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Endoscopic Treatment of Vesicoureteral Reflux in Infants. Can We Do It and Should We Do It?
Accepted Manuscript Title: Endoscopic Treatment of Vesicoureteral Reflux in Infants. Can We Do It and Should We Do It? Author: Sara Fuentes, Andrés Gómez-Fraile, Isabel Carrillo-Arroyo, Cristina Tordable-Ojeda, Daniel Cabezalí-Barbancho PII: DOI: Reference:
S0090-4295(17)30800-2 http://dx.doi.org/doi: 10.1016/j.urology.2017.08.005 URL 20599
To appear in:
Urology
Received date: Accepted date:
8-6-2017 2-8-2017
Please cite this article as: Sara Fuentes, Andrés Gómez-Fraile, Isabel Carrillo-Arroyo, Cristina Tordable-Ojeda, Daniel Cabezalí-Barbancho, Endoscopic Treatment of Vesicoureteral Reflux in Infants. Can We Do It and Should We Do It?, Urology (2017), http://dx.doi.org/doi: 10.1016/j.urology.2017.08.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX IN INFANTS. CAN WE DO IT AND SHOULD WE DO IT?
Sara Fuentes1 M.D. Ph.D.
Andrés Gómez-Fraile2. M.D. Ph.D.
Isabel Carrillo-Arroyo2. M.D.
Cristina Tordable-Ojeda2. M.D.
Daniel Cabezalí-Barbancho2. M.D.
1. Pediatric Surgery Division. Complejo Asistencial Universitario de León. C/Altos de Nava s/n 24071. León. Spain 2. Pediatric Surgery Division. 12 de Octubre University Hospital. Avda. Córdoba s/n 28034 Madrid. Spain. Corresponding author: Sara Fuentes. Postal Adress: Servicio de Cirugía Pediátrica. Complejo Asistencial Universitario de León. C/ Altos de Nava s/n 24071 León. Spain. Tfno: 0034987237400. Fax: 0034987271770. E-mail address: [email protected]
Acknowledgments: We would like to acknowledge David Brown, professional language editor and native English speaker, for proof reading the manuscript.
Abstract word count: 249 words Manuscript word count: 2458 words ABSTRACT Objective
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To evaluate the outcomes of endoscopic treatment of vesicoureteral reflux (VUR) performed on infants, and to discuss the possible role of this approach in selected cases. Material and Methods A retrospective analysis was conducted on the patients that underwent endoscopic injection of a bulking substance for VUR in our institution, and a comparison made with patients treated as infants and those treated later in life. Results A total 463 ureteric units were included (296 children), of which 47 of them were patients less than one year of age (infants, INF group), with the remaining 416 being included in a second group (children, CHL). In this study, the percentage of high grade VUR and presence of reflux nephropathy (RN) were significantly higher in younger patients. Both early failure and recurrence rate were significantly higher in the INF group when compared with CHL group. No complications were observed in the INF group. Conclusions Endoscopic treatment of VUR is feasible in patients less than one year of age. The effectiveness is lower than when patients are treated at a later age, but was still over 80% in our series. There were no complications reported related to the procedure itself or to the general anesthesia. Once it is known that it can be performed, controversy rises about the indication of treating these patients. Careful selection of cases of VUR less likely to spontaneously resolve, presence of break-through infections, and parental preference, all play a role in the decision-making process. Key words Vesicoureteral reflux, cystoscopy, urinary bladder disease, infant.
INTRODUCTION
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Endoscopic injection of a bulking substance for the treatment of vesicoureteral reflux (VUR) has become first line therapy when intervention is needed1,2. Since the publication of the technique, numerous groups have presented their experience and the good results in terms of VUR resolution3. However, in recent years, the impact of VUR resolution on urinary tract infections (UTIs) or reflux nephropathy (RN) has been discussed and reassessed4. The aim is not the resolution VUR itself anymore, and the indications have been revised5,6. Management of VUR in patients less than one year of age is widely accepted that it should be conservative1,2. However, we have all come across certain patients in our clinical practice that might make us think otherwise. Surgical management is only considered in cases of breakthrough UTIs in spite of continuous antibiotic prophylaxis (CAP). Some groups may consider changing antibiotics before planning surgical intervention, as it has been suggested that it is better to avoid the surgical approach in the first year of life, due to the fact that VUR tends to resolve spontaneously over time. However, the probability of high-grade VUR resolving is lower7. In addition, UTIs in infants are more likely to be associated with bacteremia and affect the upper urinary tract, thus increasing the risk of renal scarring8. Puri et al presented their experience with endoscopic treatment of VUR in infants less than 1 year of age, and there was as wide discussion on the indication or the necessity to overcome general anesthesia in such young patients when VUR was most likely to resolve over time9. Recent data from the Swedish Infant High-Grade Reflux Trial shows the effectiveness of endoscopic treatment in downgrading or resolving VUR10. All the data available related to management or outcome in this group of patients could be useful for selecting the best management tailored to a specific patient. The aim of this study is to analyze our data regarding endoscopic treatment of infants, comparing the results and outcomes with our overall results. A discussion is also presented on
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the pros and cons regarding treating VUR at an early age, and to try to determine possible indications.
MATERIAL AND METHODS Study design A retrospective analytical study was conducted using information gathered from patients treated in our Pediatric Surgery Division, between the years 1989 and 2008. Inclusion criteria were patients who underwent endoscopic correction of VUR, and had a long-term follow-up (at least 5 years). Patients referred from other centers were excluded, as were those for whom there was no access to their follow-up, and patients with secondary VUR. The information gathered included: 1. Patient: gender, age at diagnosis, indication for treatment, age at intervention. 2. Reflux: grade, side, presence of duplex system, initial ultrasound (US) scan, initial dimercaptosuccinic acid (DMSA) scintigraphy to assess RN. 3. Intervention: bulking substance used, outcome, recurrence, complications. Once all the information had been gathered, two groups were formed for the comparison: The group of patients treated at less than one year of age (infants INF), and the rest of the patients (children CHL). Every single ureteral unit was taken into account in the statistical analysis. The data were analyzed using SPSS® Version 17.0 (SPSS Inc. ®, USA). The Chi-square test was used for univariate comparisons, and the Fisher’s exact test was used for categorical variables.
Intervention Endoscopic treatment was indicated mainly due to the presence of break-through infections in spite of CAP. However in some of the first cases treated, indication relied on the presence of
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RN, owing to the concern regarding the influence of VUR in the final outcome of those patients. Later on, with the evidence added during the following years, RN alone was no longer an indication for endoscopic treatment. In our institution, cystoscopy is performed on an outpatient basis. Under general anesthesia, the bulking substance is injected after exploration of the bladder. The patient is discharged a few hours after the procedure. Three bulking agents have been used over the past years: first, polytetrafluoroethylene (PTFE) and polydimethylsiloxane (PDMS). Later, due to the concern regarding risk of migration of the particles, they were replaced by dextranomer / hyaluronic acid (Dx/HA). This last compound is the only one currently approved by the American Food and Drugs Administration (FDA). Patients continue regular follow up in our outpatient clinic. Cystography was performed 12 weeks after surgery, and repeated one year later.
RESULTS A total of 463 ureteric units (296 patients) were included, with 47 of them (31 patients) being less than one year old (mean 8 months, range 6 to 11 months) at the time of treatment (INF group), with the remaining 416 being included in a second group (children, CHL). The descriptive data is summarized in Table 1 and the indications for surgery in Table 2. There were some significant differences on comparing the two groups. Firstly, there are significantly more male patients than female ones in the INF group. Furthermore, the incidence of high-grade reflux, anomalies detected in the US scan, and RN, is also significantly higher in the INF. These findings correlate with the current evidence of the different features of early-diagnosed reflux against reflux in older children11. The resolution rate was 87.2% in the INF group, and 96.6% in the CHL group. These differences are statistically significant. There is also a significantly higher risk of late recurrence of VUR in the INF group (34.1% vs. 15.7%) (Table 3). Resolution rate according
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to initial VUR grade is summarized in Table 4. Among the patients with initial VUR resolution, we identified 6 cases of UTI in the INF group (14.6%) and 20 in the CHL group (5%). These patients showed recurrent VUR. There were no complications in the INF group, either regarding the procedure itself or the general anesthesia. Three complications were observed in the CHL group (post-procedure bleeding, post-procedure UTI, and uretero-vesical stenosis that required open surgery).
COMMENT More than 30 years have passed since Matoushek and Puri and O’Donnell described the subureteric endoscopic injection of a bulking agent to correct VUR12,13. The technique is well established as an effective and safe procedure, with a very low complication rate14,15. Even if its results are not as good as those of open surgery, in terms of resolving VUR, these differences are overshadowed by the much less invasiveness of the endoscopic procedure3,16. Our department was pioneer in the performance of this technique in Spain, with the first cases treated in 1979. Since then, many modifications have been adopted as regards the procedure itself, as well as its indications and follow up as new light has been shed on the pathophysiology of VUR over the years. The bulking substance used has changed several times. Dextranomer/hyaluronic acid copolymer is currently the only substance approved by the American Food and Drugs Administration (FDA). Although several substances have been used for this purpose, in our department we have previous experience with PTFE and PDMS 3. As regards the technique itself, there are two main variations described; the classic sub-ureteric approach first described by Puri and O´Donnell13 and the hydrodistention-implantation technique (HIT) described by Kirsch et al. in 200417. We have obtained good results with the original
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technique described by Puri, and therefore we have not changed it since we started endoscopic management of VUR. On the whole, the endoscopic approach in any of its variations and with different bulking agents has become first line therapy for VUR when surgical intervention is needed among most groups of pediatric urologists, and a viable alternative to long term continuous antibiotic prophylaxis (CAP), even in cases of high-grade reflux3,18. The overall success rate of the treatment is around 84% depending mainly on the bulking agent used and the reflux grade19. One meta-analysis reports a success rate after only one injection of up to 78.5% for grades I and II, 72 % for grade III, 63 % for grade IV, and 51 % for grade V3. Regarding the bulking substance used in the procedure, there have been reported success rates ranging from 84% with Dx/HA to 93% and 98% with PDMS and PTFE respectively19. The incidence of complications is very low in the different groups that have published their results20,21. Once the effectiveness and safety of the endoscopic procedure have been demonstrated, the controversy arises regarding its indications. Recent evidence leads us to re-think on the necessity of treating the VUR itself, when the final aim is to avoid UTI and secondary renal damage, and correcting VUR is not a guarantee of that22,23. Undoubtedly, it has become first line therapy when surgery is needed, unless there is any specific anatomic feature that makes it unsuitable. However, are we sure we know when surgery is not needed anymore? Is CAP always the first choice in VUR management when a patient is considered for intervention and not for surveillance? It is well known that VUR tends to resolve over time, and that it depends mainly on patient age, gender, and grade of VUR24. VUR behaves in a completely different way in different patients, and we should consider all these features in order to make the right choices regarding management. Recent data from the Swedish Reflux Trial showed that both CAP and
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endoscopic treatment reduced equally the breakthrough infections rates in girls between 1 and 2 years of age22. Concern has been also been raised regarding the long-term use of antibiotics and its consequences25. Therefore, it could be considered that endoscopic treatment might be a good choice for primary intervention in certain cases. Again, taking into account all the features of each individual patient is going to be key to making the right choices. Another issue arises at this point: patient age, in particular, the management in patients less than 1 year of age. There is general agreement among all the medical societies that these patients should be managed conservatively, either with surveillance or CAP1,2. This recommendation is given on the basis of the high probability of spontaneous resolution of VUR at this stage, as previously discussed. However, VUR seems to be a different entity when we consider infants. The incidence is higher in boys, rather than in girls, as in older age groups11. There are more high-grade refluxes diagnosed, and a higher incidence of RN. The resolution rate is also considerable in asymptomatic infants diagnosed in postnatal evaluation for prenatal hydronephrosis or sibling screening. However, the presence of bilateral highgrade reflux, RN at diagnosis, bladder dysfunction, or breakthrough febrile UTIs reduce the likelihood of spontaneous resolution24. The INF group of our study shares all these features with previously reported series, a predominance of male gender, high-grade reflux, anomalies in the US and DMSA scans at diagnosis. Although the VUR resolution rate after treatment is lower compared with the general series, according to our data, the short and long-term outcome regarding VUR resolution is no different from the patients with high grade VUR treated later. Furthermore, we reported no complications related to the technique itself or the anesthetic procedure. Therefore, we could say that it is a safe and feasible procedure and we can do it; nevertheless, should we do it?
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There is no doubt regarding the indication for treatment in the scenario of repeated UTI in spite of CAP. However, early intervention in this particular group of patients, at least after 6 months of age could be considered, especially if there are associated factors such as impaired access to health services or doubts regarding treatment compliance. We should also consider the drawbacks of long-term CAP, the increase in the risk of renal scar development after febrile UTI at this age and, certainly, parent preference8,26,27,28. Only a few groups have experience in the endoscopic treatment in infants9,29. As our institution was pioneer in performing this technique in Spain, we have treated a number of patients of less than one year of age. In the early years, most indications were due to presence of RN at a time when there was still concern about the role of an isolated VUR in the future renal function of these patients. Nowadays, the indication to treat infants in our department depends mainly on the presence of break-through UTIs, in accordance with current international guidelines1,2. When reviewing the outcome of the infants treated so far, we realized that, out of 47 ureteral units, 27 achieved VUR resolution without relapse after a period of 5 years. The treatment failed in 6 of them. Four out of these 6, finally underwent open reimplantation procedure (Cohen). Our experience with this surgery after an endoscopic procedure is that the difficulties we found with the ureteral dissection were related to the bulking substance used in the endoscopic injection rather than to the age at which it was performed. There were 14 recurrences of VUR after the endoscopic procedure in the INF group. In these patients only 6 ureteral units required further intervention due to febrile UTI, repeating an endoscopic procedure and with final resolution of VUR in all of them. Recent data from the Swedish Infant High-Grade Reflux Trial point out that, although resolution rate is higher with endoscopic treatment than with CAP, there is no difference in the final outcome regarding UTI recurrence or renal function deterioration10,29.
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Although the final outcome of these patients appeared to be no different from those in which surveillance or CAP is maintained over the first year of life, for more than 50% of them, VUR resolution led to the cessation of CAP and the close monitoring that is also important in selected cases27,28. Therefore, the possible advantages of endoscopic treatment would be: avoiding long term use of antibiotics with the expected impact on bacterial population and resistances25; avoiding the psychological impact of long-term treatment in parents or carers; as well as for conflictive families, or when there is a high suspicion of non-compliance with CAP, or problems in access to health care, in the event of UTIs. In these situations, patients affected by VUR with a lower probability of resolution could be offered endoscopic treatment in early stages as an alternative to CAP, assuming the likelihood of surgical treatment in the following years is high. There is an interesting study by Nevéus et al, regarding parent satisfaction with management of VUR that shows that there were no differences between the groups for surveillance, CAP, or endoscopic treatment. However, among children with CAP, there was a higher percentage of parents who would have chosen a different therapy if given the chance30.
CONCLUSIONS Summing up, endoscopic treatment of VUR in infants is a safe and effective procedure. Even though the effectiveness is not as good as in older children, the resolution rates are still high. Therefore, we consider that it could be an appropriate alternative in cases of break-through infections or selected cases with non-compliance, or issues related to CAP.
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BIBLIOGRAPHY 1. Peters CA, Skoog SJ, Arant BS Jr, Coop HL, Elder JS, Hudson RG, et al. Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol. 2010;184(3):1134-44. 2. Tekgül S, Riedmiller H, Hoebeke P, Kockvara R, Nijman RJ, Radmayr C, et al. EAU guidelines on vesicoureteral reflux in children. Eur Urol. 2012;62(3):534-42. 3. 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(2):716-22. 4. Brandström P, Esbjörner E, Herthelius M, Holmdahl G, Läckgren G, Nevéus T, Sillén U, Sixt R, Sjöberg I, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: I. Study design and study population characteristics. J Urol. 2010;184(1):274-9. 5. Tullus K. Vesicoureteric reflux in children. Lancet. 2015;385(9965):371-9. 6. Lopez PJ, Celis S, Reed F, Zubieta R. Vesicoureteral reflux: current management in children. Curr Urol Rep. 2014;15(10):447. 7. Sjöström S, Sillén U, Jodal U, Sameby L, Sixt R, Stokland E. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariate and multivariate analyses. J Urol. 2010;183(3):1177-84. 8. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics, 2010;126(6):108491. 9. Puri P, Mohanan N, Menezes M, Colhoun E. Endoscopic treatment of moderate and high grade vesicoureteral reflux in infants using dextranomer/hyaluronic acid. J Urol. 2007;178(4 Pt 2):1714-6; discussion 1717.
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10. Nordenström J, Holmdahl G, Brandström P, Sixt R, Stokland E, Sillén U, Sjöström S. The Swedish infant high-grade reflux trial: Study presentation and vesicoureteral reflux outcome. J Pediatr Urol. 2016;24. 11. Chand DH, Rhoades T, Poe SA, Krauss S, Strife CF. Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis. J Urol. 2003;170(4):1548-50. 12. Matouschek E: Treatment of vesicorenal reflux by transuretral teflon-injection (author’s translation). Urologe. 1981;20:263. 13. O´Donnell B, Puri P. Endoscopic correction of vesicoureteral reflux: results in 94 ureters. Brit Med J. 1986;293(6559):1404-6. 14. Läckgren G, Wåhlin N, Sköldenberg E, et al. Long-term followup children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2001;166:1887–92. 15. Vandersteen DR, Routh JC, Kirsch AJ, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. J Urol. 2006;176:1593–5. 16. Duckett JW, Walker RD, Weiss R. Surgical results: International Reflux Study in Children—United States branch. J Urol 1992; 148: 1674–75. 17. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. 2004;171:2413–6. 18. Chertin B, De Caluwé D, Puri P. Endoscopic treatment of primary grades IV and V vesicoureteral reflux in children with subureteral injection of polytetrafluoroethylene. J Urol. 2003; 169(5):1847-9. 19. Chertin B, Kocherov S. Long-term results of endoscopic treatment of vesicoureteric
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reflux with different tissue-augmenting substances. J Pediatr Urol. 2010;6(3):251-6. 20. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteric reflux: systematic review. Pediatrics 2010;125: 1010–19. 21. Chertin, B, Calhoun, E, Velayudham, M, Puri, P. Endoscopic treatment of vesicoureteral reflux: 11 to 17 years of followup. J Urol 2002;167(3):1445-6. 22. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol. 2010;184(1):286-91. 23. Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: IV. Renal damage. J Urol. 2010;184(1):292-7. 24. Sjöström S, Sillén U, Jodal U, Sameby L, Sixt R, Stokland E. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariate and multivariate analyses. J Urol. 2010;183(3):1177-84. 25. Ili
ra an
rapovi
apkun
u at-De ulovi M, Saraga M. Changes in
bacterial resistance patterns in children with urinary tract infections on antimicrobial prophylaxis at University Hospital in Split. Med Sci Monit 2011; 17: CR355–61. 26. Sjöström S, Jodal U, Sixt R, Barchelard M, Sillén U. Longitudinal development of renal damage and renal function in infants with high grade vesicoureteral reflux. J Urol. 2009;181(5):2277-83. 27. Capozza N, Lais A, Matarazzo E, et al. Treatment of vesico-ureteric reflux: a new algorithm based on parental preference. BJU Int. 2003;92:285–8. 28. Krill A, Pohl H, Belman A, et al. Parental preferences in the management of vesicoureteral reflux. J Urol. 2011;186(5):2040–4. 29. Nordenström J, Sjöström S, Sillén U, Sixt R, Brandström P. The Swedish infant highgrade reflux trial: UTI and renal damage. J Pediatr Urol. 2017;13(2):146-154.
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30. Nevéus T, Brandström P, Linnér T, Jodal U, Hansson S. Parental experiences and preferences regarding the treatment of vesicoureteral reflux. Scand J Urol Nephrol. 2012;46(1):26-30.
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Table 1. Characteristics of INF and CHL groups. INF group
CHL group
47
416
6-11 m (mean 8 m)
1-17 y (mean 4,53 y)
Male
34 (72.3%)
119 (28.6%)
Female
13 (27.7%)
297 (71.4%)
Nº ureteral units Age Gender
p<0.0001 Side Left
24 (51%)
211 (50.7%)
Right
23 (48.9%)
205 (49.3%)
p=0.8 9 (19.1%)
67 (16.1%)
I
0
3 (0.7%)
II
3 (6.4%)
109 (26.2%)
III
10 (21.3%)
212 (51%)
IV
18 (38.3%)
80 (19.2%)
V
16 (34%)
12 (2.9%)
Duplex system VUR grade
p<0.0001 US scan Normal
15 (31.9%)
284 (68.3%)
Abnormal
32 (68%)
132 (31.7%)
p<0.0001
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DMSA scan Normal
15 (31.9%)
240 (57.7%)
Abnormal
32 (68%)
176 (42.3%)
p=0.001 Bulking substance Dx/HA
14 (29.8%)
156 (37.5%)
Others
33 (70.2%)
260(62.4%)
p=0.298
Table 2. Indication for intervention. (UTI: urinary tract infection; RN: reflux nephropathy) Indication
INF group
CHL group
47
416
UTI
6 (12.8%)
88 (21.1%)
RN
30 (63.8%)
130 (31.3%)
Persistence
-
160 (38.5%)
Others
11 (23.4%)
38 (9.1%)
Nº ureteral units
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Table 3. Initial resolution rate and recurrence rate. VUR initial resolution
INF group
CHL group
Yes
41 (87.2%)
402 (96.6%)
No
6 (12.8%)
14 (3.4%)
p=0.002 Recurrence
INF group
CHL group
Yes
14 (34,1%)
63 (15.7%)
No
27 (65.9%)
339 (84.3%)
p=0.012
Table 4. Resolution rate according to initial VUR grade in both groups. Initial VUR grade
INF group
Resolution
CHL group
Resolution
I
0
-
3
3 (100%)
II
3
3 (100%)
109
104 (99%)
III
10
8 (80%)
212
194 (91.5%)
IV
18
15 (83.3%)
80
71 (88.7%)
V
16
15 (93.7%)
12
7 (58.3%)
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S0090-4295(17)30800-2 http://dx.doi.org/doi: 10.1016/j.urology.2017.08.005 URL 20599
To appear in:
Urology
Received date: Accepted date:
8-6-2017 2-8-2017
Please cite this article as: Sara Fuentes, Andrés Gómez-Fraile, Isabel Carrillo-Arroyo, Cristina Tordable-Ojeda, Daniel Cabezalí-Barbancho, Endoscopic Treatment of Vesicoureteral Reflux in Infants. Can We Do It and Should We Do It?, Urology (2017), http://dx.doi.org/doi: 10.1016/j.urology.2017.08.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX IN INFANTS. CAN WE DO IT AND SHOULD WE DO IT?
Sara Fuentes1 M.D. Ph.D.
Andrés Gómez-Fraile2. M.D. Ph.D.
Isabel Carrillo-Arroyo2. M.D.
Cristina Tordable-Ojeda2. M.D.
Daniel Cabezalí-Barbancho2. M.D.
1. Pediatric Surgery Division. Complejo Asistencial Universitario de León. C/Altos de Nava s/n 24071. León. Spain 2. Pediatric Surgery Division. 12 de Octubre University Hospital. Avda. Córdoba s/n 28034 Madrid. Spain. Corresponding author: Sara Fuentes. Postal Adress: Servicio de Cirugía Pediátrica. Complejo Asistencial Universitario de León. C/ Altos de Nava s/n 24071 León. Spain. Tfno: 0034987237400. Fax: 0034987271770. E-mail address: [email protected]
Acknowledgments: We would like to acknowledge David Brown, professional language editor and native English speaker, for proof reading the manuscript.
Abstract word count: 249 words Manuscript word count: 2458 words ABSTRACT Objective
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To evaluate the outcomes of endoscopic treatment of vesicoureteral reflux (VUR) performed on infants, and to discuss the possible role of this approach in selected cases. Material and Methods A retrospective analysis was conducted on the patients that underwent endoscopic injection of a bulking substance for VUR in our institution, and a comparison made with patients treated as infants and those treated later in life. Results A total 463 ureteric units were included (296 children), of which 47 of them were patients less than one year of age (infants, INF group), with the remaining 416 being included in a second group (children, CHL). In this study, the percentage of high grade VUR and presence of reflux nephropathy (RN) were significantly higher in younger patients. Both early failure and recurrence rate were significantly higher in the INF group when compared with CHL group. No complications were observed in the INF group. Conclusions Endoscopic treatment of VUR is feasible in patients less than one year of age. The effectiveness is lower than when patients are treated at a later age, but was still over 80% in our series. There were no complications reported related to the procedure itself or to the general anesthesia. Once it is known that it can be performed, controversy rises about the indication of treating these patients. Careful selection of cases of VUR less likely to spontaneously resolve, presence of break-through infections, and parental preference, all play a role in the decision-making process. Key words Vesicoureteral reflux, cystoscopy, urinary bladder disease, infant.
INTRODUCTION
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Endoscopic injection of a bulking substance for the treatment of vesicoureteral reflux (VUR) has become first line therapy when intervention is needed1,2. Since the publication of the technique, numerous groups have presented their experience and the good results in terms of VUR resolution3. However, in recent years, the impact of VUR resolution on urinary tract infections (UTIs) or reflux nephropathy (RN) has been discussed and reassessed4. The aim is not the resolution VUR itself anymore, and the indications have been revised5,6. Management of VUR in patients less than one year of age is widely accepted that it should be conservative1,2. However, we have all come across certain patients in our clinical practice that might make us think otherwise. Surgical management is only considered in cases of breakthrough UTIs in spite of continuous antibiotic prophylaxis (CAP). Some groups may consider changing antibiotics before planning surgical intervention, as it has been suggested that it is better to avoid the surgical approach in the first year of life, due to the fact that VUR tends to resolve spontaneously over time. However, the probability of high-grade VUR resolving is lower7. In addition, UTIs in infants are more likely to be associated with bacteremia and affect the upper urinary tract, thus increasing the risk of renal scarring8. Puri et al presented their experience with endoscopic treatment of VUR in infants less than 1 year of age, and there was as wide discussion on the indication or the necessity to overcome general anesthesia in such young patients when VUR was most likely to resolve over time9. Recent data from the Swedish Infant High-Grade Reflux Trial shows the effectiveness of endoscopic treatment in downgrading or resolving VUR10. All the data available related to management or outcome in this group of patients could be useful for selecting the best management tailored to a specific patient. The aim of this study is to analyze our data regarding endoscopic treatment of infants, comparing the results and outcomes with our overall results. A discussion is also presented on
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the pros and cons regarding treating VUR at an early age, and to try to determine possible indications.
MATERIAL AND METHODS Study design A retrospective analytical study was conducted using information gathered from patients treated in our Pediatric Surgery Division, between the years 1989 and 2008. Inclusion criteria were patients who underwent endoscopic correction of VUR, and had a long-term follow-up (at least 5 years). Patients referred from other centers were excluded, as were those for whom there was no access to their follow-up, and patients with secondary VUR. The information gathered included: 1. Patient: gender, age at diagnosis, indication for treatment, age at intervention. 2. Reflux: grade, side, presence of duplex system, initial ultrasound (US) scan, initial dimercaptosuccinic acid (DMSA) scintigraphy to assess RN. 3. Intervention: bulking substance used, outcome, recurrence, complications. Once all the information had been gathered, two groups were formed for the comparison: The group of patients treated at less than one year of age (infants INF), and the rest of the patients (children CHL). Every single ureteral unit was taken into account in the statistical analysis. The data were analyzed using SPSS® Version 17.0 (SPSS Inc. ®, USA). The Chi-square test was used for univariate comparisons, and the Fisher’s exact test was used for categorical variables.
Intervention Endoscopic treatment was indicated mainly due to the presence of break-through infections in spite of CAP. However in some of the first cases treated, indication relied on the presence of
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RN, owing to the concern regarding the influence of VUR in the final outcome of those patients. Later on, with the evidence added during the following years, RN alone was no longer an indication for endoscopic treatment. In our institution, cystoscopy is performed on an outpatient basis. Under general anesthesia, the bulking substance is injected after exploration of the bladder. The patient is discharged a few hours after the procedure. Three bulking agents have been used over the past years: first, polytetrafluoroethylene (PTFE) and polydimethylsiloxane (PDMS). Later, due to the concern regarding risk of migration of the particles, they were replaced by dextranomer / hyaluronic acid (Dx/HA). This last compound is the only one currently approved by the American Food and Drugs Administration (FDA). Patients continue regular follow up in our outpatient clinic. Cystography was performed 12 weeks after surgery, and repeated one year later.
RESULTS A total of 463 ureteric units (296 patients) were included, with 47 of them (31 patients) being less than one year old (mean 8 months, range 6 to 11 months) at the time of treatment (INF group), with the remaining 416 being included in a second group (children, CHL). The descriptive data is summarized in Table 1 and the indications for surgery in Table 2. There were some significant differences on comparing the two groups. Firstly, there are significantly more male patients than female ones in the INF group. Furthermore, the incidence of high-grade reflux, anomalies detected in the US scan, and RN, is also significantly higher in the INF. These findings correlate with the current evidence of the different features of early-diagnosed reflux against reflux in older children11. The resolution rate was 87.2% in the INF group, and 96.6% in the CHL group. These differences are statistically significant. There is also a significantly higher risk of late recurrence of VUR in the INF group (34.1% vs. 15.7%) (Table 3). Resolution rate according
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to initial VUR grade is summarized in Table 4. Among the patients with initial VUR resolution, we identified 6 cases of UTI in the INF group (14.6%) and 20 in the CHL group (5%). These patients showed recurrent VUR. There were no complications in the INF group, either regarding the procedure itself or the general anesthesia. Three complications were observed in the CHL group (post-procedure bleeding, post-procedure UTI, and uretero-vesical stenosis that required open surgery).
COMMENT More than 30 years have passed since Matoushek and Puri and O’Donnell described the subureteric endoscopic injection of a bulking agent to correct VUR12,13. The technique is well established as an effective and safe procedure, with a very low complication rate14,15. Even if its results are not as good as those of open surgery, in terms of resolving VUR, these differences are overshadowed by the much less invasiveness of the endoscopic procedure3,16. Our department was pioneer in the performance of this technique in Spain, with the first cases treated in 1979. Since then, many modifications have been adopted as regards the procedure itself, as well as its indications and follow up as new light has been shed on the pathophysiology of VUR over the years. The bulking substance used has changed several times. Dextranomer/hyaluronic acid copolymer is currently the only substance approved by the American Food and Drugs Administration (FDA). Although several substances have been used for this purpose, in our department we have previous experience with PTFE and PDMS 3. As regards the technique itself, there are two main variations described; the classic sub-ureteric approach first described by Puri and O´Donnell13 and the hydrodistention-implantation technique (HIT) described by Kirsch et al. in 200417. We have obtained good results with the original
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technique described by Puri, and therefore we have not changed it since we started endoscopic management of VUR. On the whole, the endoscopic approach in any of its variations and with different bulking agents has become first line therapy for VUR when surgical intervention is needed among most groups of pediatric urologists, and a viable alternative to long term continuous antibiotic prophylaxis (CAP), even in cases of high-grade reflux3,18. The overall success rate of the treatment is around 84% depending mainly on the bulking agent used and the reflux grade19. One meta-analysis reports a success rate after only one injection of up to 78.5% for grades I and II, 72 % for grade III, 63 % for grade IV, and 51 % for grade V3. Regarding the bulking substance used in the procedure, there have been reported success rates ranging from 84% with Dx/HA to 93% and 98% with PDMS and PTFE respectively19. The incidence of complications is very low in the different groups that have published their results20,21. Once the effectiveness and safety of the endoscopic procedure have been demonstrated, the controversy arises regarding its indications. Recent evidence leads us to re-think on the necessity of treating the VUR itself, when the final aim is to avoid UTI and secondary renal damage, and correcting VUR is not a guarantee of that22,23. Undoubtedly, it has become first line therapy when surgery is needed, unless there is any specific anatomic feature that makes it unsuitable. However, are we sure we know when surgery is not needed anymore? Is CAP always the first choice in VUR management when a patient is considered for intervention and not for surveillance? It is well known that VUR tends to resolve over time, and that it depends mainly on patient age, gender, and grade of VUR24. VUR behaves in a completely different way in different patients, and we should consider all these features in order to make the right choices regarding management. Recent data from the Swedish Reflux Trial showed that both CAP and
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endoscopic treatment reduced equally the breakthrough infections rates in girls between 1 and 2 years of age22. Concern has been also been raised regarding the long-term use of antibiotics and its consequences25. Therefore, it could be considered that endoscopic treatment might be a good choice for primary intervention in certain cases. Again, taking into account all the features of each individual patient is going to be key to making the right choices. Another issue arises at this point: patient age, in particular, the management in patients less than 1 year of age. There is general agreement among all the medical societies that these patients should be managed conservatively, either with surveillance or CAP1,2. This recommendation is given on the basis of the high probability of spontaneous resolution of VUR at this stage, as previously discussed. However, VUR seems to be a different entity when we consider infants. The incidence is higher in boys, rather than in girls, as in older age groups11. There are more high-grade refluxes diagnosed, and a higher incidence of RN. The resolution rate is also considerable in asymptomatic infants diagnosed in postnatal evaluation for prenatal hydronephrosis or sibling screening. However, the presence of bilateral highgrade reflux, RN at diagnosis, bladder dysfunction, or breakthrough febrile UTIs reduce the likelihood of spontaneous resolution24. The INF group of our study shares all these features with previously reported series, a predominance of male gender, high-grade reflux, anomalies in the US and DMSA scans at diagnosis. Although the VUR resolution rate after treatment is lower compared with the general series, according to our data, the short and long-term outcome regarding VUR resolution is no different from the patients with high grade VUR treated later. Furthermore, we reported no complications related to the technique itself or the anesthetic procedure. Therefore, we could say that it is a safe and feasible procedure and we can do it; nevertheless, should we do it?
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There is no doubt regarding the indication for treatment in the scenario of repeated UTI in spite of CAP. However, early intervention in this particular group of patients, at least after 6 months of age could be considered, especially if there are associated factors such as impaired access to health services or doubts regarding treatment compliance. We should also consider the drawbacks of long-term CAP, the increase in the risk of renal scar development after febrile UTI at this age and, certainly, parent preference8,26,27,28. Only a few groups have experience in the endoscopic treatment in infants9,29. As our institution was pioneer in performing this technique in Spain, we have treated a number of patients of less than one year of age. In the early years, most indications were due to presence of RN at a time when there was still concern about the role of an isolated VUR in the future renal function of these patients. Nowadays, the indication to treat infants in our department depends mainly on the presence of break-through UTIs, in accordance with current international guidelines1,2. When reviewing the outcome of the infants treated so far, we realized that, out of 47 ureteral units, 27 achieved VUR resolution without relapse after a period of 5 years. The treatment failed in 6 of them. Four out of these 6, finally underwent open reimplantation procedure (Cohen). Our experience with this surgery after an endoscopic procedure is that the difficulties we found with the ureteral dissection were related to the bulking substance used in the endoscopic injection rather than to the age at which it was performed. There were 14 recurrences of VUR after the endoscopic procedure in the INF group. In these patients only 6 ureteral units required further intervention due to febrile UTI, repeating an endoscopic procedure and with final resolution of VUR in all of them. Recent data from the Swedish Infant High-Grade Reflux Trial point out that, although resolution rate is higher with endoscopic treatment than with CAP, there is no difference in the final outcome regarding UTI recurrence or renal function deterioration10,29.
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Although the final outcome of these patients appeared to be no different from those in which surveillance or CAP is maintained over the first year of life, for more than 50% of them, VUR resolution led to the cessation of CAP and the close monitoring that is also important in selected cases27,28. Therefore, the possible advantages of endoscopic treatment would be: avoiding long term use of antibiotics with the expected impact on bacterial population and resistances25; avoiding the psychological impact of long-term treatment in parents or carers; as well as for conflictive families, or when there is a high suspicion of non-compliance with CAP, or problems in access to health care, in the event of UTIs. In these situations, patients affected by VUR with a lower probability of resolution could be offered endoscopic treatment in early stages as an alternative to CAP, assuming the likelihood of surgical treatment in the following years is high. There is an interesting study by Nevéus et al, regarding parent satisfaction with management of VUR that shows that there were no differences between the groups for surveillance, CAP, or endoscopic treatment. However, among children with CAP, there was a higher percentage of parents who would have chosen a different therapy if given the chance30.
CONCLUSIONS Summing up, endoscopic treatment of VUR in infants is a safe and effective procedure. Even though the effectiveness is not as good as in older children, the resolution rates are still high. Therefore, we consider that it could be an appropriate alternative in cases of break-through infections or selected cases with non-compliance, or issues related to CAP.
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BIBLIOGRAPHY 1. Peters CA, Skoog SJ, Arant BS Jr, Coop HL, Elder JS, Hudson RG, et al. Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol. 2010;184(3):1134-44. 2. Tekgül S, Riedmiller H, Hoebeke P, Kockvara R, Nijman RJ, Radmayr C, et al. EAU guidelines on vesicoureteral reflux in children. Eur Urol. 2012;62(3):534-42. 3. 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(2):716-22. 4. Brandström P, Esbjörner E, Herthelius M, Holmdahl G, Läckgren G, Nevéus T, Sillén U, Sixt R, Sjöberg I, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: I. Study design and study population characteristics. J Urol. 2010;184(1):274-9. 5. Tullus K. Vesicoureteric reflux in children. Lancet. 2015;385(9965):371-9. 6. Lopez PJ, Celis S, Reed F, Zubieta R. Vesicoureteral reflux: current management in children. Curr Urol Rep. 2014;15(10):447. 7. Sjöström S, Sillén U, Jodal U, Sameby L, Sixt R, Stokland E. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariate and multivariate analyses. J Urol. 2010;183(3):1177-84. 8. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics, 2010;126(6):108491. 9. Puri P, Mohanan N, Menezes M, Colhoun E. Endoscopic treatment of moderate and high grade vesicoureteral reflux in infants using dextranomer/hyaluronic acid. J Urol. 2007;178(4 Pt 2):1714-6; discussion 1717.
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10. Nordenström J, Holmdahl G, Brandström P, Sixt R, Stokland E, Sillén U, Sjöström S. The Swedish infant high-grade reflux trial: Study presentation and vesicoureteral reflux outcome. J Pediatr Urol. 2016;24. 11. Chand DH, Rhoades T, Poe SA, Krauss S, Strife CF. Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis. J Urol. 2003;170(4):1548-50. 12. Matouschek E: Treatment of vesicorenal reflux by transuretral teflon-injection (author’s translation). Urologe. 1981;20:263. 13. O´Donnell B, Puri P. Endoscopic correction of vesicoureteral reflux: results in 94 ureters. Brit Med J. 1986;293(6559):1404-6. 14. Läckgren G, Wåhlin N, Sköldenberg E, et al. Long-term followup children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol. 2001;166:1887–92. 15. Vandersteen DR, Routh JC, Kirsch AJ, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. J Urol. 2006;176:1593–5. 16. Duckett JW, Walker RD, Weiss R. Surgical results: International Reflux Study in Children—United States branch. J Urol 1992; 148: 1674–75. 17. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. 2004;171:2413–6. 18. Chertin B, De Caluwé D, Puri P. Endoscopic treatment of primary grades IV and V vesicoureteral reflux in children with subureteral injection of polytetrafluoroethylene. J Urol. 2003; 169(5):1847-9. 19. Chertin B, Kocherov S. Long-term results of endoscopic treatment of vesicoureteric
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reflux with different tissue-augmenting substances. J Pediatr Urol. 2010;6(3):251-6. 20. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteric reflux: systematic review. Pediatrics 2010;125: 1010–19. 21. Chertin, B, Calhoun, E, Velayudham, M, Puri, P. Endoscopic treatment of vesicoureteral reflux: 11 to 17 years of followup. J Urol 2002;167(3):1445-6. 22. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol. 2010;184(1):286-91. 23. Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: IV. Renal damage. J Urol. 2010;184(1):292-7. 24. Sjöström S, Sillén U, Jodal U, Sameby L, Sixt R, Stokland E. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariate and multivariate analyses. J Urol. 2010;183(3):1177-84. 25. Ili
ra an
rapovi
apkun
u at-De ulovi M, Saraga M. Changes in
bacterial resistance patterns in children with urinary tract infections on antimicrobial prophylaxis at University Hospital in Split. Med Sci Monit 2011; 17: CR355–61. 26. Sjöström S, Jodal U, Sixt R, Barchelard M, Sillén U. Longitudinal development of renal damage and renal function in infants with high grade vesicoureteral reflux. J Urol. 2009;181(5):2277-83. 27. Capozza N, Lais A, Matarazzo E, et al. Treatment of vesico-ureteric reflux: a new algorithm based on parental preference. BJU Int. 2003;92:285–8. 28. Krill A, Pohl H, Belman A, et al. Parental preferences in the management of vesicoureteral reflux. J Urol. 2011;186(5):2040–4. 29. Nordenström J, Sjöström S, Sillén U, Sixt R, Brandström P. The Swedish infant highgrade reflux trial: UTI and renal damage. J Pediatr Urol. 2017;13(2):146-154.
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30. Nevéus T, Brandström P, Linnér T, Jodal U, Hansson S. Parental experiences and preferences regarding the treatment of vesicoureteral reflux. Scand J Urol Nephrol. 2012;46(1):26-30.
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Table 1. Characteristics of INF and CHL groups. INF group
CHL group
47
416
6-11 m (mean 8 m)
1-17 y (mean 4,53 y)
Male
34 (72.3%)
119 (28.6%)
Female
13 (27.7%)
297 (71.4%)
Nº ureteral units Age Gender
p<0.0001 Side Left
24 (51%)
211 (50.7%)
Right
23 (48.9%)
205 (49.3%)
p=0.8 9 (19.1%)
67 (16.1%)
I
0
3 (0.7%)
II
3 (6.4%)
109 (26.2%)
III
10 (21.3%)
212 (51%)
IV
18 (38.3%)
80 (19.2%)
V
16 (34%)
12 (2.9%)
Duplex system VUR grade
p<0.0001 US scan Normal
15 (31.9%)
284 (68.3%)
Abnormal
32 (68%)
132 (31.7%)
p<0.0001
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DMSA scan Normal
15 (31.9%)
240 (57.7%)
Abnormal
32 (68%)
176 (42.3%)
p=0.001 Bulking substance Dx/HA
14 (29.8%)
156 (37.5%)
Others
33 (70.2%)
260(62.4%)
p=0.298
Table 2. Indication for intervention. (UTI: urinary tract infection; RN: reflux nephropathy) Indication
INF group
CHL group
47
416
UTI
6 (12.8%)
88 (21.1%)
RN
30 (63.8%)
130 (31.3%)
Persistence
-
160 (38.5%)
Others
11 (23.4%)
38 (9.1%)
Nº ureteral units
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Table 3. Initial resolution rate and recurrence rate. VUR initial resolution
INF group
CHL group
Yes
41 (87.2%)
402 (96.6%)
No
6 (12.8%)
14 (3.4%)
p=0.002 Recurrence
INF group
CHL group
Yes
14 (34,1%)
63 (15.7%)
No
27 (65.9%)
339 (84.3%)
p=0.012
Table 4. Resolution rate according to initial VUR grade in both groups. Initial VUR grade
INF group
Resolution
CHL group
Resolution
I
0
-
3
3 (100%)
II
3
3 (100%)
109
104 (99%)
III
10
8 (80%)
212
194 (91.5%)
IV
18
15 (83.3%)
80
71 (88.7%)
V
16
15 (93.7%)
12
7 (58.3%)
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