Prevalence and determinants of failure to thrive in children with vesico-ureteral reflux.

AIM: To assess the prevalence and determinants of failure to thrive (FTT) among patients with vesico-ureteral reflux (VUR) and evaluating the effects of supplementation on growth in patients with urinary solute losses. METHODS: We retrospectively enrolled 1277 patients with VUR (mean age at diagnosis = 6.5 months). Patients with FTT were screened for renal tubular function impairment (TFI). If fractional excretion of sodium (FENa) >2% or blood bicarbonate <20 mmol/L, supplementation was provided. RESULTS: Among 1277 patients, 56 (4.4%) had FTT. Of these, 42 (75%) presented extrarenal causes of FTT, 3 (5.4%) had chronic kidney disease (CKD), 9 (16.1%) had TFI, and 2 (3.5%) had CKD and TFI. FTT occurred in 8/208 patients (3.8%) with and in 48/1069 patients (4.5%) without (p = 0.68) recurrent urinary tract infections (UTIs). At multiple logistic regression, birthweight <10th percentile, preterm birth, TFI, identified or suspected syndromes and other diseases were predictors of FTT. Eleven (19.6%) patients with FTT had TFI; five with increased FENa and/or acidosis received supplementation and showed catch-up growth. The remaining six patients exhibited spontaneous catch-up growth. CONCLUSION: FTT was found in <5% of children with VUR. It was not determined by recurrent UTIs and was mainly associated with extrarenal causes. Supplementation with sodium and bicarbonates could be useful in selected cases.

Acute kidney injury in children hospitalised for febrile urinary tract infection.

AIM: To determine (i) prevalence and the risk factors for acute kidney injury (AKI) in children hospitalised for febrile urinary tract infection (fUTI) and (ii) role of AKI as indicator of an underlying VUR. AKI, in fact, is favoured by a reduced nephron mass, often associated to VUR. METHODS: This retrospective Italian multicentre study enrolled children aged 18 years or younger (median age = 0.5 years) discharged with a primary diagnosis of fUTI. AKI was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria. RESULTS: Of 849 children hospitalised for fUTI (44.2% females, median age 0.5 years; IQR = 1.8), 124 (14.6%) developed AKI. AKI prevalence rose to 30% in the presence of underlying congenital anomalies of the kidney and urinary tract (CAKUT). The strongest AKI predictors were presence of CAKUT (OR = 7.5; 95%CI: 3.8-15.2; p = 9.4e-09) and neutrophils levels (OR = 1.13; 95%CI: 1.08-1.2; p = 6.8e-07). At multiple logistic regression analysis, AKI during fUTI episode was a significant indicator of VUR (OR = 3.4; 95%CI: 1.7-6.9; p = 0.001) despite correction for the diagnostic covariates usually used to assess the risk of VUR after the first fUTI episode. Moreover, AKI showed the best positive likelihood ratio, positive predictive value, negative predictive value and specificity for VUR. CONCLUSION: AKI occurs in 14.6% of children hospitalised for fUTI and is a significant indicator of VUR.

Diagnostic Accuracy of Ureteric Jet Angle Measurement Using Color Doppler Ultrasonography in Children with Vesico-Ureteric Reflux: A Systematic Review.

This systematic review evaluated accuracy of ureteric jet angles on color Doppler sonography in diagnosing vesico-ureteric reflux (VUR) in children, using voiding cystourethrogram as the reference standard. Six databases were searched, yielding 13 eligible studies of an initial 429, 7 with comparable data. Risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Most studies demonstrated a correlation between increasing jet angle and VUR severity, but reporting and techniques varied, preventing meta-analysis. Ureteric jet angle sonography may have potential as a VUR triaging tool. Further investigations with rigorous methodology are required. Funding support was obtained from Queensland University of Technology. PROSPERO Registration CRD42020159799.

Use of ChatGPT in Urology and its Relevance in Clinical Practice: Is it useful?

PURPOUSE: One of the many artificial intelligence based tools that has gained popularity is the Chat-Generative Pre-Trained Transformer (ChatGPT). Due to its popularity, incorrect information provided by ChatGPT will have an impact on patient misinformation. Furthermore, it may cause misconduct as ChatGPT can mislead physicians on the decision-making pathway. Therefore, the aim of this study is to evaluate the accuracy and reproducibility of ChatGPT answers regarding urological diagnoses. MATERIALS AND METHODS: ChatGPT 3.5 version was used. The questions asked for the program involved Primary Megaureter (pMU), Enuresis and Vesicoureteral Reflux (VUR). There were three queries for each topic. The queries were inserted twice, and both responses were recorded to examine the reproducibility of ChatGPT's answers. Afterwards, both answers were combined. Finally, those rwere evaluated qualitatively by a board of three specialists. A descriptive analysis was performed. RESULTS AND CONCLUSION: ChatGPT simulated general knowledge on the researched topics. Regarding Enuresis, the provided definition was partially correct, as the generic response allowed for misinterpretation. For VUR, the response was considered appropriate. For pMU it was partially correct, lacking essential aspects of its definition such as the diameter of the dilatation of the ureter. Unnecessary exams were suggested, for Enuresis and pMU. Regarding the treatment of the conditions mentioned, it specified treatments for Enuresis that are ineffective, such as bladder training. Therefore, ChatGPT responses present a combination of accurate information, but also incomplete, ambiguous and, occasionally, misleading details.

The accuracy of cystography under general anesthesia in children with vesicoureteral reflux.

PURPOSE: To examine the accuracy of cystography under general anesthesia in children with vesicoureteral reflux (VUR). MATERIALS AND METHODS: A prospective study of children who had VUR on cystography without general anesthesia (i.e., the gold-standard), and who are candidates for endoscopic VUR repair surgery. All children subsequently underwent a cystography under general anesthesia before injection using standardized method, which was compared to the gold-standard cystography. χ2 and Mann-Whitney U tests were used to compare proportions and medians between groups. RESULTS: Between 2017 and 2021, 126 renal units in 13 boys and 50 girls were included. Median age was 3.4 years (interquartile range [IQR] 1.5-6.5). Median time from cystography without to cystography with general anesthesia was 3.8 months (IQR 2.7-6). Of the 126 renal units, 96 had VUR on cystography without general anesthesia. On dichotomous analysis (no VUR vs. any VUR) sensitivity, specificity, negative and positive predictive values of cystography under general anesthesia were 47% (45/96), 87% (26/30), 34% (26/77) and 92% (45/49), respectively. Accuracy was 56.3%; Cohen's Kappa coefficient was 0.22, indicating poor agreement. In subgroup analysis, the sensitivity of cystography under general anesthesia was significantly lower in primary VUR (20% vs. 55% in secondary VUR, p = 0.01) and active VUR (14% vs. 52% in passive VUR, p = 0.008). CONCLUSION: Cystography under general anesthesia was poorly correlated to cystography performed while the child was awake or lightly sedated. Clinical decision relying on this cystography is questionable.

Diagnostic and therapeutic management of vesico-ureteral reflux in pediatric kidney transplantation-Results of an online survey on behalf of the European Society for Paediatric Nephrology.

BACKGROUND: Vesico-ureteral reflux (VUR) is considered to be a risk factor for recurrent febrile urinary tract infections and impaired renal transplant survival. METHODS: An online survey supported by the European Society for Paediatric Nephrology was designed to evaluate current management strategies of VUR in native and transplanted kidneys of recipients aged <18 years. RESULTS: Seventy-three pediatric transplant centers from 32 countries contributed to the survey. All centers performed urological evaluation prior to pediatric kidney transplantation (KTx) with subsequent interdisciplinary discussion. Screening for VUR in native kidneys (30% in all, 70% in selected patients) led to surgical intervention in 78% (11% in all, 89% in selected patients) with a decided preference of endoscopic intervention over ureterocystoneostomy. Following KTx, continuous antibiotic prophylaxis was applied in 65% of the patients and screening for allograft VUR performed in 93% of selected patients. The main management strategies of symptomatic allograft VUR were continuous antibiotic prophylaxis (83%) and surgical treatment (74%) (endoscopic intervention 55%, redo ureterocystoneostomy 26%). CONCLUSIONS: This survey demonstrates the high variability in the management of VUR in pediatric KTx recipients, points to knowledge gaps, and might serve as a starting point for improving the care for patients with VUR in native and transplanted kidneys.

Conflicting views of physicians and surgeons concerning pediatric urinary tract infection: a comparative review.

BACKGROUND: A first febrile urinary tract infection (UTI) is a common condition in children, and pathways of management have evolved over time. OBJECTIVE: To determine the extent to which pediatricians and surgeons differ in their investigation and management of a first febrile UTI, and to evaluate the justifications for any divergence of approach. MATERIALS AND METHODS: A literature search was conducted for papers addressing investigation and/or management following a first febrile UTI in children published between 2011 and 2021. Searches were conducted on Medline, Embase, and the Cochrane Controlled Trials Register. To be eligible for inclusion, a paper was required to provide recommendations on one or more of the following: ultrasound (US) and voiding cystourethrogram (VCUG), the need for continuous antibiotic prophylaxis and surgery when vesicoureteral reflux (VUR) was detected. The authorship required at least one pediatrician or surgeon. Authorship was categorized as medical, surgical, or combined. RESULTS: Pediatricians advocated less imaging and intervention and were more inclined to adopt a "watchful-waiting" approach, confident that any significant abnormality, grades IV-V VUR in particular, should be detected following a second febrile UTI. In contrast, surgeons were more likely to recommend imaging to detect VUR (p<0.00001), and antibiotic prophylaxis (p<0.001) and/or surgical correction (p=0.004) if it was detected, concerned that any delay in diagnosis and treatment could place the child at risk of kidney damage. Papers with combined authorship displayed intermediate results. CONCLUSION: There are two distinct directions in the literature regarding the investigation of an uncomplicated first febrile UTI in a child. In general, when presented with a first febrile UTI in a child, physicians recommend fewer investigations and less treatment, in contrast to surgeons who advocate extensive investigation and aggressive intervention in the event that imaging detects an abnormality. This has the potential to confuse the carers of affected children.

Dynamic and static ultrasound features predictive of vesicoureteral reflux and renal damage in children and adolescents with neurogenic bladder.

PURPOSE: This study aimed to analyze the diagnostic accuracy of dynamic and static ultrasound (DSUS) in detecting vesicoureteral reflux (VUR) and renal scarring in a cohort of children with neurogenic bladder (NB). MATERIALS AND METHODS: A retrospective, longitudinal, observational study was conducted using the Reporting Diagnostic Accuracy Studies guideline. The DSUS (index test) data were compared with voiding cystourethrography (VCUG) and renal scintigraphy 99mTc-dimercaptosuccinic (reference tests). Overall performance for predicting VUR and renal scarring was assessed using renal pelvic diameter (RPD)/distal ureteral diameter and renal parenchymal thinning on DSUS, respectively. RESULTS: A total of 107 patients (66 girls, median age 9.6 years) participated. Seventeen patients (15.9%) presented VUR, eight bilateral. For overall reflux grade, the AUC was 0.624 for RPD and 0.630 for distal ureteral diameter. The diagnostic performance for detecting high-grade VUR was slightly better for DSUS parameters. The AUC was 0.666 for RPD and 0.691 for distal ureteral diameter. The cut-offs of 5 mm for RPD and 6.5 mm for distal ureteral diameter presented the best diagnostic odds ratio (DOR) to identify high-grade VUR. The increase of RPD during detrusor contractions showed an accuracy of 89.2%. The thinness of renal parenchyma presented an accuracy of 88% for renal scarring. CONCLUSION: DSUS predicts VUR and renal scarring in children with NB with fair to good accuracy, and all measurements exhibited a high negative predictive value (NPV). The increase in RPD during voiding or detrusor contractions proved to be the most accurate parameter for indicating the presence of VUR in this study.

Multi-institutional Validation of Improved Vesicoureteral Reflux Assessment With Simple and Machine Learning Approaches.

PURPOSE: Vesicoureteral reflux grading from voiding cystourethrograms is highly subjective with low reliability. We aimed to demonstrate improved reliability for vesicoureteral reflux grading with simple and machine learning approaches using ureteral tortuosity and dilatation on voiding cystourethrograms. MATERIALS AND METHODS: Voiding cystourethrograms were collected from our institution for training and 5 external data sets for validation. Each voiding cystourethrogram was graded by 5-7 raters to determine a consensus vesicoureteral reflux grade label and inter- and intra-rater reliability was assessed. Each voiding cystourethrogram was assessed for 4 features: ureteral tortuosity, proximal, distal, and maximum ureteral dilatation. The labels were then assigned to the combination of the 4 features. A machine learning-based model, qVUR, was trained to predict vesicoureteral reflux grade from these features and model performance was assessed by AUROC (area under the receiver-operator-characteristic). RESULTS: A total of 1,492 kidneys and ureters were collected from voiding cystourethrograms resulting in a total of 8,230 independent gradings. The internal inter-rater reliability for vesicoureteral reflux grading was 0.44 with a median percent agreement of 0.71 and low intra-rater reliability. Higher values for each feature were associated with higher vesicoureteral reflux grade. qVUR performed with an accuracy of 0.62 (AUROC=0.84) with stable performance across all external data sets. The model improved vesicoureteral reflux grade reliability by 3.6-fold compared to traditional grading (P < .001). CONCLUSIONS: In a large pediatric population from multiple institutions, we show that machine learning-based assessment for vesicoureteral reflux improves reliability compared to current grading methods. qVUR is generalizable and robust with similar accuracy to clinicians but the added prognostic value of quantitative measures warrants further study.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10-8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10-9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

Changes in Clinical Presentation and Renal Outcomes among Children with Febrile Urinary Tract Infection: 2005 vs 2015.

PURPOSE: Recent studies have demonstrated trends of decreasing voiding cystourethrogram utilization rates and delayed vesicoureteral reflux diagnosis in some children. It is possible that such delays could lead to more children sustaining repeated episodes of febrile urinary tract infection, and potential kidney injury, prior to diagnosis and treatment. MATERIALS AND METHODS: Using single institutional, cross-sectional cohorts of patients in 2 time periods (2005 and 2015), we compared clinical presentation and renal outcomes among patients 13 years and younger with history of febrile urinary tract infection presenting for initial voiding cystourethrogram. Outcomes included 1) recurrent urinary tract infection, 2) presence of vesicoureteral reflux, 3) grade of vesicoureteral reflux, and 4) renal scarring. Associations between year of presentation and outcomes of recurrent urinary tract infection and vesicoureteral reflux diagnosis were evaluated using multivariable logistic regression models. For the outcome of renal scarring, a logistic regression model was fitted for propensity score matched cohorts. RESULTS: Compared to children presenting in 2005, those in 2015 had 3 times the odds of recurrent urinary tract infection (OR 3.01, 95% CI 2.18-4.16, p <0.0001). Time period was not associated with the odds of vesicoureteral reflux (OR 0.98, 95% CI 0.77-1.23, p=0.85). Those in 2015 were more likely to present with vesicoureteral reflux grade >3 (OR 2.22, 95% CI 1.13-4.34, p=0.02) but not vesicoureteral reflux grade >2 (OR 1.11, 95% CI 0.74-1.67, p=0.60). Renal scarring was more common among children presenting in 2015 (OR 2.9, 95% CI 1.03-8.20, p=0.04). CONCLUSIONS: Compared to 2005, children presenting in 2015 for post-urinary tract infection voiding cystourethrogram have increased likelihood of recurrent urinary tract infection and renal scarring, despite similar likelihood of vesicoureteral reflux diagnosis.

Antireflux Surgery at National Surgical Quality Improvement Program-Pediatric Hospitals.

PURPOSE: This study aims to examine contemporary practice patterns and compare short-term outcomes for vesicoureteral reflux procedures (ureteral reimplant/endoscopic injection) using National Surgical Quality Improvement Program-Pediatric data. MATERIALS AND METHODS: Procedure-specific variables for antireflux surgery were developed to capture data not typically collected in National Surgical Quality Improvement Program-Pediatric (eg vesicoureteral reflux grade, urine cultures, 31-60-day followup). Descriptive statistics were performed, and logistic regression assessed associations between patient/procedural factors and outcomes (urinary tract infection, readmissions, unplanned procedures). RESULTS: In total, 2,842 patients (median age 4 years; 76% female; 68% open reimplant, 6% minimally invasive reimplant, 25% endoscopic injection) had procedure-specific variables collected from July 2016 through June 2018. Among 88 hospitals, a median of 24.5 procedures/study period were performed (range 1-148); 95% performed ≥1 open reimplant, 30% ≥1 minimally invasive reimplant, and 70% ≥1 endoscopic injection, with variability by hospital. Two-thirds of patients had urine cultures sent preoperatively, and 76% were discharged on antibiotics. Outcomes at 30 days included emergency department visits (10%), readmissions (4%), urinary tract infections (3%), and unplanned procedures (2%). Over half of patients (55%) had optional 31-60-day followup, with additional outcomes (particularly urinary tract infections) noted. Patients undergoing reimplant were younger, had higher reflux grades, and more postoperative occurrences than patients undergoing endoscopic injections. CONCLUSIONS: Contemporary data indicate that open reimplant is still the most common antireflux procedure, but procedure distribution varies by hospital. Emergency department visits are common, but unplanned procedures are rare, particularly for endoscopic injection. These data provide basis for comparing short-term complications and developing standardized perioperative pathways for antireflux surgery.

Selecting Children with Vesicoureteral Reflux Who are Most Likely to Benefit from Antibiotic Prophylaxis: Application of Machine Learning to RIVUR.

PURPOSE: Continuous antibiotic prophylaxis reduces the risk of recurrent urinary tract infection by 50% in children with vesicoureteral reflux. However, there may be subgroups in whom continuous antibiotic prophylaxis could be used more selectively. We sought to develop a machine learning model to identify such subgroups. MATERIALS AND METHODS: We used RIVUR data, randomly split into train/test in a 4:1 ratio. Two models were developed to predict recurrent urinary tract infection risk in scenario with and without continuous antibiotic prophylaxis. The test set was then used to validate recurrent urinary tract infection events and the effectiveness of continuous antibiotic prophylaxis. Predicted probabilities of recurrent urinary tract infection were generated from each model. Continuous antibiotic prophylaxis was assigned at various cutoffs of recurrent urinary tract infection risk reduction to evaluate continuous antibiotic prophylaxis effectiveness. RESULTS: A total of 607 patients (558 female/49 male, median age 12 months) were included. Predictors included vesicoureteral reflux grade, serum creatinine, race/gender, prior urinary tract infection symptoms (fever/dysuria) and weight percentiles. The AUC of the prediction model of recurrent urinary tract infection (continuous antibiotic prophylaxis/placebo) was 0.82 (95% CI 0.74-0.87). Using 10% recurrent urinary tract infection risk reduction cutoff, minimal recurrent urinary tract infection per population level can be achieved by giving continuous antibiotic prophylaxis to 40% of patients with vesicoureteral reflux instead of everyone. In a test set (121), 51 patients had continuous antibiotic prophylaxis randomization consistent with model recommendation (continuous antibiotic prophylaxis if recurrent urinary tract infection risk reduction >10%). Recurrent urinary tract infection incidence was significantly lower among this group compared to those whose continuous antibiotic prophylaxis assignment differed from model suggestion (7.5% vs 19.4%, p=0.037). CONCLUSIONS: Our predictive model identifies patients with vesicoureteral reflux who are more likely to benefit from continuous antibiotic prophylaxis, which would allow more selective, personalized use of continuous antibiotic prophylaxis with maximal benefit, while minimizing use in those with least need.

Top-Down versus Bottom-Up Approach in Children Presenting with Urinary Tract Infection: Comparative Effectiveness Analysis Using RIVUR and CUTIE Data.

PURPOSE: The initial imaging approach to children with urinary tract infection (UTI) is controversial. Along with renal/bladder ultrasound, some advocate voiding cystourethrogram (VCUG), ie a bottom-up approach, while others advocate dimercaptosuccinic acid (DMSA) scan, ie a top-down approach. Comparison of these approaches is challenging. In the RIVUR/CUTIE trials, however, all subjects underwent both VCUG and DMSA scan. Our objective was to perform a comparative effectiveness analysis of the bottom-up vs top-down approach. MATERIALS AND METHODS: We simulated 1,000 hypothetical sets of 500 children using RIVUR/CUTIE data. In the top-down approach, patients underwent initial DMSA scan, and only those with renal scarring underwent VCUG. In the bottom-up approach, the initial study was VCUG. We assumed all children with vesicoureteral reflux (VUR) received continuous antibiotic prophylaxis (CAP). Outcomes included recurrent UTI, number of VCUGs and CAP exposure. We assumed a 25% VUR prevalence in children with initial UTI with sensitivity analysis using 40% VUR prevalence. RESULTS: Median age of the original RIVUR/CUTIE cohort was 12 months. First DMSA scan was performed at a median of 8.2 weeks (IQR 5-11.8) after the index UTI. In the simulated cohort, slightly higher yet statistically significantly recurrent UTI was associated with the top-down compared with the bottom-up approach (24.4% vs 18.0%, p=0.045). On the other hand, the bottom-up approach resulted in more VCUG (100% vs 2.4%, p <0.001). Top-down resulted in fewer CAP-exposed patients (25% vs 0.4%, p <0.001) and lower overall CAP exposure (5 vs 162 days/person, p <0.001). Sensitivity analysis was performed with 40% VUR prevalence with similar results. CONCLUSIONS: The top-down approach was associated with slightly higher recurrent UTI. Compared to the bottom-up approach, it significantly reduced the need for VCUG and CAP.

Vesicoureteral reflux is it important to find?

Vesico-ureteral reflux (VUR) has long been recognized as associated with urinary tract infections (UTIs), renal scarring, and chronic kidney disease (CKD). The concept of "reflux nephropathy" was born, whereby the VUR was considered the culprit, predisposing to recurrent UTIs and providing a conduit whereby the infection could ascend to the kidneys resulting in scarring and destruction. The more severe grades of reflux were thought to place the young child at particular risk of CKD. The question being asked in this pro/con debate is whether VUR is indeed the culprit responsible for a significant proportion of children with CKD, a number of whom progress to end-stage kidney failure (ESKF), and is thus important to find and treat, or is it an innocent bystander associated with CKD and ESKF but not the cause. We believe the latter and will present convincing evidence supported by large scale prospective randomized controlled trials that VUR is not the ogre it was thought to be and is not important to find following a UTI (with some exceptions).

How I do it open distal ureteroureterostomy for ectopic ureters in infants with duplex systems and no vesicoureteral reflux under 6 months of age.

We describe a step by step technique for open distal ureteroureterostomy (UU) in infants less than 6 months presenting with duplex collecting system and upper pole ectopic ureter in the absence of vesicoureteral reflux (VUR).

Predicting Breakthrough Urinary Tract Infection: Comparative Analysis of Vesicoureteral Reflux Index, Reflux Grade and Ureteral Diameter Ratio.

PURPOSE: The vesicoureteral reflux index is a simple, validated tool for predicting resolution of reflux. Along with likelihood of spontaneous resolution identification of children at risk for febrile urinary tract infection impacts management. We evaluated the usefulness of the vesicoureteral reflux index as a predictive factor for breakthrough febrile urinary tract infection compared to reflux grade and distal ureteral diameter ratio. MATERIALS AND METHODS: Children with primary vesicoureteral reflux and detailed voiding cystourethrogram data were identified. A 1 to 6-point index was assigned, and ureteral diameter ratio was computed by measuring largest ureteral diameter within the pelvis and dividing by the distance between L1 to L3 vertebral bodies. Random forest modeling and logistic multivariable regression were employed to estimate the predictive ability of grade, ureteral diameter ratio and vesicoureteral reflux index with regard to breakthrough febrile urinary tract infection. RESULTS: We analyzed 94 girls and 45 boys with a mean±SD age of 5.4±4.7 months at diagnosis. Mean±SD length of followup was 32.1±24.5 months. A total of 13 children (9.4%) experienced breakthrough febrile urinary tract infection. On univariate analysis ureteral diameter ratio (p=0.01) and vesicoureteral reflux index (p=0.0005) were associated with breakthrough urinary tract infection, while grade (p=0.09) did not reach significance. Area under the curve was generated as a measure of accuracy for each variable and was 0.77 for the vesicoureteral reflux index, 0.71 for ureteral diameter ratio and 0.68 for grade, indicating superiority of the vesicoureteral reflux index for predicting breakthrough febrile urinary tract infection. CONCLUSIONS: Children with higher vesicoureteral reflux index are at increased risk for breakthrough febrile urinary tract infection independent of reflux grade. The vesicoureteral reflux index provides valuable prognostic information about infection risk, facilitating improved clinical decision making.

Effect of Early Oxybutynin Treatment on Posterior Urethral Valve Outcomes in Infants: A Randomized Controlled Trial.

PURPOSE: We studied the effect of oxybutynin on bladder and upper urinary tract outcomes in infants following posterior urethral valve ablation. MATERIALS AND METHODS: Patients younger than 12 months old who had undergone primary endoscopic valve ablation for posterior urethral valves were screened for eligibility. Patients who had undergone urinary diversion or had other conditions that could affect lower urinary tract function were excluded. Study patients were randomized to either oxybutynin (0.2 mg/kg 3 times daily) until toilet training or active observation. The study end points were serum creatinine, estimated glomerular filtration rate, hydronephrosis improvement, vesicoureteral reflux resolution, febrile urinary tract infection and toilet training. RESULTS: A total of 49 infants (24 receiving oxybutynin and 25 undergoing observation) were enrolled between December 2013 and September 2015 and completed at least 1 year of followup. Oxybutynin was discontinued before toilet training in 5 patients due to facial flushing in 2, bladder and upper tract dilatation in 2, and cognitive changes in 1. After a median followup of 44.2 months (range 12 to 57.6) median serum creatinine and estimated glomerular filtration rate were not significantly different between the groups (p=0.823 and p=0.722, respectively). Renal units in the oxybutynin group had a greater likelihood of hydronephrosis improvement (61.9% vs 34.8%, p=0.011) and resolution of vesicoureteral reflux (62.5% vs 25%, p=0.023). Febrile urinary tract infection (29.2% vs 40%, p=0.404), completion of toilet training (70.8% vs 76%, p=0.748) and age at toilet training (p=0.247) did not differ significantly between the oxybutynin and observation groups. CONCLUSIONS: Oxybutynin enhances hydronephrosis improvement and vesicoureteral reflux resolution following primary endoscopic valve ablation in infants but periodic monitoring is warranted.

Impact of Long-Term Low Dose Antibiotic Prophylaxis on Gut Microbiota in Children.

PURPOSE: We evaluated the effect of long-term low dose antibiotic prophylaxis on children's gut microbiota. MATERIALS AND METHODS: We conducted 16S ribosomal RNA gene sequencing using stool samples from 35 patients younger than 3 years old (median age 5.2 months; male-to-female ratio 17:18) who underwent antibiotic treatment during the acute phase of febrile urinary tract infection. Samples were collected at 5 time points, ie before, during and at 1 to 2, 3 to 4, and 5 to 6 months after febrile urinary tract infection onset and antibiotic treatment. Continuous antibiotic prophylaxis using trimethoprim-sulfamethoxazole was initiated in 23 patients with grade III or higher vesicoureteral reflux and was not administered in 12 patients without reflux. RESULTS: Within 2 weeks after initiation of treatment for febrile urinary tract infection almost all enteric bacteria belonged to the order Lactobacillales, and gut microbiota diversity decreased compared to the pretreatment level (average Shannon index 2.9 before treatment, 1.4 during treatment). The diversity recovered within 1 to 2 months after febrile urinary tract infection onset in both groups. Diversity was maintained during the study period in both groups (p=0.43). A smaller proportion of gut microbiota component belonged to the order Enterobacteriales (p=0.002) in the antibiotic prophylaxis group. CONCLUSIONS: Our results revealed that patients receiving continuous antibiotic prophylaxis had normal gut microbiota diversity, indicating that the effect of trimethoprim-sulfamethoxazole on gut microbiota was insignificant. Furthermore, prophylaxis with trimethoprim-sulfamethoxazole might selectively suppress the growth of bacteria belonging to the order Enterobacteriales, such as Escherichia coli and Klebsiella species, which are the main causative bacteria of febrile urinary tract infections.

Sprouty1 Controls Genitourinary Development via its N-Terminal Tyrosine.

BACKGROUND: Studies in mice suggest that perturbations of the GDNF-Ret signaling pathway are a major genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT). Mutations in Sprouty1, an intracellular Ret inhibitor, results in supernumerary kidneys, megaureters, and hydronephrosis in mice. But the underlying molecular mechanisms involved and which structural domains are essential for Sprouty1 function are a matter of controversy, partly because studies have so far relied on ectopic overexpression of the gene in cell lines. A conserved N-terminal tyrosine has been frequently, but not always, identified as critical for the function of Sprouty1 in vitro. METHODS: We generated Sprouty1 knockin mice bearing a tyrosine-to-alanine substitution in position 53, corresponding to the conserved N-terminal tyrosine of Sprouty1. We characterized the development of the genitourinary systems in these mice via different methods, including the use of reporter mice expressing EGFP from the Ret locus, and whole-mount cytokeratin staining. RESULTS: Mice lacking this tyrosine grow ectopic ureteric buds that will ultimately form supernumerary kidneys, a phenotype indistinguishable to that of Sprouty1 knockout mice. Sprouty1 knockin mice also present megaureters and vesicoureteral reflux, caused by failure of ureters to separate from Wolffian ducts and migrate to their definitive position. CONCLUSIONS: Tyrosine 53 is absolutely necessary for Sprouty1 function during genitourinary development in mice.