Upper pole pathologies in duplex kidneys: an analysis of predictive factors for surgery and urinary tract infections from the Mid-Atlantic Pediatric Academic Consortium.

BACKGROUND/OBJECTIVE: While there is significant data on the natural history and outcomes for prenatal hydronephrosis in simplex kidneys, duplex kidneys tend to be less studied. Management can be quite variable based on provider preference. We aimed to describe practice patterns from several tertiary academic institutions, identify clinical predictors for surgical intervention and urinary tract infection (UTI) for upper pole pathology, and demonstrate the natural history of lower pole vesicoureteral reflux (VUR). METHODS: We conducted a retrospective review of patients from 4 Mid-Atlantic institutions between 2015 and 2020. Inclusion criteria included patients with a duplex kidney with upper pole pathology and/or lower pole VUR. The primary outcome was predictive factors for surgical intervention and UTI. The secondary outcome was to assess the natural history of lower pole VUR including resolution rates by grade. Linear regression identified clinical predictors for UTI events. Multivariate logistic regression identified predictors of surgical intervention, UTI, and lower pole VUR resolution. Descriptive statistics and regression modeling analyses were performed using SAS. RESULTS: Two hundred forty-two patients were included with a total of 271 duplex renal units. Hydronephrosis grade (both SFU and UTD grading) and number of prior UTI events were statistically significant predictors for surgical intervention (p = 0.03/0.001 and p = 0.002 respectively). Ectopic ureter (p = 0.004), ureterocele (p = 0.02), and obstruction (p = 0.04) were the only pathologies predictive for surgery. Male gender and circumcision were significantly associated with decreased UTI risk (p = 0.03 and p = 0.01). On linear regression modeling, antibiotic prophylaxis after the first year of life was associated with decreased risk of further UTI events (p = 0.03); however, antibiotic prophylaxis within the first year of life did not decrease UTI risk (p = 0.14). For VUR outcomes, 65.0% of grades 1-3 VUR and 52.2% of grades 4-5 had resolution/improvement at mean time of 2.1 years. There were no predictive factors for resolution/improvement of VUR. CONCLUSIONS: Hydronephrosis grade and UTI events were significant predictors for surgical intervention for upper pole pathology. Pathologies that were predictive for surgery included ectopic ureter, ureterocele and obstruction. Male gender, circumcision and antibiotic prophylaxis after the first year of life were associated with a decreased UTI risk. Roughly 58% of lower pole VUR spontaneously improved/resolved. Identification of these risk factors aids in standardization of care practices to reduce long-term UTI risk and inform counseling with families about possible need for surgical intervention and expectations for long term outcomes.

Predicting the likelihood of prolongation of half-time among infants with initially indeterminate drainage values: A single-institution retrospective study of 535 patients with ureteropelvic junction obstruction.

INTRODUCTION AND OBJECTIVE: Prior studies have shown a broad half time (T1/2) interval on MAG3 diuresis renography (DR) that is indeterminate for obstruction. We aimed to refine and sub-divide the indeterminate range and associate it with clinically meaningful outcomes: pyeloplasty and pyeloplasty-free survival. METHODS: We identified patients <1.5 years-old at presentation with unilateral, isolated moderate to severe hydronephrosis who underwent DR from 2000 to 2016. A logistic regression model was created using T1/2 to predict surgery. An indeterminate range was defined based on patients with <90% probability of pyeloplasty or resolution. This group was sub-divided into three T1/2 intervals: 5-20, 21-40, and 41-60 min. Endpoints were pyeloplasty and pyeloplasty free survival. Indications for surgery were loss of differential renal function (DRF), worsening T1/2, family preference, and/or pain. RESULTS: Among 2025 patients with DR, 704 met criteria (169 were lost to follow up). Of the remaining 535, 218 had pyeloplasties and 317 did not. The Pyeloplasty group had significantly worse DRF, T1/2 at initial DR, and exited the study earlier, at a median age 1.1years vs 2.3 years (p < 0.001). For all patients with antenatally detected unilateral UPJ obstruction, the odds of undergoing pyeloplasty at any time increased by 1.8 times (p < 0.001 [95% CI: 1.04, 1.08]) per 10 unit increase in T1/2 until T1/2 = 60. However, in patients with intermediate drainage, five year surgery-free survival probability for patients with T1/2 5-20, 21-40, and 41-60 min were 79.7%, 46.7% and 33.3% respectively (χ2 = 41.2, P = <0.001). DISCUSSION: Previous efforts to define indeterminate drainage resulted in ranges for T1/2 that were too broad to be clinically useful. Within our endpoint-defined indeterminate range, our data show that there are significant step offs in 5-year surgery-free survival for patients with T1/2 < 20 min, 21-40 min, and 41-60 min. Although there is a steady decrease in surgery-free survival among patients with a T1/2 of 21-40 min over the first 5 years of life, half can be managed nonoperatively. These patients likely represent the true intermediate risk group and closer follow up is justified. CONCLUSIONS: Initial T1/2 on DR is predictive of future surgery. When drainage is "indeterminate" for obstruction, sub-stratification allows for more accurate prognostication.

The association between urine neutrophil gelatinase-associated lipocalin and UTI in people with neurogenic lower urinary tract dysfunction.

STUDY DESIGN: Secondary analysis of urine samples collected from a prospective within-subject clinical trial. OBJECTIVES: Describe the baseline variation in urine neutrophil gelatinase-associated lipocalin (uNGAL) levels in adults with neurogenic lower urinary tract dysfunction (NLUTD) and determine if uNGAL levels vary according to likelihood of having a UTI. SETTING: Greater Washington D.C. region. METHODS: Urine samples were collected from a cohort of adults with NLUTD from a clinical trial. Samples were divided into groups of "Not UTI", "Unlikely UTI", and "Likely UTI" based on symptoms and urine culture results. uNGAL was compared between groups using Kruskal-Wallis and post hoc Dunn's test. Mixed effects logistic model was used to assess the association of uNGAL and Likely UTI. RESULTS: Twenty-seven participants provided a total of 104 samples. uNGAL levels were lowest for the No UTI group (n = 29; 37 ng/ml interquartile range (IQR) (15, 71)), intermediate for the Unlikely UTI group (n = 67; 95 ng/ml IQR (37, 161)) and highest for the Likely UTI group (n = 8; 187 ng/ml IQR(146, 224)). uNGAL levels were higher in those with Likely UTI compared to both Unlikely UTI (p < 0.05) and No UTI (p < 0.01). uNGAL had an association with Likely UTI (OR 1.01, 95% CI (1.00-1.02), p = 0.049). CONCLUSIONS: Adults with NLUTD have notable variation in uNGAL levels in the absence of symptoms potentially due to UTI. uNGAL levels are higher in those who are likely to have UTI have higher uNGAL levels compared to those with non-specific symptoms and/or less growth on urine culture. uNGAL may have utility as a marker of UTI in people with NLUTD. SPONSORSHIP: Patient-Centered Outcomes Research Institute (PCORI) funded this work. Bioporto provided partial salary support for SLG, IL, and OKL. NGAL ELISAs were provided by Bioporto in kind.

A single intravesical instillation of Lactobacillus rhamnosus GG is safe in children and adults with neuropathic bladder: A phase Ia clinical trial.

Context/objective: Manipulation of the microbiome is an emerging approach to promote health. We conducted a Phase Ia safety study of a single bladder instillation of probiotics in asymptomatic patients with neuropathic bladder to determine the tolerability and safety of a single Lactobacillus instillation.Design: Phase Ia safety study.Setting: Outpatient rehabilitation clinic at a rehabilitation hospital (adults) and urology clinic at a free-standing children's hospital (children).Participants: Ten patients with neuropathic bladder were included: five children with spina bifida and five adults with spinal cord injury.Interventions: A single Lactobacillus rhamnosus GG (Culturelle, 20 billion live organisms) instillation.Outcome measures: After the instillation, participants self-monitored symptoms using the Urinary Symptoms Questionnaire for People with Neuropathic Bladder using Intermittent Catheterization daily for one week. Repeat urinalysis, urine culture, and 16S bacterial rRNA-based microbiome analyses were performed 7-10 days after instillation.Results: Probiotic instillation was well-tolerated. One child had upper respiratory tract symptoms during the trial, and two had transient cloudy urine. No adults reported any symptoms following instillation. Lactobacillus did not grow on culture post-instillation. There were differences in beta diversity of the urine microbiome in children vs. adults with neuropathic bladder (P < 0.0156). Lactobacillus was present in the pre-instillation urinary microbiomes all of the adults and 4 out of 5 of the pediatric subjects, and identified in 4 out of 5 of both the adult and pediatric subjects' post-instillation urinary microbiomes.Conclusion: Intravesical instillation of Culturelle probiotic may be safe and well-tolerated in patients with neuropathic bladder.

High incidence of abnormal imaging findings in circumcised boys diagnosed with urinary tract infections.

BACKGROUND: The American Academy of Pediatrics guidelines recommend delaying voiding cystourethrogram (VCUG) until the second febrile urinary tract infection (UTI). Similarly, the NICE Guidelines do not recommend VCUG after the first febrile UTI in infants and children under three years of age. Currently, there is no good clinical indicator to determine which patients would benefit from an earlier cystogram. Here, we sought to identify clinical and bacteriologic findings that are associated with an increased risk of urinary tract anatomic anomalies in pediatric males presenting to the Emergency Department with a UTI. METHODS: A retrospective review was performed of all urine cultures from the Emergency Department at our institution between 2006 and 2015. Males under 18 years of age with ≥50,000 CFU/mL of Proteus, Klebsiella, Escherichia coli, Staphylococcus, Streptococcus and Enterococcus were included. Clean catch, catheterized and suprapubic aspiration specimens were included. Bagged specimens and specimens from patients on intermittent catheterization were excluded. Ultrasound and cystogram images were reviewed when available. Univariate and multivariable Poisson regression with robust variance was used to calculate and compare prevalence ratios. Statistical analysis was performed with Stata software, version 15.1 MP (Stata Corporation, College Station, Texas, USA). RESULTS: We reviewed 1585 urine cultures, of which 812 met eligibility criteria including 619 (76.2%) E. coli, 84 (10.3%) Proteus, 55 (6.8%) Klebsiella, 29 (3.6%) Staphylococcus, 13 (1.6%) Enterococcus and 12 (1.5%) Streptococcus. Median age was six months (2.4-36 months IQR). After adjusting for age, ethnicity and bacterial species, the prevalence of dilating vesicoureteral reflux (VUR, defined as grades III-V) was 5.3 times higher in circumcised males compared to uncircumcised males (95% CI: 2.4-11.4, p = 0.001). Circumcised males had a 3.1 times increased prevalence of high-grade hydronephrosis (defined as SFU grades 3 and 4) compared to uncircumcised males (prevalence ratio: 3.1, 95% CI: 1.0-10.0, p = 0.05). Among bacterial pathogens, no patients with Proteus UTI had high-grade hydronephrosis or dilating VUR. In contrast, Staphylococcal infections were associated significantly with dilating VUR (prevalence ratio 10.1, 95% CI: 2.3, 44.8; p = 0.002) and high-grade hydronephrosis (prevalence ratio 8.1, 95% CI: 1.7, 39.7; p = 0.010). CONCLUSIONS: Circumcision status is an independent predictor of structural urinary anomalies of the bladder and upper tracts in pediatric males with UTI, therefore circumcised males should be considered for early imaging, including VCUG, after their first UTI. Furthermore, Staphylococcal infections were associated with an even higher prevalence of high-grade hydronephrosis and dilating VUR and therefore warrant early investigation with VCUG. In contrast, none of the Proteus infections, which were seen almost exclusively in uncircumcised males, were associated with dilating VUR or hydronephrosis, making initial observation more appropriate in these patients.

The Urine Microbiome of Healthy Men and Women Differs by Urine Collection Method.

PURPOSE: Compared to the microbiome of other body sites, the urinary microbiome remains poorly understood. Although noninvasive voided urine specimens are convenient, contamination by urethral microbiota may confound understanding of the bladder microbiome. Herein we compared the voiding- versus catheterization-associated urine microbiome of healthy men and women. METHODS: An asymptomatic, healthy cohort of 6 women and 14 men underwent midstream urine collection, followed by sterile catheterization of the bladder after bladder refilling. Urine samples underwent urine dipstick testing and conventional microscopy and urine cultures. Samples also underwent Illumina MiSeq-based 16S ribosomal RNA gene amplification and sequencing. RESULTS: All organisms identified by urine culture were also identified by 16S amplification; however, next-generation sequencing (NGS) also detected bacteria not identified by cultivation. Lactobacillus and Streptococcus were the most abundant species. Abundances of the 9 predominant bacterial genera differed between the urethra and bladder. Voided and catheterized microbiomes share all dominant (>1%) genera and Operational Taxonomic Units but in similar or different proportions. Hence, urethra and bladder microbiomes do not differ in taxonomic composition, but rather in taxonomic structure. Women had higher abundance of Lactobacillus and Prevotella than men. CONCLUSION: Our findings lend credence to the hypothesis that Lactobacilli are important members of the healthy urine microbiome. Our data also suggest that the microbiomes of the urethra and bladder differ from one another. In conclusion, urine collection method results in different 16S-based NGS data, likely due to the sensitivity of NGS methods enabling detection of urethral bacteria present in voided but not catheterized urine specimens.

Discrepant Rates of Hypospadias Surgical Complications: A Comparison of U.S. News & World Report and Pediatric Health Information System® Data and Published Literature.

PURPOSE: Complication rates of 5% to 10% and 12% to 23% have been observed following distal and proximal hypospadias repair, respectively. However, these rates may be overreported. We hypothesized that data from the Pediatric Health Information System would corroborate the complication rates reported in the literature and refute the rates established by U.S. News & World Report as quality metrics. MATERIALS AND METHODS: The Pediatric Health Information System database was interrogated for hypospadias and revision CPT® codes. To evaluate the appropriateness of the U.S. News & World Report code list to identify revisions, 3 CPT groups were defined. Group A included codes sought by U.S. News & World Report, group B included group A plus codes for acquired urethrocutaneous fistula in males and group C included group B plus any revision codes associated with the index procedures. To evaluate the appropriateness of U.S. News & World Report followup interval, we assessed revision rates with ever increasing followup intervals out to 7 years. Yearly revision rates were summarized by median and quantile to correlate whether median revision rates changed significantly depending on whether increased followup or enhanced code lists were used. RESULTS: Average complication rates for group A were 3.32% (range 0.48% to 7.36%) and 12.29% (3.48% to 36.36%) for distal and proximal repairs, respectively. Revision rates increased significantly from group A (median 3.32%) by inclusion of a more expansive list of CPT codes associated with revision procedures (group B, 4.26%, p <0.001 and group C, 6.37%, p <0.001) in distal hypospadias. Among proximal hypospadias cases this difference was not significant when comparing group A (12.29%) to group B (12.53%, p=0.813), but was significant when comparing group A to group C (22.14%, p <0.001). Median revision rates for distal and proximal hypospadias increased with longer followup for all 3 groups, although the upward trend was not statistically significant. CONCLUSIONS: Depending on how one defines hypospadias revision, no hospital within the Pediatric Health Information System data set meets the U.S. News & World Report definition of perfection, a finding that is supported by recent reports from some of the largest, most prolific and most highly regarded pediatric urology programs. We posit that the U.S. News & World Report quality metrics do not accurately reflect the nature of hypospadias surgery complication rates.

Intravesical Lactobacillus rhamnosus GG is safe and well tolerated in adults and children with neurogenic lower urinary tract dysfunction: first-in-human trial.

BACKGROUND: Urinary symptoms are common for people with neurogenic lower urinary tract dysfunction (NLUTD). No nonprescription approach has been proven safe and effective for self-management of urinary symptoms. Our objective was to describe the safety and tolerability of Lactobacillus rhamnosus GG (LGG®) instilled intravesically for self-management of inflammatory urinary symptoms in adults and children with NLUTD due to spinal cord injury or disease (SCI/D) and who use intermittent catheterization (IC). METHODS: A total of 103 individuals with SCI/D enrolled in an 18-month study consisting of three 6-month stages: baseline (weekly observation of urinary symptoms); intervention (self-instilled intravesical LGG® in response to more cloudy or foul-smelling urine); and washout (weekly observation of urinary symptoms). Urinary symptoms were assessed using the Urinary Symptom Questionnaire for people with neurogenic bladder using intermittent catheters (USQNB-IC). Safety was based on serious adverse events and adverse events (S/AEs) and trends in symptoms. Tolerability was defined as the independence of AE experience and willingness to use/pay for this intervention. RESULTS: A total of 74 (77%) adults and 6 (86%) of children completed the study, of whom 64 instilled LGG® for a total of 357 instillations (range 1-41 per person). There were 59 S/AEs, 44% (26/59) of which were categorized as infectious genitourinary. There was no statistical relationship between S/AEs and use or dose of the intervention. CONCLUSIONS: One or two doses of self-instilled intravesical LGG® in response to more cloudy or foul-smelling urine was safe and well tolerated among this sample of adults and children with SCI/D who have NLUTD and use IC.

Identification of Burkholderia fungorum in the urine of an individual with spinal cord injury and augmentation cystoplasty using 16S sequencing: copathogen or innocent bystander?

INTRODUCTION: People with neuropathic bladder (NB) secondary to spinal cord injury (SCI) are at risk for multiple genitourinary complications, the most frequent of which is urinary tract infection (UTI). Despite the high frequency with which UTI occurs, our understanding of the role of urinary microbes in health and disease is limited. In this paper, we present the first prospective case study integrating symptom reporting, urinalysis, urine cultivation, and 16S ribosomal ribonucleic acid (rRNA) sequencing of the urine microbiome. CASE PRESENTATION: A 55-year-old male with NB secondary to SCI contributed 12 urine samples over an 8-month period during asymptomatic, symptomatic, and postantibiotic periods. All bacteria identified on culture were present on 16S rRNA sequencing, however, 16S rRNA sequencing revealed the presence of bacteria not isolated on culture. In particular, Burkholderia fungorum was present in three samples during both asymptomatic and symptomatic periods. White blood cells of ≥5-10/high power field and leukocyte esterase ≥2 on urinalysis was associated with the presence of symptoms. DISCUSSION: In this patient, there was a predominance of pathogenic bacteria and a lack of putative probiotic bacteria during both symptomatic and asymptomatic states. Urinalysis-defined inflammatory markers were present to a greater extent during symptomatic periods compared to the asymptomatic state, which may underscore a role for urinalysis or other inflammatory markers in differentiating asymptomatic bacteriuria from UTI in patients with NB. The finding of potentially pathogenic bacteria identified by sequencing but not cultivation, suggests a need for greater understanding of the relationships amongst bacterial species in the bacteriuric neuropathic bladder.

Early Detection of Ureteropelvic Junction Obstruction Using Signal Analysis and Machine Learning: A Dynamic Solution to a Dynamic Problem.

PURPOSE: We sought to define features that describe the dynamic information in diuresis renograms for the early detection of clinically significant hydronephrosis caused by ureteropelvic junction obstruction. MATERIALS AND METHODS: We studied the diuresis renogram of 55 patients with a mean ± SD age of 75 ± 66 days who had congenital hydronephrosis at initial presentation. Five patients had bilaterally affected kidneys for a total of 60 diuresis renograms. Surgery was performed on 35 kidneys. We extracted 45 features based on curve shape and wavelet analysis from the drainage curves recorded after furosemide administration. The optimal features were selected as the combination that maximized the ROC AUC obtained from a linear support vector machine classifier trained to classify patients as with or without obstruction. Using these optimal features we performed leave 1 out cross validation to estimate the accuracy, sensitivity and specificity of our framework. Results were compared to those obtained using post-diuresis drainage half-time and the percent of clearance after 30 minutes. RESULTS: Our framework had 93% accuracy, including 91% sensitivity and 96% specificity, to predict surgical cases. This was a significant improvement over the same accuracy of 82%, including 71% sensitivity and 96% specificity obtained from half-time and 30-minute clearance using the optimal thresholds of 24.57 minutes and 55.77%, respectively. CONCLUSIONS: Our machine learning framework significantly improved the diagnostic accuracy of clinically significant hydronephrosis compared to half-time and 30-minute clearance. This aids in the clinical decision making process by offering a tool for earlier detection of severe cases and it has the potential to reduce the number of diuresis renograms required for diagnosis.

Prediction of Clinical Outcomes in Prenatal Hydronephrosis: Importance of Gravity Assisted Drainage.

PURPOSE: In infants with SFU (Society for Fetal Urology) grade 3-4 congenital hydronephrosis, 99mTc-mercaptoacetyltriglycine diuretic renography assesses differential function and drainage half-time. We routinely also include the percent of radiotracer drained after 30 minutes of diuresis as well as after 15 minutes with the patient in the upright position. We investigated whether any 1 or more of these parameters on initial diuretic renography predicts persistent or worsening drainage parameters. MATERIALS AND METHODS: Infants 6 months or younger with grade 3-4 congenital hydronephrosis who presented between January 2009 and December 2014 were identified from billing data and included in analysis if they underwent at least 1 baseline diuretic renography. Those with structural anomalies were excluded from study. Baseline and followup differential function, diuresis half-time, clearance at 30 minutes and clearance with the patient upright were abstracted and comparisons were made between those with initially indeterminate diuresis half-time who underwent pyeloplasty vs those showing spontaneous improvement. RESULTS: A total of 74 patients (82 renal units) with presumed ureteropelvic junction obstruction met inclusion/exclusion criteria. All 10 renal units with initial diuresis half-time less than 5 minutes resolved spontaneously and all 25 renal units with initial diuresis half-time greater than 75 minutes underwent pyeloplasty. Therefore, we defined the indeterminate group as the 47 renal units with initial half-time between 5 and 75 minutes. Of those 47 renal units with indeterminate initial diuresis half-time 23 (47%) underwent pyeloplasty and 25 (53%) resolved spontaneously. Indications for pyeloplasty included worsening in 17 cases, persistent obstruction in 4 and urinary tract infection in 1. Among renal units with indeterminate drainage clearance while upright and clearance at 30 minutes were the only variables that differed significantly between surgical cases and those that resolved spontaneously. CONCLUSIONS: Radiotracer clearance with the patient upright and clearance at 30 minutes are more predictive of surgical management than diuresis half-time or differential function for renal units with indeterminate drainage. They should be included in the standard assessment of ureteropelvic junction obstruction.

Redefining Healthy Urine: A Cross-Sectional Exploratory Metagenomic Study of People With and Without Bladder Dysfunction.

PURPOSE: We used the PathoScope platform to perform species level analyses of publicly available, 16S rRNA pyrosequenced, asymptomatic urine data to determine relationships between microbiomes, and clinical and functional phenotypes. MATERIALS AND METHODS: We reanalyzed previously reported, cross-sectionally acquired urine samples from 47 asymptomatic subjects, including 23 controls and 24 subjects with neuropathic bladder. Urine was originally collected by the usual method of bladder drainage and analyzed by urinalysis, culture and pyrosequencing. Urinalysis and culture values were stratified as leukocyte esterase (0, or 1 or greater), nitrite (positive or negative), pyuria (fewer than 5, or 5 or greater white blood cells per high power field), cloudy urine (positive or negative) and urine culture bacterial growth (less than 50,000, or 50,000 or greater cfu/ml). PathoScope was used for next generation sequencing alignment, bacterial classification and microbial diversity characterization. RESULTS: Subjects with neuropathic bladder were significantly more likely to have positive leukocyte esterase and pyuria, cloudy urine and bacterial growth. Of 47 samples 23 showed bacterial growth on culture and in all samples bacteria were identified by pyrosequencing. Nonneuropathic bladder urine microbiomes included greater proportions of Lactobacillus crispatus in females and Staphylococcus haemolyticus in males. The Lactobacillus community differed significantly among females depending on bladder function. Irrespective of gender the subjects with neuropathic bladder had greater proportions of Enterococcus faecalis, Proteus mirabilis and Klebsiella pneumonia. In 4 subjects with neuropathic bladder Actinobaculum sp. was detected by sequencing and by PathoScope but not by cultivation and in all cases it was associated with pyuria. CONCLUSIONS: Using PathoScope plus 16S pyrosequencing we were able to identify unique, phenotype dependent, species level microbes. Novel findings included absent L. crispatus in the urine of females with neuropathic bladder and the presence of Actinobaculum only in subjects with neuropathic bladder.

Risk Factors for Recurrent Urinary Tract Infection and Renal Scarring.

OBJECTIVES: To identify risk factors for recurrent urinary tract infection (UTI) and renal scarring in children who have had 1 or 2 febrile or symptomatic UTIs and received no antimicrobial prophylaxis. METHODS: This 2-year, multisite prospective cohort study included 305 children aged 2 to 71 months with vesicoureteral reflux (VUR) receiving placebo in the RIVUR (Randomized Intervention for Vesicoureteral Reflux) study and 195 children with no VUR observed in the CUTIE (Careful Urinary Tract Infection Evaluation) study. Primary exposure was presence of VUR; secondary exposures included bladder and bowel dysfunction (BBD), age, and race. Outcomes were recurrent febrile or symptomatic urinary tract infection (F/SUTI) and renal scarring. RESULTS: Children with VUR had higher 2-year rates of recurrent F/SUTI (Kaplan-Meier estimate 25.4% compared with 17.3% for VUR and no VUR, respectively). Other factors associated with recurrent F/SUTI included presence of BBD at baseline (adjusted hazard ratio: 2.07 [95% confidence interval (CI): 1.09-3.93]) and presence of renal scarring on the baseline (99m)Tc-labeled dimercaptosuccinic acid scan (adjusted hazard ratio: 2.88 [95% CI: 1.22-6.80]). Children with BBD and any degree of VUR had the highest risk of recurrent F/SUTI (56%). At the end of the 2-year follow-up period, 8 (5.6%) children in the no VUR group and 24 (10.2%) in the VUR group had renal scars, but the difference was not statistically significant (adjusted odds ratio: 2.05 [95% CI: 0.86-4.87]). CONCLUSIONS: VUR and BBD are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.

Most infants with dilating vesicoureteral reflux can be treated nonoperatively.

PURPOSE: Dilating vesicoureteral reflux provokes concern for physicians and parents that often leads to corrective surgery in young children. Since there are limited data describing the natural history of dilating vesicoureteral reflux in infants, we identified factors predictive of resolution/improvement in infants initially treated nonoperatively. MATERIALS AND METHODS: We reviewed the medical records of 90 infants 6 months old or younger from 2004 to 2010 who were referred for prenatal hydronephrosis or initial febrile urinary tract infection and found to have dilating vesicoureteral reflux (grade 3 or greater). Variables of interest included presentation, dimercapto-succinic acid results, sex, breakthrough febrile urinary tract infections, reflux grade and bilateral reflux. Cox regression analysis was performed to determine predictors of spontaneous resolution and/or improvement to reflux grade less than 3 as well as predictors of surgical intervention. RESULTS: Included in final analysis were 80 infants (113 renal units). Of the patients 51 (64%) experienced spontaneous resolution/improvement with a mean followup of 29 months before resolution, discharge home and/or end of followup. Only 20 patients (25%) underwent surgery. Cox regression analysis revealed that a normal initial dimercapto-succinic acid scan, initial reflux grade less than 5 and absent breakthrough febrile urinary tract infections were predictive of reflux resolution/improvement (p <0.05). Dimercapto-succinic acid scan abnormalities, prenatal hydronephrosis and breakthrough febrile urinary tract infections were significant predictors of surgery (p <0.05). CONCLUSIONS: Dilating vesicoureteral reflux in infancy often resolves/improves spontaneously. Therefore, surgery should be directed toward patients unlikely to experience resolution, ie those with an abnormal initial dimercapto-succinic acid scan, grade 5 vesicoureteral reflux and breakthrough febrile urinary tract infections.

Evaluation of differential renal function and renographic patterns in patients with dietl crisis.

PURPOSE: We analyzed preoperative and postoperative differential renal function and characterized the renographic findings in patients with ureteropelvic junction obstruction associated with Dietl crisis. MATERIALS AND METHODS: Patients with Dietl crisis who underwent pyeloplasty between January 2004 and December 2010 were classified by renographic presentation. Patients in group 1 were diagnosed with cortical retention, those in group 2 had an initial obstructed scan (T1/2 of 20 minutes or more and no cortical retention) and those in group 3 had an initial nondiagnostic scan (T1/2 of less than 20 minutes and no cortical retention). Renographic parameters were used to analyze each group. RESULTS: A total of 59 patients met criteria for study inclusion. The 13 patients in group 1 demonstrated the most significant recovery of function after pyeloplasty (mean differential renal function change 13.59%). The 38 patients in group 2 exhibited a mean differential renal function change of 43.06% (range 20% to 54.6%) and mean preoperative T1/2 of 64.31 minutes. Pyeloplasty was performed in all 8 patients in group 3 based on subsequent diagnostic scan (4 patients) or increased hydronephrosis on other imaging associated with further symptomatic episodes (4). Initial renographic patterns noted in group 3 included biphasic curves, diminished clearance after 15 minutes upright or symptoms despite nonobstructive drainage. CONCLUSIONS: Interpretation of diuretic renography requires the assimilation of multiple parameters since patients with Dietl crisis can exhibit variability in renographic patterns due to the intermittent nature of ureteropelvic junction obstruction. Cortical retention represents a specific and pathognomic finding of acute ureteropelvic junction obstruction. With appropriate evaluation of these parameters, obstruction can be reliably diagnosed and appropriate surgical candidates chosen.

Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury.

BACKGROUND: Clinical dogma is that healthy urine is sterile and the presence of bacteria with an inflammatory response is indicative of urinary tract infection (UTI). Asymptomatic bacteriuria (ABU) represents the state in which bacteria are present but the inflammatory response is negligible. Differentiating ABU from UTI is diagnostically challenging, but critical because overtreatment of ABU can perpetuate antimicrobial resistance while undertreatment of UTI can result in increased morbidity and mortality. In this study, we describe key characteristics of the healthy and ABU urine microbiomes utilizing 16S rRNA gene (16S rDNA) sequencing and metaproteomics, with the future goal of utilizing this information to personalize the treatment of UTI based on key individual characteristics. METHODS: A cross-sectional study of 26 healthy controls and 27 healthy subjects at risk for ABU due to spinal cord injury-related neuropathic bladder (NB) was conducted. Of the 27 subjects with NB, 8 voided normally, 8 utilized intermittent catheterization, and 11 utilized indwelling Foley urethral catheterization for bladder drainage. Urine was obtained by clean catch in voiders, or directly from the catheter in subjects utilizing catheters. Urinalysis, urine culture and 16S rDNA sequencing were performed on all samples, with metaproteomic analysis performed on a subsample. RESULTS: A total of 589454 quality-filtered 16S rDNA sequence reads were processed through a NextGen 16S rDNA analysis pipeline. Urine microbiomes differ by normal bladder function vs. NB, gender, type of bladder catheter utilized, and duration of NB. The top ten bacterial taxa showing the most relative abundance and change among samples were Lactobacillales, Enterobacteriales, Actinomycetales, Bacillales, Clostridiales, Bacteroidales, Burkholderiales, Pseudomonadales, Bifidobacteriales and Coriobacteriales. Metaproteomics confirmed the 16S rDNA results, and functional human protein-pathogen interactions were noted in subjects where host defenses were initiated. CONCLUSIONS: Counter to clinical belief, healthy urine is not sterile. The healthy urine microbiome is characterized by a preponderance of Lactobacillales in women and Corynebacterium in men. The presence and duration of NB and method of urinary catheterization alter the healthy urine microbiome. An integrated approach of 16S rDNA sequencing with metaproteomics improves our understanding of healthy urine and facilitates a more personalized approach to prevention and treatment of infection.

Observation of infants with SFU grades 3-4 hydronephrosis: worsening drainage with serial diuresis renography indicates surgical intervention and helps prevent loss of renal function.

PURPOSE: Early pyeloplasty is indicated for ureteropelvic junction obstruction (UPJ) obstructions with reduced differential renal function (DRF) and/or no drainage on diuretic renography (DR). Optimal management of Society of Fetal Urology (SFU) Grades 3 and 4hydronephrosis with preservation of DRF and indeterminate drainage is less straightforward. We review our experience using serial DR to guide the management of kidneys with high-grade hydronephrosis, emphasizing preservation of DRF. METHODS: After IRB approval we reviewed the charts of 1398 patients <1-year-old referred for prenatal hydronephrosis. Only patients with SFU Grades 3 and 4 hydronephrosis without ureterectasis were included in the study. Initial evaluation included a baseline DR. Follow-up included DR or ultrasound (US). RESULTS: 115 patients (125 kidneys) were eligible for study inclusion. 27 kidneys underwent early surgery (median 64 days) due to reduced DRF and/or severely impaired drainage. 98 kidneys were initially observed. Of these, 21 underwent delayed surgery (median 487 days) due to worsening drainage. Only 2 patients had an irreversible decrease in DRF of >5%. 77 kidneys demonstrated improved drainage and stable DRF. Comparison of observation (n = 77) and surgery groups (n = 48) revealed more kidneys with SFU Grade 3 hydronephrosis in the observation group (p = 0.0001). CONCLUSION: Infants with Grades 3 and 4 hydronephrosis and preserved DRF may be safely followed with serial DR. Patients with SFU Grade 4 hydronephosis are more likely to require surgery. Worsening drainage on serial DR is a useful indicator for surgical intervention which limits the number of pyeloplasties while preserving DRF.

Molecular and descriptive epidemiologyof multidrug-resistant Enterobacteriaceae in hospitalized infants.

OBJECTIVE: To investigate the epidemiology of multidrug-resistant Enterobacteriaceae (MDRE) in hospitalized infants. METHODS: From 2000 through 2005, active surveillance cultures for MDRE were performed for patients admitted to a 40-bed neonatal intensive care unit (NICU) that provides care for critically ill infants 6 months of age or younger. MDRE epidemiology and the genetic relatedness of MDRE strains determined by repetitive-sequence polymerase chain reaction were analyzed. RESULTS: Active surveillance cultures revealed that 759 (23%) of 3,370 NICU infants (or approximately 1 in 5) developed MDRE colonization or infection and that 613 (72%) of the 853 isolates with epidemiologic data available were healthcare acquired. MDRE colonization occurred more frequently (in 653 infants [86%]) than did MDRE infection (in 106 [14%]). Of the 653 infants with MDRE colonization, 119 (18%) eventually became infected, with 29 (4%) acquiring sterile site infections. The most commonly isolated organisms were the Enterobacter species, accounting for 612 (71%) of the 862 isolates. Molecular epidemiologic analysis revealed that genetic-relatedness clustering (related clusters defined as having a genetic similarity coefficient greater than 95%) varied depending on microbial species. Clustering was detected for 36 (78%) of the 46 Enterobacter aerogenes isolates, 22 (45%) of the 49 Enterobacter cloacae isolates, and 13 (59%) of the 22 Klebsiella pneumoniae isolates. CONCLUSION: Hospitalized infants are at significant risk of acquiring MDRE, specifically Enterobacter species, at the study institution. Active surveillance cultures identified colonized patients who likely contributed to the institutional reservoir of MDRE. Molecular epidemiologic studies suggest that both patient-to-patient transmission and de novo acquisition of resistance play a role in the acquisition of these organisms, and that the clinical significance of such acquisition varies by species. The high percentage of E. aerogenes isolates that demonstrated genetic clustering suggests that monitoring the prevalence of this organism could serve as a useful measure of compliance with infection control procedures.

Epidemiology of infection and colonization with vancomycin-resistant enterococci and frequency of cocolonization with methicillin-resistant Staphylococcus aureus in children.

We report the descriptive and molecular epidemiology of vancomycin-resistant enterococci (VRE) infection and colonization and cocolonization with methicillin-resistant Staphylococcus aureus (MRSA) in children. Interunit and intraunit spread of VRE was detected, and 8 cases of VRE-MRSA cocolonization were identified. Seven of these cases were identified only via active surveillance, because clinical evidence of VRE colonization was absent.

Stable prevalence but changing risk factors for sudden infant death syndrome in child care settings in 2001.

OBJECTIVE: A total of 20% of sudden infant death syndrome (SIDS) cases in the 1990s occurred in child care settings. This is much higher than the 8% expected from Census Bureau data. Factors that were associated with child care SIDS included older age; white race; older, more educated mothers; and unaccustomed prone position. Since these findings, much emphasis has been placed on promoting a safe sleep environment in child care. The objectives of this study were to determine the proportion of SIDS occurring in child care in 2001 and to assess risk factors for SIDS in child care. METHODS: We conducted a retrospective review of all SIDS deaths that occurred in 2001 in 13 US states. Information regarding demographics, SIDS risk factors, and child care arrangements were collected and analyzed. Deaths that occurred in child care were compared with deaths that occurred during parental care. RESULTS: Of 480 deaths, 79 (16.5%) occurred in child care settings. Of these child care deaths, 36.7% occurred in family child care homes, 17.7% occurred in child care centers, 21.3% occurred in relative care, and 17.7% occurred with a nanny/babysitter at home. Infants in child care were more likely to be older and to die between the hours of 8 am and 4 pm and less likely to be exposed to secondhand smoke. There was no difference in usual, found, or placed sleep position between child care and home deaths. Approximately one half of the infants who died of SIDS in both settings were found prone, and 20% of deaths in both settings were among infants who were unaccustomed to prone sleep. CONCLUSIONS: The proportion of SIDS deaths in child care has declined slightly but still remains high at 16.5%. Infants in child care are no more likely to be placed or found prone and no more likely to be on an unsafe sleep surface. Educational efforts with child care providers have been effective and should be expanded to unregulated child care providers. In addition, there may be other, yet-unidentified factors in child care that place infants in those settings at higher risk for SIDS.