Vesicoureteral Reflux Salvage Dextranomer-Hyaluronic Acid Copolymer for Persistent Reflux After Ureteral Reimplantation: Early Success Rates Yuval Bar-Yosef,* Miguel Castellan, Devandra Joshi, Andrew Labbie and Rafael Gosalbez From the Division of Pediatric Urology, Miami Children s Hospital Department of Urology, University of Miami, Miami, Florida Purpose: Endoscopic injection of dextranomer-hyaluronic acid copolymer is an accepted initial procedure to correct vesicoureteral reflux. Less data are available on its role in treating failed ureteral reimplantation. Materials and Methods: We retrospectively reviewed the charts from 2002 to 2008 and identified 21 patients (26 ureteral units) with persistent reflux after reimplantation. Results: Mean age was 7 years (range 2 to 13). Mean followup was 2 years (range 10 to 46 months). Of the 17 patients with a single system ureteral reimplantation was extravesical in 9 and intravesical in 8 with tapering performed in 5. Three patients underwent reimplantation of duplex systems and 1 underwent reimplantation due to ureterocele. Residual reflux grade was 1 to 4 in 3 (11%), 17 (65%), 3 (11%) and 3 ureteral units (11%), respectively. Dextranomer-hyaluronic acid copolymer was injected transurethrally. The mean volume injected was 1.2 ml (range 0.7 to 3). After 1 injection reflux resolved in 15 patients (71%) or a total of 20 ureteral units (77%), including 12 of 14 (86%) extravesically and 8 of 12 (66%) intravesically reimplanted units. The resolution rate improved to 84% after multiple injections. Two of the 6 patients with reflux after 1 injection had a single system, 2 had an obstructive megaureter with tapered reimplantation, 1 had a duplicated system and 1 had a ureterocele. Three of the 5 patients with persistent reflux underwent revision surgery. Ureteral abnormalities other than reflux and tapered reimplantation were associated with a statistically significant inferior success rate. Conclusions: Dextranomer-hyaluronic acid copolymer injection is an efficacious salvage procedure for persistent reflux after ureteral reimplantation. The success rate is inferior for ureteral abnormalities other than primary vesicoureteral reflux and after tapering. Abbreviations and Acronyms BBD bladder and bowel dysfunction DHA dextranomer-hyaluronic acid copolymer VUR vesicoureteral reflux Study received institutional review board approval. * Correspondence: (e-mail: yuvalbary@hotmail. com). Key Words: ureter, vesico-ureteral reflux, dextranomer-hyaluronic acid copolymer, salvage therapy, abnormalities ENDOSCOPIC injection of DHA is an accepted initial procedure to correct VUR. Ample data are available on the short-term and long-term results of the procedure. 1,2 While surgical ureteral reimplantation remains the gold standard for VUR surgical treatment with a success rate of 95% to 99%, 3 endoscopic treatment of VUR with its lower morbidity has become a widespread initial treatment option despite a lower success rate. 4,5 Surgical failure occurs and represents a therapeutic challenge. Available options in these patients are expectant treatment, reoperation or 0022-5347/11/1856-2531/0 Vol. 185, 2531-2535, June 2011 THE JOURNAL OF UROLOGY Printed in U.S.A. 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2011.01.014 www.jurology.com 2531
2532 SALVAGE DEXTRANOMER-HYALURONIC ACID COPOLYMER FOR PERSISTENT REFLUX attempted endoscopic therapy. Expectant treatment of residual VUR, especially early after ureteral reimplantation, is a valid option since later resolution has been reported. 6 Reoperative ureteral reimplantation is challenging and carries increased morbidity. Thus, endoscopic management of failed reimplantation is an attractive solution that avoids the potential hazards of revision surgery. Endoscopic DHA injection has been studied in various complicated anatomical and functional variants 7 10 but rarely in the failed postoperative setting. 11,12 We present the results of DHA injection in a cohort of patients with residual VUR after ureteral reimplantation. MATERIALS AND METHODS We identified 21 patients (26 ureteral units) with persistent reflux after ureteral reimplantation who underwent endoscopic treatment for residual VUR in 2002 to 2008. With institutional review board approval we retrospectively reviewed data from patient charts on the initial diagnosis that prompted ureteral reimplantation, reimplantation technique, residual VUR grade, BBD, volume of DHA used and persistent VUR after injection. All patients were screened for BBD signs, including urinary frequency and urgency, prolonged voiding intervals, daytime wetting, holding maneuvers and constipation. Patients with BBD were treated with medical and behavioral therapy as necessary before an attempted antireflux procedure. The injection technique was tailored according to the site and anatomy of the orifice of the ureteral unit injected. Injection was performed transurethrally via a 10Fr pediatric cystoscope in all patients. When access to the ureteral orifice was difficult, as is the case after crosstrigonal reimplantation, guidewires and ureteral catheters were used to manipulate the orifice orientation and facilitate injection. A subureteral or intraureteral injection site was used according to ureteral orifice anatomy and surgeon preference. Postoperatively patients were evaluated by renal and bladder ultrasound at 4 weeks, and by voiding cystourethrogram at 8 to 12 weeks. The chi-square test was used for statistical analysis with p 0.05 considered statistically significant. RESULTS Mean patient age at injection was 7 years (range 2 to 13). Mean followup after injection was 2 years (range 10 to 46 months). Of the 17 patients with a single system ureteral reimplantation was extravesical in 9 and intravesical in 8. Reimplantation with excisional ureteral tapering was performed in 5 of those patients. Three patients underwent reimplantation of a duplicated system and 1 underwent it for a ureterocele. The mean interval between the failed open operative procedure and DHA injection was 37 months (range 6 to 156). Seven patients were diagnosed with BBD and treated with behavioral and medical therapy before DHA injection. Residual reflux grade before injection was 1 to 4 in 3 (11%), 17 (65%), 3 (11%) and 3 ureteral units (11%), respectively. Units with grade 1 reflux were only injected when there was bilateral residual VUR with higher grade VUR of the contralateral unit. Six patients had a symptomatic presentation with urinary tract infection after ureteral reimplantation. Mean DHA volume injected was 1.2 ml (range 0.7 to 3). After 1 DHA injection procedure VUR resolved in 15 patients (71%) or 20 ureteral units (77%) and was down-graded to nondilating VUR in 25 units (96%). VUR resolved in 12 of 14 extravesically reimplanted units (86%) and in 8 of 12 intravesically reimplanted units (66%). The table lists success rates, and patient and ureteral unit characteristics. Gender, extravesical vs intravesical surgical technique, a duplicated system and BBD were not associated with procedure failure. Tapered reimplantation and an initial diagnosis other than primary VUR were statistically significant variables affecting endoscopic treatment Patient characteristics and VUR resolution rate No. Resolved/Total No. (%) p Value Gender: 0.445 M 10/15 (66) F 5/6 (83) VUR grade: I 3/3 (100) II 14/17 (82) III 2/3 (66) IV 1/3 (33) System: 0.750 Single 18/22 (82) Duplicated 3/4 (75) Pre-reimplantation diagnosis: 0.029 Primary VUR 18/21 (86) Other ureteral abnormality 2/5 (40) Obstructed megaureter 1/3 (33) Ureterocele 0/1 Ectopic ureter 1/1 (100) Implantation: 0.251 Extravesical 12/14 (86) Intravesical 8/12 (66) Cohen cross-trigonal 3/5 (60) Glenn-Anderson 3/5 (60) Politano-Leadbetter 2/2 (100) Tapered reimplantation: 0.029 No 18/21 (86) Yes 2/5 (60) BBD: 0.306 Yes 4/7 (57) No 11/14 (79)
SALVAGE DEXTRANOMER-HYALURONIC ACID COPOLYMER FOR PERSISTENT REFLUX 2533 success. The resolution rate improved to 84% (22 ureteral units) after up to 3 injections. Three of the 6 patients in whom VUR persisted after the first injection were initially diagnosed with primary VUR, including 2 with a single system ureter and 1 with a duplicated system. Two patients had an obstructive megaureter and underwent tapered reimplantation and 1 had a ureterocele. VUR resolved after multiple injections in 1 patient. In 2 of the 5 patients with persistent reflux VUR was managed expectantly while 3 underwent open surgical revision. During followup only 1 patient was diagnosed with a febrile urinary tract infection. That patient, who did not initially present with urinary tract infection after reimplantation and who had residual VUR after injection, was 1 of the 3 who later underwent open surgical revision. DISCUSSION Initial reports of the result of endoscopic injection for primary VUR were soon followed by reports of treatment for complicated anatomical and functional conditions. In 2004 Perez-Brayfield et al reported results in 69 such patients in a multicenter study. 8 The cohort included an assortment of pathological conditions, such as neurogenic bladders, previous reimplantation, duplicated systems, paraureteral diverticula, ureteroceles and ectopic ureters. The overall success rate was 68% after 1 DHA procedure. The subpopulation, which was similar to that in our study, consisted of 17 patients and yielded 88% success. The group concluded that endoscopic treatment should be considered the preferred initial therapy if VUR persisted after an initial observation period. The report by Routh et al included 373 patients (543 ureteral units) with bladder and ureteral anomalies. 7 In those cases a total of 15 ureters were previously reimplanted. The overall cure rate, defined as complete VUR resolution, was 73% at 3-month followup. On multivariate analysis DHA injection failure was not associated with any of the parameters examined. Specific cure rates in patients after ureteroneocystostomy were not provided but the OR was calculated to be 1. A limited number of groups previously investigated results in a homogeneous post-reimplantation cohort, similar to the group that we present. Before the emergence of DHA as a Food and Drug Administration approved injectable Kumar and Puri reported the results of salvage polytetrafluoroethylene injection. 13 During 10 years 40 ureteral units were injected with 68% success after the first injection and 95% success after multiple injections. Later reports concentrated on the role of DHA as a salvage modality. Kitchens et al reported their experience with DHA injection after failed reimplantation. 12 A total of 20 ureteral units were injected transurethrally or percutaneously with an overall 80% success rate. The success rate was similar for extravesical (9 of 11 cases or 82%) and intravesical (7 of 9 or 78%) techniques. The success rate in untailored ureters was 13 of 15 (87%) and for tailored ureters it was 3 of 5 (60%). A resolution rate of 86% to 100% was reported for grade 1 to 4 VUR with cure of grade 5 VUR in a third of the cases. Jung et al retrospectively reviewed their results with DHA as a salvage procedure. 11 They reviewed 12 cases (14 refluxing ureteral units) and reported the results of the 10 ureteral units with adequate followup at a mean of 10 months. VUR resolved initially in 7 of 10 patients (70%) after 1 injection and after multiple injection in all 9 with complete followup. The only clinical parameter associated with procedure failure was voiding dysfunction. Our analysis failed to prove inferior results in patients with BBD, as did the analysis by Routh et al in their diverse population of patients. 7 BBD is considered a risk factor for ureteral reimplantation and endoscopic treatment. Capozza et al reported a higher failure rate in patients with BBD and hypothesized that higher voiding pressure displaces the injectable mound. 14 Higham-Kessler et al reported that dysfunctional voiding predicts a lower success rate after a second injection. 15 Conversely Lavelle et al did not find that voiding dysfunction predicted treatment failure. 16 Läckgren et al reviewed the records of 54 patients with voiding dysfunction who were treated with DHA and compared the results to those in their entire DHA cohort. 9 Treatment was similarly effective in the 2 groups despite only a 59% resolution rate of voiding dysfunction at long-term followup. Our study has several limitations. It has a retrospective design with its inherent potential bias. Also, late failures of DHA were recently reported. Late voiding cystourethrogram 1 year after the procedure revealed recurrent VUR in 26% of 150 ureters with initially resolved VUR. 17 Our mean followup was 2 years but voiding cystourethrogram was not done after initial resolution was confirmed. We cannot rule out later recurrent VUR and, hence, our results represent the early success rate of salvage endoscopic treatment. As in all previous reports, given the rarity of failed ureteral reimplantation, the study population was small. Statistical analysis of factors affecting procedure success were inherently insufficiently powered. Despite these limitations it appears that endoscopic injection of DHA is a valid option when weighed against the options of expectant manage-
2534 SALVAGE DEXTRANOMER-HYALURONIC ACID COPOLYMER FOR PERSISTENT REFLUX ment and revision surgery. In our cohort initial diagnoses other than primary VUR as well as previous tapered reimplantation were associated with decreased success. Hence, different approaches, such as percutaneous endoscopic DHA injection or reoperative reimplantation, may be considered in that clinical scenario. Salvage DHA may still have a role even in these cases, given its minimally invasive nature and low morbidity with revision surgery reserved for DHA failure. Open surgery as well as endoscopic injection may be used as the initial therapeutic approach. Failures of initial therapy may be reapproached with the same initial modality with revision open surgery after failed reimplantation or repeat injection after endoscopic management. Alternatively after initial failure the surgeon may choose the other modality and follow failed injections with open surgery 18 or, as our study suggests, follow failed open surgery with endoscopic injection. CONCLUSIONS DHA injection is an efficacious salvage procedure for persistent reflux after ureteral reimplantation. Treatment of residual reflux after surgery for primary VUR yields excellent results. VUR results after surgery for other ureteral abnormalities and after tapered reimplantation are lower. In those cases other treatment modalities may be considered. REFERENCES 1. Stenberg A and Läckgren G: Treatment of vesicoureteral reflux in children using stabilized nonanimal hyaluronic acid/dextranomer gel (NASHA/ DX): a long-term observational study. J Pediatr Urol 2007; 3: 80. 2. Routh JC, Inman BA and Reinberg Y: Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics 2010; 125: 1010. 3. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics 1981; 67: 392. 4. Lendvay TS, Sorensen M, Cowan CA et al: The evolution of vesicoureteral reflux management in the era of dextranomer/hyaluronic acid copolymer: a pediatric health information system database study. J Urol 2006; 176: 1864. 5. Nelson CP, Copp HL, Lai J et al: Is availability of endoscopy changing initial management of vesicoureteral reflux? J Urol 2009; 182: 1152. 6. Bisignani G and Decter RM: Voiding cystourethrography after uncomplicated ureteral reimplantation in children: is it necessary? J Urol 1997; 158: 1229. EDITORIAL COMMENT 7. Routh JC, Kramer SA, Inman BA et al: Utility of dextranomer/hyaluronic acid injection in setting of bladder and ureteral anomalies. Urology 2008; 71: 435. 8. Perez-Brayfield M, Kirsch AJ, Hensle TW et al: Endoscopic treatment with dextranomer/hyaluronic acid for complex cases of vesicoureteral reflux. J Urol 2004; 172: 1614. 9. Läckgren G, Sköldenberg E and Stenberg A: Endoscopic treatment with stabilized nonanimal hyaluronic acid/dextranomer gel is effective in vesicoureteral reflux associated with bladder dysfunction. J Urol 2007; 177: 1124. 10. Molitierno JA Jr, Scherz HC and Kirsch AJ: Endoscopic injection of dextranomer hyaluronic acid copolymer for the treatment of vesicoureteral reflux in duplex ureters. J Pediatr Urol 2008; 4: 372. 11. Jung C, DeMarco RT, Lowrance WT et al: Subureteral injection of dextranomer/hyaluronic acid copolymer for persistent vesicoureteral reflux following ureteroneocystostomy. J Urol 2007; 177: 312. 12. Kitchens D, Minevich E, DeFoor W et al: Endoscopic injection of dextranomer/hyaluronic acid copolymer to correct vesicoureteral reflux following failed ureteroneocystostomy. J Urol 2006; 176: 1861. 13. Kumar R and Puri P: Endoscopic correction of vesicoureteric reflux in failed reimplanted ureters. Eur Urol 1998; 33: 98. 14. Capozza N, Lais A, Matarazzo E et al: Influence of voiding dysfunction on the outcome of endoscopic treatment for vesicoureteral reflux. J Urol 200; 168: 1695. 15. Higham-Kessler J, Reinert SE, Snodgrass WT et al: A review of failures of endoscopic treatment of vesicoureteral reflux with dextranomer microspheres. J Urol 2007; 177: 710. 16. Lavelle MT, Conlin MJ and Skoog SJ: Subureteral injection of Deflux for correction of reflux: analysis of factors predicting success. Urology 2005; 65: 564. 17. Lee EK, Gatti JM, Demarco RT et al: Long-term followup of dextranomer/hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. J Urol 2009; 181: 1869. 18. Elmore JM, Kirsch AJ, Perez-Brayfield MR et al: Salvage extravesical ureteral reimplantation after failed endoscopic surgery for vesicoureteral reflux. J Urol 2006; 176: 1158. These authors present the results of endoscopic injection in a heterogeneous group of patients in whom primary open surgery failed in a 5-year period. Many cases had complex ureteral anatomy and would be expected to have lower success after any type of surgical intervention compared to primary cases. However, most failures were low grade (I or II) and the decision to reoperate was made on clinical grounds. After failed complex surgery that required hospitalization, ureteral stents, wound care and analgesic requirements most families would welcome an endoscopic procedure even if the chances of success were thought to be compromised. With the overall 71% success rate of salvage endoscopy, which was even higher in less complicated cases (86%), the authors further defined the role of salvage endoscopic surgery in this increasingly uncommon patient population. These results are promising from an initial surgical standpoint. However other risk factors, eg the
SALVAGE DEXTRANOMER-HYALURONIC ACID COPOLYMER FOR PERSISTENT REFLUX 2535 number of preoperative urinary tract infections, preexisting scarring, gender, genetics and future BBD in the younger children, and not VUR per se can be anticipated to lead to recurrent pyelonephritis in many of these patients with a complex condition. Clinical followup in these patients and others will advance our understanding of the role of salvage surgical management for VUR. I agree with the authors that endoscopic and open surgical approaches remain viable treatment options for recurrent VUR. Andrew J. Kirsch Department of Urology Georgia Urology, P. A. Children s Healthcare of Atlanta Emory University School of Medicine Atlanta, Georgia