Vesicoureteral Reflux Treatment by Endoscopic Injection of Bulking Agents

Number: 0534

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses vesicoureteral reflux treatment by endoscopic injection of bulking agents.

1. Medical Necessity

   Aetna considers considers endoscopic injection of dextranomer/hyaluronic acid copolymer (Deflux), polydimethylsiloxane (Macroplastique), polytetrafluoroethylene (Teflon), or other bulking agents approved by the U.S. Food and Drug Administration (FDA) for vesicoureteral reflux (VUR) medically necessary for the treatment of members with primary or secondary VUR who have any of the following conditions when conservative treatments (e.g., prophylactic antibiotics and clean intermittent catheterization) have failed:

   1. Children who have had a previously unsuccessful ureteral re-implantation; or
   2. Children who have stopped taking their medication as a result of drug intolerance or parental non-compliance; or
   3. Children whose reflux is associated with a thick-walled neuropathic bladder; or
   4. Deterioration of renal parameters regardless of reflux severity; or
   5. Lower grades of reflux (grades I to III); or
   6. Persistent reflux in post-pubertal female members; or
   7. Recurrent, poorly controlled febrile urinary tract infections; or
   8. Symptomatic VUR after renal transplantation.

   Aetna considers endoscopic injections of bulking agents for VUR experimental and investigational for members who do not meet these criteria because it has insufficient evidence of effectiveness for persons who do not meet these criteria. 

   Note: Members whose condition does not improve after 3 treatment sessions are considered treatment failures and are not likely to respond to this therapy. If the member fails to respond within 3 treatment sessions, further treatments are not considered medically necessary. 

2. Experimental and Investigational

   Aetna considers endoscopic injections experimental and investigational of the following for the treatment of members with primary or secondary VUR (not an all-inclusive list) because the effectiveness of these approaches has not been established:

   1. Autologous blood;
   2. Calcium hydroxyapatite;
   3. Chondrocytes;
   4. Durasphere;
   5. Fat;
   6. Glutaraldehyde cross-linked bovine dermal collagen (Contigen, C.R. Bard, Inc., Murray Hill, NJ; Zyplast, Collagen Corporation, Palo Alto, CA);
   7. Myoblasts;
   8. Polyacrylamide hydrogel (Bulkamid);
   9. Polyacrylate-polyalcohol copolymer (Vantris).

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
52327	Cystourethroscopy (including ureteral catheterization); with subureteric injection of implant material
Other CPT codes related to the CPB:
51715	Endoscopic injection of implant material into the submucosal tissue of the urethra and/or bladder neck
74420	Urography, retrograde, with or without KUB
74450	Urethrocystography, retrograde, radiological supervision and interpretation
74455	Urethrocystography, voiding, radiological supervision and interpretation
78740	Ureteral reflux study (radiopharmaceutical voiding cystogram)
HCPCS codes covered if selection criteria are met:
Polytetrafluoroethylene (Teflon) - no specific code:
L8604	Injectable bulking agent, dextranomer / hyaluronic acid copolymer implant, urinary tract, 1 ml, includes shipping and necessary supplies
L8606	Injectable bulking agent, synthetic implant, urinary tract, 1 ml syringe, includes shipping and necessary supplies
Q3031	Collagen skin test
HCPCS codes not covered for indications listed in the CPB:
Injection, chondrocytes, fat or myoblasts - no specific code:
L8603	Injectable bulking agent, collagen implant, urinary tract, 2.5 ml syringe, includes shipping and necessary supplies
Q2026	Injection, Radiesse, 0.1 ml
ICD-10 codes covered if selection criteria are met:
N13.70 - N13.9	Vesicoureteral-reflux

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Background

Vesico-ureteral reflux (VUR) is predominantly a disorder of childhood and occurs when urine passes backwards from the bladder to the kidneys during micturition.  It is caused by vesico-ureteral sphincter incompetence.  Reflux can predispose patients to urinary tract infections and renal scarring.

Primary VUR is the consequence of a congenital abnormality of the uretero-vesical junction, in which a deficiency of the longitudinal muscle of the intra-vesical ureter leads to an insufficient valvular mechanism.  Secondary VUR is due to bladder obstruction and its resultant increased pressures.  Obstruction of the bladder can be anatomical or functional.  The most common anatomical cause of VUR is posterior urethral valves, which are found in approximately 50 % of VUR-afflicted boys.  On the other hand, anatomical obstructions in females are extremely rare.  Functional causes of VUR are far more common in girls; they include neurogenic bladder, non-neurogenic bladder, and bladder instability or dysfunction.  Urinary tract infections (bladder infections) and accompanying inflammation can contribute to the development of VUR by decreasing bladder compliance, increasing intra-vesical pressures, and by distorting and weakening the uretero-vesical junction.  Approximately 40 % of children with urinary tract infections experience VUR.

Persons who undergo this procedure in the hospital can usually be discharged within 24 hours.  More than 1 day's hospitalization is usually not necessary.

According to the International Classification System of VUR, reflux is graded I to V on the basis of the appearance of contrast in the ureter and upper collecting duct system during voiding cystourethrography:

Table: Reflux Grading

Reflux Grade	Reflux Grade Description
Grade I	Reflux into the non-dilated ureter
Grade II	Reflux into the renal pelvis, and calyces without dilation
Grade III	Mild to moderate dilation of the ureter, renal pelvis, and calyces with minimal blunting of the fornices
Grade IV	Moderate ureteral tortuosity and dilation of the renal pelvis, and calyces
Grade V	Gross dilation of the ureter, renal pelvis, and calyces, loss of papillary impressions, and ureteral tortuosity

Because of the high rate of spontaneous resolution in patients with grade I to III VUR, surgical intervention in these patients is rarely indicated.  For patients with grade IV and V reflux, surgical correction (e.g., open ureteral re-implantation or endoscopic subureteral injection of Teflon) is highly successful.

Endoscopic Teflon therapy for VUR entails injection of polytetrafluoroethylene (Teflon) paste into the submucosa at the refluxing ureteral orifice to bolster it, thus eliminating the problem.  In most patients, endoscopic injection of Teflon is performed on an outpatient basis.  Hospitalization may be necessary if patient experiences hematuria, acute urinary retention, or pelvic pain; 1 or 2 repeat injections may be needed if the initial injection fails to correct reflux.  The long-term safety of endoscopic Teflon injection has not been clearly established.  In particular, the question of whether there is a significant risk of Teflon particle migration remains unanswered.

In a recent study comparing the long-term outcome of the endoscopic correction of VUR of various injected substances, Sugiyama and colleagues (2004) stated that autologous blood is unsuitable for clinical application because of its poor durability; and the overall success rate of endoscopic surgery with glutaraldehyde cross-linked bovine dermal collagen or hyaluronan/dextranomer co-polymer was insufficient compared with surgical re-implantation.  Furthermore, Schlussel (2004) noted that glutaraldehyde cross-linked bovine dermal collagen and hyaluronan/dextranomer copolymer do not have the long-term follow-up of Teflon.

Elder et al (2007) examined the use of endoscopic injection with dextranomer/hyaluronic acid co-polymer (Dx/HA, Deflux) as a curative option and as an alternative to antibiotic prophylaxis.  The nationally representative PharMetrics Integrated Medical and Pharmaceutical database was used to conduct this retrospective analysis.  Patients less than 11 years of age who were continuously eligible and had an International Classification of Diseases (ICD-9-CM) code for VUR were identified.  Resource utilization and outcome measures were evaluated over a 6-month pre- and 12-month post-index period.  Patients diagnosed with neuropathic bladder, posterior urethral valves, bladder exstrophy, ureterocele, or duplication anomaly were excluded.  Patients were matched 3:1, antibiotic prophylaxis to Dx/HA, by age, gender, urinary tract infections (UTIs) prior to index date, and diagnosing physician specialty. The primary outcome assessed was UTIs.  Of the matched patients, 114 received a prescription for antibiotic prophylaxis and 38 underwent endoscopic injection with Dx/HA.  The average number of UTIs per year was 0.28 in the antibiotic cohort and 0.08 in the Dx/HA cohort, respectively.  The incidence rate ratio (IRR) of 4.826 (p = 0.029) revealed that the average number of UTIs was 383 % higher for patients receiving antibiotic prophylaxis compared with patients who underwent endoscopic injection.  The retrospective nature of the analysis did not allow for treatment randomization.  Due to the stringent classification of UTIs, rates of UTIs may be under-estimated in both cohorts.  The authors concluded that treatment with endoscopic injection with Dx/HA resulted in significantly fewer UTIs compared with children receiving antibiotic prophylaxis, supporting a role for Dx/HA as a first-line treatment option for patients with VUR.

Aaronson (2005) noted that open surgery remains the gold standard for the treatment of VUR.  For children with grade-I or grade-II reflux, in whom spontaneous resolution is likely, antibiotic is usually parents' treatment of choice.  On the other hand, for children with grade-IV or grade-V reflux, in which the space available for the bulking agent is very limited, and in cases of duplex ureters, in which there is a prolongation of the upper moiety non-refluxing ureter towards the bladder neck, which limits access to the refluxing orifice, open surgery is the treatment of choice.  For children with grade-III reflux, endoscopic treatment may be considered as a treatment option.  The author also stated that endoscopic treatment should also be considered for children who have had a previously unsuccessful ureteral re-implantation; those whose reflux is associated with a thick-walled neuropathic bladder; those with mild reflux who develop symptomatic break-through infections because of antibiotic resistance; or children who have stopped taking their medication as a result of drug intolerance or parental non-compliance.

Aaronson's observations regarding the use of endoscopic treatment for VUR are in agreement with the findings of other investigators (Stehr et al, 2004; Sugiyama et al, 2004; and Heidenreich et al, 2004).  Stehr et al (2004) stated that ureteral re-implantation is the operative treatment of choice in cases with high-grade VUR.  Alternatively in cases with lower-grade VUR, injection of bulking agents under the refluxive orifice can be performed.  Sugiyama et al (2004) reported that the cure rate of endoscopic surgery with bulking agents could be improved by excluding high-grade VUR from the indications for endoscopic surgery.  Heidenreich et al (2004) stated that the current indications for the surgical correction of VUR depend on the presence or absence of renal scars.  If no scars are present, primary ureteral re-implantation is only indicated in high-grade bilateral VUR, whereas in the presence of renal scars surgical correction is indicated in low/high grade reflux at a young age.  Endoscopic subureteral injections are primarily reserved for low-grade VUR with a 1 session success rate of over 90 %.  Endoscopic subureteral injections appear to be an alternative to long-term antibiotics in grade I-III VUR.

Bae and colleagues (2010) compared cure rates and complications of Deflux and polydimethylsiloxane (Macroplastique) in the treatment of VUR.  A total of 29 boys and 42 girls (total of 115 ureters) with a mean age of 6 years who had undergone endoscopic subureteral transurethral injection for VUR were enrolled.  A single subureteral injection of Macroplastique was performed in 31 ureters in 23 children (group I; grade II: n = 4; grade III: n = 12; grade IV: n = 9; grade V: n = 6), and a single subureteral injection of Deflux was performed in 84 ureters in 48 children (group II; grade II: n = 24; grade III: n = 14; grade IV: n = 25; grade V: n = 21).  Renal ultrasound was done 1 day after injection, and voiding cysto-urethrography (VCUG) was done at 3 months.  Successful reflux correction was defined as absent or grade I reflux on follow-up VCUG.  No significant difference in success rates was observed between group I and group II [80.6 % (25/31) versus 78.6 % (66/84), respectively, p > 0.05].  The following post-operative complications developed: ureteral obstruction in 2 ureters of group I and 3 ureters of group II, asymptomatic urinary tract infection in 3 patients of group I and 2 patients of group II, and bladder calcification by erosion or mucosal necrosis in 2 patients of group I.  The authors concluded that despite differences in material properties, both Deflux and Macroplastique were safe for the treatment of children with VUR.

Aubert (2010) carried out a literature review on the use of Macroplastique in VUR.  A PubMed review of the literature since 1996 resulted in the selection of 24 studies of sufficient level of evidence to assess the effectiveness and tolerance of Macroplastique in the VUR in adults and children.  The overall success rates at 1 year, 2 years and 9-years follow-up were 86 to 93 %, 80 to 92 %, and 77 to 100 %, respectively, which confirms the maintenance of good results over time, notably in VUR grade III and above.  The success rate was similar for primary and secondary VUR except for total duplicity.  Predictive criterias of success were the surgeon's experience, the low grade of VUR, and the absence of previous injection.  In comparison with other bulking agents, the higher viscosity and absence of shrinkage of the product increase its reliability.  After more than 12 years of use, no serious complication has been reported in the literature, reflecting the good tolerance of Macroplastique on the long-term.  The author concluded that published studies on the use of Macroplastique in VUR confirmed its effectiveness, around 85 % of success for all grades, in both children and adults.  The interest of Macroplastique is linked to its higher viscosity promoting a better reliability and reproducibility of the technique and its non-resorbable nature providing a permanent result, especially valuable in high-grade VUR with anatomical anomaly of the vesicoureteral junction or in VUR secondary to permanent lower urinary tract dysfunction.

The American Urological Association's guideline on management of primary VUR in children (Peters et al, 2010) recommended that patients receiving continuous antibiotic anaphylaxis with a febrile break-through UTI be considered for open surgical ureteral re-implantation or endoscopic injection of bulking agents for intervention with curative intent.

Alizadeh et al (2013) examined the incidence and presentations of ureteral obstruction following peri-ureteral injection of polyacrylate polyalcohol copolymer (PPC) for the treatment of VUR.  From January 2010 to December 2012, a total of 88 patients (28 males, and 60 females) with 128 renal refluxing units (RRU), 131 ureters and a mean age of 6.7 +/- 5.9 years (range of 4 months to 32 years) underwent endoscopic correction of their VUR, using PPC.  Exclusion criteria were dysmorphic appearing distal ureter, extra-vesical position of the ureteral orifice, persistent urethral obstruction (e.g., after previous valve ablation) and severe bladder trabeculation, making ureteral orifice unidentifiable.  Patients were followed-up by ultrasound 1 month after the injection and then every 3 months.  Cystography was performed 3 months post-operation.  Mean follow-up time was 13.1 +/- 6.8 months (range of 3 to 27 months).  Two patterns of obstruction were observed: early, during the first 3 to 4 days post-operation, in 4 patients (4 ureters; 3 %) which was associated with transient hydro-uretero-nephrosis (HUN) in 2 patients (2 ureters; 1.5 %); and late-onset obstruction in 3 patients (4 ureters; 3 %), which appeared 3 months to 1 year after surgery.  It manifested itself by urinary tract infection and uremia in 1 patient with bilateral obstruction but was asymptomatic in the other 2.  Early obstruction was managed expectantly and resolved in 3 to 12 months; however, late-onset obstruction needed catheter placement or open ureteroneocystostomy.  The authors concluded that patients who undergo endoscopic treatment for their VUR using PPC need long-term follow-up until the safety of this substance is confirmed.

Stredele and colleagues (2013) determined the long-term effect in children of endoscopic treatment VUR using different bulking agents.  Status of VUR, recurrence of UTI, and recurrence of febrile UTI were evaluated as end-points.  From 1993 to 2005, these investigators injected 229 refluxive ureters (VUR grade II to IV) in 135 children.  Mean age of the children was 55.7 months.  These researchers used collagen in 98 (years 1993 to 2000), polydimethylsiloxane in 32 (years 1999 to 2000), and dextranomer/hyaluronic acid copolymer (Dx/HA) in 99 ureters (years 2000 to 2005).  Of the 135 children, 127 underwent a VCUG (radiologic or nuclid) 3 months after the first injection, and 88 children a second VCUG (nuclid) after 37 months (mean) post-operatively.  Clinically, patients were monitored for non-febrile or febrile UTI.  Data were collected and analyzed retrospectively by chart review.  After first injection with collagen, polydimethysiloxane and Dx/HA, 52 %, 55 % and 81.5 % of the children were without VUR, respectively.  Repeated injections were successful in only 21 % (collagen) to 42 % (Dx/HA).  Of the 88 with a second VCUG, 48.5 % of the initially reflux-free children developed relapse VUR after collagen, 45.5 % after polydimethylsiloxane and 21.5 % after Dx/HA injection.  Clinically, there was a significant difference in post-operative UTI occurrence in favor of the Dx/HA group.  The authors concluded that clinically and radiologically, Dx/HA exhibited the best results, giving better protection against UTIs and a better VUR cure rate.  Moreover, there was still a risk of VUR recurrence in successfully treated children after 3 years of follow-up.

In a single-center, single-surgeon, prospective, off-label study, Cloutier and colleagues (2013) evaluated the success of endoscopic treatment for VUR using polyacrylamide hydrogel.  All patients underwent endoscopic subureteral double hydrodistention implantation technique injection followed by renal ultrasound and VCUG at 3 months post-operatively to confirm the absence of de-novo hydronephrosis and correction of VUR (grade 0).  A total of 40 patients (69 refluxing ureters) underwent polyacrylamide hydrogel injection.  Median age at surgery was 50 months.  Bilateral reflux was identified in 29 patients (73 %); 9 patients had duplex systems, 2 with reflux into both moieties.  Reflux was graded using the International Reflux Study in Children grading system, with grade I seen in 9 ureters, II in 17, III in 20, IV in 18 and V in 5.  Mean volume injected was 1.1 ml.  Success rate for grade I to III VUR at 3 months after a single treatment was 87 %, and the overall success for all grades was 81.2 %.  The authors concluded that off-label use of polyacrylamide hydrogel injection therapy for primarily low-grade VUR demonstrated that the technique and short-term success rates were comparable to the most popular bulking agent, dextranomer/hyaluronic acid.  Moreover, they stated that these results suggested that further trials comparing polyacrylamide hydrogel and dextranomer/hyaluronic acid would be worthwhile.  The main drawbacks of this study were its small sample (40 patients) size, short follow-up (3 months), and the lack of a control group.

Moore and Bolduc (2014) prospectively compared the effectiveness of polydimethylsiloxane and dextranomer/hyaluronic acid injection for treatment of VUR.  A total of 275 patients with documented VUR (grade I to V) were prospectively enrolled in a comparative study between April 2005 and February 2011 to be randomly treated endoscopically with either polydimethylsiloxane (Macroplastique) or dextranomer/hyaluronic acid copolymer (Deflux); 202 were treated with polydimethylsiloxane and 197 with dextranomer/hyaluronic acid copolymer.  Patients were followed with VCUG at 3 months and renal ultrasonography at 3 months and at 1 year.  Median follow-up was 4.3 years.  The primary outcome was surgical success (resolution versus non-resolution), and secondary outcomes included occurrence of adverse events.  Vesicoureteral reflux was fully corrected in 182 of 202 ureters (90 %) treated with polydimethylsiloxane, compared to 159 of 197 (81 %) treated with dextranomer/hyaluronic acid copolymer (p <0.05).  Obstruction was found in 5 ureters.  Uni-variate and multi-variate analyses did not allow identification of any characteristics that could explain the significant difference in the success rates except for the type of product used.  The authors presented the largest known prospective evaluation comparing 2 bulking agents for the treatment of VUR.  Endoscopic injection of polydimethylsiloxane resulted in a better success rate than dextranomer/hyaluronic acid copolymer.  The rate of resolution obtained with the latter is lower than those previously published due to the inclusion of high-grade reflux.

An UpToDate review on "Management of vesicoureteral reflux" (Matto and Greenfield, 2015) states that "Subureteric transurethral injection (STING procedure), an ambulatory day procedure, involves injecting a copolymer substance, such as dextranomer/hyaluronic acid (Dx/HA or DEFLUX) or polydimethylsiloxane, beneath the mucosa of the ureterovesical junction through a cystoscope.  This injection changes the angle and perhaps fixation of the intravesical ureter, thereby correcting reflux.  The success rate for correcting VUR by STING in one or more procedures ranges from 75 to over 90 %.  The success rate for initial correction of VUR (by ureter) varies by the severity of reflux and anatomic variables …. The success rate of a second STING procedure after an initial failed injection is high, ranging from 70 to 90 %.  The STING also has been utilized as a salvage procedure correcting VUR in 65 % of patients who failed a previous open surgical reimplantation".

Dogan and colleagues (2015) investigated the parameters which may affect the outcomes of endoscopic injection and compared the effectiveness of 2 different bulking agents both composed of dextranomer-hyaluronic acid copolymer.  The data of patients who underwent endoscopic VUR treatment between 2003 and 2012 were retrospectively reviewed.  Patients with history of previous open anti-reflux surgery, more than 1 failed endoscopic treatment for reflux, VUR caused by posterior urethral valve, duplex system and overt spinal dysraphism were excluded.  Surgical technique was the classical STING method; 1 of the 2 dextranomer-hyaluronic acid copolymer agents was used (Deflux in 109 and Dexell in 131 patients).  Both agents were composed of similar amounts of hyaluronic acid gel (15 mg in Deflux versus 17 mg in Dexell) but different sized dextranomer microspheres (80 to 250 μm in Deflux and 80 to 120 μm in Dexell).  During the follow-up, ultrasonography was performed with 3-month interval, antibiotic prophylaxis was continued until the control VCUG was taken.  Patient based success was defined as the disappearance of reflux on control VCUG performed 3 to 6 months after the operation.  Data were available for 240 patients.  Mean age and mean post-operative follow-up were 78 ± 41 months and 19 ± 18 months.  The overall success rate was 73.2 %.  Gender, laterality, grade of VUR, presence of voiding dysfunction, renal scar and pre-operative break-through infection (BTI) were not found to affect the outcome, whereas age younger than 54 months and previous history of failed endoscopic injection were found to negatively affect the outcome both in uni-variate and multi-variate analysis.  The post-operative UTI (5 febrile and 43 non-febrile) rate was 20 %.  Both uni-variate and multi-variate analysis showed that post-operative UTI was more common in patients with persisting reflux, with pre-operative BTI and in girls.  Patient characteristics, treatment outcome and post-operative UTI rate were similar regarding the used bulking agent.  No ureteral obstruction was experienced within the follow-up period.  The success rate for second injection was about 60 %, which was significantly lower than for the patients who underwent first injection.  These researchers could not find any affecting factor for this difference.  Contrary to the literature, the success rates in this study were similar in different reflux grades.  These investigators explained this finding that they valued the intra-operative orifice configuration more than the grade which can be accepted as a patient selection bias.  The lower success rate in children younger than 54 months could be explained by unstabilized bladder dynamics and higher voiding pressures in this age group, who are still in the toilet-training phase.  Despite successful endoscopic treatment, UTI might occur.  Post-operative UTI was more common in patients with persisting reflux, pre-operative BTI and girls.  The similar success rates of both bulking agents proved that dextranomer size does not affect the clinical outcome.  The authors concluded that endoscopic treatment of VUR has satisfying outcomes in properly selected cases.  Younger age (less than 54 months) and previous history of failed injection history were found to be related to unfavorable results.  Post-operative UTI occurs more frequently in patients with persisting reflux, pre-operative BTI history and girls.  The choice of one of the dextranomer-based substances did not affect the surgical outcome and post-operative UTI development.

Periureteral Injection Technique (PIT) for High-Grade Vesico-Ureteral Reflux

Asgari and colleagues (2016) noted that despite the benefits of the minimally invasive endoscopic treatment for VUR, it has a major drawback which is low success rate in high-grade VUR. For overcoming this problem, these researchers introduced a new modified technique of endoscopic treatment called periureteral injection technique (PIT).  In a pilot study, a total of 37 ureters in 19 boys and 14 girls were treated, including 3 bilateral cases.  Of 37 units, 30 (81.1 %) had grade IV and 7 (18.9 %) had grade V primary VUR (18 right, 13 left and 3 bilateral units).  Sub-ureteral injection of PPC was done at the 5-o'clock and 7-o'clock positions in which the direction of injecting needles were almost parallel.  Pre- and post-operative evaluation included urinalysis, urinary tract ultrasonography, voiding VCUG, dimercaptosuccinic acid scan and urodynamic studies.  The median age was 38 months (range of 8 to 125).  At 6 months follow-up confirmed with VCUG, the VUR disappeared in 34 (91.8 %) units and 3 units [2 (5.4 %) grade II and 1 (2.7 %) had grade III)] had down-graded VUR.  Complications included early fever due to urinary tract infection in 1 children, transient dysuria in 2 patients and low back pain in 1 patient.  The authors concluded that the success rate of PIT for treatment of high grade VUR is high.  However, they stated that further studies with more patients and longer follow-up are needed to draw final conclusion.

Bulking Agents

Blais and colleagues (2017) noted that VUR is one of the most common pathologies encountered in pediatric urology.  Better understanding of the evolution of VUR and new endoscopic surgical techniques in the last decades have led to major changes in the management of this pathology.  However, the treatment algorithm remains complex and is composed of a wide variety of options, from active surveillance to surgical treatment.  The 3 most popular techniques described in the literature are:

1. the subureteral Teflon injection (STING),
2. the hydrodistention technique (HIT), and
3. the double hydrodistention technique (double-HIT).  

STING technique was the first to be described.  The technique consists of the injection of bulking agent, regardless of the agent, into the detrusor muscle immediately beneath the ureteral orifice at the 6 o’clock position.  With the HIT, the ureter is distended with irrigation fluid from the cystoscope and the injection is made within the ureteral orifice, beneath the mucosa.  The double-HIT is similar, but 2 injections are carried out – a first injection is performed more proximally, within the ureteral tunnel, and a second injection more distally, just under the ureteral orifice.  Cross-linked bovine collagen has been the subject of many trials, revealing inconsistent success rates and high relapse rates.  The variable degree of ingrowth of native fibroblasts, the shrinkage of the bulking agent, and the reported immunological reactions after injection of collagen are reasons why cross-linked bovine collagen has been abandoned by most centers.  Injection of autologous material is appealing, as they behave as free grafts with the absence of foreign materials.  Blood, chondrocytes, fat, and myoblasts were studied.  Fat and chondrocytes showed high rates of long-term VUR recurrence.  On the other hand, blood has not been largely studied and the experimental use of myoblasts in pigs failed.  Calcium hydroxyapatite, a synthetic agent with identical chemical composition to teeth and bone, was investigated in animals and humans.  Only few studies are available in the literature and reported success rates are widely variable.  The authors stated that further studies with larger cohorts and longer follow-up are needed.  Two agents have been recently introduced for the endoscopic injection of VUR:

1. polyacrylate-polyalcohol copolymer (PPC, Vantris), and
2. polyacrylamide hydrogel (PAHG, Bulkamid).  

A multi-center survey showed a success rate of 93.8 % after a single injection of PPC.  Patients were monitored with ultrasound and voiding cystourethrogram.  Most renal refluxing units had higher-grade VUR (55.8 % Grade III and 19.5 % Grade IV) and most patients (60 %) were followed for more than 2 years.  Moreover, PPC and Dx/HA have been compared in many trials.  Endoscopic injection of PPC resulted in higher success rates.  However, concerns have been raised with PPC regarding a high rate of ureteral obstruction.  Finally, only few published series are available on PAHG.  These researchers noted that the success rate with this bulking agent appeared promising, but more trials are needed prior to extensive use.

Chung and co-workers (2018) analyzed the surgical outcomes of pneumovesicoscopic ureteral reimplantation and endoscopic injection of DX/HA in 3 tertiary centers.  The medical records of 215 patients (159 boys and 56 girls) for a total of 323 ureters underwent surgical interventions for primary VUR from February 2002 to August 2014 were reviewed.  Data on baseline demographics, pre-operative symptoms, radiological imaging studies, and post-operative outcomes were analyzed; VUR resolution was defined as when no VUR was detected by micturating cystourethrogram at 3 months or later after the intervention.  Independent t-test, Mann-Whitney U test, Fisher's Exact test, and Chi-Square test were used for different parameters.  All results with p value ≤ 0.05 were regarded as statistically significant.  The mean age at operation was 3.33 and 4.63 for re-implantation and DX/HA injection, respectively.  A total of 234 ureters underwent DX/HA injection and 92 ureters underwent pneumovesicoscopic ureteral re-implantation with mean pre-operative VUR grading of 3.1 and 4.2, respectively (p = 0.0001).  The overall VUR down-grading and resolution rates were both significantly higher in re-implantation than DX/HA injection (97.8 % versus 78.6 %; p = 0.0001 and 84.3 % versus 65 %; p  = 0.0011).  Further subgroup analyses across the different VUR gradings showed higher down-grading and resolution rates in re-implantation group than DX/HA injection for grade 4 (100 % versus 81 %; p = 0.0147 and 82.4 % versus 63 %; p = 0.0411) and grade 5 VUR (97.3 % versus 50 %; p = 0.0022 and 81.6 % versus 40 %, p = 0.0256).  DX/HA injection was associated with shorter operation time (41.5 mins versus 147.5 mins, p < 0.001), less post-operative analgesic usage (p = 0.049), and shorter hospital stay (1.06 days versus 4.44 days; p <0 .0001).  No major complications were identified in either groups.  The mean follow-up time was significantly longer in re-implantation group than DX/HA group (57.25 months versus 37.85 months, p = 0.002).  There was no significant difference in the rate of subsequent UTI development during follow-up (p = 0.8).  The authors concluded that both DX/HA injection and pneumovesicoscopic ureteral reimplantation were safe and effective treatments for VUR.  Re-implantation was associated with significantly higher VUR down-grading and resolution rates than DX/HA injection especially in the higher grade VUR while DX/HA injection had significantly shorter operation time, lower post-operative analgesic usage, and shorter hospital stay.  DX/HA injection could be considered as the first-line surgical treatment especially for lower grade VUR. Pneumovesicoscopic ureteral re-implantation could be used for higher grade reflux or those who failed DX/HA treatments.

Tekin and colleagues (2018) noted that various bulking agents were utilized for endoscopic correction of VUR.  A study reviewing multi-institutional data showed that the amount of injection material has increased over time with the purpose of improving success rates, which also resulted in costs.  These investigators noticed an opposite trend in their center since they started using a new bulking agent; they examined evolution of their practice with different bulking agents.  Records of VUR patients who underwent sub-ureteric injection with PPC and DX/HA between 2005 and 2014 were reviewed.  Variation of different parameters throughout the study period was evaluated along with the success rate. Success was defined as complete resolution of reflux.  A total of 260 patients with 384 refluxing units were included.  The success rate was higher in PPC group compared to DX/HA group. There was no statistically significant difference between years regarding distribution of VUR grade, body weight, patient height, and age in PPC group.  Despite significant reduction in injection volume, success rate did not decrease through the years with PPC.  The authors concluded that different bulking agents may require different injection volumes to achieve the same success rate in endoscopic treatment of VUR.  These researchers stated that habits gained with previous experience using other materials should be revised while using a new agent.

García-Aparicio and associates (2018) compared the radiological and clinical outcomes of endoscopic treatment of primary VUR using PPC (Vantris) or DX/HA (Deflux).  From October 2014 to April 2017, patients with primary VUR grade III to V that needed endoscopic treatment (ET) were eligible for this randomized clinical trial.  These researchers excluded toilet-trained patients with lower urinary tract symptoms.  Patients were randomized and allocated into 2 groups: PPC group and DX/HA group.  After endoscopic treatment a VCUG was performed at 6 months; if VUR was still present a second ET was performed.  Radiological success was considered if post-operative VUR grade was 0 and clinical success rate was considered if no more febrile UTI (fUTI) appeared during follow-up.  A total of 46 patients were eligible; however 2 did not accept the trial; 44 patients with 73 refluxing ureters were included.  PPC: 34 refluxing ureters; and DX/HA: 39 refluxing ureters.  Both groups were statistically homogeneous and comparable.  Mean follow-up was 27.6 months.  Radiological success rate (82.2 %) and clinical success rate (92.3 %) were similar in both groups (p > 0.05).  The volume of bulking agent used in those successfully treated was greater in DX/HA group (p < 0.05).  Distal ureter was excised in all cases of ureteral re-implantation following PPC treatment; however, distal ureter was preserved in all ureters re-implanted after DX/HA injection.  The authors concluded that PPC and DX/HA had similar outcomes, but one must warn that ureteral re-implantation following endoscopic treatment with PPC was difficult because of the peri-ureteral fibrosis.

Polyacrylate-Polyalcohol Copolymer (Vantris)

Warchoł and associates (2017) noted that the endoscopic correction of VUR in children is a well-accepted therapy in many pediatric urology centers.  Polyacrylate-polyalcohol copolymer (PPC; Vantris) is one of the tissue-augmenting substances used for endoscopic reflux therapy.  These investigators evaluated the results with PPC in children with VUR.  From 2012 to 2016, a total of 125 children (73 girls and 52 boys) aged 0.6 to 17.9 years (mean of 4.9 ± 3.58) were treated with PPC; VUR was unilateral in 64 and bilateral in 61 patients, comprising 197 RRUs grades: II in 72, III in 50, IV in 33 and V in 42.  Of these, primary reflux was present in 132 RRUs and 65 were complex cases; VCUG was performed 3 months after procedure.  Follow-up was completed in 89.6 % of patients (112 children), and 89.8 % of RRUs (177 out of 197).  Reflux resolved in 86.4 % of RRUs after single injection, in 99.4 % after second and in 100 % after the third.  The only significant, but serious complication observed was late ureteral obstruction after PPC injection correcting high grade reflux, which required ureteral re-implantation.  This complication was found in 9 out of 112 children (8 %), and in 11 out of 177 RRUs (6.2 %), 1.1 to 2.9 years (mean of 2 ± 0.7) after the PPC injection.  The longest follow-up reached 4.5 years.  The authors concluded that these findings showed that the PPC injection is an effective procedure for treating all grades of VUR with high success rate.  However, because of the possibility of late ureteral obstruction, which requires uretero-neocystostomy, long-term follow-up is mandatory.

Frankiewicz and colleagues (2020) noted that UTIs are the commonest infectious complications among kidney transplant recipients.  They occur due to the lack of an effective anti-reflux mechanism in the majority of techniques used during kidney transplantation (KTx).  Sub-ureteral injection of tissue bulking substance is a feasible alternative to open ureteral re-implantation.  To the best of the authors' knowledge, this study is the first to examine the application of polyacrylate/polyalcohol copolymer (Vantris) as the agent for minimally invasive VUR treatment.  Between January 2018 and February 2019, a total of 7 patients presenting with recurrent UTIs and the diagnosis of VUR following KTx were enrolled in the study.  Subjects underwent cystoscopy and, if possible, minimally invasive, endoscopic sub-ureteral application of 1-ml of Vantris according to the STING technique.  Endoscopic sub-ureteral injection of tissue bulking substance (polyacrylate/polyalcohol copolymer) was successfully performed in 6 patients.  In 1 patient it could not be completed because of an inconvenient location of the neo-orifice.  In 4 patients (57 %) no reduction of the reflux grade was observed in follow-up imaging.  The number of UTIs in the follow-up was significantly reduced in 6 of 7 patients (86 %) following polyacrylate/polyalcohol copolymer sub-ureteral injection.  The authors concluded that endoscopic treatment of VUR with polyacrylate/polyalcohol copolymer was a safe and effective method as a first-line treatment for patients with recurrent UTIs following KTx.  Moreover, these researchers stated that a larger number of patients with a longer follow-up period after surgery is needed to obtain clear conclusions.

Durasphere

Ozkuvanci and colleagues (2018) stated that Durasphere EXP (DEXP) is a compound of biocompatible and non-biodegradable particles of zirconium oxide covered with pyrolytic carbon.  These researchers evaluated the durability of off-label use of DEXP in the treatment of primary VUR in children.  Patients who underwent sub-ureteric injection of DEXP for the correction of primary VUR were retrospectively reviewed.  Patients aged greater than 18 years as well as those who had grade-I or grade-V VUR, anatomic abnormalities (duplicated system, hutch diverticulum), neurogenic bladder or treatment refractory voiding dysfunction were excluded.  Radiologic success was defined as the resolution of VUR at the third month control.  Success was radiographically evaluated at the end of the first year.  A total of 38 patients (9 boys, 29 girls; mean age of 6.3 ± 2.7 years) formed the study cohort; 46 RRUs received DEXP (grade II: 22; grade III: 18; grade IV: 6).  Mean volume per ureteric orifice to obtain the mound was 0.70 ± 0.16 ml.  First control VCUG was done after 3 months in all patients.  After the first VCUG, 6 patients had VUR recurrence.  Short-term radiologic success of DEXP was 84.2 %.  Rate of radiologic success at the end of the first year was 69.4 % (25/32).  Lower age (p : 0.006) and lower amount of injected material (p : 0.05) were associated with higher success rates at the end of 1 year.  The authors concluded that this was the first study to ascertain the outcomes of DEXP for treatment of primary VUR in children.  After 1 year of follow-up, DEXP had a 69.4 % success rate.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on "Management of vesicoureteral reflux" (Matto and Greenfield, 2018) does not mention Durasphere as a management tool.

Endoscopic Treatment of Symptomatic Vesicoureteral Reflux After Renal Transplantation

Akiki and colleagues (2015) examined the success of endoscopic treatment of symptomatic VUR following renal transplantation and identified factors predicting success.  Endoscopy was carried out for symptomatic VUR following renal transplantation in 38 women and 20 men between January 2000 and December 2010.  Reflux was documented by retrograde cystography and its symptomatic character was determined by at least 1 episode of acute graft pyelonephritis.  The results of endoscopic treatment were examined at 1 and 3 months, and annually, and by cystography at 3 months.  Clinical success was defined as absent acute graft pyelonephritis during follow-up.  Radiological success was defined as absent reflux on follow-up cystography at 3 months. Endoscopic treatment was successful in 32 patients (56.1 %), including 26 (65 %) who received Dx/HA and 5 (33.3 %) who received polydimethylsiloxane.  Treatment was radiologically successful in 14 patients (26.4 %) at a mean ± SD follow-up of 38 ± 33 months.  On multi-variate analysis, male gender and Dx/HA were factors predictive of clinical success.  Reflux grade did not predict success or failure.  No high-grade complication was observed.  The authors concluded that endoscopic treatment of symptomatic VUR of a transplanted kidney was effective in 50 % of the cases regardless of the bulking agent used; however, Dx/HA appeared to be more effective than polydimethylsiloxane.  These investigators stated that due to its minimally invasive nature and low morbidity endoscopic treatment with Dx/HA could be proposed as pre-operative 1^st-line treatment for symptomatic VUR of a transplanted kidney regardless of reflux grade.

Aristizabal-Alzatea and co-workers (2016) stated that renal graft pyelonephritis is a common complication following renal transplantation, often prompted by VUR.  An effective and minimally invasive strategy for managing reflux that allows a decrease in the risk of recurrent pyelonephritis is desirable.  These researchers described their experience with an endoscopic treatment with sub-ureteral injection of polydimethylsiloxane for the treatment of recurrent pyelonephritis of renal grafts secondary to VUR.  Between 2011 and 2016, a total of 17 sub-ureteral polydimethylsiloxane injection procedures were carried out.  Patient monitoring was conducted by outpatient consultation and medical record review.  The number of pyelonephritis events before and after the procedure and its safety were compared.  A total of 46 infection episodes occurred before the procedure (2.71 infections/patient/year) and 10 infection episodes occurred after the procedure (0.59 infections/patient/year), representing a 78.3 % reduction of infections/patient/year . The procedure was safe and well-tolerated, with no resultant obstructive complications or changes in renal function and no long-distance migration of the bulking agent detected by monitoring.  The authors concluded that consistent endoscopic treatment with sub-ureteral injection of the bulking agent polydimethylsiloxane to manage VUR in cases of recurrent pyelonephritis of renal grafts is a non-invasive therapeutic option with a good safety profile and success rate.

Wang and colleagues (2019) noted that VUR is one of the most common ureteric complications following renal transplantation that might cause symptomatic infections that deteriorate graft function.  Surgical re-implantation has been the standard treatment; recently, endoscopic injection has been an alternative approach.  These investigators reported their endoscopic treatment results and analyzed the long-term outcome, even in patients with less optimal graft function.  A total of 16 patients and 19 symptomatic VUR were diagnosed at mean time of 88.3 months after their transplantation.  The distribution of VUR grade was 1, 2, 8, 6, and 2 for grade I to V, respectively, with a mean VUR grade of 3.26 according to their voiding cystourethrogram images.  Endoscopic Deflux injections were carried out by a single urologist via rigid cystoscope with a beveled needle system; subjects were followed monthly thereafter.  The average number of admissions due to symptomatic UTI was 2.68/person, and the mean creatinine level before endoscopic treatment was 1.63 mg/dL.  The amount of Deflux injection was 0.7 to 1.2 ml per affected ureter; the mean creatinine level after endoscopic treatment was 1.41 mg/dL.  The estimated glomerular filtration rate (eGFR) remained stationary in both eGFR greater than 60 and eGFR less than 60 ml/min groups with a clinical success rate of 75 % in both groups.  The authors concluded that endoscopic Dx/HA was a safe and feasible therapeutic option for VUR after kidney transplantation.  These findings showed its efficacy even in transplant recipients with inferior graft function (eGFR is less than 60 ml/min).

Frankiewicz and associates (2020) noted that UTIs are the most common infectious complications among kidney recipients.  They occur due to the lack of an effective anti-reflux mechanism in the majority of techniques used during kidney transplantation.  Sub-ureteral injection of tissue bulking substance is a feasible alternative to open ureteral re-implantation.  These researchers stated that this study, to the best of their knowledge, was the 1st to examine the use of polyacrylate/polyalcohol copolymer (Vantris) as the agent for minimally invasive VUR treatment.  Between January 2018 and February 2019, a total of 7 patients presenting with recurrent UTIs and the diagnosis of VUR following kidney transplantation were enrolled in the study.  Patients qualified for the study underwent cystoscopy and, if possible, minimally invasive, endoscopic sub-ureteral application of 1-ml of polyacrylate/polyalcohol copolymer according to the sub-ureteral transurethral injection (STING) technique.  Endoscopic sub-ureteral injection of tissue bulking substance (polyacrylate/polyalcohol copolymer) was successfully performed in 6 patients.  In 1 patient it could not be completed because of an inconvenient location of the neo-orifice.  In 4 patients (57 %) no reduction of the reflux grade was observed in follow-up imaging.  The number of UTIs in the follow-up was significantly reduced in 6 of 7 patients (86 %) after polyacrylate/polyalcohol copolymer sub-ureteral injection.  The authors concluded that endoscopic treatment of VUR with polyacrylate/polyalcohol copolymer was a safe and effective method as a 1st-line treatment for patients with recurrent UTIs after kidney transplantation.

Ozkaptan and colleagues (2020) examined the outcome of endoscopic treatment of symptomatic VUR in patients with VUR in both transplanted and native renal units.  Between January 2014 and December 2019, a total of 23 transplanted patients with symptomatic VUR with reflux in both transplanted and native kidney were included in the study.  All subjects were patients with a history of kidney failure due to reflux nephropathy.  A voiding cystourethrography was carried out after at least 1 episode of acute glomerular pyelonephritis or deterioration of the graft function.  All subjects underwent a urine culture and an ultrasonic (US) evaluation pre-operatively.  A Dx/HA bulking agent was injected via an endoscope using a rigid metal needle around a double J stent.  Clinical success was defined as absent of febrile UTI during the follow-up period.  The procedure was employed in 52 effected renal units; of these, 27 were transplanted kidneys, and 25 were native kidneys.  Overall clinical success was achieved in 69.6 % (n = 16) of patients.  The success rate after the 1st procedure was 52.2 % (n = 12), whereas 17.3 % (n = 4) achieved success after the 2nd treatment.  No intra-operative complications occurred throughout the endoscopic procedure.  Minor post-operative complications included 2 (10 %) cases of self-limiting episodes of hematuria that did not require intervention.  The authors concluded that endoscopic treatment of symptomatic VUR for both transplanted ureter and native ureter was a safe treatment in most of the patients.  Therefore, endoscopic ureteral injection is a treatment modality with low morbidity that should be preferred to open surgery as 1st-line treatment in this subgroup of patients.

Balaban and co-workers (2020) examined the outcome of endoscopic treatment for symptomatic VUR disease in renal transplantation patients and determined the factors that were associated with the success rate of the treatment.  A total of 121 symptomatic VUR diseases diagnosed between 2014 and 2018 in 3,560 renal transplant patients were included in this analysis.  The results of 49 VUR cases that presented with febrile UTI and were hospitalized for antibiotic treatment were included in the study.  Reflux was detected by voiding cystourethrogram and treatment was carried out by endoscopic Deflux injection.  The result of endoscopic treatment was examined clinically by 3-month periods.  The mean time between transplantation and endoscopic treatment was 59.6 (5 to 132) months, and the mean follow-up period after the endoscopic treatment was 14 (6 to 48) months, respectively.  The success rate after the 1st injection was 59.1 % (n = 29) and 67.3 % (n = 33) after the 2nd injection.  One patient developed anuria, 1 patient febrile UTI and 4 patients developed minimal macroscopic hematuria following the procedure.  The authors concluded that endoscopic treatment of symptomatic VUR in transplanted kidney was a safe and feasible procedure.  The amount of bulking agent or duration between the transplantation and diagnosis of VUR did not have any impact on the success of the treatment; however, the younger age of the patients and the female gender appeared to have a positive effect on the outcome of the procedure.

Comparison of Sub-Ureteral Endoscopic Injection of Dextranomer/Hyaluronic Acid and Lich-Gregoir Ureteral Re-Implantation in the Treatment of Pediatric Primary Vesicoureteral Reflux

Salih et al (2021) stated that the gold standard of surgical intervention of VUR is open ureteral re-implantation with high success and low complication rates.  However, in recent years, endoscopic injection, Dx/HA, has become an effective therapy for VUR.  It is noted that limited prospective randomized trials compared the different surgical techniques of especially endoscopic injection versus open procedures.  In a prospective, randomized study, these researchers compared the outcomes of endoscopic injection of Dx/HA and Lich-Gregoir open technique of ureteral re-implantation for grades III and IV primary VUR in pediatric patients.  Between January 2016 and December 2018, a total of 60 pediatric patients with grades III and IV primary VUR were enrolled in this trial – 30 cases with 45 refluxing ureters managed by endoscopic injection of Dx/HA comprised group A; and open Lich-Gregoir technique used in the other 30 cases with 48 refluxing ureters composed of group B.  Renal US, VCUG, and renal scintigraphy were used for follow-up.  The surgical success rate, cost-effectiveness, and occurrence of complications were evaluated and compared in both groups.  A total of 60 pediatric patients with 93 refluxing ureters (41 females and 19 males) were included in this study.  The mean follow-up for all patients was 17.7 ± 7.1 months.  Overall reflux resolution was 80 % (36/45) of the ureters in group A after a single injection and 93.75 % (45/48) of the ureters in group B.  The difference between the 2 groups was not statistically significant concerning clinical or anatomical pre-operative factors and surgical success rate.  There was a statistically significant difference between the 2 groups in terms of operative time and hospital stay.  The authors concluded that this comparative study demonstrated a high success rate of open ureteral re-implantation (Lich-Gregoir) procedure over the endoscopic injection of Dx/HA therapy to manage primary VUR grades III-IV.

Deflux Treatment for Vesicoureteral Reflux Following Pediatric Renal Transplantation

Rebullar et al (2021) stated that VUR following renal transplant in the pediatric population may be associated with an increased incidence of UTIs leading to increased morbidity, including graft dysfunction and graft loss.  The non-orthotopic location of the transplanted ureter, and lack of submucosal tunnel may pose challenges in correcting the VUR using endoscopic injection techniques.  These investigators reported the findings of a systematic review examining the outcomes of endoscopic treatment of VUR using Deflux in this population.  PubMed and Embase databases were searched from October 2001 to April 2019.  Full-text English articles involving patients of less than 18 years of age at the time of transplantation, with a diagnosis of VUR post-transplantation, who underwent Deflux treatment were included.  These investigators found 6 eligible studies describing Deflux treatment outcomes in 67 pediatric patients with post-transplant VUR where VCUG confirmed the diagnosis and resolution of VUR.  The mean success rate was 36.8 %.  Ureteral obstruction occurred in 7/67 cases (10.4 %).  In all these 7 cases of obstruction, ureteric stenting was the initial management, but was only successful in 1 patient.  Open ureteroneocystostomy (UNC) was carried out in 4/7 cases, while 2/7 were managed expectantly (unknown outcomes).  Persistent VUR with UTI despite Deflux were reported in 20 out of 67 cases.  Of these, 7 were managed with prophylactic antibiotics, and 13 with UNC.  Success rates were consistently low for UNC following failed Deflux in comparison to redo UNC in transplant ureters without prior injection.  The authors concluded that low success rates were observed following injection techniques for VUR after pediatric renal transplantation.  These researchers stated that although an appealing option, Deflux may prove counter-intuitive due to the high rate of obstruction and suboptimal results if open re-implantation is needed.  Moreover, these investigators stated that a prospective, multi-center study with a larger population size may further elucidate these findings.

Various Treatment Modalities of Vesicoureteral Reflux

Xie et al (2021) noted that VUR is a risk factor for various renal problems like recurrent UTIs, pyelonephritis, renal scarring, hypertension, and other renal parenchymal defects.  The interventions followed by pediatricians include low-dose antibiotic treatment, surgical correction, and endoscopy.  In a meta-analysis, these investigators examined the advantages and drawbacks of various primary VUR therapeutic options.  The Cochrane Central Register of Controlled Trials, Medline, Embase, reference lists of journals, and abstracts from conference proceedings were all used to find RCTs.  The articles were retrieved from 1985 till 2020.  A total of 20 articles were used for the data analysis.  Surgery, long-term antibiotic prophylaxis, non-invasive techniques, and any mix of therapies are also options for treating VUR.  Two authors searched the literature separately, determining research qualifications, assessing accuracy, and extracting and entering results.  The odds ratio (OR) of these studies was used to construct the forest plot.  The random-effects model was used to pool the data.  Furthermore, the random-effects model was used with statistical significance at a p value of < 0.05 to examine the difference in side effects following treatment of VUR using different modalities.  These researchers found no statistically significant differences between surgery plus antibiotics and antibiotic alone-treated patients in terms of recurrent UTIs (OR = 0.581; 95 % CI: 0.259 to 1.30), renal parenchymal defects (OR = 1.149; 95 % CI: 0.75 to 1.754), and renal scarring (OR = 1.042; 95 % CI: 0.72 to 1.50).  However, the risk of developing pyelonephritis following surgical treatment of VUR was lesser than that in the conservative approach, that is, antibiotics (OR = 0.345; 95 % CI: 0.126 to 0.946.), positive urine culture (OR = 0.617; 95 % CI: 0.428 to 0.890), and recurrent UTIs were more common in the placebo group than in the antibiotic group (p < 0.05; OR = 0.639; 95 % CI: 0.436 to 0.936) which was statistically significant.  The authors concluded that based on current research, they recommended that a child with a UTI and significant VUR be treated conservatively at first, with surgical care reserved for children who have issues with anti-microbials or have clinically significant VUR that persists after several years of follow-up.  Furthermore, surgical correction of VUR should be treated if there are repeated breakthrough UTIs or if prophylactic anti-microbials are not accepted.

Comparison of Polyacrylate Polyalcohol Copolymer and Dextranomer/Hyaluronic Acid for the Treatment of Vesico-Ureteral Reflux

In a systematic review and meta-analysis, Gholami et al (2022) compared the effectiveness of polyacrylate polyalcohol copolymer and dextranomer-hyaluronic acid for endoscopic treatment of VUR.  These investigators searched Medline, Embase, Scopus, Web of science, Ovid, Cochrane databases, Google scholar for studies published until January 2022 in any language.  Studies that compared the success rate for endoscopic treatment of VUR in children with 2 bulking agents (i.e., polyacrylate polyalcohol copolymer (PCP) and dextranomer-hyaluronic acid [Dx/HA]) were included for this analysis.  A total of 9 studies were included in data synthesis for this meta-analysis.  Pooled data with a total of 763 ureters in PPC group and 718 ureters in Dx/HA group indicated that ureters in PPC group were more likely to undergo complete reflux resolution than Dx/HA (OR 3.80, 95 % CI: 2.71 to 5.31).  Among subgroup of patients with high-grade reflux, PPC injection had more resolution rate compared to Dx/HA patients (OR: 2.92, 95 % CI: 1.19 to 7.16).  In total, 95.81 % of the PPC group and 86.52 % of the Dx/HA group experienced success after the 3rd injection; however, a concerning complication of endoscopic treatment which was uretero-vesical junction obstruction (UVJO) was more prevalent in PPC group.  Thus, the possible benefits arising from endoscopic treatment with PPC could be offset by the costs of re-implantation surgery or stenting in the case of UVJO.  The authors concluded that these data indicated that PPC injection for the treatment of VUR was associated with a higher success rate, but concerningly, UVJO incidence was higher in the PPC group, which might negate the possible benefits of PPC injection.  However, due to the lack of studies with long-term follow-up, these researchers couldn't reach a definitive conclusion regarding the superiority of one of the bulking agents over the other.

Babu and Chandrasekharam (2022) noted that there are conflicting reports on the effectiveness of bulking agents for VUR.  In a meta-analysis, these researchers compared the outcomes of endoscopic treatment with PCP and DxHA.  They carried out a systematic review of publications between 2010 and 2020 covering databases like PubMed, Medline etc. for (endoscopic treatment) and (VUR) and (PCP or DxHA) and (recurrence or complications).  Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed; and only comparative studies were included.  Outcomes were early success defined as absence of VUR in voiding cystourethrogram at 3-months follow-up, UTI and occurrence of VUJO.  Risk of bias was analyzed with Robvis tool and odds-ratios were compared with Revman-3.0.  Among 9 studies (heterogeneity; I2 = 69 % to 79 %) all cleared the risk of bias assessment.  There was no significant difference in high-grade VUR (p = 0.94) between PCP (40 %) and DxHA (43 %).  Success rate after single injection was significantly higher (p = 0.0001) at 86 % (477/555) for PCP versus 69 % (474/685) for DxHA.  UTI rate between PCP (12 %) and DxHA (14.6 %) was not statistically significant (p = 0.54).  VUJO rate between PCP (3.9 %) and DxHA (0.8 %) was also not significantly different (p = 0.47).  Significantly lesser volume (p = 0.02) was used for PCP (0.7 ml) compared to DxHA (0.9 ml).  The authors concluded that reflux resolution was significantly higher with PCP than DxHA.  Post-injection UTI/VUJO incidence was not significantly different between them.  These researchers noted that the main drawbacks of this meta-analysis were heterogeneity and small number of studies.  They stated that further studies should focus on long-term outcomes and cost-effectiveness.

Escolino et al (2023) stated that in the past 2 decades, endoscopic injection (EI) has affirmed as a valid alternative to open surgery for management of pediatric VUR.  These investigators discussed some debated aspects such as indications, bulking agents and comparison, techniques of injection and comparison, predictive factors of success, use in specific situations.  EI is minimally invasive, well-accepted by patients and families, with short learning curve and low-morbidity profile.  It provides reflux resolution rates approaching those of open re-implantation, ranging from 69 % to 100 %; the success rate may be influenced by several factors.  Recently, it is adopted as 1st-line therapy also in high-grade reflux or complex anatomy such as duplex, bladder diverticula, ectopic ureters.  The 2 most used materials for injection are Deflux and Vantris.  The 1st is absorbable, easier to inject, has lower risk of obstruction, but can lose effectiveness over time.  The 2nd is non-absorbable, more difficult to inject, has higher risk of obstruction, but it is potentially more durable.  The 2 main techniques are STING and HIT.  The authors concluded that currently the ideal material and technique of injection has not yet clearly established, but the choice remains dependent on surgeon's preference and experience.

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References