Comparison of Subureteral Endoscopic Injection of Dextranomer/Hyaluronic Acid and Lich-Gregoir Ureteral Reimplantation in the Treatment of Pediatric Primary Vesicoureteral Reflux: A Prospective Randomized Study

Abstract

Background:

The gold standard of surgical intervention of vesicoureteral reflux (VUR) is open ureteral reimplantation with high success and low complication rates. However, in recent years, endoscopic injection, dextranomer/hyaluronic acid (Dx/HA), has become an effective therapy for VUR. It is noted that limited prospective randomized trials compare the different surgical techniques of especially endoscopic injection versus open procedures. We aimed to compare the outcomes of endoscopic injection of Dx/HA and Lich-Gregoir open technique of ureteral reimplantation for grades III and IV primary VUR in pediatric patients.

Materials and Methods:

Between January 2016 and December 2018, 60 pediatric patients with grades III and IV primary VUR were included in a prospective randomized trial. Thirty cases with 45 refluxing ureters managed by endoscopic injection of Dx/HA comprised group A. Open Lich-Gregoir technique used in the other 30 cases with 48 refluxing ureters composed of group B. Renal ultrasound, voiding cystourethrography, 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.

Results:

Sixty pediatric patients with 93 refluxing ureters (41 females and 19 males) were included in the trial. 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 two groups was not statistically significant concerning clinical or anatomical preoperative factors and surgical success rate. There was a statistically significant difference between the two groups in terms of operative time and hospital stay.

Conclusion:

This comparative study demonstrated a high success rate of open ureteral reimplantation (Lich-Gregoir) procedure over the endoscopic injection of Dx/HA therapy to manage primary VUR grades III–IV. Clinical Trial Number: NCT04798443.

Introduction

Vesicoureteral reflux (VUR) affects 1%–3% of pediatrics and, is diagnosed in a third of pediatrics with active urinary tract infection (UTI).^1,2 UTI increases the risk of pyelonephritis and renal scarring in cases with VUR, which may lead to hypertension and end-stage kidney disease.³ VUR management priorities involve preventing recurrent febrile UTI and renal scarring and reducing the treatment morbidity.⁴

The first choice of VUR treatment includes active surveillance and continuous antibiotic prophylaxis (CAP), particularly in children with a low degree of reflux where resolution is anticipated spontaneously.⁵

The gold standard of surgical intervention is open ureteral reimplantation with high success and low complication rates.⁶ Since Matouscheck first reported on the endoscopic subureteric injection procedure in 1981, and the first clinical examples described by O'Donnell in 1984, endoscopic injection dextranomer/hyaluronic acid (Dx/HA) has become an effective therapy for VUR.^1,7,8 It is noted that limited prospective randomized trials compare the different surgical techniques of especially endoscopic injection versus open procedures.

In this prospective randomized trial, we aim to compare the outcomes of Dx/HA (Dexell) endoscopic injection and Lich-Gregoir open ureteral reimplantation technique in pediatric patients for grades III and IV primary VUR.

Materials and Methods

Study design

Sixty pediatric cases with primary VUR grades III and IV were prospectively registered in a comparative intervention trial between January 2016 and December 2018. They were distributed at a 1:1 ratio by simple randomization into two groups with at least 30 cases in each group. Two experienced pediatric urologists performed endoscopic injection of Dx/HA (Dexell) for group A and open Lich-Gregoir technique for extravesical ureteric reimplantation for group B.

All subjects included in the study were children with primary VUR grades III and IV based on recent voiding cystourethrography (VCUG) older than 1 year in compliance with the International Reflux Study Committee's International Classification System.⁹

We excluded patients with a solitary kidney, ectopic ureter, ureterocele, posterior urethral valve, duplex system, neuropathic bladder, exstrophy, active infection at the time of operation, kidneys with split renal function <15% on renal scintigraphy, and untreated voiding dysfunction. Initially, any child with lower urinary tract symptoms (LUTS) in the preoperative phase received medication. A 3-day bladder diary, dysfunctional voiding symptom score questionnaire, bladder postvoid residual volume, and urodynamics in selected cases were the basis for the concept of LUTS.

The study and the method of obtaining consent were approved by our Department and Faculty's Clinical Research and Ethical Committees. Urine culture and sensitivity, serum creatinine, abdominopelvic ultrasonography, VCUG, and renal scintigraphy were performed for all patients. Recurrent UTI, impairment of renal function owing to reflux, persistence of reflux after CAP, and renal scarring presence were indications of intervention. Most of the cases were operated on for breakthrough infections, which, despite adequate CAP, are defined as febrile UTIs with positive urine cultures.

Surgical technique: Dx/HA (Dexell) injection

Subureteral endoscopic injection technique (STING), as defined by O'Donnell and Puri, was performed on group A patients under general anesthesia.⁸ The median volume of Dexell per procedure was 1 mL and injected until the ureteric orifice collapse.

Surgical technique: extravesical ureteral reimplantation (Lich-Gregoir)

Pfannenstiel incision was performed and then an extraperitoneal approach to the bladder. Complete dissection of the detrusor along a straight line of the cephalad and lateral to the ureterovesical junction for 5 cm and undermining the detrusor against the mucosa to create an anti-refluxing trough was performed. Continuity of the ureter was not interrupted. The ureter was positioned in the new tunnel and re-approximated with interrupted absorbable suture. An indwelling catheter was placed for 3–5 days.

Follow-up

Patients were assessed by general examination, serial urinalysis, and urine culture and sensitivity. Renal ultrasound was performed at 1 and 3 months, and 1 year after the intervention and a VCUG at 3–6 months. Renal scintigraphy was carried out 6 months after the procedure.

The outcomes between both groups were analyzed according to surgical success rate, median cost, and complications. The child was considered to have been cured when there was no reflux on VCUG.

Statistical analysis

IBM SPSS Statistics version 23.0 (IBM Co.) was used to collect and analyze the data. We used the chi-square or Fisher's exact tests for categorical variables. The continuous variables were evaluated by Student's t-test or Mann–Whitney U test for equal and unequal distributions, respectively. P < .05 was considered significant.

Results

Between January 2016 and December 2018, 60 patients with primary VUR with 93 refluxing ureters, grades III and IV (41 females and 19 males) were included in this prospective randomized study. Endoscopic Dx/HA (Dexell) injection procedure (group A) was performed in 30 cases with 45 refluxing ureters, and open ureteral reimplantation (Lich-Gregoir) (group B) was performed in the other 30 cases with 48 refluxing ureters.

At the time of intervention, the median age of group A and group B patients was 59 (15–102) and 52 (range 12–110) months, respectively, with no statistically significant differences. There was no statistically significant difference in the gender distribution between both groups (Table 1).

Table 1.

Patients' Characteristics

	Group A	Group B	P
Median age, months (range)	59 (15–102)	52 (12–110)	.22
Gender, n (%)
Male	10 (33.3)	9 (30)	.78
Female	20 (66.7)	21 (70)
VUR grade, n = 93 units (%)
III = 49 units	27/45 (60)	22/48 (45.8)	.68
IV = 44 units	18/45 (40)	26/48 (54.2)
Unilateral/bilateral	15/15	12/18	.37
Renal scar, n = 93 units (%)	8/45 (17.8)	11/48 (23)	.53
Voiding dysfunction, n = cases (%)	5/30 (16.7)	6/30 (20)	.49
Presentation, n = cases (%)
RUTI	21 (70)	19 (63.3)	.74
ANH	4 (13.3)	3 (10)
LUTS	3 (10)	6 (20)
Pain	2 (6.7)	2 (6.7)
Indications for surgery, n = cases (%)
BUTI	15 (50)	16 (53.3)	.91
Persistent VUR	9 (30)	8 (26.7)
Progressive VUR	5 (16.7)	4 (13.3)
Noncompliance^a	1 (3.3)	2 (6.7)

Group A: Dx/HA (Dexell) endoscopic injection.

Group B: Ureteral reimplantation (Lich-Gregoir).

Noncompliance means patients uncooperative with medical treatment.

ANH, antenatal hydronephrosis; BUTI, breakthrough urinary tract infection; Dx/HA, dextranomer/hyaluronic acid; LUTS, lower urinary tract symptoms; RUTI, recurrent urinary tract infection; VUR, vesicoureteral reflux.

The main clinical presentation in group A and group B was UTI in 21 cases (70%) and 19 cases (63%). Other presentations included antenatal hydronephrosis, LUTS with no statistically significant difference in the two groups. Voiding dysfunction was recorded in 5 cases (16.7%) and 6 cases (20%) in group A and group B, respectively. All 11 patients received medical treatment for voiding dysfunction before procedures until improvement. Recurrent UTI was present in 21 cases (70%) and 19 cases (63.3%) in group A and group B, respectively (Table 1).

The most common indication for intervention in group A and group B was breakthrough UTI, and was found in 15 cases (50%) and 16 cases (53.3%), respectively. Other indications were persistent VUR in 9 cases (30%) and 8 cases (26.7%), progressive VUR in 5 cases (16.7%) and 4 cases (13.3%), noncompliance with medical treatment in 1 case (3.3%) and 2 cases (6.7%) in group A and group B, respectively with no statistically significant difference. Between group A and group B, the reflux grade distribution was (III) in 27 and 22 units, and (IV) in 18 and 26 units, respectively, and there was no statistically significant difference. Renal scarring existed in group A of 8 renal units and group B of 11 renal units, with no statistically significant difference (Table 1).

Table 2 provides the operative and postoperative outcomes. The mean operative time was longer for the open group than for the endoscopic group (110.3 ± 18.9 minutes and 28.6 ± 7.4 minutes, respectively), with a statistically significant difference between the two groups (P < .001). No intraoperative complications in either group have been detected. For all group A cases, the hospital stay was 1 day, and the median hospital stay in group B was 4 days (range: 2–7). The difference between the two groups was statistically significant (P < .001).

Table 2.

Operative and Postoperative Outcomes

	Group A	Group B	P
Operative time (min)^a	28.6 ± 7.4	110.3 ± 18.9	<.001
Hospital stay (days)^b	1	4 (2–7)	<.001
Follow up (months)^a	18.86 ± 8.23	16.91 ± 6.98	.67
Postoperative UTI, n = cases (%)	6/30 (20)	5/30 (16.7)	.89
Success rate, n = 93 units (%)
Overall	36/45 (80)	45/48 (93.75)	.007
III	23/27 (85.1)	21/22 (95.5)
IV	13/18 (72.2)	24/26 (92.3)

Data are presented as mean ± SD.

Data are presented as median (range).

UTI, urinary tract infection.

In group A, early postoperative complications (within the first 2 weeks postoperatively) such as fever was recorded in 3 cases (10%) and obstruction in 1 case (3.3%) was managed by double J stent insertion, whereas in group B fever was recorded in 6 cases (20%) and urine leak in 2 cases (6.6%); there was a statistically significant difference between the two groups (P = .003).

As regards late complication, in group A, UTI was recorded in 6 cases (20%) (febrile UTI in 2 cases [6.7%] and nonfebrile UTI in 4 cases [13.3%]). The need for CAP was recorded in 2 patients (6.7%) and new renal scarring in 2 patients (6.7%). In group B, UTI was recorded in 5 cases (16.7%) (febrile in 3 cases [10.2%] and nonfebrile UTI in 2 cases [6.5%]). The need for CAP was recorded in 2 patients (6.7%) and new renal scarring in 2 patients (6.7%).

The mean follow-up for the total patients was 17.7 ± 7.1 months (range 8–33 months), and there was no statistically significant difference between both groups. During this period, no cases of de novo hydroureteronephrosis or contralateral VUR were reported in either group (Table 2).

Overall reflux resolution in 93 renal units 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. There was a statistically significant difference between the results of both groups (P = .007) (Table 2).

The endoscopic injection failed in 9 units, so another injection was needed in all cases with improvement in 4 cases. After the second injection, the success rate became 88.9%, and the failed 5 cases after the second injection needed to salvage open ureteral reimplantation. The three failed cases in the open group B underwent redo open ureteral reimplantation.

The median cost of a single endoscopic injection was US$ 1027 (920–1125), whereas the median cost of an open procedure was US$ 1113 (1040–1300). There was no significant difference in one injection's median cost relative to the open technique despite the latter cost being marginally higher, but there was a significant difference when two injections were indicated in failed cases.

Discussion

During the last two decades, the frequency of open reimplantation of the ureter has declined, and endoscopic injection procedures for primary VUR management have increased.¹⁰ Despite a scarcity of randomized clinical trials and insufficient long-term outcome results for endoscopic injection studies, open ureteral reimplantation is still considered the gold standard for primary VUR management.¹¹

We believe that studies comparing different surgical interventions and recommendations for treating VUR are inadequate. That may be because of the lack of prospective randomized trials that compare different surgical methods.

Our study was a prospective interventional, randomized, comparative study comparing the outcomes of endoscopic Dx/HA injection and Lich-Gregoir technique for ureteric reimplantation in grades III and IV primary VUR in pediatric patients. There were no significant differences between both groups in gender, age, clinical presentation, and distribution of VUR grades. No intraoperative complications were recorded in either group. These results were comparable with the results in many studies.^12–14

This trial's mean operative time was 28.6 minutes versus 110.3 minutes, respectively, for injection and reimplantation groups (P < .001). In the injection group, the mean operative time and hospital stay were lower than that in the open group. Our findings supported the results of the previous studies.

A correlation was observed between an increase in the injected substance volume and an increase in the success rate.¹⁵ Nonetheless, our findings do not verify this because there was no substantial difference between the injected amounts.

Pediatric urologists in the United States most commonly performed the double Hydrodistention Implantation Technique for endoscopic injection.¹⁵ We used the STING technique because our experience is better despite using other techniques recently in many cases.

The success rates reported by the various studies using Dx/HA ranged between 68% and 92%, mainly depending on the grade of VUR.^16,17 Our study's success rate after a single Dexell injection based on postoperative VCUG was 80% of the ureters (85.1% in grade III and 72.2% in grade IV).

The success rate in our experience with Dexell is similar to that reported in various studies.^18,19 Better results were stated by Kim et al. and Stredele et al. (84% and 81.5%, respectively), which could be owing to the inclusion of lower grades of VUR (grades I and II) in their studies.^20,21 Our injection group success rate was better than that that of Oswald et al., who documented a 71.4% success rate despite their assumption that postoperative grade I reflux on follow-up was successful.²²

In this study, the success rate for open extravesical ureteral reimplantation was 93.75% (95.5% in grade III and 92.3% in grade IV). In the study carried out by Aboutaleb et al., extravesical reimplantation (Lich-Gregoir technique) on 166 ureters with primary low grade (I, II, and III) VUR, success rate 3 months after the procedure was 95.8%.²³

Silay et al. documented a success rate in the extravesical reimplantation cases with grades (III, IV, and V) as 94.9%.²⁴ In our study, the extravesical reimplantation failure rate (6.25%) was comparable with that reported in the literature (7%).

After open extravesical reimplantation, there are potential complications, including wound infection, more postoperative pain, bleeding, urinary retention risk after bilateral open procedures, surgical scar, and longer recovery. In various circumstances, the open procedures may have an advantage over endoscopic injection. The first indication is a salvage procedure after the failure of injection procedures in cases of persistent high-grade VUR. Second, when the injection is difficult, multiple injection sites and high injection material are required. Third, in cases of megaureter, ureteral tailoring is required.

Regarding cost-effectiveness, there was no statistically significant difference between the median cost of one injection and the open technique in our analysis. Garcia-Aparicio et al. reported a significant difference in cost-effectiveness after one injection intervention, and after open surgery, the median cost was more in the open group, but this variance disappears after two injections.¹³

To our knowledge, this study may be the first study to compare the outcomes of endoscopic injection of Dx/HA and Lich-Gregoir open technique of ureteral reimplantation for grades III and IV primary VUR in pediatric patients in prospective randomization.

There are limitations to our study—first, the study included small number of cases. Second, longer term follow-up was not feasible in our limited study time. Third, there is no documentation of pain scores and analgesics obtained after the procedures. Further studies are required to clarify these points.

Conclusion

A high success rate of open ureteral reimplantation (Lich-Gregoir) over endoscopic injection of Dx/HA therapy in the management of primary VUR grades III and IV was identified in this comparison study.

The endoscopic injection of Dexell was superior to the Lich-Gregoir operation in terms of operative time and hospital stay. Furthermore, it is a minimally invasive procedure, with no need for ureteral or urethral stenting.

Footnotes

Authors' Contributions

E.S.: protocol development, Data Collection, article writing; H.E.: data collection, article editing; G.S.: data analysis, article writing; H.G.: data analysis, article revision.

Ethical Approval

All procedures conducted in studies involving human subjects were consistent with the Al-Azhar Faculty of Medicine Ethical Committee's ethical principles and the Declaration of Helsinki of 1964 and its later modifications or equivalent ethical principles. Ethical committee number (IRB): Uro-surg./R/2015/0011.

Informed Consent

All participants participating in the study received informed consent.

Data and Content Availability

The datasets created and analyzed during this study are not accessible to the public as this is our university's policy but are accessible on appropriate request from the corresponding author.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Lee

, Gatti

, Demarco

, Murphy

. Long-term follow up of dextranomer/hyaluronic acid injection for vesicoureteral reflux: Late failure warrants continued follow-up. J Urol, 2009; 181:1869–1874.

Koyle

, Elder

, Skoog

, Mattoo

, Pohl

, Reddy

, et al. Febrile urinary tract infection, vesicoureteral reflux, and renal scarring: Current controversies in approach to, evaluation. Pediatr Surg Int, 2011; 27:337–346.

Jodal

, Smellie

, Lax

, Hoyer

. Ten-year results of randomized treatment of children with severe vesicoureteral reflux. Final report of the International Reflux Study in Children. Pediatr Nephrol, 2006; 21:785–792.

Stein

, Dogan

, Hoebeke

, Kočvara

, Nijman

, Radmayr

, et al. Urinary tract infections in children: EAU/ESPU guidelines. Eur Urol, 2015; 67:546–458.

Sung

, Skoog

. Surgical management of vesicoureteral reflux in children. Pediatr Nephrol, 2012; 27:551–561.

Fonseca

, Tanno

, Nguyen

. Current options in the management of primary vesicoureteral reflux in children. Pediatr Clin N Am, 2012; 59:819–834.

Matousek

. New concept for treatment of vesicoureteral reflux. Endoscopic application of Teflon. Arch Esp Urol, 1981; 34:385.

O'Donnell

, Puri

. Treatment of vesicoureteral reflux by endoscopic injection of Teflon. Br Med J, 1984; 289:7.

Weiss

, Duckett

, Spitzer

. Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). The International Reflux Study in Children. J Urol, 1992; 148:1667–1673.

10.

Kurtz

, Leow

, Varda

, et al. The decline of the open ureteral reimplant in the United States: National data from 2003 to 2013. Urology, 2017; 100:193–197.

11.

Gundeti

, Boysen

, Shah

. Robot-assisted laparoscopic extravesical ureteral reimplantation: Technique modifications contribute to optimized outcomes. Eur Urol, 2016; 70:818–823.

12.

Karakus

, User İR, Kılıc

, Akçaer

, Ceylan

, Ozokutan

. The comparison of dextranomer/hyaluronic acid and polyacrylate-polyalcohol copolymers in endoscopic treatment of vesicoureteral reflux. J Pediatr Surg, 2016; 51:1496–1500.

13.

Garcia-Aparicio

, Rovira

, Blazquez-Gomez

, García-García

, Giménez-Llort

, Rodo

, et al. Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen's ureteral reimplantation for vesicoureteral reflux: Long-term results. J Pediatr Urol, 2013; 9:483–487.

14.

Esposito

, Escolino

, Lopez

, Farina

, Cerulo

, Savanelli

, et al. Surgical management of pediatric vesicoureteral reflux: A comparative study between endoscopic, laparoscopic, and open surgery. J Laparoendosc Adv Surg Tech A, 2016; 26:574–580.

15.

Kirsch

, Perez-Brayfield

, Smith

, Scherz

. The modified STING procedure to correct vesicoureteral reflux: Improved results with submucosal implantation within the intramural ureter. J Urol, 2004; 171:2413–2416.

16.

Moliterno

, Scherz

, Kirsch

. Endoscopic treatment of vesicoureteral reflux using dextranomer hyaluronic acid copolymer. J Paediatr Urol, 2008; 4:221–228.

17.

Certain

, Arafeh

, Zeldin

, Ostrovsky

, Kocherov

. Endoscopic correction of VUR using Ventris as a new nonbiodegradable tissue-augmenting substance: Three years of prospective follow-up. Urology, 2013; 82:201–204.

18.

Dogan

, Altan

, Citamak

, Bozaci

, Koni

, Tekgul

. Factors affecting the success of ET of VUR and comparison of two dextranomer based bulking agents: Does bulking substance matter?. J Pediatr Urol, 2015; 11:90.e1–e5.

19.

Moore

, Bolduc

. Prospective study of polydimethylsiloxane vs dextranomer/hyaluronic acid injection for treatment of vesicoureteral reflux. J Urol, 2014; 192:1794–1799.

20.

Kim

, Shin

, Hwang

, Oh

, Jung

, et al. Clinical efficacy and safety in children with vesicoureteral reflux of a single injection of two different bulking agents–polydimethylsiloxane (Macroplastique) or dextranomer/hyaluronic acid copolymer (Deflux): A short-term prospective comparative study. Urol Int, 2011; 87:299–303.

21.

Stredele

, Dietz

, Stehr

. Long-term results of endoscopic treatment of vesicoureteral reflux in children: Comparison of different bulking agents. J Pediatr urol, 2013; 9:71–76.

22.

Oswald

, Riccabona

, Lusardi

, Bartsch

, Radmayr

. 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; 60:894–897.

23.

Aboutaleb

, Bolduc

, Upadhyay

, Farhat

, Bägli

, Khoury

. Subureteral Polydimethylsiloxane injection versus extravesical reimplantation for primary low-grade vesicoureteral reflux in children: A comparative study. J Urol, 2003; 169:313–316.

24.

Silay

, Turan

, Kayalı Y, Başıbüyük İ, Gunaydin B, Caskurlu T, et al. Comparison of intravesical (Cohen) and extravesical (Lich-Gregoir) ureteroneocystostomy in the treatment of unilateral primary vesicoureteric reflux in children. J Pediatr Urol, 2018; 14:65.e1–65.e4.