulking agents, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, morbid events, and treatment-related morbidity. Overall, studies have reported similar rates of reflux resolution compared with ureteral reimplantation surgery and the body of evidence suggests that morbidity rates are similar or lower with bulking agents. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have VUR who have not failed medical therapy and may be ineligible for surgery who receive endoscopic treatment with periureteral bulking agents, the evidence includes RCTs. Relevant outcomes are symptoms, morbid events, and treatment-related morbidity. The RCTs, which had relatively small sample sizes in each arm, compared periureteral bulking agents with antibiotic prophylaxis and/or surveillance only and reported mixed findings. Additional, larger studies are needed before conclusions can be drawn about the efficacy of periureteral bulking agents as first-line treatment for patients with VUR. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Urological Association
In 2017, the American Urological Association reviewed and confirmed the validity of its 2010 published guideline on the management of primary VUR in children.35 The Association recommended that patients older than 1 year of age who have a febrile breakthrough urinary tract infection while receiving continuous antibiotic prophylaxis be considered for 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 its authors acknowledged the lack of robust randomized controlled trial data.

U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has not addressed the use of injectable bulking agents to treat VUR.

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov did not reveal any relevant ongoing clinical trials as of June 29, 2021.

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  11. Starmer B, McAndrew F, Corbett H. A review of novel STING bulking agents. J Pediatr Urol. Oct 2019; 15(5): 484-490. PMID 31591047
  12. Vandersteen DR, Routh JC, Kirsch AJ, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic Acid copolymer. J Urol. Oct 2006; 176(4 Pt 1): 1593-5. PMID 16952696
  13. Elder JS, Peters CA, Arant BS, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol. May 1997; 157(5): 1846-51. PMID 9112544
  14. Friedmacher F, Puri P. Ureteral Obstruction After Endoscopic Treatment of Vesicoureteral Reflux: Does the Type of Injected Bulking Agent Matter?. Curr Urol Rep. Jul 09 2019; 20(9): 49. PMID 31289951
  15. Puri P, Kutasy B, Colhoun E, et al. Single center experience with endoscopic subureteral dextranomer/hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux. J Urol. Oct 2012; 188(4 Suppl): 1485-9. PMID 22906657
  16. Dwyer ME, Husmann DA, Rathbun SR, et al. 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. Jan 2013; 189(1): 275-82. PMID 23174239
  17. Lightfoot M, Bilgutay AN, Tollin N, et al. Long-Term Clinical Outcomes and Parental Satisfaction After Dextranomer/Hyaluronic Acid (Dx/HA) Injection for Primary Vesicoureteral Reflux. Front Pediatr. 2019; 7: 392. PMID 31612121
  18. Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev. Feb 20 2019; 2: CD001532. PMID 30784039
  19. Mina-Riascos SH, Fernandez N, Garcia-Perdomo HA. Effectiveness and risks of endoscopic management compared to vesicoureteral reimplantation in patients with high-grade vesicoureteral reflux: systematic review and network meta-analysis. Eur J Pediatr. May 2021; 180(5): 1383-1391. PMID 33474581
  20. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics. May 2010; 125(5): 1010-9. PMID 20368325
  21. Garcia-Aparicio L, Rovira J, Blazquez-Gomez E, et al. 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. Aug 2013; 9(4): 483-7. PMID 23602843
  22. Salih EM, Eldamanhory H, Selmy GI, et al. Comparison of Subureteral Endoscopic Injection of Dextranomer/Hyaluronic Acid and Lich-Gregoir Ureteral Reimplantation in the Treatment of Pediatric Primary Vesicoureteral Reflux: A Prospective Randomized Study. J Laparoendosc Adv Surg Tech A. Jun 2021; 31(6): 719-723. PMID 33751917
  23. Brandstrom P, Esbjorner E, Herthelius M, et al. The Swedish reflux trial in children: I. Study design and study population characteristics. J Urol. Jul 2010; 184(1): 274-9. PMID 20478580
  24. Brandstrom P, Esbjorner E, Herthelius M, et al. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol. Jul 2010; 184(1): 286-91. PMID 20488494
  25. Brandstrom P, Neveus T, Sixt R, et al. The Swedish reflux trial in children: IV. Renal damage. J Urol. Jul 2010; 184(1): 292-7. PMID 20494369
  26. Holmdahl G, Brandstrom P, Lackgren G, et al. The Swedish reflux trial in children: II. Vesicoureteral reflux outcome. J Urol. Jul 2010; 184(1): 280-5. PMID 20488469
  27. Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr. Feb 2002; 140(2): 230-4. PMID 11865276
  28. Oswald J, Riccabona M, Lusuardi L, et al. 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. Urology. Nov 2002; 60(5): 894-7; discussion 898. PMID 12429323
  29. Moore K, Bolduc S. Prospective study of polydimethylsiloxane vs dextranomer/hyaluronic acid injection for treatment of vesicoureteral reflux. J Urol. Dec 2014; 192(6): 1794-9. PMID 24928269
  30. Kim SO, Shin BS, Hwang IS, et al. Clinical efficacy and safety in children with vesicoureteral reflux of a single injection of two different bulking agents--polydimethylsiloxane (Macroplastique) or dextranomer/hyaluronic acid copolymer (Deflux): a short-term prospective comparative study. Urol Int. 2011; 87(3): 299-303. PMID 21934268
  31. Bele U, Bratus D. Dextranomer-Hyaluronic Acid and Polyacrylate-Polyalcohol Copolymer are Equally Efficient for Endoscopic Treatment of Vesicoureteral Reflux in Children. Urol J. Aug 18 2019; 16(4): 361-365. PMID 30318569
  32. Hunziker M, Mohanan N, Puri P. 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. May 2013; 189(5): 1876-81. PMID 23159268
  33. Molitierno JA, Scherz HC, Kirsch AJ. Endoscopic injection of dextranomer hyaluronic acid copolymer for the treatment of vesicoureteral reflux in duplex ureters. J Pediatr Urol. Oct 2008; 4(5): 372-6. PMID 18790423
  34. Lackgren G, Wahlin N, Skoldenberg E, et al. Endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is effective in either double ureters or a small kidney. J Urol. Oct 2003; 170(4 Pt 2): 1551-5; discussion 1555. PMID 14501658
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Coding Section

Codes

Number

Description

CPT

52327

Cystourethroscopy (including ureteral catheterization); with subuteric injection of implant material

HCPCS

L8604

Injectable bulking agent, dextranomer/hyaluronic acid copolymer implant, urinary tract, 1 mL, includes shipping and necessary supplies

ICD-10-CM

N11.0

Nonobstructive reflux-associated chronic pyelonephritis

 

N13.70-N13.739

Vesicoureteral-reflux code range

ICD-10-PCS

 

ICD-10-PCS codes are only used for inpatient services.

 

0TV68DZ, 0TV78DZ

Surgical, urinary system, restriction, ureter (right or left), via natural or artificial opening endoscopic, intraluminal device

 

 3E0K8GC

Introduction of other therapeutic substance into genitourinary tract, via natural or artificial opening endoscopic 

Type of Service

 Surgery

 

Place of Service

 Inpatient/Outpatient

 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

 "Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

 History From 2014 Forward     

10/01/2021 

Annual review, no change to policy intent. Updating rationale and references. 

10/01/2020 

Annual review, no change to policy intent. Updating guidelines and coding. 

10/01/2019 

Annual review, updating second policy statement to say: The use of bulking agents as a treatment of vesicoureteral reflux in other clinical situations is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY. Also updating rationale. 

10/10/2018 

Annual review, no change to policy intent. Updating background and rationale. 

10/03/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

10/03/2016 

Annual review, no change to policy intent. 

10/27/2015 

Annual review, no change to policy intent. Updated background, description, rationale and references. 

10/21/2014

Annual review.  No change to policy intent. Updated description, regulatory status, rationale and references. Added related policiies, coding and policy guidelines.

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