Long-term incidence of urinary tract infection after ureteral reimplantation for primary vesicoureteral reflux *

Journal of Pediatric Urology (2013) 9, 92e98 Long-term incidence of urinary tract infection after ureteral reimplantation for primary vesicoureteral reflux * Caleb P. Nelson a, *, Katherine C. Hubert a,b, Paul J. Kokorowski a, Lin Huang c, Michaella M. Prasad a, Ilina Rosoklija a, Alan B. Retik a a Department of Urology, Hunnewell 390, Children s Hospital Boston, 300 Longwood Ave., Boston, MA 02115, USA b Harvard Pediatric Health Research Fellowship Program, Harvard Medical School, Boston, MA, USA c Clinical Research Program, Children s Hospital Boston, MA, USA Received 19 September 2011; accepted 16 December 2011 Available online 18 January 2012 KEYWORDS Vesicoureteral reflux; Ureteral reimplantation; Urinary tract infection; Pyelonephritis Abstract Objective: To determine the incidence of urinary tract infection (UTI) after ureteral reimplantation (UR) for primary vesicoureteral reflux (VUR). Materials and methods: In this retrospective review, the pyelonephritis-free survival of patients with primary VUR who underwent open UR from January 1990 to December 2002 was assessed using a Cox proportional hazards analysis. Results: 1076 patients underwent open UR for primary VUR. 73.0% were female; median age was 4.7 years. 80.1% presented with UTI. Clinical success rate for non-tapered UR was 96.5%. Median follow-up was 2.9 years. 21.8% had at least one postoperative UTI. 6.5% had postoperative pyelonephritis (POP) at a median of 21 months postoperatively. On multivariate survival analysis female gender (OR 9.97, 95% CI 3.07e32.34), preoperative VUR grade 3 (2.14, 1.25e3.69), breakthrough preoperative UTI (2.00, 1.22e3.25), and preoperative renal scarring (1.86, 1.15e2.99) were associated with POP. Conclusion: POP is rare on long-term follow-up, suggesting that UR is effective in reducing pyelonephritis in this population. ª 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. * Address for Clinical Research Program: 1 Autumn St., Boston, MA 02115, USA. * Corresponding author. Tel.: þ1 617 355 3338; fax: þ1 617 730 0474. E-mail addresses: caleb.nelson@childrens.harvard.edu (C.P. Nelson), katherine.hubert@childrens.havard.edu (K.C. Hubert), paul. kokorowski@childrens.harvard.edu (P.J. Kokorowski), lin.huang@childrens.harvard.edu (L. Huang), michaella.maloney@gmail.com (M.M. Prasad), ilina.rosoklija@childrens.harvard.edu (I. Rosoklija), alan.retik@childrens.harvard.edu (A.B. Retik). 1477-5131/$36 ª 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2011.12.009

UTI after ureteral reimplantation for VUR 93 Introduction Among children with primary vesicoureteral reflux (VUR), breakthrough urinary tract infection (UTI) has long been considered a primary indication for anti-reflux procedures (ARPs) such as ureteral reimplantation (UR). In fact, reduction in incidence of febrile UTI is one of the only clinical benefits of UR that has been demonstrated in randomized controlled trials [1]. There are limited data, however, on the long-term incidence of UTI after UR, due to the focus in the literature on technical success of the ARP rather than the long-term clinical outcomes. The 10-year results of 252 children in the International Reflux Study in Children (IRSC) demonstrated a higher proportion of children who had acute pyeloenephritis in the medical group (25%) than in the surgical group (14%) (P < 0.03) [2]. Given the requirement for grade III or IV VUR and prior UTI for study entry, however, the results of the IRSC may not be generalizable to all patients undergoing UR for the correction of primary VUR [3]. More recently, the advent of endoscopic therapy for VUR has added a new option for children needing an ARP. As with open surgery, much of the debate has focused on the technical success, or lack thereof, of endoscopic therapy. However, it has also been claimed that the incidence of post- ARP UTI is significantly lower among children who undergo endoscopic ARP compared to those who undergo UR [4]. One shortcoming of such a comparison between highly selected, non-randomized groups of patients is the fact that confounding factors such as VUR grade and a prior history of breakthrough UTIs may explain the difference between groups. The purpose of this study was to perform a retrospective review of the long-term clinical outcome after UR for primary VUR, with a particular focus on the incidence of UTI. Materials and methods We performed a retrospective chart review of records of patients who underwent UR at our institution between January 1990 and December 2002. Our surgical database was developed via analysis of billing records (to identify cases) and medical records (to identify patient characteristics and outcomes). A hospital billing database was queried to identify all UR procedures performed during the designated timeframe. The billing codes used were CPT codes 50780, 50782, 50783, 50785 and the ICD-9 code 56.74. Data were collected from electronic records and departmental and hospital paper charts. Institutional Review Board approval was obtained for this study. The inclusion criteria were patients undergoing open UR for primary VUR (radiographic grade IeV or scintigraphic grade 1e3). Primary VUR was defined as isolated VUR in the absence of other congenital or acquired anatomic or neurogenic abnormalities of the lower urinary tract. Patients with functional issues of elimination (e.g. dysfunctional voiding ) were not excluded from the primary VUR group. Indications for surgery in patients with primary VUR included breakthrough UTI, persistent VUR, change in differential renal function, development of new renal cortical scarring, parental preference or non-compliance with antibiotic therapy. Both intravesical and extravesical UR procedures were included. We excluded all patients undergoing UR for secondary VUR (that is, VUR associated with neural tube defects or other causes of neurogenic bladder, posterior urethral valves, bladder exstrophy, renal transplant, prune belly syndrome, or ureterocele) as well as repeat procedures, laparoscopic procedures, and endoscopic procedures. Preoperative VUR was graded based on the final cystogram prior to UR using the IRSC system [5]. In cases of bilateral VUR, grade was based on the worse side. When the final preoperative cystogram was a radionuclide cystogram (RNC) graded on a 1e3 scale, we used the following system to convert the RNC grade to the IRSC system: RNC grade 1 Z IRSC grade I, RNC grade 2 Z IRSC grade 2, and RNC grade 3 Z IRSC grade 4 [6]. Other patient variables recorded included gender, race/ethnicity, age at surgery, clinical presentation, occurrence of breakthrough UTI during the preoperative period, and the presence of renal scarring on imaging. Breakthrough UTI was defined as a non-febrile or febrile, culture-proven UTI while on antimicrobial prophylaxis. Renal scarring was defined as the presence of echogenic foci indicating scarring on at least one renal ultrasound and/or the presence of one or more cortical defects on at least one DMSA scan. Procedure variables included intravesical versus extravesical approach, need for ureteral tailoring (tapered or excised), and reimplantation of a single system versus a completely duplicated system (classified as duplicated if at least one duplicated system reimplanted). The primary outcome was incidence of clinical pyelonephritis during the postoperative period based on evidence in the medical record. This was defined as a culture-proven UTI involvingone or more organisms, with fever (defined as a temperature of at least 38.5 C) and/or flank pain and/or acute phase renal scintigraphy documenting evidence of acute infection. Patients whose chart indicated a diagnosis of pyelonephritis without documentation of fever were included in the group with postoperative pyelonephritis (POP). We also analyzed as a secondary outcome any UTI, defined as a non-febrile or febrile UTI with associated urinary symptoms (dysuria, frequency, suprapubic pain), confirmed by culture. The outcome variable any UTI was also based on evidence in the medical record. The number of colony-forming units (CFU) required for diagnosis of a UTI was 50,000 for catheterized specimens and 100,000 for clean-catch voided specimens. Surgical outcomes were strict technical success defined as absence of VUR on postoperative cystogram within 6 months of UR. It is not uncommon, however, for patients to have minimal or trace grade 1 VUR on their postoperative cystogram, which is likely of minimal clinical significance. Therefore, we also performed our analyses using a secondary outcome called clinical technical success which included either absent VUR or grade 1 VUR on the postoperative cystogram within 6 months of UR. Surgical outcomes were only assessed among those who underwent routine postoperative screening, since inclusion of those unscreened patients who did eventually undergo VCUG would introduce a strong selection bias because those patients had a clinical indication for VCUG. The success rate among this group therefore may not be representative of overall surgical outcomes; these data were therefore excluded from assessment of surgical outcomes.

94 C.P. Nelson et al. Bivariate and multivariable analyses were carried out using SAS software (SAS Institute, Cary, NC). Comparison of means was achieved using t-tests and ANOVA. Individual categorical variables were tested for associations using Chisquare tests. The primary outcome (pyelonephritis-free survival) was analyzed using Cox proportional hazards analysis, with multivariable models used to control for multiple independent variables. Significance level of 0.05 was applied for hypothesis testing. Results Of 1466 overall UR procedures, 1076 (73.4%) were for primary VUR, and this group represented the sample for analysis. The key patient and procedure characteristics are shown in Table 1. Most patients were female, and the median age was 4.7 years; 37.3% were grade 1e2, 19% were grade 3, 43.7% were grade 4e5. Clinical presentation was UTI in a large majority (80.1%). Of the 290 males in the study, 145 (50%) presented with UTI and of those 34 (23.5%) had at least one preoperative breakthrough UTI. An additional 11 males also had at least one preoperative breakthrough UTI. Of the 596 patients with grades IIIeIV VUR, 316 (53%) presented with a febrile UTI and of those 60 (10%) also had a preoperative breakthrough febrile UTI. Of the total 1076 patients, 382 (35.5%) had at least one preoperative DMSA scan; of those, renal scarring was noted in 63.1% (241/382). Extravesical UR was performed in 18.5%, intravesical UR in 81.5%. Ureteral tapering was required in 99 patients (8.7%). The strict technical success rate was high. Among the 846 patients who had a cystogram within 6 months of surgery (Table 1), the strict technical success rate (i.e. absence of VUR on cystogram) was 93.5%. The clinical technical success rate (i.e. either absent VUR or grade I-VUR on cystogram), was 95.3%. Finally, if UR procedures that required ureteral tailoring are excluded, the clinical technical success rate was 96.5%. Median follow-up was 2.9 years (range: 0e6.9 years) and mean follow-up was 3.4 years. Many patients continued to be seen for a number of years after UR: 29.6% had follow-up >5-years, 71.7% had more than 1 year of follow-up, 56.3% had more than 2 years, 49.1% had more than 3 years, and 37.9% had more than 4 years. Overall, the incidence of any postoperative UTI was 21.8% (Table 2). Most of these patients were diagnosed either due to lower urinary tract symptoms (dysuria, frequency, etc.) or via screening cultures. The median time to initial postoperative UTI was 8.7 months. Only eight patients had a postoperative UTI, two of them febrile, within the first 2 months following reimplantation. Of the 235 patients who had any postoperative UTI (febrile or nonfebrile), 77 (35.7%) of them were on antibiotic prophylaxis at the time of the infection. Only 70 (6.5%) patients developed clinical pyelonephritis during the postoperative period (Table 2). Pyelonephritis tended to occur significantly later in the postoperative course than did cystitis; the median time from UR to initial postoperative pyelonephritis (POP) episode was 21.3 months (range of 20 days to 4.0 years). Of the 1076 patients, 463 (43.0%) never developed either a preoperative or a postoperative febrile UTI. Of the 596 patients with grade IIIeIV VUR, 46 (7.7%) developed clinical pyelonephritis during the Table 1 Variable Patient and procedure characteristics. N Patient characteristics Age at surgery (years) Mean (SD) 5.06 (3.61) Median 4.67 Race/ethnicity White 560 (52.4%) Hispanic 45 (4.2%) Black 7 (0.7%) Native American/Alaskan 1 (0.1%) Asian 17 (1.6%) Other 3 (0.3%) Unknown/missing 443 (41.2%) Gender Male 290 (27.0%) Female 786(73%) VUR grade at last cystogram (highest side) 1 17 (1.6%) 2 375 (35.7%) 3 199 (19.0%) 4 399 (38.0%) 5 60 (5.7%) VUR laterality Unilateral left 307 (28.5%) Unilateral right 175 (16.3%) Bilateral 593 (55.2%) Clinical presentation Febrile UTI 590 (54.9%) Non-febrile UTI 271 (25.2%) Prenatal hydronephrosis 122 (11.4%) Sibling screen 44 (4.1%) Incidental 12 (1.1%) Other 35 (3.3%) Preoperative breakthrough UTI Yes 398 (37.1%) No 676 (62.9%) Preoperative renal scarring Yes 341 (31.7%) No 735 (68.3%) Procedure characteristics Bladder approach Intravesical 875 (81.5%) Extravesical 198 (18.5%) Laterality Unilateral left 307 (28.5%) Unilateral right 175 (16.3%) Bilateral 593 (55.2%) Ureteral tailoring Non-tapered 976 (91.3%) Tapered 93 (8.7%) Duplication status Duplicated renal collecting system 205 (19.1%) Single renal collecting system 870 (80.9%) Postoperative cystogram within 6 months Yes 846 (78.6%) No 230 (21.4%) (continued on next page)

UTI after ureteral reimplantation for VUR 95 Table 1 (continued) Variable 6 month technical success Overall No VUR 791 (93.5%) Grade 1 15 (1.8%) Grade 2 40 (4.7%) Tapered UR No VUR 63 (78.8%) Grade 1 4 (5.0%) Grade 2 13 (16.2%) Non-tapered UR No VUR 723 (95.0%) Grade 1 11 (1.5%) Grade 2 27 (3.5%) postoperative period. Using Cox proportional hazards analysis we analyzed factors that were associated with POP-free survival (Table 3). On bivariate analysis, significant factors included female gender, presentation with UTI, breakthrough preoperative UTI, and presence of renal scarring. Higher grade VUR (3) was a marginally significant factor associated with POP-free survival. Although there was a trend toward patients with strict technical success having a lower incidence of POP, this was not statistically significant. Age, bladder approach (extravesical versus intravesical), unilateral versus bilateral, and ureteral tailoring were not associated with POP. On multivariate analysis (Table 3), the factors significantly associated with lower POP-free survival, after controlling for other factors, included high VUR grade, female gender, history of breakthrough UTI, and preoperative scarring. Table 4 shows the predicted 5-year POP-free survival after UR, based on the findings of the multivariate Cox model. As can be seen, males are highly unlikely to develop POP, while females are much more likely to do so, particularly those with higher grade, breakthrough UTI history, and/or scarring. The far higher propensity of females to develop POP with increasing time after UR is demonstrated graphically in a KaplaneMeier curve (Fig. 1). Discussion The primary goal of this study was to determine the incidence of UTI after UR performed for primary VUR. We found Table 2 Postoperative UTI and pyelonephritis. Initial postoperative UTI None 841 (78.2%) UTI: febrile 44 (4.1%) UTI: non-febrile, symptomatic 75 (7.0%) UTI: non-febrile asymptomatic 59 (5.5%) UTI: non-febrile (symptomatic status unknown) 33 (3.1%) UTI: febrile status unknown 24 (2.2%) Median time to initial UTI 8.7 months Postoperative pyelonephritis Yes 70 (6.5%) No 1006 (93.5%) Median time to pyelonephritis 21.3 months N that, with extended follow-up, POP is relatively uncommon with only about 6% of patients diagnosed. Any UTI, febrile or not, is relatively common, with over 20% of patients diagnosed. There is surprisingly little literature describing the longterm clinical outcomes after UR. In the IRSC, the incidence of UTI over a 5-year period following surgery was 39%, while clinical pyelonephritis occurred in 10% [7]. As a randomized trial this study might be considered the gold standard, but the IRSC results are only generalizable to children with dilating VUR (IRSC grade IIIeIV). In another long-term, retrospective study of patients 10-years after UR, Beetz et al. found that, among the 83.5% of patients they could contact, 17% had experienced postoperative febrile UTI [8]. The VUR grades in this cohort spanned a wider range, with w40% of renal units having IRSC grade III [8]. In contrast to these high rates of POP, Whittam et al. reported in a recent series that of 395 patients who underwent UR febrile UTI was diagnosed in just 4.6%, although the followup time was relatively short at a mean of 15 months [9]. The low incidence of postoperative UTI (21.6%) and POP (6.4%) in our study may be due to differences in the patient populations given that our cohort included patients with all grades of VUR. In fact, higher grade VUR (3) was shown in our multivariate analysis to be associated with significantly lower POP-free survival. In our study, even patients with the same grades of VUR (IIIeIV) as those included in the IRSC had a lower incidence of POP (7.7%) than the patients in the IRSC [10]. The current series is one of the largest reported of longterm UTI outcomes across a broad cross-section of VUR patients undergoing UR. Furthermore, this is the only study to analyze postoperative UTI using a multivariate survival analysis that takes into account the varying follow-up periods seen in the study sample. Such variation in length of follow-up is inherent in retrospective reviews, but most prior articles have analyzed incidence of UTI as a simple categorical variable, rather than accounting for time to event. Whittam et al. did perform time to event analysis of possible predictors of febrile UTI following UR but theirs was limited to univariate testing [9]. In a more recent report comparing open UR with results after endoscopic ARP, Elmore et al. reported that postoperative febrile UTI occurred in 24.1% of the children after UR versus just 5% of children after endoscopic ARP [4]. However, this was a highly selected, non-randomized sample, and the preoperative breakthrough UTI rate was almost twice as high in the UR group as the endoscopic group (21% vs 10%). There are likely other confounding factors, and no multivariate analysis was performed to adjust for recognized factors that might contribute to POP (e.g. VUR grade, breakthrough UTI). There is strong evidence that nonrandomized (or poorly randomized) treatment allocation introduces significant bias into a study [10]. The hypothesis generated by a study such as the one by Elmore et al. is fascinating: does open UR disrupt host defense factors significantly more than endoscopic treatment? Without a randomized controlled trial we may never be certain; in the meantime, we must be careful in assessing the relative merits of various ARPs. There has been much recent discussion about whether the availability of endoscopic ARP should alter the indications for

96 C.P. Nelson et al. Table 3 Multivariate analysis of POP-free survival. Variable Hazard ratio P-value Multivariate hazard ratio Multivariate p-value VUR grade 3 1.68 (0.98, 2.88) 0.0579 2.14 (1.25, 3.69) 0.0059 Female gender 9.90 (3.12, 31.15) 0.0001 9.97 (3.07,32.34) 0.0001 Age 0.96 (0.89e1.03) 0.2407 e e Duplex system 0.78 (0.41e1.48) 0.4388 e e Laterality and bladder approach 0.6619 e e Extravesical e Unilateral intravesical 0.81 (0.41e1.57) Bilateral intravesical 0.76 (0.41e1.39) Ureteral tapering 0.55 (0.20e1.50) 0.2395 e e Initial clinical presentation 0.01 e e Other (did not present with UTI) e Non-febrile UTI 3.07 (0.60e15.83) Febrile UTI 3.99 (1.59e10.05) Technical success at 6 months 0.3445 e e No postoperative imaging within 6 months e No reflux 1.15 (0.57e2.34) Reflux 1.98 (0.74e5.32) Breakthrough preoperative UTI 2.60 (1.61e4.19) <0.0001 2.00 (1.22e3.25) 0.0059 Preoperative renal scarring 1.62 (1.01e2.59) 0.0453 1.86 (1.15e2.99) 0.0110 the procedure. Suggestions have appeared in the literature that endoscopic treatment should be utilized as initial therapy for patients diagnosed with VUR. Advocates argue that immediate endoscopic therapy is preferable to antimicrobial prophylaxis in children just diagnosed with VUR [11]. Current standards of care do not yet embrace such early treatment, and the available data make it clear that immediate ARP (using any method) makes little sense, since the only demonstrated benefit of ARP is prevention of recurrent febrile UTI, and a majority of newly diagnosed patients with VUR (except those with high-grade VUR) will never experience arecurrentfebrileuti[12,13]. Therefore,analgorithmthat directs all newly diagnosed VUR patients into immediate surgical treatment (even if it is the low morbidity endoscopic ARP) is destined to treat large numbers of children for whom there will not be measurable benefits. The results of our study support the idea that there are subsets of patients that may be predisposed to pyelonephritis after UR. On multivariate analysis, the factors in our study that were significantly associated with lower POP-free survival included high VUR grade, female gender, history of breakthrough UTI, and preoperative renal scarring. Our findings confirm those of the recently published Swedish reflux study which found that girls with high-grade VUR had a significantly higher rate of recurrent febrile UTIs than boys [14]. Although this study does not support any change in the indications for surgery, it documents a low rate of POP among all children who undergo reimplantation. There are probably benefits of surgery even among the subgroups that are more likely to have POP. Even among this high-risk group, however, the risk is relatively low, as our nomogram shows (Table 4). A randomized trial would be required to show if reimplantation reduces the risk of POP in this highrisk group specifically. Several authors have similarly concluded that preoperative breakthrough UTIs are also a risk factor for postoperative UTI following endoscopic ARP [15e17]. This brings into question whether patients with a history of preoperative breakthrough UTIs should be placed in a different category in terms of follow-up and counseling after either endoscopic ARP or UR. Table 4 Nomogram showing the predicted 5-year POP-free survival after UR. VUR grade Breakthrough Preop. renal Pyelonephritis-free survival (95% CI) preop. UTI scar Male Female 1e2 No No 99.6% (99.1%, 100%) 96.0% (93.6%, 98.4%) Yes 99.2% (98.3%, 100%) 92.7% (88.2%, 97.4%) Yes No 99.2% (98.1%, 100%) 92.2% (88.1%, 96.5%) Yes 98.5% (96.6%, 100%) 86.0% (78.6%, 94.1%) 3 No No 99.1% (98.1%, 100%) 91.6% (87.7%, 95.6%) Yes 98.4% (96.5%, 100%) 84.9% (78.2%, 92.3%) Yes No 98.3% (96.1%, 100%) 84.0% (77.8%, 90.6%) Yes 96.8% (93.1%, 100%) 72.3% (62.6%, 83.4%)

UTI after ureteral reimplantation for VUR 97 Funding source Dr. Hubert is supported by the Harvard Pediatric Health Services Research Fellowship Program and by grant number T32eHS019485-01 from the Agency for Healthcare Research and Quality (AHRQ), National Research Service Award (NRSA). Dr. Kokorowski is supported by grant number T32-DK60442 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Nelson is supported by grant number K23-DK088943 from NIDDK. The study sponsors had no involvement in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Figure 1 Pyelonephritis-free survival after ureteral reimplantation. There are certain limitations of this study that should be acknowledged. As a retrospective series it is subject to all of the recognized weaknesses of this methodology including selection bias and loss to follow-up. For example, outcome events that occurred subsequent to a patient s last encounter at our facility would not have been included. As noted above, we sought to control for the varying length of follow-up by using a survival analysis. Another weakness is that we could not adjust for the presence of dysfunctional elimination syndrome (DES) in our data. Although we sought in the initial data collection to do so, we found quickly that the many definitions of dysfunctional voiding used by a variety of clinicians in the study, as well as the varying treatments instituted for this, resulted in a clinical condition that was impossible to meaningfully define from a research standpoint. We recognize the clinical significance of DES in VUR, and several studies have found that DES is a significant risk factor for UTI after UR. However, we found that the I know it when I see it quality of DES rendered a strict definition impossible, and it became clear that any variable we developed would be little better than arbitrary. Although DES is not accounted for in the retrospective analysis, it is our practice to evaluate all patients with VUR for the presence of the syndrome and treat them accordingly prior to consideration of any anti-reflux procedures. This should limit the potential misclassification of a patient as having primary VUR when in fact he or she has secondary VUR. Conclusions Although some children experience UTI after UR, the incidence of postoperative clinical pyelonephritis is very low, even on very long-term follow-up. Given that most of these patients initially present with pyelonephritis, these findings support the contention that UR is effective in reducing the incidence of pyelonephritis in this population. Ethical approval This study was approved by the Institutional Review Board. Conflict of interest statement The authors do not have any conflicts of interest. Acknowledgments The authors wish to acknowledge the following for their clinical and research contributions to this study: Anthony Atala, MD, Stuart Bauer, MD, Joseph Borer, MD, Marc Cendron, MD, Bartley Cilento, Jr., MD, MPH, David Diamond, MD, Sarah Dobbins, MPH, Carlos Estrada, MD, Irina Kasarskis, MPH, Richard Lee, MD, James Mandell, MD, Hiep Nguyen, MD, Melanie Pennison, MPH, and Craig Peters, MD. References [1] Hodson E, Wheeler D, Vimalchandra D, Smith GH, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev; 2007:CD001532. [2] Jodal U, Smellie JM, Hildegard L. Ten-year results of randomized treatment of children with severe vesicoureteral reflux. final report of the International Reflux Study in Children. Pediatr Nephrol 2006;21:785e92. [3] Weiss R, Tamminen-Mobius T, Koskimies O, Obling H, Smellie JM, Hirche H, 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;148:1644e9. [4] Elmore JM, Kirsch AJ, Heiss EA, Gilchrist A, Scherz HC. Incidence of urinary tract infections in children after successful ureteral reimplantation versus endoscopic dextranomer/hyaluronic acid implantation. J Urol 2008;179: 2364e8. [5] Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics 1981;67:392e400. [6] Willi U, Treves S. Radionuclide voiding cystography. Urol Radiol 1983;5:161e73. [7] Jodal U, Koskimies O, Hanson E, Lohr G, Obling H, Smellie J, et al. Infection pattern in children with vesicoureteral reflux randomly allocated to operation or long-term antibacterial prophylaxis. The International Reflux Study in Children. J Urol 1992;148:1650e2. [8] Beetz R, Mannhardt W, Fisch M, Stein R, Thuroff JW. Longterm follow-up of 158 young adults surgically treated for vesicoureteral reflux in childhood: the ongoing risk of urinary tract infections. J Urol 2002;168:704e7.

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