Long-Term Followup of Dextranomer/Hyaluronic Acid Injection for Vesicoureteral Reflux: Late Failure Warrants Continued Followup

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1 Long-Term Followup of Dextranomer/Hyaluronic Acid Injection for Vesicoureteral Reflux: Late Failure Warrants Continued Followup Eugene K. Lee,* John M. Gatti, Romano T. DeMarco and J. Patrick Murphy From the Kansas University Medical Center, Kansas City, Kansas and Children s Mercy Hospital, Kansas City, Missouri Purpose: Dextranomer/hyaluronic acid injection of ureteral orifices is a popular option in the treatment of vesicoureteral reflux, with success rates ranging from 69% to 89%. We found only 1 study that followed patients beyond the initial postoperative voiding cystourethrogram, which describes a 96% success rate at 2 to 5 years but defines success as nondilating reflux. We examined our dextranomer/hyaluronic acid series to evaluate the long-term (1-year) outcome in children who had resolution of reflux on initial postoperative voiding cystourethrography. Materials and Methods: We retrospectively reviewed our dextranomer/hyaluronic acid experience from February of 2002 to December of We determined initial success on early (6 to 12-week) postoperative voiding cystourethrogram. We then evaluated long-term success by obtaining a voiding cystourethrogram at 1 year postoperatively in patients who were initially cured of reflux. In addition, success rates between the first and second halves of our experience were evaluated to account for surgeon experience and modification of technique. Results: Our total success rate at initial voiding cystourethrogram was 73% (246 of 337 total ureters). The success rate in the first half of our experience was 65.9% (112 of 170 ureters) and in the second half was 80.2% (134 of 167). A total of 150 ureteral units with initial successful dextranomer/hyaluronic acid treatment were evaluated at 1 year by voiding cystourethrogram. Of these ureters 111 had continued resolution of vesicoureteral reflux, for a long-term success rate of 74%. Including initial postoperative failures, the complete 1-year total success rate was 46.1% (111 of 241 ureters). Conclusions: Although the reflux resolution rates at initial postoperative voiding cystourethrogram approach those of open surgery, there is a significant failure rate at 1 year, which warrants long-term followup. Abbreviations and Acronyms DHA dextranomer/hyaluronic acid HIT hydrodistention implantation technique STING subureteral polytetrafluoroethylene injection VCUG voiding cystourethrogram VUR vesicoureteral reflux Submitted for publication September 9, Study received institutional review board approval. * Correspondence: Kansas University Medical Center, 3901 Rainbow Blvd., Kansas City, Kansas (telephone: ; elee@ kumc.edu). Key Words: deflux, dextranomer-hyaluronic acid copolymer, follow-up studies, vesico-ureteral reflux VESICOURETERAL reflux is a relatively common entity in the pediatric population, affecting approximately 1% to 3% of children. 1,2 In the presence of a urinary tract infection reflux will increase the incidence of pyelonephritis, which may lead to renal scarring. This condition may eventually result in hypertension and end-stage renal disease. 3,4 For most clinicians the therapeutic algorithm for vesicoureteral reflux begins with medical treatment and close surveillance, especially in patients with /09/ /0 Vol. 181, , April 2009 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI: /j.juro

2 1870 LONG-TERM FOLLOWUP OF DEXTRANOMER/HYALURONIC ACID FOR VESICOURETERAL REFLUX low grade reflux, which often resolves spontaneously. However, spontaneous resolution is less likely to occur in older patients and those with higher grade reflux, who often will require some form of surgical treatment. When repair is warranted open vesicoureteral reimplantation is arguably considered the gold standard. However, many clinicians have begun to treat reflux with a less invasive approach. Subureteral bulking agents for VUR were first introduced in Since 2001, when the Food and Drug Administration approved DHA, it has become the agent of choice for endoscopic treatment of VUR due to its ease of use and minimal associated morbidity. In fact, between 2002 and 2004 the mean number of injections annually per institution increased from 17 to 66, and the number of reflux procedures per institution increased from 75 to Several studies have documented the effectiveness of DHA injections to range from 69% to 89%. 7,8 However, long-term followup is lacking, as well as strict criteria for what is considered a success. One meta-analysis that examined all types of injections, including DHA, demonstrated a primary success rate of 78.5% for grades I and II, 72% for grade III, 63% for grade IV and 51% for grade V reflux. 9 Many of the studies in this meta-analysis had limited followup, with only 1 VCUG within the first 3 to 4 months postoperatively. 10 There exists 1 DHA study that had longer followup after an initial successful VCUG. 11 However, this group had long-term data for only 49 patients, and defined resolution of VUR as nondilating reflux. The authors of that study found that of the 49 patients with no reflux at 3 and 12 months 96% had continued resolution of VUR at 2 and 5 years. Given the paucity of information regarding the long-term results of DHA, it has been our practice to repeat VCUG at 1 year prospectively regardless of success on the initial study. We present our longterm data on DHA in the treatment of VUR. MATERIALS AND METHODS After institutional review board approval was obtained a retrospective DHA database was created using patient information from February 2002 through December Data included age, date of operation, grade of reflux at initial presentation, preoperative status (the prune belly syndrome, neurogenic bladder, severe voiding dysfunction, ectopic ureter, ureterocele) and VCUG results. Patients were not excluded based on any existing condition, although those with voiding dysfunction were treated before consideration for DHA injection. These patients underwent timed voiding, an aggressive bowel regimen and anticholinergic therapy. The success rate at initial postoperative VCUG (6 to 12 weeks) was first determined and subdivided by grade. Cases deemed successful on postoperative VCUG were then evaluated with a repeat study at 1 year. This patient group was also subdivided by grade. Patients who did not undergo 1-year followup VCUG were contacted via telephone as well as by mail on at least 1 occasion. This contact was made to retain as many patients as possible for office followups and long-term VCUG results. All procedures were performed by 1 of 2 pediatric urologists at our institution (JPM or JMG). The technique involved use of an 18 gauge needle (included by the manufacturer) primed with DHA, which was injected into the subureteral space. In the second half of our experience the volume instilled was increased to larger amounts (approximately 1 cc per ureter). The technique was also modified approximately between the first and second halves of our experience, reflecting our transition from the STING method to HIT, as described by Kirsch et al. 8 We compared outcomes between the first and second halves of our surgical experience, to account for the learning curve of the procedure as well as for modification of the technique. We attempted to answer the question of whether surgeon experience and change in technique would alter long-term success. All data analyses were performed using SAS version Descriptive statistics were reported, as well as 95% confidence intervals for proportions. RESULTS Our retrospective DHA database included 219 consecutive patients (337 ureteral units) treated between February 2002 and December 2005 (table 1). A flow chart of our study design is shown in figure 1. Postoperative VCUG at approximately 6 to 12 weeks revealed a success rate of 73% (246 of 337 Table 1. Preoperative demographics for children undergoing DHA injection No. VUR grade (%): I 26 (7.7) II 142 (42.1) III 110 (32.6) IV 48 (14.2) V 11 (3.3) Mean mos age (range) 79.5 (7 119) No. gender (%): M 41 (18.7) F 178 (81.3) No. etiology: Prune belly syndrome/posterior urethral valves 3 Neurogenic bladder 23 Complex/significant voiding dysfunction 26 Ectopic ureter 2 Ureteroceles 4

3 LONG-TERM FOLLOWUP OF DEXTRANOMER/HYALURONIC ACID FOR VESICOURETERAL REFLUX Total Ureters Immediate Success Immediate Failure One-year Success One-year Failure Lost/Refused F/U Early/Immediate Success Rate 246/337 = 73% One-year success rate in ureters with initial resolution 111/(111+39) = 73% One-year overall (cumulative) success rates 111/( [Immediate Failures]) = 46.1% Figure 1. Flow chart of study design. F/U, followup ureteral units). Patients who had initial resolution of reflux on VCUG underwent a repeat study at 1 year, which demonstrated a success rate of 74% (111 of 150 ureters). When the 91 ureters with initial treatment failure were added to the delayed failures at 1 year the total success rate at 1 year was 46.1% (111 of 241 ureters, table 2). The minority of cases with a complex preoperative status followed a similar distribution of success and, therefore, are not reported separately. Table 2. VCUG results in ureteral units No. Successes Initial Postop VCUG/Total No. Units (%) No. Successes 1-Yr Postop VCUG/Total No. Units (%) No. Successes/ Total No. Units (%)* VUR grade: I 19/26 (73.1) 10/10 (100) 10/17 (58.8) II 118/142 (83.1) 60/74 (81.1) 60/98 (61.2) III 78/110 (70.9) 29/46 (63.0) 29/78 (37.2) IV 26/48 (54.2) 10/15 (66.7) 10/37 (27.0) V 5/11 (45.5) 2/5 (40) 2/11 (18.2) Totals 246/337 (73.0) 111/150 (74.0) 111/241 (46.1) * Includes initial and late failures. Following successful initial VCUG 74 patients (96 ureteral units) did not undergo complete followup. However, even if all 96 ureteral units had durable results at 1 year, the total success rate would still be only 61.4% (207 of 337 ureters). Demographics for the 74 patients without 1-year followup are outlined in table 3. This patient population was similar to the original group. Table 3. Demographics for 96 ureteral units without 1-year followup No. VUR grade (%): I 9 (9.4) II 44 (45.8) III 32 (33.3) IV 11 (11.5) V 0 (0) Mean mos age (range) 82.5 (10 181) No. gender (%): M 9 (12.2) F 65 (87.8) No. etiology: Prune belly syndrome/posterior urethral valves 1 Neurogenic bladder 5 Complex/significant voiding dysfunction 7 Ectopic ureter 0 Ureteroceles 2

4 1872 LONG-TERM FOLLOWUP OF DEXTRANOMER/HYALURONIC ACID FOR VESICOURETERAL REFLUX The first and second halves of the surgical experience were divided by a transition point of techniques (STING vs HIT), as well as a likely time when the learning curve had been met. The success rate on initial postoperative VCUG was 65.9% (112 of 170 ureters) during the first half of the surgical experience and 80.2% (134 of 167) during the second half. At 1-year followup VCUG was performed only in ureters with initial success. At reevaluation the success rate was 74.2% (49 of 66 ureters) for the first half of the surgical experience and 73.8% (62 of 84) for the second half (fig. 2). A statistically significant difference between experience halves was found only in the immediate postoperative VCUGs, as shown by nonoverlapping 95% confidence intervals (first half 0.59 to 0.73, second half 0.74 to 0.86). There was no statistical difference between the first and second halves of the series on 1-year VCUG, since the 95% confidence intervals overlapped. Immediate postoperative and 1-year VCUG comparisons by grade are provided in figures 3 and 4. DISCUSSION Our initial experience with DHA was similar to existing studies, with a postoperative VCUG success rate of 73%. At further evaluation with VCUG 1 year after endoscopic treatment 39 of 150 ureters exhibited VUR, resulting in a recurrence rate of 26% and Figure 3. Comparison of success rates at initial postoperative evaluation based on first vs second half of series. an overall cumulative failure rate of 54% (130 of 241 ureters). Our results, which reveal an overall success rate of only 46%, are extremely sobering, especially since only 74% of the initially successful cases Figure 2. Success rates at initial postoperative evaluation and 1-year followup

5 LONG-TERM FOLLOWUP OF DEXTRANOMER/HYALURONIC ACID FOR VESICOURETERAL REFLUX 1873 Figure 4. Comparison of success rates at 1-year followup based on first vs second half of series. remained so at 1 year. This finding leads us to believe that other studies, if reevaluated beyond the initial VCUG, would yield similar findings. Because of our results, it is our belief that DHA is more appropriate for lower grades of reflux. Similar to previous studies, we found the greatest success in ureters with lower grade VUR, especially grades I and II, which had continued resolution of 100% and 79.8%, respectively, at 1 year. This belief supports a recent article by Benoit et al, 12 who did a cost analysis of DHA injection vs ureteral reimplantation. They concluded that the patients with the most costeffective results had grades I and II (and possibly unilateral grade III) reflux. This group went on to document that DHA injection at diagnosis is not as cost-effective as traditional management for most grades of reflux. Furthermore, traditional management (ureteral reimplantation in cases of failed medical therapy) is more cost-effective than DHA injection at diagnosis for grades IV and V reflux due to the lower success rates of DHA injection. 13 Another study supporting the notion that endoscopic injections are better suited for lower grade reflux was reported by Lorenzo et al. 14 On multivariate analysis this group found that the factors predicting successful injection were surgeon experience, number of previous injections and preoperative VUR grade. They found the highest success rates (78%) in patients with grade I to III reflux. Another aspect of our series that we evaluated was the difference between the first and second halves of our surgical experience. This approach took into consideration the achievement of a steep learning curve, as well as a modification of technique between the STING method and HIT. Our results mirror those of Lorenzo et al, 14 as we also observed a significant improvement in success rates with increased surgeon experience, based on postoperative VCUG between the first and second halves of the study. However, the results ultimately did not endure at the 1-year VCUG. The sharp decline in success in long-term studies likely relates to a shift in the DHA material. We found that among patients who underwent ureteral reimplantation after DHA many had blebs that had moved beyond the site of initial subureteral injection. Whether initial placement was correct may be questioned but we found that our initial success rates were consistent with other studies. This outcome leads us to conclude that surgeon experience and modified technique may account for initial improvement but do not predict long-term durability. One important clinical question unanswered by this study is whether residual low grade reflux without clinical evidence of recurrence, ie urinary tract infection, is important. Should we have included grade I cases as successes in VUR management? This question was among the difficulties in a metaanalysis performed by Elder et al in 2006, who found that several studies were using no reflux and grade I reflux as end points. 9 We believe that using no reflux as an end point is more consistent with our initial goal of curing and not just improving VUR. Elmore et al recently reported that their DHA population had fewer urinary tract infections compared to their open surgery group. 15 Their explanation for this phenomenon includes the possibility that open ureteral reimplantation may change the dynamics of the bladder as well create more scarring, which in turn creates a more favorable environment for bacterial adherence. In our experience we had several patients with symptomatic as well as asymptomatic urinary tract infections. However, we believed that, as a retrospective chart review, inclusion of these data would have been incomplete and confounding. Two studies have documented urinary tract infections following successful DHA injection. Chi et al reported their data on 159 patients, of whom 95% had preoperative urinary tract infections. 16 All patients had resolution of reflux after DHA injection. On followup 40 patients (25%) had recurrent urinary tract infections, of which half were febrile. Reimaging was done in 15 patients with recurrent febrile infections, and 7 had recurrent reflux. Another study of 45 patients who had undergone successful DHA injection demonstrated that 12 (27%) had recurrent urinary tract infections. 17 On reimaging with VCUG 10 of these patients (83%) had re-

6 1874 LONG-TERM FOLLOWUP OF DEXTRANOMER/HYALURONIC ACID FOR VESICOURETERAL REFLUX current VUR. These findings underscore the need for close, continued followup. There are limitations to our study that are inherent in a retrospective review. In particular, followup is not complete. Of the 246 ureteral units with an initial successful postoperative VCUG reevaluation was not performed in 96 (74 patients) at 1 year. Telephone calls were made and letters were mailed to all patient families. We contacted a majority of patients but many parents elected not to put their child through another invasive study. As a result, complete followup may have shown a greater success rate for the injections. Quite possibly, patients who did not undergo repeat VCUG were doing well clinically. CONCLUSIONS DHA injections can be extremely valuable when used in the correct setting. Our findings would suggest that DHA is most appropriately used in grades I and II reflux, where the chances of durability are the highest. Furthermore, we acknowledge that patients and their families may prefer a trial of a minimally invasive procedure to resolve VUR before being subjected to a major open operation, regardless of cost-effectiveness. Because of the limitations of this retrospective study, a prospective study is under way to confirm the accuracy of these findings. At present, we continue to offer DHA injections in appropriate cases but recommend continued followup. REFERENCES 1. Wheeler D, Vimalachandra D, Hodson E, Roy L, Smith G and Craig J: Antibiotics and surgery for vesicoureteric reflux: a meta-analysis of randomized controlled trials. Arch Dis Child 2003; 88: 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: Lomberg H: Properties of Escherichia coli in patients with renal scarring. J Infect Dis 1989; 159: Majd M, Rushton HG, Jantausch B and Wiedermann BL: Relationship among vesicoureteral reflux, p-fimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection. J Pediatr 1991; 119: Matouschek E: Die behandlung des vesikorenalen refluxes durch transurethrale einspritzung von Teflon paste. Urologe A 1981; 20: Lendvay TS, Sorensen M, Cowan CA, Joyner BD, Mitchell MM and Grady RW: 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: EDITORIAL COMMENTS 7. Routh JC, Reinberg Y, Ashley RA, Inman BA, Wolpert JJ, Vandersteen DR et al: Multivariate comparison of the efficacy of intraureteral versus subtrigonal techniques of dextranomer/hyaluronic acid injection. J Urol 2007; 178: Kirsch A, 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: Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R et al: Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175: Yucel S, Gupta A and Snodgrass W: Multivariate analysis of factors predicting success with dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol 2007; 177: Lackgren G, Wahlin N, Skoldenberg E and Stenberg A: Long-term followup of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2001; 166: Benoit RM, Peele PB and Docimo SG: The costeffectiveness of dextranomer/hyaluronic acid copolymer for the management of vesicoureteral reflux. 1: substitution for surgical management. J Urol 2006; 176: Benoit RM, Peele PB, Cannon GM Jr and Docimo SG: The cost-effectiveness of dextranomer/hyaluronic acid copolymer for the management of vesicoureteral reflux. 2. Reflux correction at the time of diagnosis as a substitute for traditional management. J Urol 2006; 176: Lorenzo AJ, Pippi Salle JL, Barroso U, Cook A, Grober E, Wallis MC et al: What are the most powerful determinants of endoscopic vesicoureteral reflux correction? Multivariate analysis of a single institution experience during 6 years. J Urol 2006; 176: Elmore JM, Kirsch AJ, Heiss EA, Gilchrist A and Scherz HC: Incidence of urinary tract infections in children after successful ureteral reimplantation versus endoscopic dextranomer/hyaluronic acid implantation. J Urol 2008; 179: Chi A, Gupta A and Snodgrass W: Urinary tract infection following successful dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol 2008; 179: Sedberry-Ross S, Rice DC, Pohl HG, Belman AB, Majd M and Rushton HG: Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid. J Urol, part 2, 2008; 180: This study documents the major pitfall of using dextranomer/hyaluronic acid its unpredictable durability. In the early experience of Lackgren et al 13% of ureters that were successfully treated with DHA exhibited reflux again 1 year after injection (reference 11 in article). More recently, others have reported the phenomenon of recurrent reflux in association with urinary tract infection and febrile pyelonephritis after initial treatment success (reference 17 in article). 1 As Lee et al have also observed, long-term failure can occur after use of the HIT, wherein more DHA is injected. In fact, the 1-year failure rates of the HIT and STING technique were almost identical approximately 26%. Instead of being definitively cured of their reflux, there now exists a large population of children who may require

7 LONG-TERM FOLLOWUP OF DEXTRANOMER/HYALURONIC ACID FOR VESICOURETERAL REFLUX 1875 monitoring for urinary infection. If an infection occurs, these children would be subject to further radiographic evaluation and possible resumption of antibiotic prophylaxis or surgery. It is important that parents be counseled regarding the possibility of these additional interventions if DHA is elected. The DHA implant may not be inert or stable enough in all individuals to confer lifelong correction. 2 Therefore, it seems that the algorithm for treating vesicoureteral reflux has not been finally determined. Saul P. Greenfield Department of Pediatric Urology Women and Children s Hospital of Buffalo Buffalo, New York REFERENCES 1. Traxel E, DeFoor W, Reddy P, Sheldon C and Minevich E: Multivariate analysis of risk factors for urinary tract infections after endoscopic injection of dextranomerhyaluronic acid. Presented at annual meeting of American Academy of Pediatrics, Section on Urology, Boston, Massachusetts, October 10 13, Broderick K, Thompson JH, Khan A and Greenfield SP: Giant cell reaction with phagocytosis adjacent to dextranomer/hyaluronic acid (Deflux) implant: possible reason for Deflux failure. J Pediatr Urol 2008; 4: 319. The authors report long-term followup of VUR treatment with DHA. Since the most common surgical procedures performed by pediatric urologists have success rates of greater than 90%, it is sobering that DHA treatment ultimately failed in 54% of patients. Complex anatomy, surgeon experience and technique are considered when evaluating surgical success rates. Similar to other studies (reference 14 in article), the authors found no outcome differences based on patient anatomy. There were no significant differences in long-term successful VUR treatment between the first and second halves of surgeon experience or the techniques used. Ultimately, these factors had little influence on end results. Successful treatment was VUR grade dependent. Patients with lower grades of VUR faired better initially and in the long term. However, even in this group the overall success rate at 1 year was only 60%, which is lower than the reported natural resolution rate (approximately 80%). 1 It is concerning when long-term surgical success rates are lower than the natural resolution rate of the disease. Future efforts should be made to identify which population is best served by DHA endoscopic treatment. Additionally, we should no longer accept short-term followup clinically or in the reported literature, but should insist at a minimum that 1-year followup be obtained. Sherry Sedberry-Ross Division of Pediatric Urology Children s National Medical Center Washington, D. C. REFERENCE 1. Schwab CW Jr, Wu HY, Selman H, Smith GH, Snyder HM III and Canning DA: Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol 2002; 168: 2594.