Periureteral Bulking Agents as a Treatment of Vesicoureteral Reflux

POLICY NUMBER

A.7.01.102

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.

Vesicoureteral Reflux

Vesicoureteral reflux (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. Although the exact prevalence of VUR in the general population is unknown, a meta-analysis of more than 250 articles revealed its occurrence in 31.1% of children who were evaluated for a UTI and 17.2% in those with normal kidneys who underwent a voiding cystourethrogram for other indications, such as hydronephrosis.

DiagnosisIn most cases, VUR is diagnosed after a febrile UTI episode or abnormality seen on ultrasound imaging. Approximately one- third of children with UTIs are found to have VUR. 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; therefore, siblings may also be examined.

The criterion standard for diagnosis is voiding cystourethrography, a procedure that involves catheterization of the bladder. According to the 2011 American Academy of Pediatrics guideline on the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months of age (reaffirmed in 2016), voiding cystourethrography should not be performed routinely after the first febrile UTI. Voiding cystourethrography is indicated if renal and bladder ultrasonography reveals hydonephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances. 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. Other factors found to be associated with the likelihood of spontaneous resolution of VUR and/or renal injury include age, sex, laterality, the presence of renal scars, presence of voiding dysfunction, and history of urinary tract infection.

TreatmentTreatment strategiesfor VUR include bladder training, antibiotic prophylaxis, and surgical modification of the ureter to correct the underlying reflux. Vesicoureteral reflux 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. The decision to administer prophylactic antibiotic treatmentincludes consideration of potential adverse events of long-term antibiotic therapy, 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. Advances in surgical technique, including the use of a lower abdominal transverse incision, have led to smaller scars. 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. Some centers have reported using laparoscopic antireflux surgery, but this is technically difficult and not widespread. Robotic-assisted laparoscopic methods are being developed to overcome some of the technical difficulties.

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. 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 AgentsThe use of bulking agents in the treatment of VUR has been reported for over 20 years and is 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 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 coated ureteral tunnel. More recently, the HIT (hydrodistension of the ureteric orifice and injection of bulking agents in the mid to distal submucosal tunnel at the 6 o'clock position) and double HIT (modified HIT with proximal and distal intraluminal submucosal injections) techniques have gained favor; a meta-analysis revealed that overall VUR resolution was 82.5% with HIT as compared to 71.4% with STING (p<.00001). These endoscopic procedures can be performed in an outpatient setting.

A variety of bulking agents have been tested for biocompatibility and absence of migration. Some compounds used in clinical studies are collagen (Contigen® [Allergan, Coolock, note: this product is no longer commercially available]), Zyderm® and Zyplast® [use discontinued due to immune reaction concerns], polytetrafluoroethylene paste (Teflon) [use discontinued due to concerns regarding particle migration], polydimethylsiloxane (Macroplastique®) [use discontinued due to concerns of malignant potential], calcium hydroxyapatite (Coaptite®), dextranomer/hyaluronic acid copolymer (Deflux®, Dexell®, or Dx/HA), polyacrylamide hydrogel (Bulkamid® [Axonics]), and polyacrylate-polyalcohol copolymer (Vantris® [Promedon]).

Adverse EventsAccording 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. In comparison, on average, a 2% (range, 0% to 9%) ureteral obstruction and reoperation rate has been reported following ureteral reimplantation. In 2019, Friedmacher and colleague estimated the incidence of ureteral obstruction following endoscopic injections of various substances (ie, Dx/HA, polyacrylate polyalcohol, poldimethylsiloxane, calcium hydroxyapatite, polytetrafluoroethylene, or collagen) in 25 publications. Results revealed ureteral obstruction to be a rare complication after endoscopic correction of VUR, generally occurring in less than 1% of treated cases independent of the injected substance, volume, and technique.

A large series published by Puri and colleagues retrospectively reported on 1,551 children injected with Dx/HA for high-grade VUR. 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 and colleagues (2013) compared the rate of febrile UTIs in 2 cohorts of patients with VUR. 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=.24). Lightfoot and colleagues (2019) evaluated long-term outcomes after Dx/HA injection for primary VUR in 99 patients (median follow-up: 8.4 years). Results revealed that a secondary surgery was performed in 13 (13.1%) patients, which was most commonly a repeat Dx/HA injection. Only 3 (3%) patients required open or laparoscopic surgery after Dx/HA injection. Additionally, of the 83 (84.7%) patients reporting ≥1 febrile UTIs preoperatively, only 9 (10.8%) reported postoperative occurrence of febrile UTIs.

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” and remains the only FDA-approved bulking agent for VUR. Contraindications include patients with nonfunctioning kidney(s), Hutch diverticulum, ureterocele, active voiding dysfunction, and ongoing urinary tract infection. Duplicated ureters were initially considered a contraindication to Deflux treatment, but this was changed to a precaution in 2007.

POLICY

Periureteral bulking agents may be considered medically necessary as a treatment of vesicoureteral reflux grades II, III, or 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.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

5/8/2008: Policy added.

07/30/2010: Policy description updated regarding new treatment approaches. Medically necessary policy statement revised to add “when medical therapy has failed" and to delete the word “open” before surgical intervention. FEP verbiage added to the Policy Exceptions section. Added definition of investigative services to the policy guidelines. Added bulking agent HCPCS codes L8603, L8604, and L8606.

12/30/2010: Policy reviewed; no changes.

12/01/2011: Policy reviewed; no changes.

12/13/2013: Policy reviewed; no changes to policy statement. Deleted duplicated ureter as a contraindication in the policy guidelines.

12/05/2014: Policy reviewed; description updated. Policy statements unchanged.

08/31/2015: Medical policy revised to add ICD-10 codes.

12/01/2015: Policy description updated regarding bulking agents. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

05/31/2016: Policy number A.7.01.102 added.

09/13/2017: Policy description updated. Policy statements unchanged.

08/23/2018: Policy description updated regarding adverse events associated with the use of bulking agents. Policy statements unchanged.

09/11/2019: Policy reviewed; no changes.

09/10/2020: Policy description updated regarding vesicoureteral reflux, bulking agents, and adverse events. Policy statements unchanged.

12/09/2021: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

10/11/2022: Policy reviewed; no changes.

09/22/2023: Policy description updated regarding bulking agents. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

09/13/2024: Policy reviewed; no changes.

09/18/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross & Blue Shield Association Policy # 7.01.102

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

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