The RiVUR Study Outcomes and Implications on the Management of Vesicoureteral Reflux.

The Randomized intervention for Vesicoureteral Reflux (RiVUR) study was an effort by the National Institute of Health to identify the most significant question on the management of vesicoureteral reflux (VUR), i.e. Did antibiotic prophylaxis reduce the incidence of recurrent urinary tract infections (UTI) in children with VUR? During the initial phases of the RiVUR study, several similar studies were performed that seemed to indicate a lack of benefit of antibiotic prophylaxis in VUR. However, few of these studies had the rigorous methodology and true randomization of the pediatric cohort that was studied in RiVUR. Additionally, many of these studies included children of wide age ranges and inconsistent assessments were used for identification of UTI and VUR. In 2011, the American Academy of Pediatrics (AAP) published a guideline statement for the evaluation of initial UTI in febrile children aged 2 to 24 months, which recommended against performing a Voiding Cystourethrogram (VCUG) in all children with a confirmed UTI. The goal of the AAP guidelines was to reduce the number of VCUGs being performed and potentially to reduce the number of children diagnosed with low grade VUR that seems to have low potential to cause renal injury. The RiVUR study included over 600 children identified with VUR after a 1st or 2nd febrile UTI randomized to prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMZ), or placebo and followed over a study timeline for 2 years. Overall, a 50% reduction was noted in the incidence of recurrent febrile UTI with the utilization of prophylaxis as compared to placebo. Additional sub-group analyses have been performed on the cohorts of the study; these are also evaluated in this review to determine the overall impact of the RiVUR study on the current management of VUR.

Complete primary repair of bladder exstrophy: a systematic review.

OBJECTIVES: Complete primary repair of exstrophy (CPRE) was established as a method to reduce numbers of procedures for the reconstruction of bladder exstrophy (BE). Performed since 1989, some suggest it as a replacement for the staged reconstructive procedure, the gold standard. Does CPRE reduce the numbers of procedures for reconstruction of BE? METHODS: Literature was reviewed from 1989 to 2016, and articles evaluating outcomes of patients undergoing CPRE, extracted. Effort was made to obtain final data from each reporting institution/group. Eleven articles meeting criteria were evaluated for qualitative systematic review. Age at initial closure, complications, additional procedures, and outcomes were evaluated to provide an overview of CPRE. RESULTS: Ten groups reported BE management using the CPRE technique. 236 patients (153 boys; 72 girls; 11 unknown sex) had primary closure ranging from birth to 5.6 years. Osteotomy was favored by most in infants closed beyond the first 72 h of life along with spica cast immobilization. Three groups recommended concomitant augmentation for infants with small bladder capacities. Ureteral reimplantation was required in 58 patients with recurrent urinary tract infections resistant to prophylaxis. Hypospadias repair was required for most boys having complete penile disassembly, and most children eventually required bladder neck reconstruction (BNR) for continence. Overall, voiding without BNR was noted in 16-37% of children in the reported series. CONCLUSIONS: Complete primary repair of exstrophy has been suggested as a single procedure for the management of BE. Literature review suggests most patients require multiple procedures to complete reconstruction and attain continence.

Laboratory Findings After Urinary Tract Infection and Antimicrobial Prophylaxis in Children With Vesicoureteral Reflux.

It is a common practice to monitor blood tests in patients receiving long-term trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis for recurrent urinary tract infections. This multicenter, randomized, placebo-controlled trial enrolled 607 children aged 2 to 71 months with vesicoureteral reflux diagnosed after symptomatic urinary tract infection. Study participants received TMP-SMZ (n = 302) or placebo (n = 305) and were followed for 2 years. Serum electrolytes (n ≥ 370), creatinine (n = 310), and complete blood counts (n ≥ 206) were measured at study entry and at the 24-month study conclusion. We found no significant electrolyte, renal, or hematologic abnormalities when comparing the treatment and placebo groups. We observed changes in several laboratory parameters in both treatment and placebo groups as would normally be expected with physiologic maturation. Changes were within the normal range for age. Long-term use of TMP-SMX had no treatment effect on complete blood count, serum electrolytes, or creatinine. Our findings do not support routine monitoring of these laboratory tests in children receiving long-term TMP-SMZ prophylaxis.

Cost-Utility of Antimicrobial Prophylaxis for Treatment of Children With Vesicoureteral Reflux.

Objective: Antimicrobial prophylaxis for children with vesicoureteral reflux (VUR) reduces recurrences of urinary tract infection (UTI) but requires daily antimicrobials for extended periods. We used a cost-utility model to evaluate whether the benefits of antimicrobial prophylaxis outweigh its risks and, if so, to investigate whether the benefits and risks vary according to grade of VUR. Methods: We compared the cost per quality-adjusted life-year (QALY) gained in four treatment strategies in children aged <6 years diagnosed with VUR after a first UTI, considering these treatment strategies: (1) prophylaxis for all children with VUR, (2) prophylaxis for children with Grade III or Grade IV VUR, (3) prophylaxis for children with Grade IV VUR, and (4) no prophylaxis. Costs and effectiveness were estimated over the patient's lifetime. We used $100,000/QALY gained as the threshold for considering a treatment strategy cost effective. Results: Based on current data and plausible ranges to account for data uncertainty, prophylaxis of children with Grades IV VUR costs $37,903 per QALY gained. Treating children with Grade III and IV VUR costs an additional $302,024 per QALY gained. Treating children with all grades of VUR costs an additional $339,740 per QALY gained. Conclusions: Treating children with Grades I, II, and III VUR with long-term antimicrobial prophylaxis costs substantially more than interventions typically considered economically reasonable. Prophylaxis in children with Grade IV VUR is cost effective.

External Genital Development, Urethra Formation, and Hypospadias Induction in Guinea Pig: A Double Zipper Model for Human Urethral Development.

OBJECTIVE: To determine whether the guinea pig phallus would be an appropriate model of human penile development, we characterized the embryology and sexual differentiation of guinea pig external genitalia and attended to induce hypospadias in males and tubular urethra formation in females pharmacologically. MATERIALS AND METHODS: The external genitalia of guinea pig were collected from genital swelling initiation to newborn stages, and scanning electronic microscopy and histology were performed to visualize the morphology and structure. Immunohistochemistry was used to determine the androgen receptor localization. Bicalutamide and methyltestosterone were given to pregnant dams to reveal the role and timing of androgen in guinea pig penile masculinization. RESULTS: Canalization and dorsal-to-ventral movement of the urethral canal develops the urethral groove in both sexes, and then the males perform distal-opening-proximal-closing to form tubular urethra. More nuclear-localized androgen receptor is found in proximal genital tubercles of males than in females at (E) 29. Antiandrogen treatment at E26-E30 can cause hypospadias, and methyltestosterone administration at E27-E31 can induce tubular urethra formation in females. CONCLUSION: Fetal development of the guinea pig phallus is homologous to that of humans. Although guinea pig has structures similar to mouse, the urethral groove and the tubular urethra formation are more similar to humans. Antiandrogen treatment causes hypospadias in males and additional androgen induces tubular urethra formation in females. Thus, guinea pig is an appropriate model for further study of cellular and molecular mechanisms involved in distal-opening-proximal-closing in tubular urethra formation and the evaluation of the pathophysiological processes of hypospadias.

Interobserver variability for interpretation of DMSA scans in the RIVUR trial.

INTRODUCTION: Technetium-99m dimercaptosuccinic acid (DMSA) renal scans are used in the diagnosis of renal scarring. In the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial that randomized 607 children, DMSA renal scans were used for evaluating the presence and the severity of renal scarring. OBJECTIVE: The aim was to determine interobserver variability in reporting of DMSA renal scans in the RIVUR trial. STUDY DESIGN: We compared DMSA renal scan reports for renal scarring and acute pyelonephritis from all non-reference local radiologists (ALRs) at study sites with adjudicated as well as non-adjudicated reports from two reference radiologists (RRs) of the RIVUR trial. Two-way comparisons of concordant and discrepant responses were analyzed using an unweighted kappa statistic between the ALR and the adjudicated RR interpretations. All analyses were performed using SAS v 9.4 (SAS institute 2015) and significance was determined at the 0.05 level. RESULTS: Of the 2872 kidneys evaluated, adjudicated RR reports had 119 (4%) kidneys with renal scarring compared with 212 (7%) by the ALRs. For 79% kidneys the grading for scarring reported by ALRs was either upgraded (24%) or downgraded (55%) by RRs. For acute pyelonephritis (n = 2924), adjudicated RR reports had 85 (3%) kidneys with pyelonephritis compared with 151 (5%) by the ALRs. For 85% kidneys, the grading for pyelonephritis reported by the ALRs was either upgraded (28%) or downgraded (57%) by the RRs. A three-way comparison revealed that all three (RR1, RR2, and ALR) agreed over presence of renal scarring in 19% cases and two of the three agreed in 80% cases. The respective numbers for pyelonephritis were 13% and 84%. The agreement rate for all DMSA scan reports between the RRs and the ALRs was 93%. DISCUSSION: The study revealed significant interobserver variability in the reporting of abnormal DMSA renal scans compared with the previously published studies. A noteworthy limitation was a lack of uniformity in local reporting of the scans. CONCLUSIONS: Our study highlights the need for optimizing the clinical yield of DMSA renal scans by more specific guidelines, particularly for standardized and uniform interpretation.

Variation in the level of detail in pediatric voiding cystourethrogram reports.

INTRODUCTION: Voiding cystourethrogram (VCUG) provides a wealth of data on urinary tract function and anatomy, but few standards exist for reporting VCUG findings. OBJECTIVE: We aimed to assess variability in VCUG reports and to test our hypothesis that VCUG reports from pediatric facilities and pediatric radiologists are more complete than those performed at other facilities or by non-pediatric radiologists. STUDY DESIGN: We analyzed original VCUG reports from children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial. A 23-item checklist was created and used to evaluate reporting of technical (e.g. catheter size), anatomic (e.g. vesicoureteral reflux (VUR) presence and grade, bladder shape), and functional information (e.g. bladder emptying). Radiologists were classified as pediatric or non-pediatric radiologists. Facilities were categorized as to whether they were a free-standing pediatric hospital (FSPH), a pediatric "hospital within a hospital" (PHWH), a non-pediatric hospital (NPH), or an outpatient radiology facility (ORF). Multivariate linear regression was used to analyze factors associated with the completeness of the VCUG reports (percent of items reported from the 23-item checklist). RESULTS: Six-hundred and two VCUGs were performed at 90 institutions. Of those, 76% were read by a pediatric radiologist, and 49% were performed at a FSPH (Table). On average, less than half of the 23 items in our standardized assessment tool were included in VCUG reports (mean 48%, SD 12). The completeness of reports varied by facility type: 51% complete at FSPH (SD 11), 50% at PHWH (SD 10), 36% at NPH (SD 11), and 43% at ORF (SD 8) (p < 0.0001). In multivariate analysis, VCUG reports generated at NPH or ORF had 8% fewer items included (95% CI 3.0-12.8, p < 0.01), and those generated at PHWH did not differ from those generated at FSPH. Reports read by a non-pediatric radiologist had 6% fewer items included (95% CI 3-9.7; p < 0.01) compared with those read by a pediatric radiologist. DISCUSSION: There is substantial underreporting of findings in VCUG reports when assessing a widely represented sample of routine, community-generated reports using an idealized standard. Although VUR was often reported, other crucial anatomic and functional findings of the VCUG were consistently underreported across all facility types. CONCLUSION: Although pediatric radiologist and pediatric hospitals generated more complete VCUG reports compared with those having non-pediatric origins, the differences are small when considering the substantial underreporting of VCUG findings in general. This underscores the opportunities for improvement in reporting of VCUG findings.

Reliability of grading of vesicoureteral reflux and other findings on voiding cystourethrography.

INTRODUCTION: Voiding cystourethrography (VCUG) is the modality of choice to diagnose vesicoureteral reflux (VUR). Although grading of VUR is essential for prognosis and clinical decision-making, the inter-observer reliability for grading has been shown to vary substantially. The Randomized Intervention for Children with VesicoUreteral Reflux (RIVUR) trial provides a large cohort of children with VUR to better understand the reliability of VCUG findings. OBJECTIVE: To determine the inter-observer consistency of the grade of VUR and other VCUG findings in a large cohort of children with VUR. STUDY DESIGN: The RIVUR trial is a randomized controlled trial of antimicrobial prophylaxis in children with VUR diagnosed after UTI. Each enrollment VCUG was read by a local clinical (i.e. non-reference) radiologist, and independently by two blinded RIVUR reference radiologists. Reference radiologists' disagreements were adjudicated for trial purposes. The grade of VUR and other VCUG findings were extracted from the local clinical radiologist's report. The unit of analysis included individual ureters and individual participants. We compared the three interpretations for grading of VUR and other VCUG findings to determine the inter-observer reliability. RESULTS: Six-hundred and two non-reference radiology reports from 90 institutions were reviewed and yielded the grade of VUR for 560 left and 524 right ureters. All three radiologists agreed on VUR grade in only 59% of ureters; two of three agreed on 39% of ureters; and all three disagreed on 2% of ureters (Table). Agreement was better (≥92%) for other VCUG findings (e.g. bladder shape "normal"). The non-reference radiologists' grade of VUR differed from the reference radiologists' adjudicated grade by exactly one grade level in 19% of ureters, and by two or more grade levels in 2.2% of ureters. When the participant was the unit of analysis, all three radiologists agreed on the grade of VUR in both ureters in just 43% of cases. DISCUSSION: Our study shows considerable and clinically relevant variability in grading VUR by VCUG. This variability was consistent when comparing non-reference to the adjudicated reference radiologists' assessment and the reference radiologists to each other. This study was limited to children with a history of UTI and grade I-IV VUR and may not be generalizable to all children who have a VCUG. CONCLUSION: The considerable inter-observer variability in VUR grading has both research and clinical implications, as study design, risk stratification, and clinical decision-making rely heavily on grades of VUR.

Antimicrobial Resistance and Urinary Tract Infection Recurrence.

BACKGROUND: The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that recurrent urinary tract infections (rUTI) with resistant organisms were more common in the trimethoprim-sulfamethoxazole prophylaxis (TSP) arm. We describe factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) resistance of rUTIs in RIVUR. METHODS: Children aged 2 to 71 months with first or second UTI (index UTI) and grade I to IV vesicoureteral reflux (VUR) were randomized to TSP or placebo and followed for 2 years. Factors associated with TMP-SMX-resistant rUTI were evaluated. RESULTS: Among 571 included children, 48% were <12 months old, 43% had grade II VUR, and 38% had grade III VUR. Recurrent UTI occurred in 34 of 278 children receiving TSP versus 67 of 293 children receiving placebo. Among those with rUTI, 76% (26/34) of subjects receiving TSP had TMP-SMX-resistant organisms versus 28% (19/67) of subjects receiving placebo (P < .001). The proportion of TMP-SMX-resistant rUTI decreased over time: in the TSP arm, 96% were resistant during the initial 6 months versus 38% resistant during the final 6 months; corresponding proportions for the placebo arm were 32% and 11%. Among children receiving TSP, 7 (13%) of 55 with TMP-SMX-resistant index UTI had rUTI, whereas 27 (12%) of 223 with TMP-SMX-susceptible index UTI had rUTI (adjusted hazard ratio 1.38, 95% confidence interval 0.54-3.56). Corresponding proportions in placebo arm were 17 (26%) of 65 and 50 (22%) of 228 (adjusted hazard ratio 1.33, 95% confidence interval 0.74-2.38). CONCLUSIONS: Although TMP-SMX resistance is more common among children treated with TSP versus placebo, resistance decreased over time. Among children treated with TSP, there was no significant difference in UTI recurrence between those with TMP-SMX-resistant index UTI versus TMP-SMX-susceptible UTI.

Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial.

BACKGROUND AND OBJECTIVES: The main objectives of the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial were to evaluate the role of antimicrobial prophylaxis in the prevention of recurrent urinary tract infection (UTI) and renal scarring in children with vesicoureteral reflux (VUR). We present a comprehensive evaluation of renal scarring outcomes in RIVUR trial participants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This multicenter, randomized, placebo-controlled trial enrolled 607 children aged 2-71 months with grade 1-4 VUR diagnosed after a first or second febrile or symptomatic UTI. Study participants received trimethoprim-sulfamethoxazole or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up (99m)technetium dimercaptosuccinic acid (DMSA) renal scans that were reviewed independently by two blinded reference radiologists. RESULTS: At the end of the study, 58 (10%) of 599 children and 63 (5%) of 1197 renal units had renal scarring. New renal scarring did not differ between the prophylaxis and placebo groups (6% versus 7%, respectively). Children with renal scarring were significantly older (median age, 26 versus 11 months; P=0.01), had a second UTI before enrollment (odds ratio [OR], 2.85; 95% confidence interval [95% CI], 1.38 to 5.92), were more likely to be Hispanic (OR, 2.22; 95% CI, 1.13 to 4.34), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). The proportion of new scars in renal units with grade 4 VUR was significantly higher than in units with no VUR (OR, 24.2; 95% CI, 6.4 to 91.2). CONCLUSIONS: Significantly more renal scarring was seen in relatively older children and in those with a second episode of febrile or symptomatic UTI before randomization. Preexisting and new renal scars occurred significantly more in renal units with grade 4 VUR than in those with low-grade or no VUR. Antimicrobial prophylaxis did not decrease the risk of renal scarring.

Recurrent Urinary Tract Infections in Children With Bladder and Bowel Dysfunction.

BACKGROUND: Little generalizable information is available on the outcomes of children diagnosed with bladder and bowel dysfunction (BBD) after a urinary tract infection (UTI). Our objectives were to describe the clinical characteristics of children with BBD and to examine the effects of BBD on patient outcomes in children with and without vesicoureteral reflux (VUR). METHODS: We combined data from 2 longitudinal studies (Randomized Intervention for Children With Vesicoureteral Reflux and Careful Urinary Tract Infection Evaluation) in which children <6 years of age with a first or second UTI were followed for 2 years. We compared outcomes for children with and without BBD, children with and without VUR, and children with VUR randomly assigned to prophylaxis or placebo. The outcomes examined were incidence of recurrent UTIs, renal scarring, surgical intervention, resolution of VUR, and treatment failure. RESULTS: BBD was present at baseline in 54% of the 181 toilet-trained children included; 94% of children with BBD reported daytime wetting, withholding maneuvers, or constipation. In children not on antimicrobial prophylaxis, 51% of those with both BBD and VUR experienced recurrent UTIs, compared with 20% of those with VUR alone, 35% with BBD alone, and 32% with neither BBD nor VUR. BBD was not associated with any of the other outcomes investigated. CONCLUSIONS: Among toilet-trained children, those with both BBD and VUR are at higher risk of developing recurrent UTIs than children with isolated VUR or children with isolated BBD and, accordingly, exhibit the greatest benefit from antimicrobial prophylaxis.

The role of antimicrobial prophylaxis in the management of children with vesicoureteral reflux--the RIVUR study outcomes.

The role of antimicrobial prophylaxis for the prevention of recurrent urinary tract infections in children with vesicoureteral reflux that was identified following a urinary tract infection has been the source of considerable debate. Prior studies had failed to show a benefit in the prevention of recurrent infection. The National Institutes of Health funded the Randomized Intervention for Vesicoureteral Reflux (RIVUR) study to determine if there was a benefit to the use of prophylaxis. Results of the RIVUR study indicated that there was a 50% reduction in the risk of recurrent urinary tract infection in those children on the prophylaxis arm. Adverse events with the use of prophylaxis were noted to be few. Renal scarring was noted in only a small number of children at study entry and no reduction in scarring was noted between the placebo and the treated groups. The impact of the RIVUR study on the current evaluation and management of children with urinary tract infections and vesicoureteral reflux is detailed.

Antimicrobial prophylaxis for children with vesicoureteral reflux.

BACKGROUND: Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. METHODS: In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. RESULTS: Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. CONCLUSIONS: Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.).