PIC cystography in occult vesicoureteral reflux: A systematic review highlighting its utility in children with recurrent urinary tract infections and normal VCUG.

BACKGROUND: Vesicoureteral reflux (VUR) affects 1-2% of children, predisposing them to pyelonephritis, renal scarring, and reflux nephropathy. Treatment aims to prevent febrile urinary tract infections (f-UTI) and long-term sequelae. While guidelines differ, the current consensus proposes individual risk-stratification and subsequent management strategies. Here, we systematically analyzed the current literature on Positional Instillation of Contrast Cystography (PIC) for individualized diagnostics in patients with recurrent f-UTIs. OBJECTIVE: We present a comprehensive qualitative and quantitative synthesis. Outcomes were: 1. the ability of PIC to predict VUR in patients with negative voiding cystographies (VCUG), 2. the ability of PIC to predict occult contralateral VUR, 3. the correlation of occult VUR in PIC with dimercaptosuccinic acid (DMSA) scan findings, and 4. the incidence of postoperative f-UTI in children treated for occult VUR picked up on PIC. STUDY DESIGN: We conducted a systematic review following the PRISMA guidelines, applying the following inclusion criteria: Children with occult VUR in PIC with negative VCUG. RESULTS: We included nine studies with 496 symptomatic patients with a mean age of 6.8 years, published between 2003 and 2021. PIC detected VUR in 73% of patients. Out of them, 81% had low-grade and 19% high-grade VUR. Occult contralateral VUR was present in 41% children. The presence of renal scars on DMSA scan was 1.39 times more likely with occult VUR on PIC. 85% of patients did not experience recurrent f-UTIs after PIC and subsequent treatment. DISCUSSION: PIC can detect occult VUR in patients with recurrent f-UTIs in whom VCUG is negative. However, we recommend a cautious approach in the use of PIC in clinical practice until further prospective studies confirm the validity of our outcome measures. CONCLUSION: Identification, risk stratification, and prompt action are central in managing VUR. PIC can be helpful in identifying VUR in patients with recurrent f-UTI.

Controlled long term outcome of pyloromyotomy for pyloric stenosis: No long-term adverse effect.

PURPOSE: Pyloromyotomy for pyloric stenosis is one of the more common surgical procedures performed on infants. The long-term effects of the procedure are however unclear. The purpose of this study was to study the effects into adult life, compare them with controls and to see if there is a need for structured follow up of patients. METHODS: Of the 101 patients operated for pyloric stenosis between 1972 and 1974 at our tertiary referral center 91 could be traced. They were all invited to participate in the study and were sent validated questionnaires (PAGI-SYM, GIQLI) as well as a study-specific questionnaire examining the use of antacid drugs, incidence of gastroscopy and abdominal surgery. Sixty patients responded (66%, mean age 45 years, 46 male) and were included. Thereafter, 600 age and sex-matched controls were sent the same questionnaires. 132 responded (22%, 90 male) and were includes as controls. RESULTS: No significant differences could be found in any of the examined parameters when looking at the whole material or the male patients. Female patients had higher PAGI-SYM-scores for post prandial fullness (mean 1.11 vs 0.43, P = 0.035) and heartburn (mean 0.59 vs 0.14, P = 0.043) when compared to controls. CONCLUSIONS: The present study shows that most patients operated for pyloric stenosis during infancy experience no negative effects into adulthood. The finding in the female patient group is interesting but is unlikely to have any clinical implications. The results from this study strongly implicate that there is no need for follow up of patients into adulthood. LEVEL OF EVIDENCE: Level III.

Non-Animal Stabilized Hyaluronic Acid/Dextranomer Gel (NASHA/Dx, Deflux) for Endoscopic Treatment of Vesicoureteral Reflux: What Have We Learned Over the Last 20 Years?

Non-animal stabilized hyaluronic acid/dextranomer gel (Deflux; NASHA/Dx) was developed as a treatment for vesicoureteral reflux (VUR) in the 1990s. To mark 20 years since the US approval of this agent, we reviewed its properties, best practice for application, and the available clinical safety and efficacy data. Long-term or randomized, controlled studies of treatment with NASHA/Dx have reported VUR resolution rates of 59%-100% with low rates of febrile urinary tract infection post-treatment (4%-25%), indicating long-term protection of the kidneys. An individualized approach VUR management is advocated, and NASHA/Dx is a viable option for many patients requiring intervention.

Management of Vesicoureteral Reflux: What Have We Learned Over the Last 20 Years?

Vesicoureteral reflux (VUR) is associated with increased risks of urinary tract infection, renal scarring and reflux nephropathy. We review advancements over the last two decades in our understanding and management of VUR. Over time, the condition may resolve spontaneously but it can persist for many years and bladder/bowel dysfunction is often involved. Some factors that increase the likelihood of persistence (e.g., high grade) also increase the risk of renal scarring. Voiding cystourethrography (VCUG) is generally considered the definitive method for diagnosing VUR, and helpful in determining the need for treatment. However, this procedure causes distress and radiation exposure. Therefore, strategies to reduce clinicians' reliance upon VCUG (e.g., after a VUR treatment procedure) have been developed. There are several options for managing patients with VUR. Observation is suitable only for patients at low risk of renal injury. Antibiotic prophylaxis can reduce the incidence of UTIs, but drawbacks such as antibiotic resistance and incomplete adherence mean that this option is not viable for long-term use. Long-term studies of endoscopic injection have helped us understand factors influencing use and the effectiveness of this procedure. Ureteral reimplantation is still performed commonly, and robot-assisted laparoscopic methods are gaining popularity. Over the last 20 years, there has been a shift toward more conservative management of VUR with an individualized, risk-based approach. For continued treatment improvement, better identification of children at risk of renal scarring, robust evidence regarding the available interventions, and an improved VUR grading system are needed.

SLC20A1 Is Involved in Urinary Tract and Urorectal Development.

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.

Proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx) for endoscopic treatment of grade IV vesicoureteral reflux: Long-term observational study.

BACKGROUND: Since 1993, children aged >1 year with persistent grade III-V vesicoureteral reflux (VUR) and febrile urinary tract infections (UTIs) attending Uppsala University Hospital have undergone endoscopic injection with proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx; Deflux®). OBJECTIVE: Investigate long-term incidence of UTI, bladder dysfunction, ureteral reimplantation and overall clinical findings following endoscopic injection of NASHA/Dx. STUDY DESIGN: Children with grade IV VUR diagnosed by voiding cystourethrogram (VCUG) and dilating VUR persisting for >1 year were included in this study. 15-25 years after endoscopic treatment, patients' hospital charts were studied. Information on bladder function and UTIs was obtained via questionnaire, 8-18 years after endoscopic treatment. RESULTS: 185 patients (69 boys, 116 girls) were included in the study; 237 grade IV VUR ureters were treated. All study patients were diagnosed with VUR after a febrile UTI (i.e. pyelonephritis). According to the last voiding cystourethrogram, 69% of ureters showed a positive response (VUR grade 0-I), 7% had VUR grade II and 23% had VUR grade ≥ III. 46 patients (25%) required ureteral reimplantation during follow-up. Among patients treated during the second 5-year period compared with the first (1998-2003 versus 1993-1998), there was a significant decrease in the rate of ureteral reimplantation (31% vs 16%; p = 0.0365). This difference may be attributable to developments over time in the injection technique. UTIs occurred in 30 patients (21% of the evaluable population): 28 females and 2 males. Febrile UTIs were reported in 14 patients (10%), all females. Forty-nine patients (34%) had bladder problems (e.g. underactivity, overactivity, incontinence). Five patients underwent ureteral reimplantation 'late', 6-10 years after the last endoscopic injection. In one male patient, calcification around the NASHA/Dx implantation site was observed during routine examination 2 years after endoscopic treatment; no intervention was required. No safety issues were observed in the remaining 97% of the study population. CONCLUSIONS: This study represents the longest published follow-up of Grade IV VUR patients undergoing endoscopic treatment. Three-quarters of patients did not need ureteral reimplantation. Optimal injection technique and higher injection volume were associated with a reduced ureteral reimplantation rate. Treatment with NASHA/Dx was durable and well tolerated: long-term risks of UTI, bladder dysfunction and recurrent VUR were low.

Changes of arterial pressure following relief of obstruction in adults with hydronephrosis.

BACKGROUND: As much as 20% of all cases of hypertension are associated with kidney malfunctions. We have previously demonstrated in animals and in pediatric patients that hydronephrosis causes hypertension, which was attenuated by surgical relief of the ureteropelvic junction (UPJ) obstruction. This retrospective cohort study aimed to investigate: (1) the proposed link between hydronephrosis, due to UPJ obstruction, and elevated arterial pressure in adults; and (2) if elevated blood pressure in patients with hydronephrosis might be another indication for surgery. MATERIALS AND METHODS: Medical records of 212 patients undergoing surgical management of hydronephrosis, due to UPJ obstruction, between 2000 and 2016 were assessed. After excluding patients with confounding conditions and treatments, paired arterial pressures (i.e. before/after surgery) were compared in 49 patients (35 years old; 95% CI 29-39). Split renal function was evaluated by using mercaptoacetyltriglycine (MAG3) renography before surgical management of the hydronephrotic kidney. RESULTS: Systolic (-11 mmHg; 95% CI 6-15 mmHg), diastolic (-8 mmHg; 95% CI 4-11 mmHg), and mean arterial (-9 mmHg; 95% CI 6-12) pressures were significantly reduced after relief of the obstruction (p < 0.001). Split renal function of the hydronephrotic kidney was 39% (95% CI 37-41). No correlations were found between MAG3 and blood pressure level before surgery or between MAG3 and the reduction of blood pressure after surgical management of the UPJ obstruction. CONCLUSIONS: In adults with hydronephrosis, blood pressure was reduced following relief of the obstruction. Our findings suggest that elevated arterial pressure should be taken into account as an indication to surgically correct hydronephrosis.

Standardization of pediatric uroradiological terms: a multidisciplinary European glossary.

To promote the standardization of nephro-uroradiological terms used in children, the European Society of Paediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication between different clinicians involved in pediatric urology and nephrology.

Standardization of pediatric uroradiological terms: A multidisciplinary European glossary.

To promote the standardization of nephro-uroradiological terms used in children, the European Society of Pediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication among different clinicians involved in pediatric urology and nephrology.

Current trends in dextranomer hyaluronic acid copolymer (Deflux) injection technique for endoscopic treatment of vesicoureteral reflux.

OBJECTIVE: To determine the current preferred injection technique(s) for endoscopic management of pediatric vesicoureteral reflux (VUR). Since the approval of dextranomer hyaluronic acid copolymer (Dx/HA) in 2001, injection methods have evolved and now include the hydrodistention implantation technique (HIT) and double HIT as well as subureteral transurethral injection (STING) method. METHODS: In July 2012, 278 pediatric urologists in the United States were contacted to complete a 15-question survey regarding Dx/HA injection technique(s) currently used in their practice. RESULTS: Fifty board-certified pediatric urologists completed the survey for a response rate of 18%. Most respondents (60%) were in a single-specialty group practice, and 12% were affiliated with an academic- or university-based practice. Respondents reported seeing a mean of 159 pediatric patients (range, 40-400 patients) with VUR annually, and 94% used Dx/HA ≥4 times in the past year. Forty-seven respondents (94%) reported using double HIT over the course of their career compared with 36 (72%) for STING and 30 (60%) for HIT (P <.05). Double HIT gained widespread acceptance between 2007 and 2008, paralleled by a decline in use of other injection techniques. A significantly higher percentage currently perform double HIT (92%) compared with either STING (24%) or HIT (34%; P <.001). Respondents reported the use of double HIT 15 times more often than STING technique and 5 times more often than HIT during the past 12 months (P <.001). CONCLUSION: The double HIT method is currently the most commonly performed technique for endoscopic correction of VUR by pediatric urologists in the United States.

Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder.

Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P = 8.88 × 10(-5); follow-up: P = 0.0025; combined: 1.09 × 10(-6)) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P = 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.

Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region.

BACKGROUND: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. METHODS: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. RESULTS: New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes. CONCLUSION: Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation.

A case with bladder exstrophy and unbalanced X chromosome rearrangement.

INTRODUCTION: Bladder exstrophy is a rare congenital malformation of the bladder and is believed to be a complex disorder with genetic and environmental background. We describe a young adult female with an isolated bladder exstrophy and with an X chromosome aberration. Patients and METHODS: Karyotyping identified an X chromosome rearrangement that was further characterized with array comparative genomic hybridization (CGH) and confirmed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization (FISH) analysis. RESULTS: The identified X chromosome rearrangement in our index patient consists of a gain of chromosomal material in region Xq26.3- > qter and loss in region Xp22.12- > pter. This aberration was also carried by her mother and sister, none with bladder exstrophy. All three have a disproportionate short stature, as expected due to the deletion of one of the copies of the SHOX gene on Xp22.3. X-inactivation studies revealed a complete skewed inactivation pattern in carriers. Crossover events in the maternal germline furthermore resulted in different genetic material on the rearranged X chromosome between the index patient and her sister. CONCLUSION: Our findings suggest an X-linked genetic risk factor for bladder exstrophy.

The Swedish reflux trial in children: II. Vesicoureteral reflux outcome.

PURPOSE: We compared reflux status in children with dilating vesicoureteral reflux treated in 3 groups, including low dose antibiotic prophylaxis, endoscopic therapy and a surveillance group on antibiotic treatment only for febrile urinary tract infection. MATERIALS AND METHODS: A total of 203 children 1 to younger than 2 years with grade III-IV reflux were recruited into this open, randomized, controlled trial. Endoscopic treatment was done with dextranomer/hyaluronic acid copolymer. The main end point was reflux status after 2 years. Data were analyzed by the intent to treat principle. RESULTS: Reflux status improved in all 3 treatment arms. Of patients in the prophylaxis, endoscopic and surveillance groups 39%, 71% and 47%, respectively, had reflux resolution or downgrading to grade I-II after 2 years. This was significantly more common in the endoscopic than in the prophylaxis and surveillance groups (p = 0.0002 and 0.0030, respectively). After 1 or 2 injections 86% of patients in the endoscopic group had no or grade I-II reflux but recurrent dilating reflux was seen in 20% after 2 years. CONCLUSIONS: Endoscopic treatment resulted in dilating reflux resolution or downgrading in most treated children. After 2 years endoscopic treatment results were significantly better than the spontaneous resolution rate or downgrading in the prophylaxis and surveillance groups. However, of concern is the common reappearance of dilating reflux after 2 years.

The Swedish reflux trial in children: I. Study design and study population characteristics.

PURPOSE: We compared the rates of febrile urinary tract infection, kidney damage and reflux resolution in children with vesicoureteral reflux treated in 3 ways, including antibiotic prophylaxis, endoscopic therapy and surveillance with antibiotics only for symptomatic urinary tract infection. MATERIALS AND METHODS: Children 1 to younger than 2 years with grade III-IV reflux were recruited into this prospective, open, randomized, controlled, multicenter study and followed for 2 years after randomization. The main study end points were recurrent febrile urinary tract infection, renal status on dimercapto-succinic acid scintigraphy and reflux status. Outcomes were analyzed by the intent to treat principle. RESULTS: During a 6-year period 128 girls and 75 boys entered the study. In 96% of cases reflux was detected after urinary tract infection. The randomization procedure was successful and resulted in 3 groups matched for relevant factors. Recruitment was slower than anticipated but after patients were entered adherence to the protocol was good. Of the children 93% were followed for the intended 2 years without a treatment arm change. All except 2 patients completed 2-year followup scintigraphy. CONCLUSIONS: Recruitment was difficult but a substantial number of children were entered and randomly assigned to 3 groups with similar basic characteristics. Good adherence to the protocol made it possible to address the central study questions.

Pharmacokinetics and pharmacodynamics of propiverine in children aged between 5 and 10 years with symptoms of overactive bladder.

BACKGROUND AND OBJECTIVES: Pharmacokinetic studies in children are particularly required for drugs with intensive hepatic and regioselective intestinal elimination and pharmacological effects that may be critical for absorption at therapeutic doses, such as a delay in intestinal transit. One example is the antimuscarinic drug propiverine, the pharmacokinetics of which were evaluated in the present study in children with symptoms of overactive bladder. METHODS: The pharmacokinetics of immediate-release propiverine were studied in a dose-escalating, parallel-group study (propiverine 5, 10 and 15 mg twice daily for 14 days) in 25 subjects (11 females and 14 males aged 5-10 years; bodyweight 17-44 kg; body mass index 14-21 kg/m2) with symptoms of overactive bladder during waking hours. Serum concentration-time curves of propiverine and its major metabolite propiverine N-oxide (M-5) were evaluated up to 3 hours and 8 hours after the first and last administration, respectively, using liquid chromatography with tandem mass spectrometry. The voiding frequency, number of incontinence and urgency episodes, single voided volume and urine flow variables were measured before and after treatment. RESULTS: Significant dose-related increases in the serum exposure (the area under the concentration-time curve, the maximum concentration and the minimum concentration) with propiverine and M-5 in the dose groups < or =0.3 mg/kg and 0.3 to < or =0.45 mg/kg after both single-dose and repeated-dose administration were found. The elimination half-lives of propiverine and M-5 at steady state were no different (mean +/- SD 12.2 +/- 11.2 and 14.5 +/- 9.94 hours, respectively). Higher doses did not result in additional dose-proportional increases in the respective pharmacokinetic parameters, particularly not after repeated-dose treatment. The voiding frequency, voided volume and urge symptoms were beneficially changed from baseline; significant dose-dependent changes were not observed. Most of the adverse events that were probably or possibly drug related were reported for patients in the high-dose group (>0.45 mg/kg). CONCLUSIONS: The disposition of propiverine is dose related after repeated administration of the recommended doses below 0.45 mg/kg (0.3-0.45 mg/kg) twice daily in children aged 5-10 years with symptoms of overactive bladder and urinary incontinence. ( TRIAL REGISTRATION NUMBERS: [clinicaltrials.gov] NCT00795925; [EudraCT] 2004-001243-30).

22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment.

Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.

Endoscopic treatment of vesicoureteral reflux: Current status.

Vesicoureteral reflux (VUR) affects around 1% of all children. It carries an increased risk of febrile urinary tract infections (UTIs) and is associated with impaired renal function. Endoscopic treatment with NASHA/Dx gel (dextranomer microspheres in a stabilized hyaluronic acid-based gel of nonanimal origin) is minimally invasive, well tolerated and provides cure rates approaching those of open surgery: approximately 90% in several studies. It has also been shown to be effective in a variety of 'complicated' cases. Endoscopic treatment is therefore considered preferable to open surgery and long-term antibiotic prophylaxis. Nontreatment of VUR is being discussed as an alternative option, whereby children are treated with antibiotics only when UTIs occur. Considering all the available evidence, however, active intervention with endoscopic treatment remains preferable. A new approach to managing VUR may nevertheless be considered, with treatment decisions based not only on the grade of reflux, but also factors such as age, sex, renal scarring, and bladder dysfunction. Open surgery would be reserved for use only in the ( approximately )10% of children not responding to endoscopic treatment, and patients with refluxing primary megaureter.