PEDIATRIC UROLOGY A Comparison Between Dextranomer/ Hyaluronic Acid and Polyacrylate Polyalcohol Copolymer as Bulking Agents for Treating Primary Vesicoureteral Reflux Farshid Alizadeh1, Iman Omidi1, Saeid Haghdani2*, Mohammad Hatef Khorrami1, Mohammad Hossein Izadpanahi1, Mehrdad Mohammadi Sichani1 Purpose: In recent years, endoscopic subureteral injection has gained popularity as a therapeutic alternative to open surgery because of its high success rates and low morbidity. We compared the success and complication rates of Polyacrylate polyalcohol copolymer (PPC) and Dextranomer/Hyaluronic acid (Dx/HA) in the endoscopic treatment of VUR. Materials & Methods: We retrospectively reviewed the patients who underwent endoscopic correction of their VUR by subureteric injection of PPC or Dx/HA from Jan 2010 to April 2016. The injection technique was STING (subureteric), distal HIT (intraureteric), and double HIT according the hydrodistention (HD) grade. The success rate, injection technique, injection volume, VUR grade, and obstruction rate were evaluated and compared between two groups. Results: 107 renal refluxing units (RRU) with a mean age 55.23 ± 36.58 months and 64 RRU with a mean age 52.13 ± 31.66 months were treated in Dx/HA and PPC groups, respectively. The PPC group showed a more suc- cessful outcome in comparison to the Dx/HA group (92.2% versus 75.7% of the RRU with P < .001) at 3 months follow up. The injection technique was not significantly different between two groups. In PPC group the success rate was decreased significantly with increasing reflux grade but this reduction was not statistically significant in Dx/HA group. The injected volume was significantly more in PPC group; in addition, there was statistically sig- nificant correlation between injected volume of the bulking agent and obstruction rate. However, the obstruction rate did not establish significant difference between the two groups (P = .83), however it was earlier in Vantris (4 months versus 22 months). Conclusion: Our investigation approved PPC as a more effective material, regardless of other confounding vari- ables such as reflux grade, learning cure, and technique of injection, in endoscopic treatment of VUR. In addition, the other remarkable point is this effectiveness is not accompanied by more post-operation obstruction. Keywords: vesicoureteral reflux; Dextranomer/ hyaluronic acid; polyacrylate polyalcohol copolymer; endoscop- ic treatment INTRODUCTION Vesicoureteral reflux (VUR), the abnormal flow of urine from the bladder into the ureters or kidneys, is the most common urological anomaly in children(1). The primary goal of therapy in VUR is to prevent py- elonephritis which can lead to long-term sequelaes such as renal scarring, hypertension, reduced somatic growth, renal insufficiency and end-stage renal disease (2,3). Treatment routes for VUR include observation, antibiotic prophylaxis, and surgical intervention(4,5). Ureteroneocystostomy is the gold standard of surgical therapy with the success rate of greater than 95%(6). In recent years, endoscopic subureteral injection has been introduced as a therapeutic alternative to open surgery because of its high success rates about 80-95%, low in- cidence of complications, its minimally invasive nature and short hospital stay (7-9). This technique was initially described by Matouschek in 1981(10) and the first case series was reported by O’Donnell and Puri in 1984 (11). 1Department of Urology, Isfahan University of Medical Sciences (IUMS), Isfahan, Iran. 2Department of Urology, Hasheminejad Kidney Research Center (HKRC), Iran University of Medical Science, Tehran, Iran. *Correspondence: Hasheminejad Kidney Research Center (HKRC), Iran University of Medical Science, Tehran, Iran. Postal address: Hasheminejad Kidney Center, North Valiasr street, Vanak Square, Tehran, Iran. Tel: +989133154014. Fax: +983136284154. Email: Saeed_haghdani@yahoo.com. Received September 2017 & acceted May 2018 Since then, different materials have been used in subu- reteral injection which include: collagen, polytetrafluo- roethylene (Teflon®)(12), polydimethylsiloxane (Mac- roplastique®) (13), calcium hydroxyapatite (Coaptite®) (14), Dextranomer/Hyaluronic acid copolymer (Dx/HA, Deflux)(8) and recently, Polyacrylate polyalcohol copol- ymer(15). In 2001, the Food and Drug Administration approved Dextranomer/Hyaluronic acid copolymer (Deflux; Q-Med Scandinavia, Uppsala, Sweden) for subureter- al injection and thereafter, the endoscopic management of VUR has emerged as a first line treatment of VUR worldwide(8). Dx/HA is a viscous biocompatible gel consisting of dextranomer microspheres of 80 to 120 µm in diam- eter and non-animal hyaluronic acid. The overall suc- cess rate, depending on the VUR grade, stated in the literature ranges between 68 and 92% (9,16). In these conclusions, the long term recurrence rate of 10% to Pediatric Urology 174 Vol 16 No 02 March-April 2019 175 26% with Dx/HA propel researchers into another tis- sue-augmenting substance in order to reach better long- term efficacy in the endoscopic treatment of VUR(16-19). Some have recommended that the biodegradable nature of Dx/HA is responsible for the concluding VUR recur- rence (17). Therefore, Polyacrylate polyalcohol copoly- mer (PPC, Vantris, Promedon, Cordoba, Argentina) as a new non-biodegradable tissue-augmenting substance was developed. Polyacrylate Polyalcohol Copolymer is a biocompatible agent with an average diameter of 300µm made of microparticles of PPC in glycerol and physiological solution (20). The overall success rate of PPC in the literature was reported to be between 83.6% and 94.9% in the short-term follow-up(15,20,21). In addi- tion, one study with over three years follow up showed no VUR recurrence with PPC(21). The comparative stud- ies between these two agents in literature are rare(22-24). There are controversial results in short term observa- tions. While some studies presented PPC as the more successful substance, Pogorelic et al.(25) study showed no significant difference in cure rates between the Vur- dex and PPC. In this study, we compared the success rate of PPC and Dx/HA in the endoscopic treatment of VUR with considering other suggested variables such as the injection technique and volume. MATERIALS AND METHODS We retrospectively reviewed the records of patients un- der the age of 15 years who fulfilled inclusion criteria of the study and underwent endoscopic correction of their VUR by a single pediatric urologist (FA) from Jan 2010 to April 2016. Before the April 2013, patients were treated by subureteric injection of PPC (43 patients, 64 RRU) and after that time, by Dx/HA injection (65 pa- tients, 107 RRU). Inclusion criteria included patients with diagnosis of unilateral or bilateral primary VUR grades II–V with breakthrough UTIs despite prophylactic antibiotics, persistent VUR after a period of observation, poor com- pliance with prophylactic antibiotics, and evidence of new renal scarring on a 99-m technetium dimercap- to-succinic acid (DMSA) renal scan. Grade I VUR were treated only if accompanied by a contralateral higher grade reflux. The first evaluation of patients after UTI or finding of hydronephrosis on ultrasound study was with voiding cystourethrography (VCUG) and reflux grading was performed according to the International Classification System (International Reflux Study Committee). The preoperative work-up included a detailed history and physical examination, a VCUG, a urinalysis and cul- ture. Before surgery, all patients were evaluated for the presence of neurologic deficits, dysfunctional voiding and/or constipation. If any symptoms of enuresis, noc- turia, urgency, frequency (documented by a voiding di- ary), postponement, holding maneuvers, urinary and/or fecal incontinence or constipation existed, a flowmetry/ pelvic floor electromyography (EMG) was performed to check for the presence of dysfunctional voiding (DV). This test was also performed if increased bladder wall thickness (>3 mm with full bladder) or increased post-void residual urine were observed on ultrasound in the absence of active UTI or bladder outflow obstruc- tion. A formal pressure-flow study was performed in patients with significant bladder wall trabeculation on VCUG or documented neurological abnormalities. All patients with proven DV were first treated by biofeed- back-assisted pelvic floor muscle training. We considered the VUR to be secondary if it was ac- companied by a known neurologic deficit, severe form of DV (Hinman syndrome) or documented urethral ob- struction (e.g. posterior urethral valve). Exclusion cri- teria were isolated grade I VUR, active UTI at the time of surgery, past history of open ureteroneocystostomy or subtrigonal injection of bulking agents, anatomical anomalies of the urinary tract (concomitant uretero- pelvic junction obstruction, double urinary collecting system, ectopic ureter, posterior urethral valve) and alterations in bladder dynamics (untreated DV and neu- ropathic bladder). The Committee of Ethics approved the protocol, and parents signed a written informed consent before op- eration. Technique In the operation room, cystoscopy was performed by a 8-9.8 Fr offset lens, Wolf cystourethroscope and if the ureteral orifice was in the extravesical position (not diagnosed on VCUG), the patient was considered ineli- gible for endoscopic surgery. The injection technique was STING (subureteric) in the absence of hydrodistention (HD) of the ureteral orifice, distal HIT (intraureteric) when the HD was grade 1 or 2, and double HIT in the presence HD grade 3. A com- bination of HIT and STING was used whenever a slit- like orifice and disappearance of HD was not achieved by HIT alone. The material was injected until complete coaptation of the ureter was achieved and the type and volume of injected agent was recorded. The patient was discharged the evening of the day of surgery if no fever or significant hematuria was observed. After discharge from hospital, prophylactic oral cephalexin 15mg/Kg at bed time was prescribed until post-operative imaging showed reflux resolution or down-grading to Grade A on RNC. Follow up study Follow-up radionuclide cystography (RNC) was per- formed 3 months after the operation or after any episode of febrile UTI in patients who had been cured of their reflux. According to the protocol, repeat RNC in cured patients was performed only in the presence of febrile UTI or new-onset hydroureteronephrosis (HUN). Renal and bladder ultrasound was performed at the post-oper- ative month one, every 3 months during the first year, every 6 months during the next 2 years and then, yearly. If a new-onset HUN or exacerbation of the previous one was observed, a repeat RNC and a Lasix renogram was requested. We devided post-operative ureteral obstruc- tion into early and late. Early-onset obstruction presents with renal colic in the early post-operative period and resolves spontaneously, while late-onset obstruction presents with urinary tract infection, creatinine rise (in bilateral cases) or as an incidental finding on post-op- erative imaging. Success was defined as complete VUR resolution. In patients with bilateral reflux, if resolution occurred in one side, the operation was considered to be failed. Data were entered into the SPSS software (IBM Corpo- ration, New York, United States), version 22. Fisher’s exact test, Mann-Whitney U test, t-test and one-way ANOVA were used for analyzing the data. Bulking agents for treating primary vesicoureteral reflux-Alizadeh et al. Pediatric Urology 176 RESULTS One hundred and seven RRU and 64 RRU were treated in Dx/HA and PPC groups, respectively. The demo- graphic data and patients’ characteristic are presented in Table 1. The success was achieved in 92.2% (59) RRU in PPC group and 75.7% (81) RRU in Dx/HA group (P < .001). By Mann-Whitney test, in reflux grade in PPC group the success rate was decreased significantly with in- creasing reflux grade (P = .04) but this reduction was not statistically significant in Dx/HA group (P = .30). In post-operative period, early-onset obstruction was observed in 3 (4.7%) and 4 (3.7%) RRU in PPC and Dx/HA groups, respectively while late-onset ureteral obstruction occurred in 2 (3.1%) and 2 (1.9%) of RRU in PPC and Dx/HA groups, respectively. The obstruc- tion rate did not establish significant difference between the two groups (P = .83). However, in patients with late-onset obstruction, the mean time from injection to obstruction was longer in Dx/HA group (22 moths vs. 4 months). The Spearman analysis showed statistically significant correlation between injected volume of the bulking agent and obstruction rate in PPC group (r=0.24, P = .04); however, the Dx/HA group failed to confirm this relationship (P = .52). During the follow-up, 4 patients (10.2%) in the PPC group and 7 patients (18.4%) in the Dx/HA group who had been cured of their VUR, developed febrile UTI that underwent repeat RNC. One patient (25%) in the former group showed recurrence of VUR while this fig- ure was 4 (57%) in the latter group. DISCUSSION In our study the PPC group showed a more successful outcome (92.2% of the RRU and 90.6% of the patients) in comparison to the Dx/HA group (75.7% of the RRU and 58.4% of the patients). These results were in ac- cordance with previous investigations. Karakus et al.(22) compared these two agents which revealed PPC promis- es higher resolution rate than Dx/HA (88.6% vs 70.3%), although the former group had markedly higher uret- erovesical junction obstruction. In another comparative study, reflux resolved after the first Deflux injection in 63% of RRU and Vantris injection in 92.7% of RRU(24). However, in Turk et al. study(23) the overall treatment success rate was 79% in Dx/HA group and 81% in PPC group which was not significantly different. The overall success rate reported with use of Dx/HA ranged between 68–92% based on the VUR grade (8,16,24,26). One study that examined Dx/HA, demonstrat- ed a success rate of 78.5% for grades I and II, 72% for grade III, 63% for grade IV and 51% for grade V reflux which revealed this hypothesis that increasing the grade of reflux decrease the success rate of treatment with this material(27). Although our result did not demonstrate any significant decrease in success rate in grade IV and V VUR in the Dx/HA group. PPC comes from the family of Acrylics, particles of po- lyacrylate polyalcohol copolymer immersed in a glyc- erol and physiological solution carrier. When injected in soft tissues, it causes a bulkiness that remains sta- ble(28). A multicentric study comprising 88 renal units treated with PPC showed the overall success rate about 83.6%(20). In Sencan study(29), the accumulative suc- cess rate after the injection of PPC at the end of the first year was 98.1%. Chertin et al. reported the success rate of PPC after a single injection as 94.9% (15). They Bulking agents for treating primary vesicoureteral reflux-Alizadeh et al. Table 1. Demographic data and patients’ characteristic in both groups. Characteristics PPC group Dx/HA group P value Mean Age (months) 52.13 ± 31.66 55.23 ± 36.58 0.57 Sex Male 10(15.6%) 22(20.6%) 0.54 Female 54(84.4%) 85(79.4%) Laterality of VUR Left 35(54.7%) 53(49.5%) 0.53 Right 29(45.3%) 54(50.5%) Hx of UTI 60(93.8%) 81(75.7%) 0.003 pre-operative renal cortical scar 47(74.6%) 45(48.9%) 0.001 Variables PPC group Dx/HA group P value Injection technique 0.36 HIT 16 (25%) 40 (37.4%) Double HIT 6 (9.4%) 11 (10.3%) STING 20 (31.2%) 25 (23.4%) HIT+STING 22 (34.4%) 31 (29%) Injected volume(mL) 0.78 ± 0.39 0.58 ± 0.30 0.001 VUR Grade (RRU) I 2 (3.1%) 6 (5.6%) 0.93 II 11 (17.2%) 13 (12.1%) III 21 (32.8%) 42 (39.3%) IV 20 (31.2%) 27 (25.2%) V 10 (15.6%) 19 (17.8%) Follow up (months) 17.17 ± 12.81 18.81 ± 11.92 0.4 Table 2. Procedural detail in both groups. Vol 16 No 02 March-April 2019 177 also demonstrate cure of reflux with a single injection in 92.1% of all patients in one year follow up. In War- chol study, reflux resolved in 93% of all treated RRUs after first procedure, and in 100% after the second pro- cedure. For high grade VUR, that is IV and V, success was achieved in almost 90% after the first injection and 100% after the second injection(24). Chertin et al. eval- uated prospectively the long term efficacy of PPC in children with VUR which showed no VUR recurrence in 3 years of follow-up, while recurrence rate with Dx/ HA ranges from 10% to 26% in long term follow up (21,30). Radiographic investigation in the Sedberry-Ross et al. and Swedish Reflux Study also demonstrated high radiographic recurrence (27%-38%) that was attributed to biodegradable nature of Dx/HA(31,32). The use of PPC to correct grades IV and V is also very efficient with an overall success rate achieved of over 80% (33,34). But in our study the success rate decreased in PPC (but not the Dx/HA) group significantly with increasing reflux grade. Technique of injection is suggested as another variable for success rate of materials in recent literature. Single subureteral transurethral injection (STING) technique was used first time in 1984 for the endoscopic treat- ment of pediatric VUR(35). The suggested injection site is 2 to 3 mm below the affected ureteric orifice, at the 6 o’clock position. Hydrodistention Implantation Tech- nique (HIT), which entails inserting the needle into the submucosal tunnel of the ureter via hydrodistention has been introduced in 2004 (16). Kirsh et al. by using Hy- drodistention Implantation Technique injection (HIT), showed the short-term results with the endoscopic correction close to those results after open surgery. A success rate of 92% using the HIT procedure com- pared with the 79% using the STING procedure was reported(16). Yucel et al.(36) and Watters et al.(37) found no differences on VUR resolution rate between the two techniques. Double Hydrodistention Implantation Technique was also described by these researchers (38). Double HIT, included two intraluminal ureteric tunnel injections which involves both proximal and distal in- traureteral injections. Kalisvaart et al. revealed 96% clinical success with double HIT after 1 year of fol- low-up(38). Akin et al.(39) observed a higher success rate with double HIT treatment compared to HIT. However, our data did not show significant difference between HIT and double HIT technique in either study groups. Another important factor, predicting the success rate of the procedure, is learning curve. In our study groups this variable was omitted because the same surgeon did the procedure in both groups after passing the learning curve during the fellowship training program. In fact, although Dx/HA injection was done after PPC injec- tion, this group had lower success rate. Therefore, the effect of surgeon’s experience as the cause of difference in success rate is precluded. Complications following endoscopic injection are rare and including mainly obstruction of the vesicoureteric junction and development of a new contralateral VUR. In our Dx/HA group and PPC group 5.6% and 7.8% of patients developed obstruction respectively, with no statistically significant difference between them. Al- though several variables involve in the likelihood of obstruction, the amount of injection material was not related to obstruction frequency in our data. There is not unanimous result in this field and controversial obser- vations have been presented up to now(40). One differ- ence was the mean time to obstruction that was longer in the Dx/HA group (22 vs. 4 months). This finding suggest that long-term follow-up should be rigorous, especially in patients who receive Dx/HA. This study has some limitations such as small sample size of groups, lack of follow-up RNC after reflux res- olution in all patients, non-randomized nature of the study and different inclusion criteria which contained more UTI history and scar formation in PPC group. These problems demand more studies with detailed date and longer follow up. CONCLUSIONS Our investigation approved PPC as a more effective material, regardless of other confounding variables such as reflux grade, learning cure, and technique of injection, in endoscopic treatment of VUR. In addition, the other remarkable point is this effectiveness is not accompanied by more post-operation obstruction. CONFLICT OF INTEREST None declared. REFERENCES 1. Savage DC, Wilson MI, McHardy M, Dewar DA, Fee WM. Covert bacteriuria of childhood. A clinical and epidemiological study. Arch Dis Child. 1973;48:8-20. 2. Jacobson SH, Hansson S, Jakobsson B. Vesico-ureteric reflux: occurrence and long- term risks. 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