Canan Kocaoglu. S (16) DOI: doi: /j.jpedsurg Reference: YJPSU 57646

Transcription

1 Accepted Manuscript Endoscopic treatment of grades IV and V vesicoureteral reflux with two bulking substances: Dextranomer hyaluronic acid copolymer versus polyacrylate polyalcohol copolymer in children Canan Kocaoglu PII: S (16) DOI: doi: /j.jpedsurg Reference: YJPSU To appear in: Journal of Pediatric Surgery Received date: 4 January 2016 Revised date: 8 March 2016 Accepted date: 20 March 2016 Please cite this article as: Kocaoglu Canan, Endoscopic treatment of grades IV and V vesicoureteral reflux with two bulking substances: Dextranomer hyaluronic acid copolymer versus polyacrylate polyalcohol copolymer in children, Journal of Pediatric Surgery (2016), doi: /j.jpedsurg This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Endoscopic treatment of grades IV and V vesicoureteral reflux with two bulking substances: Dextranomer hyaluronic acid copolymer versus polyacrylate polyalcohol copolymer in children Canan Kocaoglu, MD* Konya Education and Research Hospital, Department of Pediatric Surgery, Meram Yeni Yol, Konya, Turkey, drckocaoglu@hotmail.com *Corresponding author: Canan Kocaoglu, M.D. Konya Education and Research Hospital, Department of Pediatric Surgery, Meram, Konya/TURKEY Tel: Fax: drckocaoglu@hotmail.com The study was presented at The Current Aproaches in Treatment of Vesicoureteral Reflux (VUR) 2013 Workshops September 29th-October1th, 2013 in Istanbul, Turkey. Conflict of interest: None. Grants or Financial Support: None declared. The study was approved by the ethics committee of the Medical School of Necmettin Erbakan University.

3 Abstract Purpose: We aimed at evaluating the efficacy and complications of two bulking substances: Dextranomer/hyaluronic acid copolymer(dx/ha;dexell ) versus polyacrylate polyalcohol copolymer(ppc;vantris ) in subureteric injection treatment of children with high grades (grades IV-V) vesicoureteral reflux(vur). Methods: Data of patients undergoing endoscopic treatment of high grade VUR (January 2009-August 2015) were retrospectively investigated. Patients with high grade VUR caused by posterior urethral valve, duplex system, paraureteral diverticula and neurogenic bladder were excluded. Classical subureteric injection method(sting) was used. Seventy-three children (45 girls and 28 boys) who had 88 refluxing renal units(rrus) with grades IV-V VUR(n=64/n=24) underwent endoscopic treatment using Dx/Ha(n=63 RRUs) and PPC(n=25 RRUs). Results: Mean age of patients in Dx/Ha and PPC groups were 6(3) and 6(3.75)year(p=0.81), and volumes of these substances given were 1.3(1) and 1(0.5)mL (p=0.003), respectively. Overall, for the first endoscopic injection, success rate of grades IV-V VUR per RRU was 53.9% with Dx/Ha, compared to 80% in PPC-injected group,(p=0.024). Late ureterovesical junction obstruction developed only in one patient in PPC-injected group. No ureteral obstruction was observed in Dx/Ha-injected group. Conclusions: Endoscopic injection of PPC resulted in significantly higher success rate, compared to Dx/Ha in subureteric injection treatment of children with high grade VUR. However, the development of late ureterovesical junction obstruction should also be taken into account in PPC injection. Keywords: endoscopic injection, high grade vesicoureteral reflux, vantris, polyacrylate polyalcohol copolymer, Dextranomer/ hyaluronic acid copolymer, Dexell

4 Introduction Vesicoureteral reflux (VUR) is a common problem in childhood period, and its prevalance in normal children has been estimated to be between % [1]. Endoscopic treatment of primary VUR by subureteral injection (STING) is a modality used in children in the last three decades [2]. Because of being a relatively easy and minimal invasive procedure, STING is an alternative method to open surgery and long-term antibiotic prophilaxis. However, the most significant negative side of endoscopic treatment is that its success rate is lower, especially in high grade VUR than open surgery. In order to increase the success rate of endoscopic treatment, additional injections may be required [3]. Additionally, the experience of the surgeon, the content of substance used for injection, submucosal stability of injected substance, and the grade of VUR are the factors known to affect the success of procedure [4,5]. The aim of our study was to evaluate the efficacy and complications of two bulking substances: Dextranomer/ hyaluronic acid copolymer (Dx/Ha; Dexell ) versus polyacrylate polyalcohol copolymer (PPC; Vantris ) in endoscopic treatment of children with grades IV and V VUR. 1. Materials and Methods The data of patients undergoing endoscopic treatment of high grade VUR between January 2009 and August 2015 were retrospectively reviewed. Patients with grades IV and V reflux were considered high grade reflux. The following were included into the study as parameters we analyzed: sex, age when the first injection was given, grade and laterality of VUR, number of injections, volume and type of substaces used for injection, ureteral orifice configuration, complications after surgery and outcome. Endoscopic treatment was performed in 73 children (45 girls and 28 boys) who had 88 refluxing renal units (RRUs) with grades IV and V VUR using Dx/Ha and PPC, injected as a total of 63 and 25 RRUs, respectively. Of

5 total 88 RRUs, 64 were grade IV VUR while 24 were grade V. The demographic data and distribution of patients characteristics are presented in Table 1. The selection of substance was dependent on the availability of the material in the hospital, in accordance with the reimbursement conditions of the social security system in Turkey. VUR was diagnosed by voiding cystourethrogram (VCUG) and classified under the International Classification System constituted by the International Reflux Study Committee [6]. Our indication of endoscopic treatment was high grade VUR along with breakthrough urinary tract infection (UTI), progressive renal scarring and nonresolution of VUR only in a few pre-school children. Patients with high grade VUR caused by posterior urethral valve, duplex system, ectopic ureter, paraureteral diverticula and neurogenic bladder were excluded. Children who had symptoms of dysfunctional voiding or constipation were treated conservatively before endoscopic correction. Endoscopic treatment was performed under general anesthesia with a pediatric cystoscope (9.5 F and 11 F Olympus ), and a Williams cystoscopic injection needle of 3.7 F, 23 gauge and 35 cm (Cook ) was used for the injections by a single surgeon (C.K.) through STING, a technique similar to that described in literature [7,8]. The usual technique of STING with the needle introduced submucosally under the ureteral orifice at 6-o clock position was used in all patients, except for four patients with a widely open orifice in whom the injection was performed with the hydrodistention implantation technique. The injection of bulking substances was continued until the volcanic bulge was observed, raising the ureteral meatus onto the dome of the mound. In most of the patients, endoscopic injection was performed as an outpatient procedure. Antibiotic prophylaxis was used perioperatively and after STING, continued until the reflux was documented to resolve on postoperative cystogram. Control VCUG was performed at the third postoperative month. Preoperative evaluation consisted of urinalysis and culture, renal and bladder ultrasonography, dimercaptosuccinic acid scan, and videouro-dynamic studies.

6 Postoperative studies included renal and bladder ultrasonography, urinalysis and urine culture performed on the 10th day, and at the 1st, and 3rd months after the procedure. The success of STING was defined as the elimination of VUR with a single injection. After the VUR was resolved, these children were followed up clinically and radiologically with renal ultrasound at1st year and every 2 years. Complications were classified as UTI, progressive ureteral dilatation and neocontralateral VUR. Statistical analyses were performed using SPSS for Windows 15.0 (SPSS, Chicago, IL). The appropriateness of variables to normal distribution rates was evaluated with visual histogram and probability graphics using analytic methods such as the Kolmogorov-Smirnov and Shapir-Wilk tests. Descriptive analyses were shown using median and interquartile range (IQR) for abnormal variables, and frequency tables for ordinal variables. The univariate analyses to identify variables associated with patient outcome were investigated using the chisquare, Fisher s exact, and Mann-Whitney U tests where they were appropriate. In multivariate analyses, the possible factors identified with univariate analyses were further entered into the logistic regression analyses to determine independent predictors of patient outcome. The receiver operating characteristic (ROC) curve analysis was performed to determine optimal cutoff values related to ages. p < 0.05 was considered statistically significant. An ethical approval was obtained from the ethical committee of Meram Medical School of Necmettin Erbakan University in Konya, Turkey. 2. Results Median intraoperational age (IQR) was 6 (3) years (range 10 months-13 years) for Dx/Ha-injected group and 6 (3.75) years (range 2,5-14 years) for PPC-injected group.

7 For the first endoscopic injection, the success rates per RRU for grades IV and V VUR were 53.9% (34/63) in those injected with Dx/Ha, compared to 80% (20/25) in those with PPC (p = 0.024) although the success rates were found as 64% (41/64) for grade IV VUR and 54% (13/24) for grade V VUR. After the first injection, while a complete resolution was obtained in 24 of 44 grade IV VUR in Dx/Ha-injected group, 17 of 20 grade IV VUR in RRUs in PPC-injected group displayed a complete resolution (p=0.019). For grade V VUR after the first injection, although a complete resolution was obtained in 10 of 19 RRUs in Dx/Ha-injected group, three of five RRUs in PPC-injected group displayed a complete resolution (p=0.769) (Table 2). We were able to find no difference in the distribution of such parameters as sex (boy vs girl, via chi-square test, p=0.149), median age at the first injection (Dx/Ha group vs PPC group, via Mann-Whitney U test, p=0.81), ureteral orifice configuration (normal cone vs shapes of stadium, horseshoe, golf hole and lateral pillar defect, via chisquare test, p=0.061), degree (grade IV vs V, via chi-square test, p=0.335) and laterality of VUR (unilateral vs bilateral VUR, via chi-square test, p=0.158), which were likely to cause such a difference. The median injected volumes of bulking substances per ureter (IQR) were 1.3 (1) ml for Dx/Ha and 1 (0.5) ml for PPC (via Mann-Whitney U test, p = 0.003), and only the volume of the bulking substance was significant (Table 1). After the second injection, the repair of VUR was also obtained as 19.0% (12/63) (cumulative 69.8%) in those injected with Dx/Ha and as 4% (1/25) (cumulative 84%) in those with PPC (p=0.073). In two of 63 RRUs injected with Dx/Ha, a regression to grade I VUR was observed only after the first injection. Ureteroneocystostomy was performed in 20.6% (13 RRUs) of Dx/Ha-injected group and in 12% (3 RRUs) of PPC group (p=0.026). Of our patients, only three patients from Dx/Ha and one from PPC-injected group (4.45%) were lost to follow-up after the first and second injections, respectively. Mean follow-up time was 31 months (range 4 58 months).

8 Patients with high grade VUR that were treated with STING were compared as to whether the resolution of VUR was observed or not, to identify predictive factors of success. Based on the univariate analysis, the type and volume of substances, and age were found to be significant, and the findings are presented in Table 3. On the other hand, the multivariate analysis performed with logistic regression method showed that only age and type of substances affected the success rate of STING, as independent of sex, laterality, volume of substances and grade of VUR [Odds Ratio:1.34 (95% CI: ) and Odds Ratio: 0.25 (95% CI: )] ( p<0.05). Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cutoff values about ages. Cutoff values: 6< sensitivity: 54.55%, specificity: 78.79%, area under the curve (AUC) 0.713, 95% confidence interval (CI) (p=0.0001). One ureteral obstruction was witnessed within the follow-up period in PPC group. Due to grade II VUR on the right ureter and grade IV on the left, a six-year-old girl was endoscopically treated with injections of PPC (1.0 cc to right ureteral orifice and 1.4 cc to left uretaral orifice). Both ureteral orifices were seen as normally localized, but in stadiumshaped. On controlling VCUG performed three months later, bilateral reflux was determined to be ameliorated. Intermittent abdominal pain was determined in the patient during followup. Also, hydroureteronephrosis was observed on the left on her controlling ultrasonography at month 6. Hydroureteronephrosis progressed to grade IV at the 20th postoperative month. Considering the development of late ureterovesical junction obstruction, cystoscopy was repeated at the 20th postoperative month. On cystoscopy, the stenosis of left ureteral orifice was observed. Ablation was performed via Holmium YAG laser in PPC tubercule in the left orifice. Some part of the content was drained via grasper, and a JJ catheter was placed. At month 5, the JJ catheter was removed. On controlling ultrasonoraphy, it was detected that hydroneprosis was decreased on the left; uretary width was disappeared; and, paranchimal

9 thickness was almost equalled (right, 10 mm and left, 9 mm). No ureteral obstruction was seen within the follow-up period in Dx/Ha group; however, one peroperative iatrogenic bladder diverticulum was occured and due to the diverticulum, postoperative urinary retention was developed. Thirteen patients (8 in Dx/Ha and 5 in PPC-injected groups) developed UTI during the follow-up period with a normal postoperative VCUG (p=0.324). Four patiens were detected to have neocontralateral VUR on control VCUG in Dx/Ha-injected group, and of these four patients, three were corrected via a single endoscopic injection in both recurrent and neocontralateral VUR while the fourth was corrected with ureteroneocystotomy. No VCUG was routinely performed one year after the procedure. We consider that except for VCUG performed routinely at month 3, VCUG should only be performed in patients with recurrent UTI or its recurrent symptoms one year after injections. 3. Discussion VUR is one of the common problems encountered in childhood period. The main goals in managing children with VUR are to prevent recurrent UTI and renal injury, and minimize the morbidity of treatment and follow-up. Treatment options for managing VUR include the following modalities: long-term antibiotic prophylaxis, observation or intermittent therapy with the management of bladder/bowel dysfunction, the treatment of UTI whenever it occurs, open surgery, laparoscopic surgery and minimally invasive endoscopic injection. Despite the high success rate of ureteral reimplantation, endoscopic treatment is considered by many as the gold standard, especially for low grade VUR because of its less invasive character and high success rate similar to open surgery [9]. Overall success rate reported by different groups of authors ranges between 68 to 92%, depending mainly on the grade of VUR [7,10,11]. In our study, after the first endoscopic injection, success rate per

10 RRU for grades IV and V VUR was 53.9% in those injected with Dx/Ha and 80% with PPC (p=0.024). Grade of VUR is one of the most important factors affecting the success rate of endoscopic treatment. A meta-analysis performed by Elder et al. [5] revealed that success rate becomes decreased as reflux grade increases. In the same meta-analysis, high grade VUR (grades IV and V) was reported to be treated with variable success rates, and the single treatment resolution rate for grades IV and V VUR was found to be 63% and 51%, respectively. As consistent with the findings reported in the meta-analysis, we found the success rates as 64% for grade IV VUR and 54% for grade V VUR after the first injection. Since its first description in 1984, endoscopic injection of VUR has been the subject of many studies with multiple bulking substances [12]. Synthetic and absorbable Dx/HA copolymer is the only substance approved by FDA (The Food and Drug Administration) and used in the treatment of VUR. Particle size of Dx/Ha is more than 80μm. This reduces the migration probability of the substance and causes no allergic reactions. Two weeks after the injection, hyaluronic acid is absorbed from the injection field, and microparticles of dextranomer are retained [13]. Despite the overall high success rates reported by different authors, there still remain concerns about short-term follow-up of most series, as well as intriguing data found recently regarding the high incidence of VUR recurrence following successful Dx/Ha treatment. These results led us to investigate whether another tissue augmenting substance could achieve long-term efficacy or obtain a complete correction of VUR [14]. In 2008, Ormaechea et al. [15] published a report where the effect a new tissueaugmenting substance called PPC was investigated. So, synthetic and non-absorbable PPC became another new substance used to treat VUR, the size and fibrotic capsule of which remain 320 μm and 70 μm after implantation, respectively. The bulging effect at ureteral orifice remains within years, because it cannot be absorbed when the substance is injected into

11 soft tissues. No foreign material reaction, cytotoxicity, necrosis and migration within a 1-year follow-up after the injection of PPC were observed in animal research models. The stability of fibrotic capsule for a long time is an important advantage in achieving long-term success [16]. In our study, we compared the effectiveness and complications of these two bulking substances: Dx/Ha and PPC in subureteric injection treatment of children with grades IV-V VUR. Comparing Dx/Ha injections with PPC for the subureteral endoscopic injection of VUR, only a single study in which no statistically significant difference was detected between Dx/Ha and PPC has been performed and published so far [17]. To the best of our knowledge, our study is also the first to compare Dx/Ha with PPC for the subureteral endoscopic injection of grades IV and V VUR. A systematic review showed a 77% success rate at the 3rd month with Dx/Ha and a negative influence of high VUR grade on outcomes [18]. In a study performed by Capozza et al. [19], only 41% of success rate was reported for grade IV VUR with Dexell, while Hsieh et al. [20] reported 75.7% of succes rate in grade IV and 55.6% in grade V VUR with Dx/Ha. As parallel to the findings reported in these studies, we found that the use of Dx/Ha to treat VUR in children had success rates of 54.5% for grade IV and 52.6% for grade V VUR after the first injection. A multicentered study reported that the initial experience with PPC for all grades VUR had an 83.6% of success rate [16]. In another study, it was reported that the use of PPC to treat grades IV and V VUR in young children had an overall success rate of 83.3% [21]. On the other hand, Corbetta et al. [22] reported a succes rate of 90% for grade IV and 50% succes rate for grade V VUR with PPC. As consistent with the findings reported by Corbetta et al., a 77% of succes rate for grade IV VUR and a 67% of succes rate for grade V VUR were reported with PPC in the study by Chertin et al [23]. As similar to the findings of these studies, we also determined that the use of PPC to treat VUR in children had success rates of 85% in grade IV and 60% in grade V VUR.

12 In our patients with grades IV-V VUR, the success rate was found as 53.9% in those treated with Dx/Ha while as 80% in those treated with PPC in the first injection (p=0.024). We found no difference in the distribution of the parameters such as sex, median age at the first injection, ureteral orifice configuration, degree and laterality of VUR, which were likely to cause such a difference. On the other hand, in terms of factors affecting the success rate, only age and type of substances were found to be effective. Dx/Ha (1.3 ml) was used at a greater amount per ureter, compared to PPC (1.0 ml). Because of its high molecular mass and large particle size, PPC can provide adequate bulkiness at the ureteral orifice in lower volumes. Both products are delivered in a 1-mL syringe, and once a syringe is used, no content can be preserved until the next intervention. Because the cost of a 1-mL syringe of Dx/Ha is about 50% lower than that of PPC in Turkey, the cost of Dx/Ha per each RRU is nearly equal that of PPC. As to complications, the primary aim of anti-reflux interventions is to prevent reflux of urine into kidneys rather than preventing UTI. Despite a successful endoscopic or open antireflux procedure, it is known that UTI might occur. Although being decreased, the number and incidence of UTI never get to zero per cent [24]. Similarly, despite a successful endoscopic treatment, nonfebrile UTI was detected in 13 patients in our study, but no significant difference was found between both groups. In most of the settings, no complications develop in endoscopic subureteric injection procedures. Even so, the only procedure-related important complication is the postoperative obstruction of ureteral orifice, usually transient and requiring no intervention. Nonetheless, ureteral obstruction might be significant and require intervention in a very small percent of patients, reported to be less than 1% with Dx/Ha [25]. In a recent study, however, Mazzone et al. [26] reported some disturbing figures showing that 5.7% of patients injected with Dx/Ha

13 displayed ureterovesical junction obstruction and required ureteral reimplantation or stent insertion. Reporting obsruction rates as 1.2%, 5-6%, 1.1% and 3%, various studies have suggested recently that PPC leads to obstruction in endoscopic treatment [16,21,27,28]. In our series of 25 RRUs, late ureterovesical junction obstruction was detected in only one (4%) patient in PPC group, while no obstruction was observed in Dx/Ha-injected group. In two studies reporting controversial findings related to orifice configuration in the prevention of VUR, Trsinar et al. [29] emphasized that VUR, hydro-distention grade and orifice configuration are likely to cause unsuccessful endoscopic treatment of VUR, while Fashid et al. reported no significant relationship between ureteral orifice configuration and success rate of VUR [30]. Likewise, no significant difference was found between normal cone, and shapes of stadium, horseshoe, golf hole and lateral pillar defect in our study. Among the limitations in our study, the following points may be suggested: the numbers of participants are relatively small with 25 in PPC group versus 63 in Dx/Ha group; the duration of follow-ups was relatively short; and, the study was non-randomised and retrospective. In conclusion, endoscopic injection of PPC resulted in a significant higher success rate, compared to that of Dx/Ha copolymer in subureteric injection treatment of children with grade IV VUR. Even so, Dx/Ha and PPC had equal success rate for grade V. Therefore, we recommend that patients undergoing endoscopic treatment of PPC for the treatment of VUR need long-term follow-ups, despite reflux showing complete resolution after injection. The development of late ureterovesical junction obstruction should be kept in mind by pediatric surgeons in performing PPC injection.

14 References: [1] Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol 2000;30: [2] O Donnell B, Puri P. Endoscopic correction of primary vesicoureteric reflux: results in 94 ureters. Br Med J 1986;2: [3] Yu TJ, Chang LC. Use of collagen for endoscopic correction in complicated vesicoureteral reflux. Scan J Urol Nep 2007;41: [4] Aaronson IA, Rames RA, Greene WB, Walsh LG, Hasal UA, Garen PD. Endoscopic treatment of reflux: migration of Teflon to the lungs and brain. Eur Urol 1993;23: [5] Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R, Kirsch A, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006;175(2): [6] Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics 1981;67(3): [7] Chertin B, Puri P. Endoscopic management of vesicoureteral reflux: does it stand the test of time? Eur Urol 2002;42: [8] Chertin B, De Caluwè D, Puri P. Endoscopic treatment of primarygrades IV and V vesicoureteral reflux in children with subureteral injection of polytetrafluoroethylene. J Urol 2003;169: [9] Garcia-Aparicio L, Rovira J, Blazquez-Gomez E, García-García L, Giménez-Llort A, Rodo J, 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(4): [10] Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004;171: [11] Elder JS, Shah MB, Batiste LR, Eaddy M. Part 3: Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux. Curr Med Res Opin 2007;23(Suppl 4): [12] Diamond DA, Mattoo TK. Endoscopic treatment of primary vesicoureteral reflux. N Engl J Med 2012;366: [13] Tsai CC, Lin V, Tang L. Injectable biomaterials for incontinence and vesico-ureteral reflux: current status and future promise. J Biomed Mater Res B Appl Biomater 2006;77: [14] Chertin B, Arafeh WA, Zeldin A, Kocherov S. Preliminary data on endoscopic treatment of vesicoureteric reflux with polyacrylate polyalcohol copolymer (Vantris ): surgical outcome following single injection. J Pediatr Urol 2011;7(6): [15] Ormaechea M, Paladini M, Pisano R, Scagliotti M, Sambuelli R, Lopez S, et al. Vantris, a biocompatible, synthetic, nonbiodegradable, easy-to-inject bulking substance. Evaluation of local tissular reaction, localized migration and long-distance migration. Arch Esp Urol 2008;61(2): [16] Ormaechea M, Ruiz E, Denes E, Gimenez F, Dénes FT, Moldes J, et al. New tissue bulking agent (polyacrylate polyalcohol) for treating vesicoureteral reflux: preliminary results in children. J Urol 2010;183: [17] Turk A, Selimoglu A, Demir K, Celik O, Saglam E, Tarhan F. Endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer and dextranomer/hyaluronic acid in adults. Int Braz J Urol 2014;40(3): [18] Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics 2010;125: [19] Capozza N, Patricolo M, Lais A, Matarazzo E, Caione P. Endoscopic treatment of vesicoureteralreflux: twelve years experience. Urol Int 2001;67(3): [20] Hsieh MH, Madden-Fuentes RJ, Lindsay NE, Roth DR. Treatment of pediatric vesicoureteral reflux using endoscopic injection of hyaluronic acid/dextranomer gel: intermediate-term experience by a single surgeon. Urology 2010;76(1): [21] De Badiola FI, Soria R, Vagni RL, Ormaechea MN, Moldes JM, Benmaor C. Results of Treatment of Grades IV and V Vesicoureteral Reflux with Endoscopic Injection of Polyacrylate Polyalcohol Copolymer. Front Pediatr 2013;1:32.

15 [22] Corbetta JP, Bortagaray JI, Weller S, Ruiz J, Burek C, Sager C, et al. The use of polyacrylatepolyalcohol copolymer hydrogel in the endoscopic treatment of primary vesicoureteral reflux in children. J Pediatr Surg 2015;50(3): [23] Chertin B, Arafeh WA, Zeldin A, Ostrovsky IA, Kocherov S. Endoscopic Correction of VUR Using Vantrisas a New Non-biodegradable Tissue Augmenting Substance: Three Years of Prospective Follow-up. Urology 2013;82(1): [24] Hunziker M, Mohanan N, D Asta F, Puri P. Incidence of febrile urinary tract infections in children after successful endoscopic treatment of vesicoureteral reflux: a long-term follow-up. J Pediatr 2012;160(6): [25] Vandersteen DR, Routh JC, Kirsch AJ, Scherz HC, Ritchey ML, Shapiro E, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic Acid copolymer. J Urol 2006;176: [26] Mazzone L, Gobet R, González R, Zweifel N, Weber DM.. Ureteral obstruction following injection of dextranomer/hyaluronic acid copolymer: an infrequent but relevant complication. J Pediatr Urol. 2012;8: [27] Şencan A, Yıldırım H, Özkan KU, Uçan B, Karkıner A, Hoşgör M. Late ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcoholcopolymer. Urology 2014;84(5): [28] Alizadeh F, Mazdak H, Khorrami MH, Khalighinejad P, Shoureshi P. Postoperative ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer (Vantris ). J Pediatr Urol 2013;9(4): [29] Trsinar B, Cotic D, Oblak C. Possible causes of unsuccessful endoscopic collagen treatment of vesicoureteric reflux in children. Eur Urol 1999;36: [30] Alizadeh F, Shahdoost AA, Zargham M, Tadayon F, Joozdani RH, Arezegar H. The influence of ureteral orifice configuration on the success rate of endoscopic treatment of vesicoureteral reflux. Adv Biomed Res 2013;2:1.

16 Table 1. Demographic data and distribution of patients characteristics Dx/Ha PPC P value Patients Median intraoperational age (year) (IQR) Boys n 23 (43%) 5 (25%).149 a Girls n 30 (57%) 15 (75%) Bilateral n 22 (41.5%) 12 (60%).158 a Unilateral n 31 (58.5%) 8 (40%) 6 (3) 6 (3.75).810 b RRUs Median volume of injected substance (ml) (IQR) Grade IV n 44 (70%) 20 (80%).335 a Grade V n 19 (30%) 5 (20%) 1.3 (1) 1 (0.5).003 b Orifice configuration n 15(23.8%) 11(44%).061 a Lateral pillar defects n 2 5 Stadium-shaped n 5 3 Golf hole n 8 2 Form of horseshoe n - 1 Dx/Ha, dextranomer/hyaluronic acid copolymer; PPC, polyacrylate polyalcohol copolymer; IQR, interquartile range; RRUs, refluxing renal units a, chi-square test. b, Manne-Whitney U test.

17 Table 2. Outcome of endoscopic correction of VUR after first injection (chi-square test) Dx/Ha PPC P value RRU n Success n (%) RRU n Success n (%) Grade IV (54.5) (85).019 Grade V (52.6) 5 3 (60).769 Total (53.9) (80).024 Dx/Ha, dextranomer/hyaluronic acid copolymer; PPC, polyacrylate polyalcohol copolymer;

18 Table 3. Comparison of success rate of STING regarding several factors (chi-square test) Success Failure P value Median age (year) 7(4) 5(3).001 (IQR) Sex Boys n Girls n Laterality Bilateral n Unilateral n Median volume of 1(0.7) 1.5(1).012 substances (ml)(iqr) Substances Dx/Ha n PPC n 21 4 Grade IV n V n Orifice configuration Normal n Others n Dx/Ha, dextranomer/hyaluronic acid copolymer; PPC, polyacrylate polyalcohol copolymer; IQR, interquartile range