Sherry S. Ross

TNXB Mutations Can Cause Vesicoureteral Reflux

Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.

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.

Variation in definitions of urinary tract infections in spina bifida patients: a systematic review.

OBJECTIVE: Urinary tract infections (UTIs) are a common source of morbidity among children with spina bifida (SB) and are a frequently reported outcome in studies of this patient population. However, the criteria for a diagnosis of UTI are often not stated. We evaluated the literature on SB patients for the criteria that authors use to define parameters in reporting UTI outcomes. METHODS: Embase and Medline were queried with the medical subject heading terms “spinal dysraphism,” “myelomeningocele,” “infection,” and “urinary tract infection.” A second search with the exploded term “spina bifida” and “urinary tract infection” was performed. Original research studies reporting a UTI outcome in SB patients were included and evaluated by 2 independent reviewers for the presence of a UTI definition and diagnostic criteria. RESULTS: We identified 872 publications, of which 124 met inclusion criteria. Forty-five of 124 (36.3%) studies reporting UTI as an outcome provided a definition of UTI. Of 124 studies, 28 (22.6%) were published in pediatric journals and 69 (55.6%) in urology journals. A definition of UTI was provided in 11 (39.3%) and 26 (37.7%) studies, respectively. “Fever, culture, and symptoms” defined a UTI in 17 of 45 studies. Journal category and presence of UTI definitions did not correlate (P = .71). CONCLUSIONS: Explicit definitions for UTI are heterogeneous and infrequently applied in studies of SB patients, limiting study reliability and estimates of true UTI rates in this population. Future studies will benefit from the development and application of a standard definition for UTI in this population.

Enhanced Susceptibility to Urinary Tract Infection in the Spinal Cord-Injured Host with Neurogenic Bladder

ABSTRACT Neurogenic bladder predisposes to recurrent urinary tract infections (UTI) and renal failure, and susceptibility is commonly ascribed to urinary stasis from elevated residual urine volumes. Escherichia coli UTI was modeled in the spinal cord-injured (SCI) rat with the hypothesis that SCI animals would require fewer bacteria to establish infection, have an exaggerated inflammatory response, and have delayed clearance of infection compared to normal-voiding controls. T10 SCI rats and controls had median infectious doses (ID50) of 102 and 105 CFU, respectively. Mean residual volumes in the SCI animals did not correlate with susceptibility to initiation of UTI or outcome. In the acute infection, control and SCI rats developed acute cystitis and pyelitis without acute differences in histopathological scores of inflammation. However, in vivo imaging of infected animals revealed persistently higher levels of bacteria in the SCI urine and bladders than were seen for controls over 2 weeks. Likewise, at 2 weeks, acute and chronic inflammatory infiltrates persisted in the bladders and kidneys of SCI rats, whereas inflammation largely resolved within the controls. Together these data demonstrate that SCI rats exhibit delayed clearance of infection and exaggerated inflammatory responses in bladders and kidneys; however, the severity of residual volumes does not predict increased susceptibility to UTI. These studies suggest that host-dependent mechanisms that are discrete from alterations in bladder physiology influence UTI susceptibility with the SCI-neurogenic bladder. This model will allow elucidation of SCI-neurogenic bladder-mediated changes in host response that yield UTI susceptibility and may lead to new preventative and therapeutic options.

Urinary Tract Infection and Neurogenic Bladder

Urinary tract infections (UTIs) are frequent, recurrent, and lifelong for patients with neurogenic bladder and present challenges in diagnosis and treatment. Patients often present without classic symptoms of UTI but with abdominal or back pain, increased spasticity, and urinary incontinence. Failure to recognize and treat infections can quickly lead to life-threatening autonomic dysreflexia or sepsis, whereas overtreatment contributes to antibiotic resistance, thus limiting future treatment options. Multiple prevention methods are used but evidence-based practices are few. Prevention and treatment of symptomatic UTI requires a multimodal approach that focuses on bladder management as well as accurate diagnosis and appropriate antibiotic treatment.

Inflammatory Response to Escherichia coli Urinary Tract Infection in the Neurogenic Bladder of the Spinal Cord Injured Host

PURPOSE Urinary tract infections cause significant morbidity in patients with spinal cord injury. An in vivo spinal cord injured rat model of experimental Escherichia coli urinary tract infection mimics human disease with enhanced susceptibility to urinary tract infection compared to controls. We hypothesized that a dysregulated inflammatory response contributes to enhanced susceptibility to urinary tract infection. MATERIALS AND METHODS Spinal cord injured and sham injured rats were inoculated transurethrally with E. coli. Transcript levels of 84 inflammatory pathway genes were measured in bladder tissue of each group before infection, 24 hours after infection and after 5 days of antibiotic therapy. RESULTS Before infection quantitative polymerase chain reaction array revealed greater than twofold up-regulation in the proinflammatory factor transcripts slc11a1, ccl4 and il1β, and down-regulation of the antimicrobial peptides lcn2 and mpo in spinal cord injured vs control bladders. At 24 hours after infection spinal cord injured bladders showed an attenuated innate immune response with decreased expression of il6, slc11a1, il1β and lcn2, and decreased il10 and slpi expression compared to controls. Despite clearance of bacteriuria with antibiotics spinal cord injured rats had delayed induction of il6 transcription and a delayed anti-inflammatory response with decreased il10 and slpi transcript levels relative to controls. CONCLUSIONS Spinal cord injured bladders fail to mount a characteristic inflammatory response to E. coli infection and cannot suppress inflammation after infection is eliminated. This may lead to increased susceptibility to urinary tract infection and persistent chronic inflammation through neural mediated pathways, which to our knowledge remain to be defined.

Estimating the Nationwide, Hospital Based Economic Impact of Pediatric Urolithiasis

PURPOSE The incidence of urolithiasis is increasing in children and adolescents but the economic impact of this problem is unclear. We examined 2 large databases to estimate the nationwide economic impact of pediatric urolithiasis. MATERIALS AND METHODS We analyzed the 2009 NEDS and KID, used ICD-9-CM codes to identify children 18 years or younger diagnosed with urolithiasis and abstracted demographic and charge data from each database. RESULTS We identified 7,348 weighted inpatient discharges in KID and 33,038 emergency department weighted encounters in NEDS. Of the patients 32% and 36% were male, respectively. Inpatients were younger than those who presented to the ED (mean age 13.9 vs 15.7 years). Most patients had private insurance (52.9% to 57.2%) and the South was the most common geographic region (39.5% to 44.4%). The most common procedures were ureteral stent placement in 20.4% to 24.1% of cases, followed by ureteroscopy in 3.8% to 4.4%. Median charges per admission were

Resolution rate of isolated low-grade hydronephrosis diagnosed within the first year of life

13,922 for a weighted total of

The association between caudal anesthesia and increased risk of postoperative surgical complications in boys undergoing hypospadias repair

229 million per year. Median emergency department charges were

Experience with Glycerin for Antegrade Continence Enema in Patients with Neurogenic Bowel

3,991 per encounter for a weighted total of