The Role of Endoscopic Treatment in the Management of Grade V Primary Vesicoureteral Reflux

european urology 52 (2007) 1505 1510 available at www.sciencedirect.com journal homepage: www.europeanurology.com Pediatric Urology The Role of Endoscopic Treatment in the Management of Grade V Primary Vesicoureteral Reflux Maria N. Menezes a, Prem Puri a,b,c, * a The National Children s Hospital, Dublin, Ireland b The Children s Research Centre, Our Lady s Children s Hospital, Dublin, Ireland c University College Dublin, Dublin, Ireland Article info Article history: Accepted April 26, 2007 Published online ahead of print on May 7, 2007 Keywords: Endoscopic treatment High-grade vesicoureteral reflux Reflux nephropathy Abstract Objectives: Although endoscopic treatment provides a high rate of success in children with grades II IV vesicoureteral reflux (VUR), its role in the management of grade V reflux has been questioned. In this study we reviewed our 21-yr experience of endoscopic treatment in children with grade V primary VUR. Methods: We retrospectively reviewed the medical records of 132 children who underwent endoscopic treatment for primary grade V reflux from 1984 to 2004. VUR was unilateral in 39 patients and bilateral in 34, and 59 patients had ipsilateral grade V reflux with a lower grade of VUR on the contralateral side. Endoscopic treatment was performed in a total of 166 grade V ureters; polytetrafluoroethylene was used from 1984 to 2000 and dextranomer/hyaluronic acid from 2001 to 2004. Median followup was 12.2 yr and mean follow-up was 13.4 yr. Results: VUR was completely resolved after first injection in 88 (53%) ureters and downgraded to grade I or II in 26 (15.7%). VUR resolved after a second and third injection in 36 (21.7%) and 10 (6%) of ureters, respectively. Endoscopic treatment failed to correct VUR in 6 (3.6%) ureters, requiring ureteral reimplantation in 5 and nephrectomy in 1. Thirteen patients developed urinary tract infections during the follow-up period, and on investigation 9 ureters (5.4%) had recurrence of VUR. No injection or morbidity related to tissue-augmenting substances was noted in any patient. Conclusion: Endoscopic treatment should be the first-line of treatment in management of grade V vesicoureteral reflux. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. The Children s Research Centre, Our Lady s Children s Hospital, Crumlin, Dublin 12, Ireland. Tel. +35314096420. E-mail address: prem.puri@ucd.ie (P. Puri). 0302-2838/$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.04.082

1506 european urology 52 (2007) 1505 1510 1. Introduction The association of high-grade vesicoureteral reflux (VUR) and renal parenchymal damage is well recognised [1 3]. Reflux nephropathy is a major cause of end-stage renal failure in children and young adults. Recently, a database study of Italian children with chronic renal failure reported that patients with VUR accounted for 26% of the children, the majority having grade IV/V reflux [3]. Several antireflux procedures have been described in the management of high-grade VUR. The majority entail opening the bladder and performing a variety of procedures on ureters. These operations are effective, but not free from complications even in the best hands. Surgery in children, particularly infants with high-grade VUR with dilated ureters, carries a higher rate of failure and morbidity than in children with lower-grade reflux and nondilated ureters. The American Urological Association report on VUR [4] reported persistence of VUR in 19.3% of ureters after reimplantation of ureters for grade V reflux. The rate of obstruction after ureteral reimplantation needing reoperation reported by the American Urological Association in 33 studies was 0.3 9.1% [4]. Endoscopic approach has been used successfully to treat VUR in children for the past two decades [5 7]. Most pediatric urologists acknowledge that endoscopic treatment provides a high rate of success in children with grades II IV VUR. However, some have questioned the role of endoscopic treatment in the management of grade V reflux [8 10]. In this study we reviewed our 21-yr experience of endoscopic treatment in children with grade V primary VUR. 2. Materials and methods We retrospectively reviewed the medical records of 132 children (81 males and 51 females) who underwent endoscopic treatment for uncomplicated primary grade V reflux from 1984 to 2004. The diagnosis of grade V VUR was made on the basis of a voiding cystourethrogram (VCUG) and according to the International Classification of Reflux. VCUG was carried out in children with symptomatic urinary tract infection and for those who were screened for familial reflux. VUR was unilateral in 39 patients and bilateral in 34. Fifty-nine patients had grade V reflux on the ipsilateral side and a lower grade of VUR on the contralateral side. Patients age ranged from 3 mo to 14 yr (mean age: 3.3 yr). The males ranged in age from 3 mo to 12 yr and the females from 4 mo to 14 yr. Forty-six children were younger than 1 yr. Endoscopic treatment was performed in a total of 166 grade V ureters with the use of tissueaugmenting substances: polytetrafluoroethylene from 1984 to 2000 and dextranomer/hyaluronic acid from 2001 to 2004. Polytetrafluoroethylene was used in 149 ureters and dextranomer/hyaluronic acid in 17 ureters. The paste was injected with the use of a disposable 4F Puri catheter through a cystoscope [6]. In children with grade V VUR, injection was done by inserting the needle not below, but rather directly into the affected ureteral orifice to increase the length of the intravesical ureter and to create a slit-like orifice. The volume of the paste injected ranged from 0.2 to 1.2 ml for dextranomer/hyaluronic acid and 0.1 to 1 ml for polytetrafluoroethylene per ureter. All the procedures were carried out by a single surgeon. Seventy-seven (46.4%) of the 166 ureters showed renal scarring on a preoperative dimercaptosuccinic acid (DMSA) scan. Antibiotic prophylaxis was prescribed for 12 wk after the procedure. VCUG and renal ultrasound were performed 3 mo later. Endoscopic treatment was considered successful if VUR resolved or was downgraded to grade I or II. The side-effects investigated were clinical parameters of haematuria or loin pain on the side of the injection and sonographic evidence of ureteral obstruction. Up to 1996, VCUG was performed at 1 and 3 yr as well following endoscopic treatment. Renal and bladder ultrasound were done yearly for the first 3 yr and then once every 2 yr to monitor closely the results of the procedure. The appearance of the upper urinary tract and the size/position of implants were assessed on ultrasound. Two monthly urine examinations were performed postoperatively for 1 yr. Follow-up DMSA scans were performed every 3 yr. Median follow-up was 12.2 yr and mean follow-up was 13.4 yr (range: 2 21). 3. Results All patients underwent endoscopic treatment as an outpatient procedure and the procedure was well tolerated. VUR was completely resolved after first injection in 88 (53%) ureters and downgraded to grade I or II in 26 (15.7%), requiring no further treatment (Fig. 1). VUR resolved after a second and third injection in 36 (21.7%) and 10 (6%) ureters, respectively. Endoscopic treatment failed to correct VUR in 6 (3.6%) ureters, requiring ureteral reimplantation in 5 and nephrectomy in 1. The patient who underwent a nephrectomy was a child who had only Fig. 1 Result of endoscopic treatment in grade V primary vesicoureteric reflux (n = 166).

european urology 52 (2007) 1505 1510 1507 12% function in the kidney. He had persistent reflux after endoscopic treatment; because he was having recurring urinary tract infections, we decided to do a nephrectomy. Thirteen patients developed urinary tract infections during the follow-up period. These were detected if the patient became symptomatic or on routinely performed postoperative 2-monthly urine examinations. On investigation recurrence of VUR was noted in 9 ureters (5.4%). Of these 9 ureters, 5 (55.5%) had high-grade VUR and were corrected by a single repeat endoscopic treatment; 4 (44.5%) had low-grade VUR, which did not require any treatment. All recurrences occurred within 3 yr of the initial treatment. No injection-related morbidity or untoward effects from the tissue-augmenting substances was noted in any patient. At follow-up there were no significant changes in the size of the implants on bladder ultrasound. Follow-up DMSA scans at 3-yr intervals did not reveal any worsening of renal scarring after endoscopic treatment, except in one patient. 4. Discussion Various options are available for the treatment of grade V VUR. For many years, ureteral reimplantation has been considered the gold standard in the treatment of high-grade VUR. However, it is an invasive procedure and results in longer hospital stay, and also is not free of complications such as vesicoureteral obstruction. In addition persistence of VUR following ureteral reimplantation for grade V disease has been reported to be as high as 19.3% [4]. A recent study compared the success rates for antireflux surgery for primary VUR and found success rates of 97.5%, 92%, and 90% for extravesical ureteral reimplantation, intravesical ureteral reimplantation, and endoscopic correction, respectively [11]. Endoscopic correction of VUR has the advantages of being performed as an outpatient procedure, which is quick and simple to perform and can be easily repeated in cases of failure after the first injection. The other alternative of long-term antibiotic prophylaxis in the management of VUR is dependent on patient compliance and has the danger of bacterial resistance with possible breakthrough urinary tract infections. Moreover, Schawb et al. [12] reported that yearly spontaneous resolution rates for grades IV and V reflux was only 5% and median time to resolution under antibiotic treatment could take up to 9.5 yr for grade IV reflux. Furthermore, the International Reflux Study in children (European section of the study) as well as the American Urological Association reported a reflux resolution rate of less than 10% in bilateral grade IV VUR after 5 yr of medical therapy [13 15]. Most pediatric urologists agree that there is a spontaneous resolution rate of VUR in boys during the first year of life. Sjostrom et al. [16] noted that, in infants with grades IV and V reflux, there was a spontaneous resolution rate of 29% in boys and 4% in girls in the first year and thereafter an annual resolution rate of only 9% for both boys and girls [16]. However, all these studies have also shown that observational therapy does carry an ongoing risk of renal scarring. Parental preference with respect to choice of treatment is an important factor to consider. A study by Ogan et al. [17] had shown that 60% of parents would choose endoscopic treatment over reimplantation, if they were predicted to require more than 3 yr of antibiotic prophylaxis. A more recent study showed that 80% of parents prefer endoscopic treatment to antibiotic prophylaxis and open surgery when given a free choice after detailed information about all three treatment options [18]. Although most pediatric urologists acknowledge that endoscopic treatment of VUR provides a high rate of success in patients with grades II IV VUR, some have questioned its role in the management of grade V reflux because of the high incidence of failure [8 10]. Our 21-yr experience and long-term follow-up clearly shows that endoscopic treatment of grade V VUR is not only feasible but also effective. In the current study, VUR was completely resolved after first injection of tissue-augmenting substance in 53% of ureters and downgraded to grade I or II in 16%, requiring no further treatment. Endoscopic treatment failed to correct VUR in only 3.6% of grade V refluxing ureters, requiring reimplantation of ureters. In our study, the procedure was well tolerated with no side-effects, as also seen in other series [7,19]. Failure of the initial endoscopic treatment has been reported to be due to poor technique, location of the ureteral orifice, mound displacement, or faster biodegradation of the material before the onset of adequate collagen deposition within the implant [20,21]. We believe that the accuracy of the injection technique plays an important role in the correction of grade V reflux. These patients have a short submucosal ureter or congenital absence of the intramural part, accompanied by a wide lateral orifice, which would require the injection needle to be inserted directly into the affected ureteral orifice instead of below it. To our knowledge this is the longest follow-up study of a series of children with high-grade VUR

1508 european urology 52 (2007) 1505 1510 treated endoscopically. There are no comparative studies in which grade V VUR has been treated by open surgery or antibiotic prophylaxis and patients followed up for 21 yr. In our study, any patient who had a urinary tract infection during follow-up had a repeat VCUG. Thirteen (8.1%) patients developed urinary tract infections during the follow-up and half of them showed recurrence of VUR. Low recurrence rate and the fact that none of them required ureteral reimplantation are reassuring. The long-term results of this study showed no clinically untoward effects in any patient with the use of tissue-augmenting substances for the subureteral endoscopic injection. Since 2001, dextranomer/hyaluronic acid copolymer has been approved by the US Food and Drug Administration (FDA) as an acceptable tissue-augmenting substance for subureteral injection for the treatment of VUR in children. This substance is biodegradable and consists of larger particles, thus decreasing the potential for migration. Since the approval of dextranomer/ hyaluronic acid by the FDA, this minimally invasive endoscopic approach has gained popularity in the management of VUR in children. The present study has clearly shown that this approach is also effective in eradicating grade V VUR in children. 5. Conclusion Endoscopic treatment provides a high success in the management of grade V reflux. This outpatient procedure should be the first-line of treatment in management of grade V vesicoureteral reflux. Conflicts of interest The authors have nothing to disclose. References [1] Caione P, Ciofetta G, Collura G, Morano S, Capozza N. Renal damage in vesico-ureteric reflux. BJU Int 2004; 93:591 5. [2] Gonzalez E, Papazyan J, Girardin E. Impact of vesicoureteral reflux on the size of renal lesions after an episode of acute pyelonephritis. J Urol 2005;173:571 4. [3] Marra G, Oppezzo C, Ardissino G, et al. Severe vesicoureteral reflux and chronic renal failure: a condition peculiar to male gender? Data from the Italkid Project. J Pediatr 2004;144:677 80. [4] Elder JS, Peters CA, Arant BS, et al. Pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157:1846 51. [5] O Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic injection of Teflon. Br Med J (Clin Res Ed) 1984;289:7 9. [6] Puri P. Endoscopic correction of primary vesicoureteric reflux by subureteric injection of polytetrafluoroethylene. Lancet 1990;335:1320 2. [7] Lackgren G, Wahlin N, Stenberg A. Endoscopic treatment of children with vesicoureteric reflux. Acta Pediatr 1999;431(Suppl):62 5. [8] Stenberg A, Lackgren G. A new bioimplant for the endoscopic treatment of vesicoureteral reflux: experimental and short-term clinical results. J Urol 1995;154:800 3. [9] Van Capelle J, De Haan T, El Sayed W, Azmy A. The longterm outcome of the endoscopic subureteric implantation of polydimethylsiloxane for treating vesicoureteric reflux in children: a retrospective analysis of the first 195 consecutive patients in two European centres. BJU Int 2004;94:1348 51. [10] Routh JC, Vandersteen DR, Pfefferle H, Wolpert JJ, Reinberg Y. Single center experience with endoscopic management of vesicoureteral reflux in children. J Urol 2006;175:1889 92. [11] Aboutaleb H, Bolduc S, Bagli DJ, Khoury AE. Correlation of vesicoureteric reflux with degree of hydronephrosis and the impact of antireflux surgery. J Urol 2003;170: 1560 2. [12] Schwab Jr CW, Wu H, Selman H, Smith GHH, Snyder III HM, Canning DA. Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol 2002;168:2594 9. [13] Weiss R, Tamminen-Mobius T, Koskimies O, et al. Characteristics at entry of children with severe primary vesicoureteral reflux recruited for a multicenter, international therapeutic trial comparing medical and surgical management. J Urol 1992;148:1644 7. [14] Weiss R, Duckett J, Spitzer A, on behalf of the International Reflux Study in Children. Results of a randomised clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). J Urol 1992;148: 1667 70. [15] Elder JS, Peters CA, Arant BS, et al. Report on the management of primary vesicoureteral reflux in children. Baltimore: American Urological Association, Inc; 1997. [16] Sjostrom S, Sillen U, Bachelard M, Hansson S, Stokland E. Spontaneous resolution of high grade infantile vesicoureteral reflux. J Urol 2004;172:694 7. [17] Ogan K, Pohl HG, Carlson D, Belman AB, Rushton HG. Parental preferences in the management of vesicoureteric reflux. J Urol 2001;166:240 3. [18] Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M, Caione P. Treatment of vesicoureteric reflux: a new algorithm based on parental preference. BJU Int 2003; 92:285 8. [19] Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. Modified STING procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004;171:2413 6.

european urology 52 (2007) 1505 1510 1509 [20] Diamond D, Caldamone AA, Bauer SB, Retik AB. Mechanisms of failure of endoscopic treatment of vesicoureteral reflux based on endoscopic anatomy. J Urol 2003; 170:1556 9. [21] Yucel S, Ucar M, Guntekin E, Kukul E, Melikoglu M, Baykara M. The effect of location of the ureteric orifice on the efficacy of endoscopic injection to correct vesicoureteric reflux. BJU Int 2005;95:1314 8. Editorial Comment on: The Role of Endoscopic Treatment in the Management of Grade V Primary Vesicoureteral Reflux Jonathan C. Routh Department of Urology, Mayo Clinic, Rochester, MN, USA routh.jonathan@mayo.edu Yuri Reinberg Division of Pediatric Urology, Pediatric Surgical Associates, Minneapolis, MN, USA This study by Menezes and Puri [1] retrospectively reviews a single surgeon s experience with endoscopic injection of periureteral bulking agents in children with grade V reflux. The authors are to be congratulated on their lengthy experience and impressively high success rates. However, the conclusion of this study, specifically that injection should be the first-line treatment for children with grade V reflux, may be overstated based on the data presented. As a retrospective review of one surgeon s experience with one treatment modality, it is impossible to conclude from this article that endoscopic injection is superior to ureteral reimplantation or even to observation. This latter point is important because 81 male patients were included in the study cohort, and as the authors acknowledge, the problem in many male infants will spontaneously resolve without intervention. The degree to which this tendency may have influenced the authors cure rate is unclear. Moreover, the definition of cure for vesicoureteral reflux is open to debate. In this article, grade II reflux or less is considered adequate, meriting no further treatment. However, other authors define cure as grade 0 [2 4] or grade I [5]. This makes it difficult to draw meaningful comparisons among studies. A consensus definition is needed to establish a foundation for future research. Lastly, if one of the world s most experienced surgeons and endoscopists can achieve only a 53% cure rate with one injection, what can those of us with less experience realistically expect to achieve? Previous data from multiple surgeons would suggest that a 32% cure rate may be more realistic. For all its faults, ureteral reimplantation cures over 80% of patients, even more if downgrading to grade I/II reflux is considered a success [4]. Although this article is a testament to the potential of endoscopic treatment, it should not be interpreted as proof of superiority over other treatment modalities. References [1] Menezes MN, Puri P. The role of endoscopic treatment in the management of grade V primary vesicoureteral reflux. Eur Urol 2007;52:1505 10. [2] Routh JC, Vandersteen DR, Pfefferle H, et al. Single center experience with endoscopic management of vesicoureteral reflux in children. J Urol 2006;175:1889 92. [3] Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. Modified STING procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004;171:2413 6. [4] Elder JS, Peters CA, Arant BS, et al. Pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157:1846 51. [5] Stenberg A, Lackgren G. A new bioimplant for the endoscopic treatment of vesicoureteral reflux: Experimental and short-term clinical results. J Urol 1995;154:800 3 DOI: 10.1016/j.eururo.2007.04.083 DOI of original article: 10.1016/j.eururo.2007.04.082 Editorial Comment on: The Role of Endoscopic Treatment in the Management of Grade V Primary Vesicoureteral Reflux Arianna Lesma Pediatric Urology Section, Department of Urology, IRCCS San Raffaele, Vita-Salute University, Milan, Italy lesma.arianna@hsr.it Vesicoureteral reflux (VUR) is not a disease in and of itself but is rather a symptom that must be interpreted in the context of the entire urinary tract. The approach to each child has to consider the child s gender, reflux grade, age, kind of presentation (urinary tract infection [UTI], sibling screening, antenatal diagnosis), renal status, spon-

1510 european urology 52 (2007) 1505 1510 taneous resolution, and compliance with treatment. Puri and Menezes highlight the possibility of considering endoscopic treatment as the first-line therapeutic option for primary grade V VUR since they report complete resolution of VUR or downgrading to grade I or II after a single injection in 53% and 15.7% of ureters, respectively [1]. Nevertheless, 46 of 132 children of the series (35%) were under 1 yr of age when they underwent endoscopic treatment and some injections were performed when they were 3 4 mo of age. This creates concerns about overtreating and overestimating injection success rates related to the possibility of spontaneous downgrading and resolution of VUR at this age. Moreover, the study population consists of children who underwent voiding cystourethrography because of symptomatic UTI or familial reflux, but no case of asymptomatic grade V VUR diagnosed because of prenatal hydronephrosis is reported. This may represent a bias of the study or it may suggest that the authors propose a different therapeutic management in this specific patient population. It is worth noting that the authors report the results obtained by experienced hands because all injections were performed by a single surgeon with 21 yr of experience in the endoscopic treatment of grade V VUR. Open surgical correction of grade V VUR approaches a 80% success rate in experienced hands, with VUR downgrading in 19% of cases [2]. With this scenario in mind, the pediatric urologist must consider the benefits and risks of each modern therapeutic option when deciding on the course of therapy. References [1] Menezes MN, Puri P. The role of endoscopic treatment in the management of grade V primary vesicoureteral reflux. Eur Urol 2007;52:1505 10. [2] Elder JS, Peters CA, Arant Jr BS, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157:1846 51. DOI: 10.1016/j.eururo.2007.04.084 DOI of original article: 10.1016/j.eururo.2007.04.082