Understanding factors influencing primary treatment with intradetrusor onabotulinumtoxinA versus augmentation cystoplasty in patients with spina bifida.

PURPOSE: Surgical interventions in the urologic management of children with neurogenic bladder secondary to spina bifida aim to preserve upper tract function, prevent urinary tract infections, and optimize quality of life. However, since the introduction of intravesical onabotulinumtoxinA (Botox) in the management of these patients, the indications for choosing Botox over augmentation cystoplasty (AC) remain undefined. The objective of this study was to determine which factors lead patients to undergo Botox versus AC as a primary surgical treatment after failing medical management. METHODS: We retrospectively reviewed the records of pediatric patients with myelomeningocele undergoing either primary Botox or primary AC at our institution between 2013 and 2018. We recorded demographic and clinical information. We identified 10 important clinical decision-making factors: bladder trabeculation, vesicoureteral reflux, or hydronephrosis on imaging; end-filling pressure (EFP) ≥40 cm H2O, detrusor overactivity, detrusor-sphincter dyssynergia, or reduced capacity on urodynamic studies; physician-perceived bladder hostility; and patient/family desire for continence and independence. The presence of these factors was compared between patients undergoing either primary Botox or primary AC. RESULTS: We identified 14 and 50 myelomeningocele patients who underwent primary AC and primary Botox, respectively. We found no significant differences in age, sex, race, or history of reconstructive surgery (antegrade continence enema or catheterizable channel). For the 10 decision-making factors, desire for independence/continence (p = <0.001) and reduced capacity (p = 0.002) were significantly associated with AC, while trabeculation (p = 0.006), EFP ≥40 cm H2O (p = 0.029), rising slope (p = 0.019), and physician-perceived hostility (p = 0.012) were significantly more common with Botox. CONCLUSIONS: At our institution, quality of life measures prompted AC over objective urodynamic or imaging findings before attempting Botox. These findings support a shared decision-making approach when considering surgical intervention for neurogenic bladder secondary to myelomeningocele.

Inhibition of hypoxia-inducible factor-prolyl hydroxylation protects from cyclophosphamide-induced bladder injury and urinary dysfunction.

Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Activation of the oxygen-regulated hypoxia-inducible factor (HIF) pathway has been shown to protect mucosal membranes by increasing the expression of cytoprotective genes and by suppressing inflammation. The activity of HIF is controlled by prolyl hydroxylase domain (PHD) dioxygenases, which have been exploited as therapeutic targets for the treatment of anemia of chronic kidney disease. Here, we established a mouse model of acute cyclophosphamide (CYP)-induced blood-urine barrier disruption associated with inflammation and severe urinary dysfunction to investigate the HIF-PHD axis in inflammatory bladder injury. We found that systemic administration of dimethyloxalylglycine or molidustat, two small-molecule inhibitors of HIF-prolyl hydroxylases, profoundly mitigated CYP-induced bladder injury and inflammation as assessed by morphological analysis of transmural edema and urothelial integrity and by measuring tissue cytokine expression. Void spot analysis to examine bladder function quantitatively demonstrated that HIF-prolyl hydroxylase inhibitor administration normalized micturition patterns and protected against CYP-induced alteration of urinary frequency and micturition patterns. Our study highlights the therapeutic potential of HIF-activating small-molecule compounds for the prevention or therapy of bladder injury and urinary dysfunction due to blood-urine barrier disruption.NEW & NOTEWORTHY Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Here, we demonstrate that pharmacological inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylation prevented bladder injury and protected from urinary dysfunction in a mouse model of cyclophosphamide-induced disruption of the blood-urine barrier. Our study highlights a potential role for HIF-activating small-molecule compounds in the prevention or therapy of bladder injury and urinary dysfunction and provides a rationale for future clinical studies.

Data highlighting phenotypic diversity of urine-associated Escherichia coli isolates.

This article provides a reusable dataset describing detailed phenotypic and associated clinical parameters in n=303 clinical isolates of urinary Escherichia coli collected at Vanderbilt University Medical Center. De-identified clinical data collected with each isolate are detailed here and correlated to biofilm abundance and metabolomics data. Biofilm-abundance data were collected for each isolate under different in vitro conditions along with datasets quantifying biofilm abundance of each isolate under different conditions. Metabolomics data were collected from a subset of bacterial strains isolated from uncomplicated cases of cystitis or cases with no apparent symptoms accompanying colonization. For more insight, please see "Defining a Molecular Signature for Uropathogenic versus Urocolonizing Escherichia coli: The Status of the Field and New Clinical Opportunities" [1].

Defining a Molecular Signature for Uropathogenic versus Urocolonizing Escherichia coli: The Status of the Field and New Clinical Opportunities.

Urinary tract infections (UTIs) represent a major burden across the population, although key facets of their pathophysiology and host interaction remain unclear. Escherichia coli epitomizes these obstacles: this gram-negative bacterial species is the most prevalent agent of UTIs worldwide and can also colonize the urogenital tract in a phenomenon known as asymptomatic bacteriuria (ASB). Unfortunately, at the level of the individual E. coli strains, the relationship between UTI and ASB is poorly defined, confounding our understanding of microbial pathogenesis and strategies for clinical management. Unlike diarrheagenic pathotypes of E. coli, the definition of uropathogenic E. coli (UPEC) remains phenomenologic, without conserved phenotypes and known genetic determinants that rigorously distinguish UTI- and ASB-associated strains. This article provides a cross-disciplinary review of the current issues from interrelated mechanistic and diagnostic perspectives and describes new opportunities by which clinical resources can be leveraged to overcome molecular challenges. Specifically, we present our work harnessing a large collection of patient-derived isolates to identify features that do (and do not) distinguish UTI- from ASB-associated E. coli strains. Analyses of biofilm formation, previously reported to be higher in ASB strains, revealed extensive phenotypic heterogeneity that did not correlate with symptomatology. However, metabolomic experiments revealed distinct signatures between ASB and cystitis isolates, including in the purine pathway (previously shown to be critical for intracellular survival during acute infection). Together, these studies demonstrate how large-scale, wild-type approaches can help dissect the physiology of colonization versus infection, suggesting that the molecular definition of UPEC may rest at the level of global bacterial metabolism.

Current State of Fetal Intervention for Lower Urinary Tract Obstruction.

PURPOSE OF THE REVIEW: In this article, we explore the origins of intervention of fetal lower urinary tract obstruction, and we specifically discuss the background and recent outcomes of vesicoamniotic shunt placement and fetal cystoscopy. The article seeks to provide a comprehensive overview of the field while bringing the reader quickly up to speed on the pertinent literature and the critical data that are available to guide decision-making regarding intervention. RECENT FINDINGS: Appropriate patient selection for fetal intervention remains challenging despite advances in prenatal imaging. Both a randomized controlled trial and multiple systematic reviews show evidence of a perinatal survival benefit following fetal intervention but rates of renal morbidity remain very high. Despite 30 years of research, fetal lower urinary tract obstruction remains a difficulty entity to treat. Intervention may lead to survival, but physicians and caregivers must remain alert for the distinct possibility of long-term renal morbidity in survivors.

Update on Continent Catheterizable Channels and the Timing of their Complications.

PURPOSE: We previously reported catheterizable channel associated outcomes and concluded that the incidence of postoperative complications was greatest in the first 2 years after surgery. At that time our followup was short. In this series we sought to determine whether complications continued to accumulate with longer followup in an updated cohort of patients. MATERIALS AND METHODS: We comprehensively reviewed the outcomes in 81 consecutive patients who underwent construction of a MACE (Malone antegrade continence enema) and/or a Mitrofanoff channel in association with complex genitourinary reconstruction. Mean followup was 80.1 months. Outcomes of these 119 stomas were classified by Clavien-Dindo grade and time to complication. RESULTS: The 48 unique, channel related events (40.3%) necessitated a total of 70 interventions with a mean 24.2 months to the first event. Difficult catheterization was the most common event, occurring in 20.1% of channels an average of 29.9 months after surgery. Stomal stenosis was also common, developing in 12.6% of channels at an average of 19.9 months after surgery. Unique complications clustered in the first 2 years, after which there was a statistically significant decline (p = 0.0013). High grade complications similarly clustered (p <0.0001). Channel composition was significantly associated with rates of difficult catheterization events. CONCLUSIONS: Compared to our previous cohort of patients with similar volume but shorter followup, our assumption that channel associated complications cluster postoperatively and then decrease significantly was correct. Our current and more detailed series demonstrates that the rate of postoperative complications decreases with time. However, with longer followup patients continue to experience lower grade events requiring fewer interventions.

Purine Biosynthesis Metabolically Constrains Intracellular Survival of Uropathogenic Escherichia coli.

The ability to de novo synthesize purines has been associated with the intracellular survival of multiple bacterial pathogens. Uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections, undergoes a transient intracellular lifestyle during which bacteria clonally expand into multicellular bacterial communities within the cytoplasm of bladder epithelial cells. Here, we characterized the contribution of the conserved de novo purine biosynthesis-associated locus cvpA-purF to UPEC pathogenesis. Deletion of cvpA-purF, or of purF alone, abolished de novo purine biosynthesis but did not impact bacterial adherence properties in vitro or in the bladder lumen. However, upon internalization by bladder epithelial cells, UPEC deficient in de novo purine biosynthesis was unable to expand into intracytoplasmic bacterial communities over time, unless it was extrachromosomally complemented. These findings indicate that UPEC is deprived of purine nucleotides within the intracellular niche and relies on de novo purine synthesis to meet this metabolic requirement.

To tell or not: parental thoughts on disclosure of urologic surgery to their child.

PURPOSE: Literature pertaining to surgical disclosure to the pediatric patient is lacking. We hypothesized parents would find it difficult to disclose urologic surgery to a child. MATERIALS AND METHODS: Parents of patients <5 years old undergoing urologic surgery were contacted for telephone survey. Parents were asked about future plans of surgical disclosure, comfort with disclosure, and any support received. RESULTS: 98 parents consented to study participation. 87% of surgeries were on the genitalia with 62% being minor genitalia surgery (i.e. circumcision). 70% of parents would tell their child about minor genital surgery while 84% would tell about major genital surgery (p=0.07). 4 of 20 parents of children undergoing hypospadias repair (major genital surgery) did not plan to tell their child about surgery. All parents of children undergoing non-genital surgery would tell. Of all parents planning to tell their children about surgery, only 14% were nervous. 34% of parents would find guidance in talking to their child helpful despite the majority (90%) stating no guidance had ever been provided. CONCLUSIONS: Parents seem comfortable discussing urologic surgeries with a child but about 1/3 would appreciate further counseling. 20% of parents of children undergoing hypospadias repair hope to avoid telling their child.

To tell or not: parental thoughts on disclosure of urologic surgery to their child

Literature pertaining to surgical disclosure to the pediatric patient is lacking. We hypothesized parents would find it difficult to disclose urologic surgery to a child.

Long-term follow-up of children who underwent severe hypospadias repair using an online survey with validated questionnaires.

OBJECTIVE: Few studies of hypospadias repair in childhood have used validated questionnaires to investigate outcomes of cosmesis, urinary function, and sexual function in adulthood. We sought to investigate long-term outcomes in adult patients who had undergone severe hypospadias repair as children using an existing web-based application available to multiple institutions in order to develop an online patient survey of previously validated questionnaires. MATERIALS AND METHODS: Patients aged 18 years or older who underwent severe hypospadias repair between 1992 and 1997 at our institution were contacted to complete an online survey. Through medical chart reviews, we analyzed the location of meatus, type of repair, and complications. The online survey included questions about penile appearance, and validated questionnaires to assess urinary and sexual function. RESULTS: Of 58 patients who met the inclusion criteria, we contacted 19, and 13 completed the survey. Fifty-nine percent had complications, with an average of 2.2 procedures per patient. Most (85.0%) were satisfied with penile appearance, although 38.0% had residual penile curvature. Hypospadias patients had mean lower orgasmic function than normal controls. Mean scores for urinary function and other domains of sexual function were similar to normal controls. CONCLUSIONS: Although the majority of adult patients were satisfied with the outcomes of penile appearance, urinary function, and sexual function, our online survey suggests decreased lower orgasmic function as measured by validated questionnaire. An online survey accessible to multiple institutions with validated questionnaires may facilitate assessment of long-term hypospadias results.

Outcomes of incontinent ileovesicostomy in the pediatric patient.

PURPOSE: Ileovesicostomy is a reconstructive option in complex urological cases but pediatric specific outcomes are lacking. We report our results with pediatric ileovesicostomy. MATERIALS AND METHODS: We retrospectively evaluated patients younger than 18 years undergoing incontinent ileovesicostomy at Vanderbilt University. History, urinary tract management and operative course were reviewed in the electronic medical record. Particular attention was given to immediate and long-term postoperative complications. RESULTS: Nine patients underwent incontinent ileovesicostomy between 2000 and 2013 at a mean age of 10.3 years (range 1.4 to 15.5). Surgical indication was sequelae of neurogenic or nonneurogenic neurogenic bladder (such as infection or worsening hydronephrosis) in 5 patients, reversal of vesicostomy in 3 and closure of cloacal exstrophy in 1. All 9 patients were thought incapable of reliable clean intermittent catheterization due to family unwillingness, poor social support or patient refusal. Median followup was 11.5 months (mean 48.2, range 1.3 to 144.8). Immediate postoperative complications included ileus requiring total parenteral nutrition and a wound infection in 1 patient. Long-term complications included urinary tract infection in 2 patients (febrile in 1 and positive culture for foul smelling urine in 1), stomal issues in 2 and temporary urethral leakage in 1. Constipation affected 3 children in long-term followup (all with neurogenic bowel preoperatively). Postoperative creatinine was stable or improved in all patients. CONCLUSIONS: Ileovesicostomy is a viable approach in children left with few other options, particularly those who are noncompliant or physically/socially unable to handle catheterization. This operation can help keep such patients out of diapers.

Development of upper tract stones in patients with congenital neurogenic bladder.

OBJECTIVE: Patients with neurogenic bladder are at increased risk of developing upper tract stones. We hypothesized that patients with lower urinary tract stone disease are at greater risk of developing upper tract stones. METHODS: We performed a 10-year retrospective case-control study of patients with neurogenic bladder to determine the association between bladder and upper tract stones. Independent risk factors for upper tract stones were assessed. Cases and controls were matched 1:1. Univariable analysis was performed by Fisher's exact test and the Mann-Whitney U test. Multivariable logistic regression was performed. RESULTS: 52 cases and controls were identified. Cases were significantly more likely to be non-ambulatory, have bowel-urinary tract interposition, thoracic level dysraphism, and history of bladder stones. On multivariable analysis, independent predictors of stone formation were male sex (OR 2.82; p = 0.02), dysraphism involving the thoracic spine (OR 3.37; p = 0.014) bowel-urinary tract interposition (OR 2.611; p = 0.038), and a history of bladder stones (OR 3.57; p = 0.015). CONCLUSION: Patients with neurogenic bladder are at increased risk for upper tract stones. The presence of bladder stones may herald the development of upper tract stones. The predictors of stone disease identified should guide prospective studies to better understand the natural history of upper tract stone development in this population.

Analysis of an intervention to reduce parental anxiety prior to voiding cystourethrogram.

PURPOSE: The voiding cystourethrogram (VCUG) is a common imaging test in pediatric urology that can be associated with anxiety in the child and parent. We hypothesized that education by mailed brochure would decrease pre-procedure parental anxiety. METHODS: Families of children scheduled for VCUG were randomized into an experimental group that was mailed an educational brochure about the VCUG and a control group. Immediately prior to the procedure, parental anxiety was assessed with the self-administered State-Trait Anxiety Inventory (STAI). The parent repeated the STAI at home after the VCUG and answered brief questions about educational resources used to prepare for the VUCG. RESULTS: We enrolled 105 families (47 experimental, 58 control). Parental state anxiety was higher before the procedure than after the procedure (p < 0.001). Younger parents had greater pre-procedure state anxiety (p = 0.007). Contrary to our expectations, pre-procedure state anxiety did not differ between control and experimental groups. However, parents in the experimental group demonstrated less anxiety with some individual items in the questionnaire. CONCLUSION: An educational brochure mailed to families prior to VCUG did not decrease pre-procedure parental state anxiety. However, the educational brochure can ensure accurate dissemination of information to help families prepare for this potentially distressing procedure.

Incidence of abnormal imaging and recurrent pyelonephritis after first febrile urinary tract infection in children 2 to 24 months old.

PURPOSE: The AAP (American Academy of Pediatrics) no longer recommends voiding cystourethrogram in children 2 to 24 months old who present with a first urinary tract infection if renal-bladder ultrasound is normal. We identified factors associated with abnormal imaging and recurrent pyelonephritis in this population. MATERIALS AND METHODS: We retrospectively evaluated children diagnosed with a first episode of pyelonephritis at age 2 to 24 months using de-identified electronic medical record data from an institutional database. Data included age at first urinary tract infection, gender, race/ethnicity, need for hospitalization, intravenous antibiotic use, history of abnormal prenatal ultrasound, renal-bladder ultrasound and voiding cystourethrogram results, urinary tract infection recurrence and surgical intervention. Risk factors for abnormal imaging and urinary tract infection recurrence were analyzed by univariate logistic regression, the chi-square test and survival analysis. RESULTS: We identified 174 patients. Of the 154 renal-bladder ultrasounds performed 59 (38%) were abnormal. Abnormal prenatal ultrasound (p = 0.01) and the need for hospitalization (p = 0.02) predicted abnormal renal-bladder ultrasound. Of the 95 patients with normal renal-bladder ultrasound 84 underwent voiding cystourethrogram. Vesicoureteral reflux was more likely in patients who were white (p = 0.003), female (p = 0.02) and older (p = 0.04). Despite normal renal-bladder ultrasound, 23 of 84 patients (24%) had dilating vesicoureteral reflux. Of the 95 patients with normal renal-bladder ultrasound 14 (15%) had recurrent pyelonephritis and 7 (7%) went on to surgical intervention. CONCLUSIONS: Despite normal renal-bladder ultrasound after a first pyelonephritis episode, a child may still have vesicoureteral reflux, recurrent pyelonephritis and the need for surgical intervention. If voiding cystourethrogram is deferred, parents should be counseled on these risks.

Modulation of the hypoxic response following partial bladder outlet obstruction.

PURPOSE: Tissue level hypoxia has been noted in animal models of partial bladder outlet obstruction. The key mechanisms linking hypoxia and obstruction induced bladder dysfunction remain unknown. 2-Methoxyestradiol is a natural derivative of 17ß-estradiol and is currently used as an oncologic agent for its ability to regulate the hypoxia pathway. We investigated the ability of 2-methoxyestradiol to modulate the hypoxia response in a mouse model of bladder obstruction. MATERIALS AND METHODS: A group of 5 to 6-week-old female C57BL/6 mice underwent oophorectomy and partial bladder outlet obstruction. Obstructed animals received a subcutaneous pellet of cholesterol placebo (7) or 2-methoxyestradiol plus cholesterol (7). Age matched controls underwent oophorectomy only (8). After 4 weeks the bladders of mice with partial bladder outlet obstruction and of unobstructed animals were harvested. Bladder sections (5 µm) were immunostained for Hypoxyprobe™-1, glucose transporter 1 and hypoxia inducible factor-1α. Real-time polymerase chain reaction was performed for hypoxia inducible factor-1α and lysyl oxidase. Statistical analysis was performed using 1-way ANOVA and the Wilcoxon rank sum test. RESULTS: Immunostaining for glucose transporter 1 and Hypoxyprobe-1 revealed the presence of tissue hypoxia after partial bladder outlet obstruction. Immunostaining and real-time polymerase chain reaction demonstrated the up-regulation of hypoxia inducible factor-1α in mice after partial bladder outlet obstruction compared to controls (p = 0.0394). Although not statistically significant, a trend toward lower gene expression of hypoxia inducible factor-1α was seen in mice receiving 2-methoxyestradiol compared to placebo (p = 0.0625). Compared to placebo, 2-methoxyestradiol treatment increased lysyl oxidase expression (p = 0.007). CONCLUSIONS: Murine partial bladder outlet obstruction resulted in hypoxia and up-regulation of the hypoxia inducible factor-1 pathway. Subcutaneous 2-methoxyestradiol administration attenuated this response and may be a viable tool to study the role of hypoxia after partial bladder outlet obstruction.

Long-term urological impact of fetal myelomeningocele closure.

PURPOSE: Between 1997 and 2002 a large number of fetal myelomeningocele closures were performed at our institution. Previously early reports showed little improvement in neonatal bladder function after fetal back closure. We evaluated the long-term urological impact of this procedure. MATERIALS AND METHODS: Using a combination of retrospective review and survey questionnaire we reviewed the records of 28 patients in whom fetal myelomeningocele closure was done at our institution between 1997 and 2002. The areas addressed included medical management for neurogenic bladder and bowel, need for lower urinary tract reconstruction and functional bladder assessment by videourodynamics. Parameters after fetal myelomeningocele closure were compared to those of 33 age and sex matched patients with myelomeningocele who underwent standard postnatal closure. RESULTS: We reviewed the records of 28 patients after fetal myelomeningocele closure. At a mean age of 9.6 years 23 used clean intermittent catheterization to manage the bladder, 24 required a bowel regimen to manage constipation and 6 underwent lower urinary tract reconstruction with enterocystoplasty and a catheterizable bladder channel. Videourodynamics performed in 14 patients at a mean age of 7.4 years revealed decreased bladder capacity in 71%, detrusor overactivity in 35% and increased detrusor pressure in 25%. Compared to age and sex matched children who underwent postnatal closure we noted no significant differences in bladder management, urinary tract surgery or urodynamics. CONCLUSIONS: Neurogenic bowel and bladder management continues to be a significant issue for patients after fetal myelomeningocele closure. After fetal surgery patients should be followed closely, similar to patients who undergo postnatal closure.

The usefulness of lumbosacral magnetic resonance imaging in the management of isolated dysfunctional elimination.

PURPOSE: Magnetic resonance imaging is sometimes used to rule out spinal pathology in patients with dysfunctional elimination, although its usefulness in this setting is unclear. We determined the usefulness of magnetic resonance imaging in children with isolated dysfunctional elimination, and normal cutaneous, neurological and orthopedic examinations. MATERIALS AND METHODS: We reviewed the records of children with dysfunctional elimination who underwent lumbosacral magnetic resonance imaging and identified those who were neurologically normal and who had normal cutaneous back examinations. Our primary goal was to determine the rate at which magnetic resonance imaging identified a spinal abnormality in this population. Univariate analysis was performed to assess the association of several clinical variables with a radiographic abnormality on magnetic resonance imaging. RESULTS: Between 2000 and 2009 a total of 49 lumbosacral magnetic resonance imaging studies were performed in 29 females and 18 males with a mean age of 8.5 years (range 2.1 to 17). Four of the 49 imaging studies (8%) revealed a radiographic abnormality but in only 1 (2%) was clinically significant spinal pathology identified, that is filum lipoma causing cord tethering. Findings on the 3 remaining abnormal imaging studies were considered unrelated to bladder dysfunction. No clinical, demographic or videourodynamic findings were associated with a radiographic abnormality on magnetic resonance imaging. CONCLUSIONS: In children with isolated dysfunctional elimination complaints, and normal neurological, orthopedic and back examinations the diagnostic yield of lumbosacral magnetic resonance imaging is low but not zero. We suggest that spinal magnetic resonance imaging be used judiciously and as a test of last resort in these children.

The urologist's role in the management of spina bifida: a continuum of care.

Caring for the child with spina bifida necessitates lifelong care by a coordinated team of health care providers, and the urologist plays a vital role in this team. The most important management goal of the urologist is the early establishment and consistent maintenance of a lower pressure urinary reservoir. Ensuring social continence along with its attendant social independence provides some of the greatest management challenges. In those patients who fail medical therapy, surgeons, caregivers, and patients must understand the scope of lower urinary tract reconstruction, the need for strict compliance, and the possibility of future surgery. In this article, we review the recent advances in spina bifida management.