Vesicoureteral reflux: surgery versus medical treatment
Sofia Sjöström 2
1 Pediatric surgery and urology, Queen Silvia Childrens Hospital, Sahlgrens Academy, Gothenburg, Schweden
2 Pediatric surgery and urology, Queen Silvia Childrens Hospital, Sahlgrens Academy, Göteborg, Schweden
Vesicoureteral reflux is most often diagnosed after febrile urinary tract infection during childhood or at follow-up after a prenatal ultrasound showing dilated upper urinary tracts. The goal of any medical or surgical treatment is to prevent urinary tract infection, which can result in acquired renal damage and in the long run hypertension and chronic renal failure.
The condition is heterogeneous and is usually regarded as a congenital urinary abnormality, but may just as well occur due to a functional or neurogenic bladder dysfunction. The grade of reflux and the grade of congenital renal damage varies.
The treatment options are surveillance with prompt treatment of febrile urinary tract infection, low dosage antibiotic prophylaxis and different surgical methods to cure the reflux.
Despite grade of reflux the spontaneous resolution rate is high, which makes conservative treatment safe if no complications occur. Asymptomatic children with low-grade reflux need no further follow-up or treatment, but in grade 3–5 reflux, there is no consensus yet about which treatment is the best. The treatment should be designed individually for every patient depending on age, sex, grade of reflux, dilatation of the urinary tract, recurrent UTI and microbial resistance, compliance to treatment, bladder dysfunction and type of renal damage.
Summary of recommendations
Strategy of treatment depends on age of the child, sex, grade of reflux, co-existing obstruction, recurrent pyelonephritis, bladder dysfunction and renal damage.
The treatment aims to:
- Prevent urinary tract infections
- Prevent progressive renal damage
- Minimize complications or harms from unnecessary treatment
- Due to high spontaneous reflux resolution rate of all grades of reflux, most children should be treated conservatively, if no complications occurs (GoR A)
- Asymptomatic children with reflux grade 1–2 need no further follow-up or treatment (GoR A).
- Children with reflux grade 3–5 are recommended antibacterial prophylaxis, boys during the first year of life, girls until potty-trained (GoR A).
- When using antibacterial prophylaxis, side effects and development of bacterial resistance must be taken in consideration (GoR A).
- Diagnosis and treatment of urinary tract infection must be treated promptly and effectively taking into account that children with VUR more often have infection caused by non-E. coli than children with uncomplicated UTI’s (GoR B).
- Bladder and bowel dysfunction increases the risk of recurrent UTI and should probably be treated (GoR B).
- Circumcision can be considered in predisposed young boys (GoR C).
- Surgical correction of reflux with endoscopic treatment or open surgery including mini-invasive techniques could be used if recurrent UTI and/or progressive renal damage. It has been shown to reduce incidence of pyelonephritis and may have a modest beneficial effect on reducing the incidence of acquired renal scarring (GoR A).
- There is no surgical treatment that is superior to any others when it comes to prevention of recurrent UTI and progression of renal damage (GoR C).
Vesicoureteral reflux (VUR) is the pathological retrograde backflow of urine through an incompetent vesicoureteric junction. Normally the oblique entrance of the ureter though the detrusor muscle and the mucosa of the bladder wall creates a valve-mechanism preventing retrograde flow of urine from the bladder to the upper urinary tract. This mechanism can be altered either by a congenital anomaly at the formation of the ureteric orifice or caused by functional or neurogenic bladder-dysfunction. The prevalence of VUR is about 1% in children and it is found in 25–30% investigated after urinary tract infection (UTI) , . VUR is diagnosed through voiding cystourethrography (VCU) and is graded 1–5 depending on the severity of ureteral and renal pelvis dilatation .
VUR and UTI
VUR does no harm to the kidney per se if the urine is sterile, but it increases the risk of bacterial contamination to the renal pelvis, which could lead to pyelonephritis and renal scarring . Recurrent pyelonephritis should be treated promptly to avoid progress of renal damage , , which can lead to impaired glomerular function, hypertension and in some cases even end stage chronic kidney disease (CKD) , , , . The main goal in the treatment of VUR is to prevent repeated UTI’s and to minimize the risk of acquired renal damage. The risk of recurrent febrile UTI (fUTI) in VUR patients is multifactorial and variables increasing the risk are high-grade (dilated) VUR, bladder and bowel dysfunction, history of prior fUTI, renal damage, male sex during infancy and female sex after the first year of life , . In some recent publications computerised models for predicting fUTI in children with primary VUR are presented using multiple variables of the above mentioned for risk grading in the individual patient with accuracy of about 75% , . Children with congenital urinary abnormalities more often have infections with non-E.coli than other children with UTI , , which must be taken into considerations when choosing treatment.
VUR and renal damage
Besides the risk of renal scarring from pyelonephritis, most often seen as defects in the renal contour apically or caudally, high-grade VUR (4–5) is also associated with a congenital renal abnormality shown as a small kidney with generalised poor uptake and/or lowered differential renal function (DRF) seen in technetium DMSA scans , , . This defect probably represents poor development during gestation (dysplasia or hypoplasia) rather than a consequence of UTI. The risk of renal damage, both acquired (focal) and congenital (generalised) increases with increasing grade of VUR .
VUR and lower urinary tract dysfunction (LUTD)
Many children with high-grade VUR have lower urinary tract dysfunction with a large bladder capacity and increased post void residual (PVR) or overactive bladder (OAB) with symptoms of bladder instability and infrequent voiding and/or constipation , . Lower urinary tract dysfunction and renal damage are both risk factors for recurrent UTI, especially in children with VUR , , . Evaluation of bladder and bowel function through bowel and micturition diary, measurements of flow and post void residual (PVR) is therefore of great importance in the management of children with VUR. Lower urinary tract dysfunction in VUR patients is also associated with less probability of spontaneous resolution of reflux , , .
Special concerns regarding VUR in girls versus boys and younger versus older children
Generally VUR is more common in girls than in boys with a ratio of 4:1 in children older than 1 year . In infants diagnosed with VUR <1 year of age on the other hand, there is a clear predominance of males where high-grade VUR is often accompanied by congenital renal dysplasia , . These infants with high-grade VUR often develop lower urinary tract dysfunction characterized by large capacity bladder with high post void residual (PVR). The risk of recurrent febrile UTI (FUTI) is highest during infancy, especially in boys with declining number of infections after the infant year . Girls with VUR seem to have a continuous risk of new infections even after potty training , . Prompt treatment of febrile UTI is considered especially warranted in infants, since the kidneys in children less than two years of age are more prone to renal scarring secondary to ascending infections , .
VUR and spontaneous resolution
Spontaneous resolution of VUR over time is seen in 30–50% of children with dilated reflux (grade 3–5) and the resolution rate in undilated reflux (grade 1–2) is up to 80% within 4–5 years of follow-up , . Spontaneous resolution is also depending on age, sex (higher in boys during the infant year), uni or bilaterality of VUR, lower urinary tract dysfunction (LUTD), and prevalence of renal damage at diagnosis , , . Therefore individualized risk evaluation must be made in each patient before choosing optimal treatment.
The optimal treatment of VUR in children is constantly re-evaluated in the dialogue between paediatricians and paediatric urologists. Even though the subject has been the topic of hundreds of publications during the last decades, still the grade of evidence for different treatment options of medical or surgical intervention with the overall am of making a difference in preserving renal function in a long-term perspective is surprisingly low.
A systematic literature search was performed, with end date March 2016, in PubMed and Cochrane databases with the following key words (VUR OR vesicoureteral reflux OR vesicoureteral reflux) AND (treatment OR therapy OR surgery) and the following limitations (filters) Randomized Controlled Trial; Systematic Reviews; Meta-Analysis, English abstract available, only peer reviewed.
A total of 264 publications were identified, which were screened by title and abstract. After exclusion of duplicates, irrelevant or to old publications a total of 43 were included into the review (analysis), supplemented by 2 studies known to the authors published after March 2016.
The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using ICUD standards (for details see Preface).
Antibiotic prophylaxis (CAP) or surveillance
For a long time antibiotic prophylaxis has been a standard initial management in children with all grades of VUR. This is questioned today, both because of that new studies have shown that the effectiveness of CAP is doubtful and because of fear of the raising antimicrobial resistance. The poor compliance to treatment, estimated to be only 40% will lower the effectiveness and that must also be taken into consideration .
For low grade or asymptomatic reflux there is low or no evidence today that CAP will prevent UTI or renal damage , , , , , ,  (LoE 1a) but if the child presents with dilating reflux or a history of recurrent UTI’s there are studies that have shown that prophylaxis is superior to surveillance concerning prevention of UTI , , ,  (LoE 1b). In contrast to this, the American RIVUR study showed that CAP reduced the risk for UTI regardless of reflux grade (grade 2–4) , which made authors of recent meta-analyses to recommend prophylaxis to children with all grades of reflux , . It is shown that CAP increases the risk of infection due to antibiotic resistant bacteria ,  (LoE 1a). In the Swedish reflux study, where 1 year old children with persisting grade 3–4 VUR were randomized to surveillance, CAP or endoscopic treatment and followed for 2 years there was a significant difference between girls and boys, with a higher risk of UTI for girls without prophylaxis. These results led to the recommendation to stop CAP at 1 year of age in boys and continued prophylactic treatment in girls until potty-trained .
The evidence for CAP to prevent renal scarring is minimal according to several Cochrane reports , ,  (LoE 1a). A study that has been able to show a significant higher risk to develop renal scarring without treatment, was the Swedish reflux study . Furthermore, in a Cochrane report from 2011  it was stated that 33 children would need long-term antibiotic prophylaxis to prevent one more child developing kidney damage over the course of 2–3 years.
Randomised controlled studies evaluating antibiotic prophylaxis versus surveillance in VUR children is summarised in Table 1.
|Author, year||Study size (N=)||Patient age (years)||VUR grade||Intervention and Objectives||Results|
|Craig et al.,
Low dose antibiotic prophylaxis versus placebo in infants with VUR diagnosed after antenatal hydronephrosis or heredityPrimary objective reduction of UTI and prevention of new renal damage
|Antibiotic prophylaxis to asymptomatic VUR infants did not significantly reduce the frequency of UTI or new renal damage during the first 3 years of life.|
|Garin et al.,
|236 (113 VUR patients)||<18||0–3||
Antibiotic prophylaxis versus surveillance in children diagnosed with acute pyelonephritisPrimary objectives to evaluate the role of VUR in the risk for UTI. Evaluating reduction of UTI and prevention of new renal damage with antibiotic prophylaxis
Mild/moderate VUR does not increase the risk for UTI, pyelonephritis or renal scarring in children after UTI.Antibiotic prophylaxis does not reduce the risk for UTI, pyelonephritis or renal scarring after 1 year follow-up
|Montini et al. (PREDICT),
|338 (128 VUR patients)||<7||0–3||
Antibiotic prophylaxis versus surveillance in children after a first febrile UTIPrimary objective reduction of UTI. Secondary objective reduction of new renal damage
|Antibiotic prophylaxis does not reduce the rate of febrile urinary tract infections. No difference in renal outcome between treatment groups.|
|Pennesi et al., 2008 ||100||<3||2–4||
Antibiotic prophylaxis versus surveillance in VUR children after a first acute pyelonephritisPrimary objectives reduction of UTI and prevention of new renal damage
|No difference in pyelonephritic episodes or new renal damage between treatment groups after 2 years of follow-up|
|Rossey-Kesler et al., 2008 ||225||<3||1–3||
Antibiotic prophylaxis versus surveillance in young children with low grade VURPrimary objective reduction of UTI
|No difference in occurrence of UTI between treatment groups overall, but antibiotic prophylaxis significantly reduced UTI in boys with grade 3 VUR after 18 months follow-up.|
|PRIVENT Craig et al., 2009 ||576 (243 VUR patients)||<18||0–5||
Low dose antibiotic prophylaxis versus surveillance in predisposed childrenPrimary objective reduction of UTI
|Low dose antibiotic treatment decreases the number of UTI in predisposed children|
|The Swedish reflux trial in children, Brandström et al., 2010 , ||203||1–2||3–4||
Three armed study evaluating surveillance versus antibiotic prophylaxis versus endoscopic treatment in young children with VURPrimary objectives reduction of UTI , prevention of new renal damage (and resolution of VUR)
Antibiotic prophylaxis and endoscopic treatment both reduced the number of UTI in girls compared to surveillance and prophylaxis reduced the frequency of new renal damage in girls.No difference between active treatment and surveillance in boys.
|Hari et al.,
Antibiotic prophylaxis versus placebo in children with VUR and UTIPrimary objectives reduction of UTI and prevention of new renal damage
Long-term antibiotic prophylaxis is associated with increased risk of UTI and increased risk of infections with resistant bacteria’sNo difference in new renal damage after 1 year follow-up.
|RIVUR, Hoberman et al., 2014 ||697||0.5–3||1–2, 3–4||
Antibiotic prophylaxis versus placebo in children with VUR after first UTI.Primary objectives prevention of UTI and prevention of new renal damage
|Antibiotic prophylaxis reduces the risk of UTI but no difference between treatment groups in new renal damage.|
The use of probiotics has been suggested to reduce the number of UTI in children with VUR, but in a RCT where probiotics was compared to CAP no treatment was superior to the other  (LoE 1b).
Bladder/bowel dysfunction (BBD)
Treatment of BBD is considered to be an import factor in the care of children with VUR. Even though identified as a risk factor for persistent reflux and recurrent UTI in several observational studies, there are few RCT and meta analyses that has been able to show a general or specific urotherapeutic treatment that reduces the risk for UTI and renal scars  in a pediatric VUR population (LoE 1b). Sillén initiated clean intermittent catheterization (CIC) in a small cohort of VUR patients with recurrent fUTI and bladder dysfunction and found no effect on spontaneous resolution of VUR . In two studies evaluating treatment of bladder dysfunction in VUR patients they found no evidence of advantages of anticholinergic therapy on UTI recurrences  or reflux resolution . In one study treatment with alfa blockers in children with BBD resulted in reflux down-grading, but effect on UTI and renal scars were not shown .
To reduce number of UTI in children with VUR, circumcision in infant boys is an option, even if there is scarce with evidence (LoE 3). In a study from Turkey it was shown that circumcision decreases colonization of periurethral bacterial pathogenic flora and circumcision plus CAP reduces risk of UTI in boys with low-grade VUR .
If reflux resolution is the main goal, it is well known that open surgical procedure with reimplantation of the ureter have good results with abolishing of reflux grade 1–4 in >97% and in grade 5 in >80% , , , , , . This is to be compared with spontaneous disappearance of the reflux with resolution rates of 30–50% (LoE 1a). In the International Reflux study it was shown that surgery was superior to medical treatment concerning recurrent pyelonephritis but there was no difference in renal outcome, even in long-term follow up of 10 years , , , , . The same results were found in another study comparing open surgery to CAP in VUR children . This was shown to be true even in severe bilateral disease . Still it must be considered that open surgery needs a long hospital stay and is a stressful event for the child and family.
Endoscopic treatments (ET)
Endoscopic treatment is today a well established method and meta analyses has shown that ET abolish or down grade the reflux on average in 77% of ureters injected  (LoE 1a). This seems to be independently of type of bulking material , ,  and perhaps the results could be improved by the injection technique used . The results also depend on the grade of reflux, with lower efficiency in grade 5 and bilateral reflux , , . This is shown in the Swedish infant high-grade reflux study with 100% success rate in unilateral grade 4 to 30% in bilateral grade 5 . The study shows that it is also doable with ET in infants. In infants, it must be taken into consideration that high grade reflux is often a complex malformation with bladder dysfunction and/or vesicoureteral obstruction, making ET less suitable and patient selection important. ET is more efficient than surveillance and prophylaxis in reflux resolution but a concern is the recurrence rate of about 20% after 2 year follow-up , .
Looking at the effect on frequency of UTI and renal damage the ET results are comparable to open surgery.
Minimal invasive methods
Minimal invasive anti-reflux techniques including laparoscopic and robotic assisted surgery are increasing in popularity but there are no randomized studies available supporting the superiority versus other surgical methods (LoE 4). We found one case control study comparing miniureteroneocystostomy to ET presenting greater success of this minimal invasive technique in VUR outcome .
Randomised controlled trials comparing surgical intervention with antibiotic prophylaxis are summarized in Table 2.
|Author, year||Study size (N=)||Patient age (years)||VUR grade||Intervention and Objectives||Results|
|Birmingham reflux study group, 1983 , 1987 ||161||0–15||1–5*
Open surgery versus non operative managementPrimary objectives differences in UTI, renal damage and renal function
No difference between treatment groups in breakthrough UTI, renal function or renal damageVUR resolved in 98% of surgical and 50% of medical treated.
|The International Reflux Study in Children, European branch, 1992 , , 1998 , 2003 , 2006 ||
306 (5-years follow-up)252 (10-years follow-up)
Open surgery versus antibiotic prophylaxisPrimary objectives differences in UTI, renal damage and renal function
Higher incidence of febrile UTI in medical group at 5 years
No difference between treatment groups in renal damage or renal function at 5 yearsHigher incidence of febrile UTI in medical group but no difference in renal outcome at 10 years
|The International Reflux Study in Children, American branch, 1992 , ||132||<11||3–4||Open surgery versus antibiotic prophylaxis||
Higher incidence of febrile UTI in medical groupNo differences in renal damage or renal function at 5 years
|Smellie et al., 2001 ||52||1–12||3–5 bilateral VUR and nephropathy||
Open surgery versus antibiotic prophylaxisPrimary objective change in renal function (GFR)
|No difference between treatment groups in renal function (GFR ) after 10 years|
|Capozza et al., 2002 ||61||2–4||>1, mean 4||
Endoscopic treatment versus antibiotic prophylaxisPrimary objective differences in VUR resolution
Differences in UTI or renal damage not evaluatedET superior to antibiotic prophylaxis in VUR resolution
|The Swedish reflux trial in children, Brandström et al., 2010 , , ||203||1–2||3–4||
Endoscopic treatment versus antibiotic prophylaxis versus surveillancePrimary objectives differences in UTI, Renal damage and VUR resolution.
Antibiotic prophylaxis and endoscopic treatment both reduce UTI in girls compared to surveillance and antibiotic treatment reduce new renal damage in girls. No difference between active treatment and surveillance in boys.ET superior to medical treatment or surveillance in VUR resolution
|The Swedish Infant High-Grade Reflux Trial, Nordenström et al., 2017 , ||77||<8 months||4–5||
Endoscopic treatment versus antibiotic prophylaxisPrimary objectives differences in UTI, renal damage, VUR resolution and bladder function.
No differences in UTI or renal damage in total study populationET superior to antibiotic prophylaxis in VUR resolution
Vesicoureteral reflux is a complex topic, and a risk-oriented therapy should account for this complexity. Symptomatic high-grade reflux with recurrent UTI needs therapy, but there is no difference in outcome concerning number of pyelonephritis and acquired renal scars if the child is put on antibiotic prophylaxis or endoscopic treatment or open surgery. In the decision making you must take into account the drawbacks with CAP with compliance to treatment, side effects of the medicine and antimicrobial resistance. On the other hand all operative management needs anestethia and expensive hospital care. ET is a simpler method but the result concerning reflux resolution is inferior to open surgery.
Conservative treatment also includes treatment of bowel and bladder dysfunction. It is known that BBD is a risk factor for UTI and renal cortical scaring. Reflux resolution and endoscopic surgical success rate is also dependent on BBD. Still, it is hard to prove that general or specific treatments of the dysfunction will change renal outcome or frequency of UTI.
There is minimal evidence in the literature that any treatment of low-grade reflux will reduce number of UTI and renal damage.
Both in Europe and in America guidelines on vesicoureteral reflux are established. In 2012 the EAU guidelines on Vesicoureteral reflux was published . AUA organised in 2005 the Vesicoureteral Reflux Guideline Update Committee and a summary of the work was published in 2010 . The guidelines have in common that the management is based on the goals of minimizing the risk of acute infection and renal injury, while minimizing the morbidity of investigations and management and avoid overtreatment. In the guidelines the management is dependent on age, sex, BBD, UTI and reflux grade and is summarised by Routh et al. in a publication from 2012 (Table 3) .
|Organization||Patient age, year||BBD||Febrile UTI||VUR grade||Initial management||Indication for surgery|
|1–5||No||Either||All||CAP||Persistent VUR, breakthrough UTI|
|1–5||Yes||Yes||I–III||Treat BBD, CAP||Persistent VUR, breakthrough UTI|
|1–5||Yes||Yes||IV–V||Treat BBD, CAP vs surgery||Persistent VUR, breakthrough UTI|
|>5||No||No||All||CAP||Persistent VUR, breakthrough UTI|
|>5||Either||Yes||All||Treat BBD if present, CAP vs surgery||Persistent VUR, breakthrough UTI|
|AUA||<1||N/A||No||I–II||Observation or CAP, consider circumcision in boys||Breakthrough UTI|
|<1||N/A||No||III–V||CAP, consider circumcision in boys||Breakthrough UTI|
|<1||N/A||Yes||All||CAP, consider circumcision in boys||Initial vs after breakthrough UTI|
|>1||Yes||Both||All||Treat BBD, CAP||Initial vs after breakthrough UTI|
|>1||No||Both||All||Consider CAP (if renal scar, recurrent UTI)||–|
Generally when it comes to management of VUR there are few randomised controlled trials comparing different treatment strategies. In recent years there are numerous publications comparing the outcome of VUR resolution with different endoscopic techniques or bulking agents but there are very few with the aim of identifying risk patients for progressive renal damage or interventions that actually means a difference in long-time renal outcome.
Moreover both RCT and observational studies merge cohorts with different ages, different grades of reflux and other risk factors such as LUTD and renal damage. Conclusions about the optimal individualized treatment for each patient can therefore seldom be made. Bladder dysfunction increases the risk of UTI, renal damage and persistence of VUR but very few controlled studies evaluate the role of targeted treatment towards LUTD in VUR patients.
We call for randomised controlled studies with patient stratification that takes into account more risk factors than the primary VUR and with a primary objective significantly reducing the risk of UTI or even more specific saving renal function.
References Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol. 2000 Sep;30(9):587-93. DOI: 10.1007/s002470000263
 Skoog SJ, Peters CA, Arant BS Jr, Copp HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M. Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis. J Urol. 2010 Sep;184(3):1145-51. DOI: 10.1016/j.juro.2010.05.066
 Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Möbius TE. International system of radiographic grading of vesicoureteric reflux. International Reflux Study in Children. Pediatr Radiol. 1985;15(2):105-9. DOI: 10.1007/BF02388714
 Smellie JM, Ransley PG, Normand IC, Prescod N, Edwards D. Development of new renal scars: a collaborative study. Br Med J (Clin Res Ed). 1985 Jun 29;290(6486):1957-60. DOI: 10.1136/bmj.290.6486.1957
 Coulthard MG, Verber I, Jani JC, Lawson GR, Stuart CA, Sharma V, Lamb WH, Keir MJ. Can prompt treatment of childhood UTI prevent kidney scarring? Pediatr Nephrol. 2009 Oct;24(10):2059-63. DOI: 10.1007/s00467-009-1233-7
 Oh MM, Kim JW, Park MG, Kim JJ, Yoo KH, Moon du G. The impact of therapeutic delay time on acute scintigraphic lesion and ultimate scar formation in children with first febrile UTI. Eur J Pediatr. 2012 Mar;171(3):565-70. DOI: 10.1007/s00431-011-1614-3
 Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol. 1998 Nov;12(9):727-36. DOI: 10.1007/s004670050535
 Jacobson SH, Eklöf O, Eriksson CG, Lins LE, Tidgren B, Winberg J. Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. BMJ. 1989 Sep;299(6701):703-6. DOI: 10.1136/bmj.299.6701.703
 Round J, Fitzgerald AC, Hulme C, Lakhanpaul M, Tullus K. Urinary tract infections in children and the risk of ESRF. Acta Paediatr. 2012 Mar;101(3):278-82. DOI: 10.1111/j.1651-2227.2011.02542.x
 Peters C, Rushton HG. Vesicoureteral reflux associated renal damage: congenital reflux nephropathy and acquired renal scarring. J Urol. 2010 Jul;184(1):265-73. DOI: 10.1016/j.juro.2010.03.076
 Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998 Sep;160(3 Pt 2):1019-22. DOI: 10.1016/S0022-5347(01)62686-7
 Hidas G, Billimek J, Nam A, Soltani T, Kelly MS, Selby B, Dorgalli C, Wehbi E, McAleer I, McLorie G, Greenfield S, Kaplan SH, Khoury AE. Predicting the Risk of Breakthrough Urinary Tract Infections: Primary Vesicoureteral Reflux. J Urol. 2015 Nov;194(5):1396-401. DOI: 10.1016/j.juro.2015.06.019
 Arlen AM, Alexander SE, Wald M, Cooper CS. Computer model predicting breakthrough febrile urinary tract infection in children with primary vesicoureteral reflux. J Pediatr Urol. 2016 Oct;12(5):288.e1-288.e5. DOI: 10.1016/j.jpurol.2016.03.005
 Park S, Song SH, Lee C, Kim JW, Kim KS. Bacterial pathogens in first febrile urinary tract infection affect breakthrough infections in infants with vesicoureteral reflux treated with prophylactic antibiotics. Urology. 2013 Jun;81(6):1342-5. DOI: 10.1016/j.urology.2012.11.014
 Williams G, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001534. DOI: 10.1002/14651858.CD001534.pub3
 Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG. The characteristics of primary vesico-ureteric reflux in male and female infants with pre-natal hydronephrosis. Br J Urol. 1997 Aug;80(2):319-27. DOI: 10.1046/j.1464-410X.1997.00309.x
 Sjöström S, Sillén U, Bachelard M, Hansson S, Stokland E. Spontaneous resolution of high grade infantile vesicoureteral reflux. J Urol. 2004 Aug;172(2):694-8; discussion 699. DOI: 10.1097/01.ju.0000130747.89561.cf
 Risdon RA. The small scarred kidney in childhood. Pediatr Nephrol. 1993 Aug;7(4):361-4. DOI: 10.1007/BF00857538
 Ural Z, Ulman I, Avanoglu A. Bladder dynamics and vesicoureteral reflux: factors associated with idiopathic lower urinary tract dysfunction in children. J Urol. 2008 Apr;179(4):1564-7. DOI: 10.1016/j.juro.2007.11.095
 Keren R, Shaikh N, Pohl H, Gravens-Mueller L, Ivanova A, Zaoutis L, Patel M, deBerardinis R, Parker A, Bhatnagar S, Haralam MA, Pope M, Kearney D, Sprague B, Barrera R, Viteri B, Egigueron M, Shah N, Hoberman A. Risk Factors for Recurrent Urinary Tract Infection and Renal Scarring. Pediatrics. 2015 Jul;136(1):e13-21. DOI: 10.1542/peds.2015-0409
 Snodgrass W. The impact of treated dysfunctional voiding on the nonsurgical management of vesicoureteral reflux. J Urol. 1998 Nov;160(5):1823-5. DOI: 10.1016/S0022-5347(01)62425-X
 Yeung CK, Sreedhar B, Sihoe JD, Sit FK. Renal and bladder functional status at diagnosis as predictive factors for the outcome of primary vesicoureteral reflux in children. J Urol. 2006 Sep;176(3):1152-6; discussion 1156-7. DOI: 10.1016/j.juro.2006.04.053
 Godley ML, Desai D, Yeung CK, Dhillon HK, Duffy PG, Ransley PG. The relationship between early renal status, and the resolution of vesico-ureteric reflux and bladder function at 16 months. BJU Int. 2001 Apr;87(6):457-62. DOI: 10.1046/j.1464-410X.2001.00094.x
 Gorelick MH, Shaw KN. Screening tests for urinary tract infection in children: A meta-analysis. Pediatrics. 1999 Nov;104(5):e54. DOI: 10.1542/peds.104.5.e54
 Sjöström S, Jodal U, Sixt R, Bachelard M, Sillén U. Longitudinal development of renal damage and renal function in infants with high grade vesicoureteral reflux. J Urol. 2009 May;181(5):2277-83. DOI: 10.1016/j.juro.2009.01.051
 Zorc JJ, Levine DA, Platt SL, Dayan PS, Macias CG, Krief W, Schor J, Bank D, Shaw KN, Kuppermann N; Multicenter RSV-SBI Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Clinical and demographic factors associated with urinary tract infection in young febrile infants. Pediatrics. 2005 Sep;116(3):644-8. DOI: 10.1542/peds.2004-1825
 Hellström A, Hanson E, Hansson S, Hjälmås K, Jodal U. Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child. 1991 Feb;66(2):232-4. DOI: 10.1136/adc.66.2.232
 Coulthard MG, Lambert HJ, Keir MJ. Occurrence of renal scars in children after their first referral for urinary tract infection. BMJ. 1997 Oct;315(7113):918-9. DOI: 10.1136/bmj.315.7113.918
 Piepsz A, Tamminen-Möbius T, Reiners C, Heikkilä J, Kivisaari A, Nilsson NJ, Sixt R, Risdon RA, Smellie JM, Söderborg B. Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux dimercaptosuccinic acid findings. International Reflux Study Group in Europe. Eur J Pediatr. 1998 Sep;157(9):753-8.
 Benador D, Benador N, Slosman D, Mermillod B, Girardin E. Are younger children at highest risk of renal sequelae after pyelonephritis? Lancet. 1997 Jan 4;349(9044):17-9. DOI: 10.1016/S0140-6736(96)06126-0
 Estrada CR Jr, Passerotti CC, Graham DA, Peters CA, Bauer SB, Diamond DA, Cilento BG Jr, Borer JG, Cendron M, Nelson CP, Lee RS, Zhou J, Retik AB, Nguyen HT. Nomograms for predicting annual resolution rate of primary vesicoureteral reflux: results from 2,462 children. J Urol. 2009 Oct;182(4):1535-41. DOI: 10.1016/j.juro.2009.06.053
 Elder JS, Peters CA, Arant BS Jr, Ewalt DH, Hawtrey CE, Hurwitz RS, Parrott TS, Snyder HM 3rd, Weiss RA, Woolf SH, Hasselblad V. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol. 1997 May;157(5):1846-51. DOI: 10.1097/00005392-199705000-00093
 Copp HL, Nelson CP, Shortliffe LD, Lai J, Saigal CS, Kennedy WA; Urologic Diseases in America Project. Compliance with antibiotic prophylaxis in children with vesicoureteral reflux: results from a national pharmacy claims database. J Urol. 2010 May;183(5):1994-9. DOI: 10.1016/j.juro.2010.01.036
 Peters CA, Skoog SJ, Arant BS Jr, Copp HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M. Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol. 2010 Sep;184(3):1134-44. DOI: 10.1016/j.juro.2010.05.065
 Roussey-Kesler G, Gadjos V, Idres N, Horen B, Ichay L, Leclair MD, Raymond F, Grellier A, Hazart I, de Parscau L, Salomon R, Champion G, Leroy V, Guigonis V, Siret D, Palcoux JB, Taque S, Lemoigne A, Nguyen JM, Guyot C. Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J Urol. 2008 Feb;179(2):674-9; discussion 679. DOI: 10.1016/j.juro.2007.09.090
 Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics. 2006 Mar;117(3):626-32. DOI: 10.1542/peds.2005-1362
 Montini G, Rigon L, Zucchetta P, Fregonese F, Toffolo A, Gobber D, Cecchin D, Pavanello L, Molinari PP, Maschio F, Zanchetta S, Cassar W, Casadio L, Crivellaro C, Fortunati P, Corsini A, Calderan A, Comacchio S, Tommasi L, Hewitt IK, Da Dalt L, Zacchello G, Dall'Amico R; IRIS Group. Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial. Pediatrics. 2008 Nov;122(5):1064-71. DOI: 10.1542/peds.2007-3770
 Hari P, Hari S, Sinha A, Kumar R, Kapil A, Pandey RM, Bagga A. Antibiotic prophylaxis in the management of vesicoureteric reflux: a randomized double-blind placebo-controlled trial. Pediatr Nephrol. 2015 Mar;30(3):479-86. DOI: 10.1007/s00467-014-2943-z
 Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, Minisini S, Ventura A; North East Italy Prophylaxis in VUR study group. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics. 2008 Jun;121(6):e1489-94. DOI: 10.1542/peds.2007-2652
 Craig J, Roy LP, Sureshkumar P, Burke J, Powell H, Hodson E. (2002). Long-term antibiotics to prevent urinary tract infection in children with isolated vesicoureteric reflux: A placebo-controlled randomized trial. Nephrology, suppl. 2002;13.
 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 Jul;184(1):286-91. DOI: 10.1016/j.juro.2010.01.061
 Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, et al. Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children. New England Journal of Medicine. 2009 Oct 29;361(18):1748–59. DOI: 10.1056/NEJMoa0902295
 Leslie B, Moore K, Salle JL, Khoury AE, Cook A, Braga LH, Bägli DJ, Lorenzo AJ. Outcome of antibiotic prophylaxis discontinuation in patients with persistent vesicoureteral reflux initially presenting with febrile urinary tract infection: time to event analysis. J Urol. 2010 Sep;184(3):1093-8. DOI: 10.1016/j.juro.2010.05.013
 RIVUR Trial Investigators, Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R, Pohl HG, Kropp BP, Skoog SJ, Nelson CP, Moxey-Mims M, Chesney RW, Carpenter MA. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med. 2014 Jun 19;370(25):2367-76. DOI: 10.1056/NEJMoa1401811
 de Bessa J Jr, de Carvalho Mrad FC, Mendes EF, Bessa MC, Paschoalin VP, Tiraboschi RB, Sammour ZM, Gomes CM, Braga LH, Bastos Netto JM. Antibiotic prophylaxis for prevention of febrile urinary tract infections in children with vesicoureteral reflux: a meta-analysis of randomized, controlled trials comparing dilated to nondilated vesicoureteral reflux. J Urol. 2015 May;193(5 Suppl):1772-7. DOI: 10.1016/j.juro.2014.10.092
 Wang HH, Gbadegesin RA, Foreman JW, Nagaraj SK, Wigfall DR, Wiener JS, Routh JC. Efficacy of antibiotic prophylaxis in children with vesicoureteral reflux: systematic review and meta-analysis. J Urol. 2015 Mar;193(3):963-9. DOI: 10.1016/j.juro.2014.08.112
 Nagler EV, Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Hodson EM, editor. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2011. DOI: 10.1002/14651858.CD001532.pub4
 Wheeler D, Vimalachandra D, Hodson E, Smith G, Craig J. Interventions for primary vesicoureteric reflux. Hodson E, editor. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2004. DOI: 10.1002/14651858.CD001532.pub2
 Hodson EM, Wheeler DM, Smith GH, Craig JC, Vimalachandra D. Interventions for primary vesicoureteric reflux. Hodson EM, editor. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2007. DOI: 10.1002/14651858.CD001532.pub3
 Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish Reflux Trial in Children: IV. Renal Damage. The Journal of Urology. 2010 Jul;184(1):292–7. DOI: 10.1016/j.juro.2010.01.060
 Lee SJ, Shim YH, Cho SJ, Lee JW. Probiotics prophylaxis in children with persistent primary vesicoureteral reflux. Pediatr Nephrol. 2007 Sep;22(9):1315-20. DOI: 10.1007/s00467-007-0507-1
 Sillén U, Holmdahl G, Hellström AL, Sjöström S, Sölsnes E. Treatment of bladder dysfunction and high grade vesicoureteral reflux does not influence the spontaneous resolution rate. J Urol. 2007 Jan;177(1):325-9; discussion 329-30. DOI: 10.1016/j.juro.2006.09.009
 Ahn SH, Shim SY, Lee JW, Cho SJ, Lee SJ. The Effect of an Anticholinergic Agent(Oxybutynin) on Spontaneous Resolution of Primary Vesicoureteral Reflux. Journal of the Korean Society of Pediatric Nephrology. 2003;7(2):174-80.
 Kajbafzadeh A-M, Baradaran N, Sadeghi Z, Tourchi A, Saeedi P, Madani A, et al. Vesicoureteral Reflux and Primary Bladder Neck Dysfunction in Children: Urodynamic Evaluation and Randomized, Double-Blind, Clinical Trial on Effect of α-Blocker Therapy. The Journal of Urology. 2010 Nov;184(5):2128–33. DOI: 10.1016/j.juro.2010.06.132
 Gücük A, Burgu B, Gökçe İ, Mermerkaya M, Soygür T. Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR? Journal of Pediatric Urology. 2013 Dec;9(6):1131–6. DOI: 10.1016/j.jpurol.2013.04.014
 Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux: two years’ observation in 96 children. BMJ. 1983 Jul 16;287(6386):171–4. DOI: 10.1136/bmj.287.6386.171
 Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: five years’ observation. Birmingham Reflux Study Group. BMJ. 1987 Jul 25;295(6592):237–41. DOI: 10.1136/bmj.295.6592.237
 Garcia-Aparicio L, Rovira J, Blazquez-Gomez E, García-García L, Giménez-Llort A, Rodo J, et al. Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen’s ureteral reimplantation for vesicoureteral reflux: Long-term results. Journal of Pediatric Urology. 2013 Aug;9(4):483–7. DOI: 10.1016/j.jpurol.2013.03.003
 Hjälmås K, Löhr G, Tamminen-Möbius T, Seppänen J, Olbing H, Wikström S. Surgical Results in the International Reflux Study in Children (Europe). The Journal of Urology. 1992 Nov;148(5):1657–61. DOI: 10.1016/S0022-5347(17)36996-3
 Routh JC, Bogaert GA, Kaefer M, Manzoni G, Park JM, Retik AB, Rushton HG, Snodgrass WT, Wilcox DT. Vesicoureteral reflux: current trends in diagnosis, screening, and treatment. Eur Urol. 2012 Apr;61(4):773-82. DOI: 10.1016/j.eururo.2012.01.002
 Venhola M, Huttunen NP, Uhari M. Meta-analysis of vesicoureteral reflux and urinary tract infection in children. Scand J Urol Nephrol. 2006;40(2):98-102. DOI: 10.1080/00365590500499529
 Jodal U, Koskimies O, Hanson E, Löhr G, Olbing H, Smellie J, et al. Infection Pattern in Children with Vesicoureteral Reflux Randomly Allocated to Operation or Long-Term Antibacterial Prophylaxis. The Journal of Urology. 1992 Nov;148(5):1650–2. DOI: 10.1016/S0022-5347(17)36994-X
 Jodal U, Smellie JM, Lax H, Hoyer PF. Ten-year results of randomized treatment of children with severe vesicoureteral reflux. Final report of the International Reflux Study in Children. Pediatric Nephrology. 2006 Mar 25;21(6):785–92. DOI: 10.1007/s00467-006-0063-0
 Olbing H, Smellie JM, Jodal U, Lax H. New renal scars in children with severe VUR: a 10-year study of randomized treatment. Pediatric Nephrology. 2003 Nov 1;18(11):1128–31. DOI: 10.1007/s00467-003-1256-4
 Weiss R, Duckett J, Spitzer A. Results of A Randomized Clinical Trial of Medical Versus Surgical Management of Infants and Children with Grades III and IV Primary Vesicoureteral Reflux (United States). The Journal of Urology. 1992 Nov;148(5):1667–73. DOI: 10.1016/S0022-5347(17)36998-7
 Elo J, Tallgren LG, Alfthan O, Sarna S. Character of Urinary Tract Infections and Pyelonephritic Renal Scarring After Antireflux Surgery. The Journal of Urology. 1983 Feb;129(2):343–6. DOI: 10.1016/S0022-5347(17)52089-3
 Smellie JM, Barratt TM, Chantler C, Gordon I, Prescod NP, Ransley PG, Woolf AS. Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial. The Lancet. 2001 Apr;357(9265):1329–33. DOI: 10.1016/S0140-6736(00)04520-7
 Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics. 2010 May;125(5):1010-9. DOI: 10.1542/peds.2009-2225
 Habeeb Abid M. 504 Comparative study between the use of dextranomer hyaluronic acid copolymer (Dexel) versus polyacrylate polyalcohol copolymer (Vantris) in the endoscopic treatment of vesicoureteral reflux (VUR) in children. European Urology Supplements. 2015 Apr;14(2):e504. DOI: 10.1016/S1569-9056(15)60497-3
 Moore K, Bolduc S. Prospective Study of Polydimethylsiloxane vs Dextranomer/Hyaluronic Acid Injection for Treatment of Vesicoureteral Reflux. The Journal of Urology. 2014 Dec;192(6):1794–800. DOI: 10.1016/j.juro.2014.05.116
 Oswald J, Riccabona M, Lusuardi L, Bartsch G, Radmayr C. Prospective comparison and 1-year follow-up of a single endoscopic subureteral polydimethylsiloxane versus dextranomer/hyaluronic acid copolymer injection for treatment of vesicoureteral reflux in children. Urology. 2002 Nov;60(5):894–7. DOI: 10.1016/S0090-4295(02)01903-9
 Akin M, Erginel B, Karadag CA, Yildiz A, Özçelik GS, Sever N, et al. A comparison of the double hydrodistention implantation technique (HIT) and the HIT with a polyacrylate/polyalcohol copolymer (PPC) for the endoscopic treatment of primary vesicoureteral reflux. International Urology and Nephrology. 2014 Jun 26;46(11):2057–61. DOI: 10.1007/s11255-014-0771-5
 Capozza N, Caione P. Dextranomer/hyaluronic acid copolymer implantation for vesico-ureteral reflux: A randomized comparison with antibiotic prophylaxis. The Journal of Pediatrics. 2002 Feb;140(2):230–4. DOI: 10.1067/mpd.2002.121380
 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. The Journal of Urology. 2006 Feb;175(2):716–22. DOI: 10.1016/S0022-5347(05)00210-7
 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. 2017 Apr;13(2):130-138. DOI: 10.1016/j.jpurol.2016.08.026
 Holmdahl G, Brandström P, Läckgren G, Sillén U, Stokland E, Jodal U, et al. The Swedish Reflux Trial in Children: II. Vesicoureteral Reflux Outcome. The Journal of Urology. 2010 Jul;184(1):280–5. DOI: 10.1016/j.juro.2010.01.059
 Lee EK, Gatti JM, Demarco RT, Murphy JP. Long-term followup of dextranomer/hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. J Urol. 2009 Apr;181(4):1869-74; discussion 1874-5. DOI: 10.1016/j.juro.2008.12.005
 Ashley R, Vandersteen D. Outcome analysis of mini-ureteroneocystostomy versus dextranomer/hyaluronic acid copolymer injection for unilateral vesicoureteral reflux. J Urol. 2008 Oct;180(4 Suppl):1611-3; discussion 1614. DOI: 10.1016/j.juro.2008.04.084
 Duckett JW, Dixon walker R, Weiss R. Surgical Results: International Reflux Study in Children—United States Branch. The Journal of Urology. 1992 Nov;148(5):1674–5. DOI: 10.1016/S0022-5347(17)36999-9
 Nordenström J, Sjöström S, Sillén U, Sixt R, Brandström P. The Swedish infant high-grade reflux trial: UTI and renal damage. Journal of Pediatric Urology. 2017 Feb;13(2):146-154. DOI: 10.1016/j.jpurol.2016.12.023
 Tekgül S, Riedmiller H, Hoebeke P, Kočvara R, Nijman RJ, Radmayr C, Stein R, Dogan HS; European Association of Urology. EAU guidelines on vesicoureteral reflux in children. Eur Urol. 2012 Sep;62(3):534-42. DOI: 10.1016/j.eururo.2012.05.059