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Hyaluronic Acid Copolymer for Persistent Vesicoureteral Reflux Following Ureteroneocystostomy
Subureteral Injection of Dextranomer/Hyaluronic Acid Copolymer for Persistent Vesicoureteral Reflux Following Ureteroneocystostomy Charlie Jung, Romano T. DeMarco, William T. Lowrance, John C. Pope, IV, Mark C. Adams, Mary S. Dietrich and John W. Brock, III From the Department of Pediatric Urology, Vanderbilt Children’s Hospital, Nashville, Tennessee
Purpose: We sought to evaluate the use of subureteral dextranomer/hyaluronic acid copolymer injection for persistent vesicoureteral reflux following ureteroneocystostomy. Materials and Methods: We performed a retrospective review of patients who had undergone dextranomer/hyaluronic acid injection between 2002 and 2005 for persistent vesicoureteral reflux following ureteroneocystostomy. Analysis included evaluation of patient demographics, reflux grades, voiding dysfunction, reflux resolution rates and operative complications. Success was defined as no reflux on voiding cystourethrogram at 1 to 6 months postoperatively. Results: A total of 12 cases with 14 refluxing ureters were reviewed. Of the 12 patients treated 9 (10 ureters) had adequate followup. Mean followup was 10 months. Seven of 10 ureters (70%) demonstrated resolution of reflux after the initial injection. A second dextranomer/hyaluronic acid injection resulted in complete resolution in 2 of the 3 failed ureters (67%). Resolution in the remaining failed ureter could not be assessed due to insufficient patient followup. In children with adequate followup success was ultimately achieved in 9 of 9 ureters (100%) using up to 2 injections. A comparison of clinical factors between patients with success after the initial injection and those requiring 2 injections showed that the presence of persistent voiding dysfunction was the only parameter that was statistically significant. All patients tolerated the procedure without complications. Conclusions: Considering the difficulties inherent in repeat surgery and the high success rate of dextranomer/hyaluronic acid injection in this series, this treatment is an appealing and reasonable option for patients with persistent vesicoureteral reflux following open ureteroneocystostomy. Key Words: vesico-ureteral reflux, dextranomer-hyaluronic acid copolymer, reoperation
reatment options for VUR include observation with antibiotic prophylaxis, open ureteroneocystostomy and subureteral injection of bulking agents. Dextranomer/hyaluronic acid copolymer is the only agent approved by the United States Food and Drug Administration for endoscopic correction of VUR in children. Among treatment options open surgery provides the best chance of cure, with reported success rates greater than 95%.1 For patients who fail open surgery treatment options remain essentially unchanged. However, in these children open surgery is not as attractive an option due to the inherent difficulties present with repeat surgery. Observation is usually the most reasonable initial course, since many of these patients have resolution of VUR with time.2,3 For children with VUR despite adequate observation, Dx/HA injection, due to its low risk profile, is an appealing option. Although numerous studies have supported Dx/HA injection as first line treatment for primary VUR, the specific use of Dx/HA injection for persistent VUR after open surgery has not been well documented.4 –9 The purpose of this study was to evaluate this particular indication.
tent VUR following ureteroneocystostomy. Analysis included evaluation of patient demographics, VUR grade, voiding dysfunction, VUR resolution rates and operative complications. Reflux was graded from I to V based on the International Classification System. Children were determined to have voiding dysfunction by history if they had 1 or a combination of urinary symptoms that included frequency, urgency, incontinence and infrequent voiding. Before Dx/HA injection all patients initially were observed with prophylactic antibiotics except those with breakthrough urinary tract infections. Children with voiding dysfunction were treated aggressively with behavioral therapy, medical therapy or both. Patients with persistent voiding dysfunction despite aggressive therapy underwent urodynamic evaluation before Dx/HA injection. Observation was continued for at least 8 months before resorting to Dx/HA injection. Followup after injection consisted of renal ultrasound at 1 month postoperatively and VCUG at 1 to 6 months postoperatively. Success was defined as absence of VUR on postoperative VCUG. Subureteral Dx/HA injection was performed with the patient under general anesthesia and in the dorsal lithotomy position. A 9.5Fr cystoscope with an offset lens was used to enter the bladder and Dx/HA was injected into the refluxing orifice using either the traditional or modified STING technique.10,11 Injection continued until a characteristic volcanolike mound was produced that sufficiently occluded the orifice. Repeat injections were used if the previous injection did not produce a satisfactory mound.
T
MATERIALS AND METHODS We retrospectively reviewed patients who underwent subureteral Dx/HA injection between 2002 and 2005 for persis-
Submitted June 20, 2006.
0022-5347/07/1771-0312/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
312
Vol. 177, 312-315, January 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.08.084
VESICOURETERAL REFLUX AFTER URETERONEOCYSTOSTOMY Using chi-square and Mann-Whitney tests, numerous clinical variables were compared between ureters with success after a single Dx/HA injection and those requiring a second injection. The chi-square test was used for categorical variables (eg Dx/HA technique) and the MannWhitney test was used for continuous variables (eg age). A p value ⬍0.05 was considered statistically significant. RESULTS A total of 12 patients (10 girls and 2 boys) with 14 refluxing ureters were reviewed. Patient age ranged from 20 to 181 months (mean 70). Persistent VUR was discovered during evaluation of urinary tract infections or during routine VCUG following complex ureteral reconstructive procedures such as ureterocele excision. Many of these patients had clinical characteristics before open ureteroneocystostomy that placed them at increased risk for failure. These characteristics included 3 ureters with grade V VUR, 3 with an associated ureterocele, 1 with prior open ureteroneocystostomy and 1 with an associated neurogenic bladder secondary to the caudal regression syndrome. Essentially, 8 of the 14 ureters (57%) had some risk factor associated with worse outcomes after reimplantation. Nine ureters were reimplanted using either the standard or modified Politano-Leadbetter technique, 2 were reimplanted using the Glenn-Anderson technique and 1 was reimplanted using the Cohen cross-trigonal technique. Ureteral tapering was required for 2 ureters. Common sheath reimplantation was required for 4 ureters. Before Dx/HA injection patients were observed for an average of 29 months from discovery of surgical failure. Of the 12 patients (14 ureters) treated with Dx/HA 9 (10) had adequate followup. The remaining 3 patients (4 ureters) were lost to followup. Mean followup was 10 months. All patients tolerated the procedure without complications. In regard to clinical parameters before Dx/HA injection, 5 of the 10 refluxing ureters were associated with voiding dysfunction. Furthermore, before Dx/HA 2 ureters exhibited grade I, 3 grade II, 3 grade III and 2 grade IV reflux. Mean injected volume was 1.7 ml (range 1 to 4). Seven ureters were treated using the traditional STING technique, and 3 were treated with the modified STING technique. The Cohen crosstrigonal reimplanted ureter was injected at the 6 o’clock position with the needle at a right angle to the ureter. Seven of the 10 ureters (70%) had resolution of VUR after the initial injection. Of the 3 ureters that failed reflux was unchanged grade I in 1, downgraded from grade IV to grade I in 1, and resolved ipsilateral grade II in 1 with new contralateral grade II VUR. When chi-square and Mann-Whitney tests were used to compare clinical parameters between the 7 ureters with success and the 3 with failure after the initial injection the presence of persistent voiding dysfunction was the only variable that proved to be statistically significant (see table). All 3 ureters requiring a second injection were associated with persistent voiding dysfunction. Six of the 7 ureters with success after a single injection had no associated persistent voiding dysfunction. Patient age and sex, pre-reimplant VUR grade, pre-reimplant risk factors, reimplant technique, VUR grade change from before to after reimplant, preDx/HA VUR grade, pre-Dx/HA persistent voiding dysfunction, time from reimplant failure to Dx/HA injection, injec-
313
Comparison of variables between ureters with success and failure after initial Dx/HA injection
No. ureters Mean mos pt age Female-to-male ratio No. pre-reimplant VUR grade: 0 (no VUR) I II III IV V No. pre-reimplant risk factors: Duplication Ureterocele Previous open reimplant Neurogenic bladder Megaureter Reimplant technique: Politano-Leadbetter Cohen cross-trigonal Glenn-Anderson Common sheath Tapering Ureterocele excision No. VUR grade change from before to after reimplant: Decrease Increase or new onset No change No. pre-Dx/HA VUR grade: 0 (no VUR) I II III IV V No. pre-Dx/HA persistent voiding dysfunction Mean mos from reimplant failure to Dx/HA No. Dx/HA technique: STING Modified STING Mean vol Dx/HA vol (range) Mean mos followup
Successes
Failures
p Value
7 57.6 2.5:1
3 74.3 2:1
2 0 1 1 2 1
1 0 0 0 0 2
2 2 1 1 1
0 0 0 0 1
0.301 0.301 0.490 0.490 0.490
3 1 2 2 1 2
3 0 0 1 1 0
0.091 0.490 0.301 0.880 0.490 0.301 0.356
2 2 3
2 1 0
0 1 2 3 1 0 1
0 1 1 0 1 0 3
0.011
25.4
52
0.491
0.648 0.880 0.455
0.559
0.880 5 2 1.7 (1–4) 7.3
2 1 1.7 (1–2) 18
0.705 0.066
tion technique, volume of injection and mean followup were all statistically insignificant between ureters with success and those with failure after the initial injection. A second Dx/HA injection resulted in complete resolution in 2 of the 3 failed ureters (67%). Success of the remaining failed ureter could not be assessed due to insufficient followup. Of the 9 ureters with complete followup after initial and second injections ultimate success was achieved in all using up to 2 injections. DISCUSSION Although many studies support the overall effectiveness of Dx/HA injection for the treatment of primary VUR, most of these series exclude patients with a history of open ureteroneocystostomy.4 –9 Nonetheless, a small number of series have described the use of bulking agents for this particular patient population, and the results are promising.12–16 The first study evaluated 19 patients with VUR after renal transplantation and revealed a low success rate of 30%.12 Gaschignard et al reported a higher success rate of 75% in 12 patients with VUR after Cohen cross-trigonal reimplantation.13 Kumar and Puri reported on 40 ureters with success rates of 68% after the initial injection, 85% after 2 injections and 95% after 3 injections.14 Similarly, 78% of 23 total
314
VESICOURETERAL REFLUX AFTER URETERONEOCYSTOSTOMY
ureters achieved success in the series by Capozza et al.15 Most recently, Perez-Brayfield et al reported on 17 patients with an 88% success rate after a single Dx/HA injection.16 The current study also demonstrated promising results for Dx/HA injection, with a 70% success rate after 1 injection and a 100% success rate after 2 injections. Many of the general principles of endoscopic treatment with bulking agents defined in previous studies held true for this particular series. Specifically, voiding dysfunction seemed to be associated with an increased risk of failure. Capozza et al reported similar findings and argued that high voiding pressures resulted in displacement of Dx/HA.17 Additionally, the risk of contralateral VUR was small (10%). Contralateral VUR rates reported in the literature range from 4.5% to 12.5%.8,18,19 Lastly, patients tolerated the procedure well without major complications.4 –9 Contrary to other studies, reflux grade before Dx/HA injection did not correlate with success after injection in this study.4 – 6,8,11 Puri9 and Lavelle19 et al also failed to find a correlation between baseline VUR grade and success after injection. Analyzing a similar patient population as the current study, Perez-Brayfield et al also failed to find this correlation.16 For the most part no obvious clinical factors were more prevalent in the ureters that required a second Dx/HA injection. These ureters were not associated with more complex reconstruction or tapering. Moreover, although all 3 ureters were treated with Politano-Leadbetter reimplantation, the majority of ureters in this series were treated with this same reimplantation. Interestingly, although it would seem technically more difficult to inject a Cohen cross-trigonal ureter, the single cross-trigonal ureter included in the study had success after the initial injection. In fact, Gaschignard et al only included patients with VUR after Cohen cross-trigonal reimplantation and achieved similar results.13 Lastly, the injection technique or the volume injected was not noticeably different in these 3 ureters vs the others. Future studies with larger numbers of patients will help further evaluate these various factors and their impact on success. Based on previous studies, the overall success rate is high for this complex patient population. One simple explanation is that Dx/HA injection is an overall effective treatment option, even for ureters with complex anatomy.16,20 Another explanation is that the small number of patients evaluated and the short overall followup in the current and most other studies result in overestimation of success. Lastly, it is possible patients failing open surgery are specifically good candidates for endoscopic injection and are more likely to have success. Patients failing open surgery may be good candidates for Dx/HA injection because of certain components of success previously established through open surgery. For example ureters with high grade VUR preoperatively may fail due to large ureteral diameter rather than inadequate tunnel length or insufficient muscular backing. For ureters with ureteroceles perhaps failure is due to insufficient muscular backing rather than insufficient tunnel length or large ureteral diameter. It is possible that these ureters fail open surgery only partially, rather than completely. Therefore, it is possible that the success of Dx/HA in patients failing open surgery is due to its ability to narrow sufficiently the ureteral orifice in the setting of adequate ureteral tunnel
length, or its ability to provide additional ureteral backing support in the setting of insufficient muscular backing. In essence, the overall effect of Dx/HA could be additive to the components of success previously established through open surgery. Repeat surgery, in general, involves longer operative times, more difficult surgical planes, additional risks and less eventual success. Moreover, repeat surgery may be difficult, given the complexity of many of the initial surgeries. Extravesical ureteral mobilization is often necessary to establish adequate ureteral length. Psoas hitch, Boari flap or transureteroureterostomy may be necessary. Risks of devascularization and injury to the contralateral ureter, especially for cross-trigonal ureters, further complicate matters.16 Certainly, the initial course for patients failing open surgery should be observation, since the majority of these patients have resolution of VUR with time.2,3 In this study patients were observed for an average of 29 months before Dx/HA injection. Nonetheless, considering the general difficulties associated with repeat surgery and the promising results from this and other series, Dx/HA injection after an initial course of observation is a reasonable option for patients with VUR after open surgical correction.
CONCLUSIONS Despite the high success rate of open ureteral reimplantation, failures occur. In experienced hands they usually occur in patients with high grade VUR or following complex lower urinary tract reconstruction. Considering the difficulties inherent in repeat surgery and the high success rate of Dx/HA injection in this and other studies, Dx/HA is an appealing and reasonable option for patients failing open surgery.
Abbreviations and Acronyms Dx/HA STING VCUG VUR
⫽ ⫽ ⫽ ⫽
dextranomer/hyaluronic acid subureteral transurethral injection voiding cystourethrogram vesicoureteral reflux
REFERENCES 1.
Elder JS, Peters CA, Arant BS Jr, Ewalt DH, Hawtrey CE, Hurwitz RS et al: Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157: 1846. 2. Bisignani G and Decter RM: Voiding cystourethrography after uncomplicated ureteral reimplantation in children: is it necessary? J Urol 1997; 158: 1229. 3. Grossklaus DJ, Pope JC IV, Adams MC and Brock JW III: Is postoperative cystography necessary after ureteral reimplantation? Urology 2001; 58: 1041. 4. Stenberg A and Lackgren G: A new bioimplant for the endoscopic treatment of vesicoureteral reflux: experimental and short-term clinical results. J Urol 1995; 154: 800. 5. Lackgren G, Wahlin N, Skoldenberg E and Stenberg A: Longterm followup of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2001; 166: 1887. 6. Capozza N and Caione P: Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized
VESICOURETERAL REFLUX AFTER URETERONEOCYSTOSTOMY
7.
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12.
comparison with antibiotic prophylaxis. J Pediatr 2002; 140: 230. Oswald J, Riccabona M, Lusuardi L, Bartsch G and Radmayr C: 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. Kirsch AJ, Perez-Brayfield MR and Scherz HC: Minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the Children’s Hospitals of Atlanta experience. J Urol 2003; 170: 211. Puri P, Chertin B, Velayudham M, Dass L and Colhoun E: Treatment of vesicoureteral reflux by endoscopic injection of dextranomer/hyaluronic acid copolymer: preliminary results. J Urol 2003; 170: 1541. O’Donnell B and Puri P: Treatment of vesicoureteric reflux by endoscopic injection of Teflon. Br Med J (Clin Res Ed) 1984; 289: 7. Kirsch AJ, Perez-Brayfield M, Smith EA and Scherz HC: The modified STING procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413. Cloix P, Gelet A, Desmettre D, Cochat P, Garnier JL, Dubernard JM et al: Endoscopic treatment of vesicoureteral reflux in transplanted kidneys. Br J Urol 1993; 72: 20.
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Gaschignard N, Plattner V, Boullanger P and Heloury Y: Endoscopic treatment of residual vesico-ureteral reflux after reimplantation in children: twelve cases. Prog Urol 1997; 7: 618. Kumar R and Puri P: Endoscopic correction of vesicoureteral reflux in failed reimplanted ureters. Eur Urol 1998; 33: 98. Capozza N, Patricolo M, Lais A, Matarazzo E and Caione P: Endoscopic treatment of vesico-ureteral reflux: twelve years’ experience. Urol Int 2001; 67: 228. Perez-Brayfield M, Kirsch AJ, Hensle TW, Koyle MA, Furness P and Scherz HC: Endoscopic treatment with dextranomer/ hyaluronic acid for complex cases of vesicoureteral reflux. J Urol 2004; 172: 1614. Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M and Caione P: Influence of voiding dysfunction on the outcome of endoscopic treatment for vesicoureteral reflux. J Urol 2002; 168: 1695. Kumar R and Puri P: Newly diagnosed contralateral reflux after successful unilateral endoscopic correction: is it due to the pop-off mechanism? J Urol 1997; 158: 1213. Lavelle MT, Conlin MJ and Skoog SJ: Subureteral injection of Deflux for correction of reflux: analysis of factors predicting success. Urology 2005; 65: 564. Lackgren G, Wahlin N, Skoldenberg E, Neveus T and Stenberg A: Endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is effective in either double ureters or a small kidney. J Urol 2003 170: 1551.
Purpose: We sought to evaluate the use of subureteral dextranomer/hyaluronic acid copolymer injection for persistent vesicoureteral reflux following ureteroneocystostomy. Materials and Methods: We performed a retrospective review of patients who had undergone dextranomer/hyaluronic acid injection between 2002 and 2005 for persistent vesicoureteral reflux following ureteroneocystostomy. Analysis included evaluation of patient demographics, reflux grades, voiding dysfunction, reflux resolution rates and operative complications. Success was defined as no reflux on voiding cystourethrogram at 1 to 6 months postoperatively. Results: A total of 12 cases with 14 refluxing ureters were reviewed. Of the 12 patients treated 9 (10 ureters) had adequate followup. Mean followup was 10 months. Seven of 10 ureters (70%) demonstrated resolution of reflux after the initial injection. A second dextranomer/hyaluronic acid injection resulted in complete resolution in 2 of the 3 failed ureters (67%). Resolution in the remaining failed ureter could not be assessed due to insufficient patient followup. In children with adequate followup success was ultimately achieved in 9 of 9 ureters (100%) using up to 2 injections. A comparison of clinical factors between patients with success after the initial injection and those requiring 2 injections showed that the presence of persistent voiding dysfunction was the only parameter that was statistically significant. All patients tolerated the procedure without complications. Conclusions: Considering the difficulties inherent in repeat surgery and the high success rate of dextranomer/hyaluronic acid injection in this series, this treatment is an appealing and reasonable option for patients with persistent vesicoureteral reflux following open ureteroneocystostomy. Key Words: vesico-ureteral reflux, dextranomer-hyaluronic acid copolymer, reoperation
reatment options for VUR include observation with antibiotic prophylaxis, open ureteroneocystostomy and subureteral injection of bulking agents. Dextranomer/hyaluronic acid copolymer is the only agent approved by the United States Food and Drug Administration for endoscopic correction of VUR in children. Among treatment options open surgery provides the best chance of cure, with reported success rates greater than 95%.1 For patients who fail open surgery treatment options remain essentially unchanged. However, in these children open surgery is not as attractive an option due to the inherent difficulties present with repeat surgery. Observation is usually the most reasonable initial course, since many of these patients have resolution of VUR with time.2,3 For children with VUR despite adequate observation, Dx/HA injection, due to its low risk profile, is an appealing option. Although numerous studies have supported Dx/HA injection as first line treatment for primary VUR, the specific use of Dx/HA injection for persistent VUR after open surgery has not been well documented.4 –9 The purpose of this study was to evaluate this particular indication.
tent VUR following ureteroneocystostomy. Analysis included evaluation of patient demographics, VUR grade, voiding dysfunction, VUR resolution rates and operative complications. Reflux was graded from I to V based on the International Classification System. Children were determined to have voiding dysfunction by history if they had 1 or a combination of urinary symptoms that included frequency, urgency, incontinence and infrequent voiding. Before Dx/HA injection all patients initially were observed with prophylactic antibiotics except those with breakthrough urinary tract infections. Children with voiding dysfunction were treated aggressively with behavioral therapy, medical therapy or both. Patients with persistent voiding dysfunction despite aggressive therapy underwent urodynamic evaluation before Dx/HA injection. Observation was continued for at least 8 months before resorting to Dx/HA injection. Followup after injection consisted of renal ultrasound at 1 month postoperatively and VCUG at 1 to 6 months postoperatively. Success was defined as absence of VUR on postoperative VCUG. Subureteral Dx/HA injection was performed with the patient under general anesthesia and in the dorsal lithotomy position. A 9.5Fr cystoscope with an offset lens was used to enter the bladder and Dx/HA was injected into the refluxing orifice using either the traditional or modified STING technique.10,11 Injection continued until a characteristic volcanolike mound was produced that sufficiently occluded the orifice. Repeat injections were used if the previous injection did not produce a satisfactory mound.
T
MATERIALS AND METHODS We retrospectively reviewed patients who underwent subureteral Dx/HA injection between 2002 and 2005 for persis-
Submitted June 20, 2006.
0022-5347/07/1771-0312/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
312
Vol. 177, 312-315, January 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.08.084
VESICOURETERAL REFLUX AFTER URETERONEOCYSTOSTOMY Using chi-square and Mann-Whitney tests, numerous clinical variables were compared between ureters with success after a single Dx/HA injection and those requiring a second injection. The chi-square test was used for categorical variables (eg Dx/HA technique) and the MannWhitney test was used for continuous variables (eg age). A p value ⬍0.05 was considered statistically significant. RESULTS A total of 12 patients (10 girls and 2 boys) with 14 refluxing ureters were reviewed. Patient age ranged from 20 to 181 months (mean 70). Persistent VUR was discovered during evaluation of urinary tract infections or during routine VCUG following complex ureteral reconstructive procedures such as ureterocele excision. Many of these patients had clinical characteristics before open ureteroneocystostomy that placed them at increased risk for failure. These characteristics included 3 ureters with grade V VUR, 3 with an associated ureterocele, 1 with prior open ureteroneocystostomy and 1 with an associated neurogenic bladder secondary to the caudal regression syndrome. Essentially, 8 of the 14 ureters (57%) had some risk factor associated with worse outcomes after reimplantation. Nine ureters were reimplanted using either the standard or modified Politano-Leadbetter technique, 2 were reimplanted using the Glenn-Anderson technique and 1 was reimplanted using the Cohen cross-trigonal technique. Ureteral tapering was required for 2 ureters. Common sheath reimplantation was required for 4 ureters. Before Dx/HA injection patients were observed for an average of 29 months from discovery of surgical failure. Of the 12 patients (14 ureters) treated with Dx/HA 9 (10) had adequate followup. The remaining 3 patients (4 ureters) were lost to followup. Mean followup was 10 months. All patients tolerated the procedure without complications. In regard to clinical parameters before Dx/HA injection, 5 of the 10 refluxing ureters were associated with voiding dysfunction. Furthermore, before Dx/HA 2 ureters exhibited grade I, 3 grade II, 3 grade III and 2 grade IV reflux. Mean injected volume was 1.7 ml (range 1 to 4). Seven ureters were treated using the traditional STING technique, and 3 were treated with the modified STING technique. The Cohen crosstrigonal reimplanted ureter was injected at the 6 o’clock position with the needle at a right angle to the ureter. Seven of the 10 ureters (70%) had resolution of VUR after the initial injection. Of the 3 ureters that failed reflux was unchanged grade I in 1, downgraded from grade IV to grade I in 1, and resolved ipsilateral grade II in 1 with new contralateral grade II VUR. When chi-square and Mann-Whitney tests were used to compare clinical parameters between the 7 ureters with success and the 3 with failure after the initial injection the presence of persistent voiding dysfunction was the only variable that proved to be statistically significant (see table). All 3 ureters requiring a second injection were associated with persistent voiding dysfunction. Six of the 7 ureters with success after a single injection had no associated persistent voiding dysfunction. Patient age and sex, pre-reimplant VUR grade, pre-reimplant risk factors, reimplant technique, VUR grade change from before to after reimplant, preDx/HA VUR grade, pre-Dx/HA persistent voiding dysfunction, time from reimplant failure to Dx/HA injection, injec-
313
Comparison of variables between ureters with success and failure after initial Dx/HA injection
No. ureters Mean mos pt age Female-to-male ratio No. pre-reimplant VUR grade: 0 (no VUR) I II III IV V No. pre-reimplant risk factors: Duplication Ureterocele Previous open reimplant Neurogenic bladder Megaureter Reimplant technique: Politano-Leadbetter Cohen cross-trigonal Glenn-Anderson Common sheath Tapering Ureterocele excision No. VUR grade change from before to after reimplant: Decrease Increase or new onset No change No. pre-Dx/HA VUR grade: 0 (no VUR) I II III IV V No. pre-Dx/HA persistent voiding dysfunction Mean mos from reimplant failure to Dx/HA No. Dx/HA technique: STING Modified STING Mean vol Dx/HA vol (range) Mean mos followup
Successes
Failures
p Value
7 57.6 2.5:1
3 74.3 2:1
2 0 1 1 2 1
1 0 0 0 0 2
2 2 1 1 1
0 0 0 0 1
0.301 0.301 0.490 0.490 0.490
3 1 2 2 1 2
3 0 0 1 1 0
0.091 0.490 0.301 0.880 0.490 0.301 0.356
2 2 3
2 1 0
0 1 2 3 1 0 1
0 1 1 0 1 0 3
0.011
25.4
52
0.491
0.648 0.880 0.455
0.559
0.880 5 2 1.7 (1–4) 7.3
2 1 1.7 (1–2) 18
0.705 0.066
tion technique, volume of injection and mean followup were all statistically insignificant between ureters with success and those with failure after the initial injection. A second Dx/HA injection resulted in complete resolution in 2 of the 3 failed ureters (67%). Success of the remaining failed ureter could not be assessed due to insufficient followup. Of the 9 ureters with complete followup after initial and second injections ultimate success was achieved in all using up to 2 injections. DISCUSSION Although many studies support the overall effectiveness of Dx/HA injection for the treatment of primary VUR, most of these series exclude patients with a history of open ureteroneocystostomy.4 –9 Nonetheless, a small number of series have described the use of bulking agents for this particular patient population, and the results are promising.12–16 The first study evaluated 19 patients with VUR after renal transplantation and revealed a low success rate of 30%.12 Gaschignard et al reported a higher success rate of 75% in 12 patients with VUR after Cohen cross-trigonal reimplantation.13 Kumar and Puri reported on 40 ureters with success rates of 68% after the initial injection, 85% after 2 injections and 95% after 3 injections.14 Similarly, 78% of 23 total
314
VESICOURETERAL REFLUX AFTER URETERONEOCYSTOSTOMY
ureters achieved success in the series by Capozza et al.15 Most recently, Perez-Brayfield et al reported on 17 patients with an 88% success rate after a single Dx/HA injection.16 The current study also demonstrated promising results for Dx/HA injection, with a 70% success rate after 1 injection and a 100% success rate after 2 injections. Many of the general principles of endoscopic treatment with bulking agents defined in previous studies held true for this particular series. Specifically, voiding dysfunction seemed to be associated with an increased risk of failure. Capozza et al reported similar findings and argued that high voiding pressures resulted in displacement of Dx/HA.17 Additionally, the risk of contralateral VUR was small (10%). Contralateral VUR rates reported in the literature range from 4.5% to 12.5%.8,18,19 Lastly, patients tolerated the procedure well without major complications.4 –9 Contrary to other studies, reflux grade before Dx/HA injection did not correlate with success after injection in this study.4 – 6,8,11 Puri9 and Lavelle19 et al also failed to find a correlation between baseline VUR grade and success after injection. Analyzing a similar patient population as the current study, Perez-Brayfield et al also failed to find this correlation.16 For the most part no obvious clinical factors were more prevalent in the ureters that required a second Dx/HA injection. These ureters were not associated with more complex reconstruction or tapering. Moreover, although all 3 ureters were treated with Politano-Leadbetter reimplantation, the majority of ureters in this series were treated with this same reimplantation. Interestingly, although it would seem technically more difficult to inject a Cohen cross-trigonal ureter, the single cross-trigonal ureter included in the study had success after the initial injection. In fact, Gaschignard et al only included patients with VUR after Cohen cross-trigonal reimplantation and achieved similar results.13 Lastly, the injection technique or the volume injected was not noticeably different in these 3 ureters vs the others. Future studies with larger numbers of patients will help further evaluate these various factors and their impact on success. Based on previous studies, the overall success rate is high for this complex patient population. One simple explanation is that Dx/HA injection is an overall effective treatment option, even for ureters with complex anatomy.16,20 Another explanation is that the small number of patients evaluated and the short overall followup in the current and most other studies result in overestimation of success. Lastly, it is possible patients failing open surgery are specifically good candidates for endoscopic injection and are more likely to have success. Patients failing open surgery may be good candidates for Dx/HA injection because of certain components of success previously established through open surgery. For example ureters with high grade VUR preoperatively may fail due to large ureteral diameter rather than inadequate tunnel length or insufficient muscular backing. For ureters with ureteroceles perhaps failure is due to insufficient muscular backing rather than insufficient tunnel length or large ureteral diameter. It is possible that these ureters fail open surgery only partially, rather than completely. Therefore, it is possible that the success of Dx/HA in patients failing open surgery is due to its ability to narrow sufficiently the ureteral orifice in the setting of adequate ureteral tunnel
length, or its ability to provide additional ureteral backing support in the setting of insufficient muscular backing. In essence, the overall effect of Dx/HA could be additive to the components of success previously established through open surgery. Repeat surgery, in general, involves longer operative times, more difficult surgical planes, additional risks and less eventual success. Moreover, repeat surgery may be difficult, given the complexity of many of the initial surgeries. Extravesical ureteral mobilization is often necessary to establish adequate ureteral length. Psoas hitch, Boari flap or transureteroureterostomy may be necessary. Risks of devascularization and injury to the contralateral ureter, especially for cross-trigonal ureters, further complicate matters.16 Certainly, the initial course for patients failing open surgery should be observation, since the majority of these patients have resolution of VUR with time.2,3 In this study patients were observed for an average of 29 months before Dx/HA injection. Nonetheless, considering the general difficulties associated with repeat surgery and the promising results from this and other series, Dx/HA injection after an initial course of observation is a reasonable option for patients with VUR after open surgical correction.
CONCLUSIONS Despite the high success rate of open ureteral reimplantation, failures occur. In experienced hands they usually occur in patients with high grade VUR or following complex lower urinary tract reconstruction. Considering the difficulties inherent in repeat surgery and the high success rate of Dx/HA injection in this and other studies, Dx/HA is an appealing and reasonable option for patients failing open surgery.
Abbreviations and Acronyms Dx/HA STING VCUG VUR
⫽ ⫽ ⫽ ⫽
dextranomer/hyaluronic acid subureteral transurethral injection voiding cystourethrogram vesicoureteral reflux
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