Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder upward toward the kidney, and is most commonly seen in children. The primary management strategies have been use of 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.

Treatment of vesicoureteral reflux (VUR) is based on the assumptions 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 30-40 years. (1)

In most cases, VUR is diagnosed during evaluation of urinary tract infections. About one third of children with UTIs are found to have VUR. (2) 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, and less severe reflux (i.e. grade I and II) is associated with higher rates of spontaneous resolution and treatment success. (3, 4) Other factors that have been 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 urinary tract infection. (1)

Treatment strategies for VUR 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. (3, 4) The decision to administer prophylactic antibiotic treatment includes the consideration of 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 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 which 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 (6), so many children may not benefit from treatment. 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.

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 (subureteral 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.” Tegress was voluntarily withdrawn from the market by CR Bard as of January 31, 2007.

Related Policies:

7.01.19 Periurethral Bulking Agents for the Treatment of Incontinence

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 considered investigational.

The use of bulking agents is contraindicated in patients with non-functioning kidney(s), hutch diverticuli, duplicated ureters, active voiding dysfunction, and ongoing urinary tract infection.

Coding Issues:

CPT code 52327 would apply to the use of any bulking agent, including Deflux, to treat VUR:

52327: Cystourethroscopy (including ureteral catheterization); with subureteric injection of implant material.

Effective 1/1/09, there is a specific HCPCS code for Deflux:

L8604: Injectable bulking agent, dextranomer/hyaluronic acid copolymer implant, urinary tract, 1 ml, includes shipping and necessary supplies

Prior to 2009, HCPCS Code L8606 was sometimes used to describe the use of Deflux; however, the code was not a perfect match, since Deflux is a copolymer that includes some non-synthetic material. HCPCS code L8606 was created for totally synthetic bulking agents (i.e., Macroplastique), while HCPCS code L8603 describes the use of collagen. These codes were originally designed to address the use of bulking agents as a treatment of urinary incontinence.

L8603: Injectable bulking agent, collagen implant, urinary tract, 2.5-ml syringe, includes shipping and necessary supplies.

L8606: Injectable bulking agents, synthetic implant, urinary tract, 1-ml syringe, includes shipping and necessary supplies.

Bilateral treatment of VUR is typical, therefore, each of the above codes could be used twice.

BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDA-approved devices may be assessed on the basis of their medical necessity.

Treatment of vesicoureteral reflux (VUR) with periuretral bulking agents is proposed as: 1) an alternative to other types of surgery for patients with high-grade VUR (predominantly grades IIII-IV) who have failed or are non-compliant with prophylactic antibiotics; and 2) an alternative to prophylactic antibiotics for patients with lower grade or high-grade VUR. Appropriate outcomes for the comparison of bulking agents and other types of surgery are resolution of reflux and reduction in the rate of urinary tract infections and pyelonephritis. Since prophylactic antibiotic use does not treat the underlying reflux, reduction in the rate of UTIs and pyelonephritis are reasonable outcomes for studies comparing antibiotics and bulking agents. Differences in morbidity are also important outcomes for both proposed uses.

An initial literature search was performed in 2005. The policy was updated regularly with a literature review using MEDLINE; most recently, the literature was searched through August 2009. Following is a summary of literature to date on use of periureteral bulking agents to treat VUR.

The Cochrane library conducted a review of randomized controlled trials on treatments for VUR. The review was available at the time the policy was developed, and it was updated in 2007. (7) The Cochrane review had limited ability to evaluate the efficacy of bulking agents, however, because the primary analysis combined studies on open surgery and bulking agents into the category of ‘surgical intervention’. The review is useful for examining the assumption that VUR increases the risk of complications. Overall, the authors concluded that no significant differences in the risk of UTI or renal parenchymal injury were found in a meta-analysis of 7 trials with 847 evaluable patients comparing antibiotic prophylaxis to combined surgery (open and bulking agents) 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. 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.
The Cochrane review identified 2 trials on dextranomer/hyaluronic acid copolymer (Deflux), and did not pool estimates of these trials. The individual trials are reviewed below:

Capozza and colleagues reported on the results of a study of 61 children 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). (8) The 2001 approval by the U.S. Food and Drug Administration (FDA) 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 at month 12, 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. (9) 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.

Additional Studies

Since the 2007 Cochrane report, no additional randomized studies have been reported. 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. (10) 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.

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. (11). 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. (12,13) One of the larger case series was by a European group and reported on 692 children (1,101 ureters) treated with the STING procedure. (14) 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). (15) 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. (14, 16) 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. (17) 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. (18) In comparison, an average 2% (range of 0% to 9%) ureteral obstruction and reoperation rate has been reported following ureteral reimplantation. (19)

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. (20) 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.

References:

1. Cooper CS. Diagnosis and management of vesicoureteral reflux in children. Nat Rev Urol 2009; 6(9):481-9.
2. Smellie JM, Poulton A, Prescod NP. Retrospective study of children with renal scarring associated with reflux and urinary infection. Br Med J 1994; 308(6938):1193-6.
3. Arant BS. Medical management of mild and moderate vesicoureteral reflux: follow up studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study Group. J Urol 1992; 148(5 pt 2):1683-7.
4. Tamminen-Mobius T, Brunier E, Ebel KD et al. 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.
5. Hayn MH, Smaldone MC, Ost MC et al. Minimally invasive treatment of vesicoureteral reflux. Urol Clin North Am 2008; 35(3):477-88.
6. McMillan ZM, Austin JC, Knudson MJ et al. Bladder volume at onset of reflux on initial cystogram predicts spontaneous resolution. J Urol 2006; 176(4 pt 2):1838-41.
7. Hodson EM, Wheeler DM, Vimalchandra D et al. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2007; (3):CD001532.
8. Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr 2002; 140(2):230-4.
9. 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 2002; 60(5):894-8.
10. Elder JS, Diaz M, Caldamone AA et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175(2):716-22.
11. Ashley R, Vandersteen D. Outcome analysis of mini-ureteroneocystostomy versus dextranomer/hyaluronic acid copolymer injection for unilateral vesicoureteral reflux. J Urol 2008; 180(4 suppl):1611-4.
12. Lavelle MT, Conlin MJ, Skoog SJ. Subureteral injection of Deflux for correction of reflux: analysis of factors predicting success. Urology 2005; 65(3):564-7.
13. Capozza N, Lais A, Nappo S et al. The role of endoscopic treatment of vesicoureteral reflux: a 17-year experience. J Urol 2004; 172(4 pt 2):1626-9.
14. Puri P, Pirker M, Mohanan N et al. 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.
15. Dawrant MJ, Mohanan N, Puri P. Endoscopic treatment for high grade vesicoureteral reflux in infants. J Urol 2006; 176(4 pt 2):1847-50.
16. Lackgren G, Wahlin N, Skoldenberg E et al. Long-term follow-up of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2001; 166(5):1887-92.
17. Lee EK, Gatti JM, DeMarco RT et al. Long-term followup of dextranomer/hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. J Urol 2009; 181(4):1869-75.
18. Vandersteen DR, Routh JC, Kirsch AJ et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. J Urol 2006; 176(4 pt 1):1593-5.
19. 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 1997: 157(5):1846-51.
20. American Urological Association. Policy statement: Use of Deflux® in the management of vesicoureteral reflux. October 2007. Accessible at:
    http://www.auanet.org/content/guidelines-and-quality-care/policy-statements/u/use-of-deflux-in-the-management-of-vesicoureteral-reflux.cfm.

Deflux
Vesicoureteral Reflux, Bulking Agents
VUR