Analysis of Kidney Ultrasound Dimensions by Body Habitus and Position.

PURPOSE: Renal dimensions are an important assessment of the genitourinary tract used to evaluate critical aspects of renal growth and development. Understanding the effect of patient position is important to use and interpret these parameters. In this prospective study we determined the effect of patient position and general body habitus on renal length and parenchymal area in children undergoing renal ultrasound. MATERIALS AND METHODS: Between October 2010 and January 2011 children underwent renal ultrasound while prone and supine. Bilateral renal length and renal parenchymal area were measured. Pearson and Bland-Altman statistical analyses were used to examine correlations, measurement bias and the degree of agreement between methods. RESULTS: Renal length measurements in both positions were complete for 201 right and 196 left kidneys. Parenchymal area measurements were complete for both kidneys in 177 children. When compared individually, supine and prone measures of renal length and parenchymal area highly correlated on Pearson analysis (greater than 0.96 and greater than 0.89, respectively). When compared by method, Bland-Altman analyses of differences vs means showed greater than 50% variance, representing wide limits of agreement with poor interrelation. Neither persistent systematic bias nor body habitus influenced results. CONCLUSIONS: While Pearson analysis showed high correlation for supine and prone renal measurements, Bland-Altman analysis of renal length and parenchymal area demonstrated wide limits of agreement, not allowing interchangeable use of prone and supine measurements. As such, renal ultrasound should specify standardized positions and benchmarks. These results provide guidance to standardize renal ultrasound measurements when renal size is used as an indicator of kidney health.

Three differentiation states risk-stratify bladder cancer into distinct subtypes.

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.

Testosterone changes bladder and kidney structure in juvenile male rats.

PURPOSE: Testosterone affects male development, maturation and aging but limited data exist on testosterone effects on the juvenile genitourinary system. We hypothesized that testosterone has bladder and kidney developmental effects, and investigated this in juvenile male rats. MATERIALS AND METHODS: To examine the testosterone effect 21-day-old prepubertal male Wistar rats were divided into 3 groups of 12 each, including sham orchiectomy as controls, and bilateral orchiectomy with vehicle and bilateral orchiectomy with testosterone. Starting at age 28 days (week 0) testosterone enanthate (5 mg/100 gm) or vehicle was injected weekly. Testosterone was measured at study week 0 before injection, and at weeks 1, 6 and 16. Whole bladders and kidneys were evaluated for androgen receptor, bladder collagen-to-smooth muscle ratio, and renal morphometry and immunohistochemistry. RESULTS: Testosterone was not detectable at week 0 in all groups. It remained undetectable at weeks 1, 6 and 16 in the orchiectomy plus vehicle group. Testosterone levels were physiological in controls and rats with orchiectomy plus testosterone but levels were higher in the latter than in the former group. Rats with orchiectomy plus testosterone had increased bladder-to-body and kidney-to-body weight ratios (p<0.01 and <0.05, respectively), and decreased collagen-to-smooth muscle ratio than the orchiectomy plus vehicle and control groups. Rats with orchiectomy plus testosterone had a lower renal total glomerular count (p<0.01) but increased androgen receptor density. CONCLUSIONS: In juvenile male rats testosterone was associated with increased bladder and renal mass, and increased bladder smooth muscle. Testosterone associated kidneys also appeared to have fewer but larger glomeruli. These data support an important role for sex hormones in structural and functional development of the bladder and kidney.

Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells.

Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44(+)CK5(+)CK20(-)). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% beta-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.

Pregnancy and severely reduced renal mass: A stress model showing renal hyperfiltration.

Pregnancy may increase signs of renovascular stress. We compared pregnant sham operated (S) and 5/6 nephrectomy (NX) rats to examine the effect of pregnancy on reduced nephron number. Blood pressure (BP), heart rate (HR), body weight (BW), food/water intake, serum creatinine (Cr), urinalyses were assessed weekly, and end pregnancy renal histology examined. NX showed decreased BW, elevated BP and Cr, and proteinuria. Histology revealed increased glomerular volume, increased tubular diameter and interstitial inflammation and fibrosis. This pilot shows that a pregnant 5/6th nephrectomy rat is a reliable model in which to evaluate renovascular stress with reduced nephrons.

Trends in hospitalization for pediatric pyelonephritis: a population based study of California from 1985 to 2006.

PURPOSE: We examined trends in pediatric hospitalization for pyelonephritis from 1985 to 2006 and identified factors associated with admission. MATERIALS AND METHODS: We performed a population based analysis of hospital discharges using the Office of Statewide Health Planning and Development database to evaluate trends in California regarding pediatric hospitalizations for pyelonephritis from 1985 to 2006. Multivariable logistic regression was performed to identify factors associated with admission for pyelonephritis. RESULTS: A total of 46,300 children were hospitalized for pyelonephritis in California from 1985 to 2006. The overall rate of hospitalization for pyelonephritis increased by greater than 80%, from 17 per 100,000 children in the California population in 1985 to 31 per 100,000 in 2005. This change was primarily due to the nearly ninefold increase in pyelonephritis hospitalizations observed in children younger than 1 year, from 28 per 100,000 in 1985 to 238 per 100,000 in 2005. Among children younger than 1 year males without private insurance and of nonwhite race had increased odds of hospitalization, while females with private insurance and of Asian race had increased odds of hospitalization, compared with nonprivate insurance and white race, respectively. CONCLUSIONS: A significant increase in hospital admissions for pyelonephritis, primarily in children younger than 1 year, occurred in California between 1985 and 2006. Further studies are needed to establish the cause of this striking increase and to determine why certain pediatric populations are at increased risk for hospitalization.

Compliance with antibiotic prophylaxis in children with vesicoureteral reflux: results from a national pharmacy claims database.

PURPOSE: Antibiotic prophylaxis is commonly used for medical management of vesicoureteral reflux. Little information exists on compliance with antibiotic prophylaxis in patients with vesicoureteral reflux. MATERIALS AND METHODS: We queried the i3 Innovus (Ingenix) pharmacy claims 2002 to 2007 database for patients 18 years old or younger with vesicoureteral reflux (ICD-9 code 593.7 plus claim for cystogram) and analyzed those with at least 1 year of followup data. Criteria for management with antibiotic prophylaxis were 2 or more 30-day supplies of antibiotic prescriptions, or 4 or more 14-day supplies of prescriptions if the antibiotic was a penicillin or cephalosporin. Antibiotic prophylaxis compliance was determined using a medication possession ratio, an estimate of the proportion of time that patients have a prescribed drug available for use. Compliance was established as a medication possession ratio of 80% or greater, meaning coverage with antibiotic prophylaxis for 80% of the year or more. RESULTS: Of 9,496 patients with vesicoureteral reflux 5,342 (56.3%) were treated with antibiotic prophylaxis. Most patients were female (81%) and 5 years old or younger (79%). Trimethoprims/sulfonamides were most commonly prescribed (62%) and antiseptics were next (24%). Of patients prescribed antibiotic prophylaxis 40% were compliant. Compliance was lower for 6 to 10-year-olds (OR 0.71, 95% CI 0.61-0.83) and 11 to 18-year-olds (OR 0.56, 95% CI 0.41-0.79) compared to younger children (5 years or less). Increased compliance was associated with 1 or more hospitalizations (OR 1.70, 95% CI 1.48-1.97) and 1 or more urologist visits (OR 1.41, 95% CI 1.25-1.58). CONCLUSIONS: Among patients with vesicoureteral reflux who are prescribed prophylactic antibiotics 40% are compliant with treatment. Young age, frequent hospitalization and specialist visits are associated with compliance. This knowledge may help to develop effective interventions to improve compliance and underscores the importance of reporting compliance in clinical studies evaluating the usefulness of antibiotic prophylaxis in vesicoureteral reflux management.

Evaluation of dynamic contrast-enhanced MRI in detecting renal scarring in a rat injury model.

PURPOSE: To create a reliable rat model with small renal cortical scars and evaluate the accuracy and sensitivity of dynamic contrast-enhanced MRI in detecting the kinds of lesions that are associated with reflux nephropathy. MATERIALS AND METHODS: In 16 rats, three unilateral renal cortical lesions were created using either electrocautery or pure alcohol with the contralateral kidney serving as control. MRI on a 1.5 Tesla GE Signa was performed 10-14 days after surgery. After bolus injection of 0.2 mM/Kg Gd-DTPA, sequential MRI acquisitions were performed using a 4-inch quadrature birdcage coil. Renal and scar volumes and pathology were compared after scanning and killing. RESULTS: Of the 48 points of injury, 40 (83%) in the 16 rats were detected grossly. Under microscopy, 36 injuries (75%) were detected on mid-kidney cross-sections. The average lesion was 4.2 mm(3) corresponding to 0.5% of the kidney volume. Using pathological findings as the gold standard, the sensitivity and specificity of scar detection using MRI was 69% and 93%, respectively. CONCLUSION: A rat model was created to demonstrate the sensitivity of dynamic contrast-enhanced MRI for detecting renal scars. Alcohol and electrocautery created reliable renal scars that were confirmed pathologically. MRI detected these lesions that averaged 4.2 mm(3) (0.5% total renal volume) with sensitivity and specificity of 69% and 93%, respectively.

Quantitative ultrasound renal parenchymal area correlates with renal volume and identifies reflux nephropathy.

PURPOSE: Studies show that renal volume on magnetic resonance imaging correlates with differential function and is decreased in children with vesicoureteral reflux diagnosed after urinary tract infection. We examined the correlation between ultrasound renal parenchymal area and magnetic resonance imaging volume to determine whether quantitative ultrasound renal parenchymal area might be a reliable, less costly and less invasive substitute for renal magnetic resonance imaging volume. MATERIALS AND METHODS: To determine the correlation of ultrasound renal parenchymal area with magnetic resonance imaging, we identified 82 children with primary vesicoureteral reflux who underwent renal magnetic resonance imaging and ultrasound. Magnetic resonance imaging volume was compared with ultrasound renal parenchymal area, renal length and calculated ellipsoid volume. To determine the correlation of ultrasound renal parenchymal area with reflux grade, ultrasound renal parenchymal area was examined in 96 children with reflux and urinary tract infection, and in 52 with reflux without urinary tract infection. Linear regression and multivariate analysis were performed to find the relationship between ultrasound renal parenchymal area and reflux grade. RESULTS: The correlation of ultrasound renal parenchymal area with magnetic resonance imaging volume was superior to that of renal length and calculated ellipsoid volume (r(2) = 0.90 vs 0.83 and 0.84, respectively). Hydronephrosis did not affect the correlation. On multiple regression analysis in children with reflux and urinary tract infection higher reflux grade correlated with decreased ultrasound renal parenchymal area (p = 0.0016). In children with reflux without urinary tract infection reflux grade did not correlate with decreased ultrasound renal parenchymal area (p = 0.47). CONCLUSIONS: Ultrasound renal parenchymal area correlates closely with magnetic resonance imaging derived 3-dimensional renal volume and is capable of detecting progressive renal area loss in patients with reflux and urinary tract infection. More studies are necessary to verify whether data from more invasive tests, such as renal magnetic resonance imaging and dimercapto-succinic acid scan, may be attained from ultrasound renal parenchymal area alone.

Certification, recertification, and maintenance: continuing to learn.

The process of certification, recertification, and maintenance of certification is mandated by the American Board of Urology as a member Board of the American Board of Medical Specialties. The history of maintenance of certification parallels that of private regulation of medical schools and postgraduate medical education (residency) and other nonmedical areas in which public trust is involved. Current trends in information technology that allow data gathering that measure medical practice and recognition of failure mandate that urologists practice with current knowledge. This will be documented in the maintenance of certification process.

The management of renal angiomyolipomas in a patient with tuberous sclerosis.

BACKGROUND: A 17-year-old girl, who was diagnosed with tuberous sclerosis in infancy, presented with multiple bilateral renal masses, the largest of which was 6.0 cm in diameter on the left side. INVESTIGATIONS: History and physical examination, ultrasonography, MRI, CT, magnetic resonance angiography, and measurement of serial creatinine levels. DIAGNOSIS: Bilateral angiomyolipomas.Management Observation, serial imaging, embolization and infarction.

A case of ectopic dysplastic kidney and ectopic ureter diagnosed by MRI.

BACKGROUND: A 14-year-old girl with a solitary right kidney had continuous urinary incontinence. Four months previously she had undergone surgical resection of a vaginal septum associated with uterus didelphys, which was causing obstructed menstrual flow. She was toilet trained at the age of 2 years, had a normal voiding pattern, and had no history or family history of incontinence. INVESTIGATIONS: Pelvic examination, abdominal and pelvic ultrasonography, renal scintigraphy, voiding cystourethrography, abdominal and pelvic MRI, fluoroscopic retrograde vaginography, vaginoscopy, cystourethroscopy after administration of indigo carmine, laparoscopy, and pathologic examination of the excised specimen. DIAGNOSIS: Ectopic ureter draining into the vagina associated with a contralateral dysplastic kidney. MANAGEMENT: Laparoscopic nephrectomy of the left renal remnant and ligation of the left distal ureter.

Management of Wilms tumor: current standard of care.

Wilms tumor is the most common renal malignancy in children. In the 1930s, overall survival for children with Wilms tumor was approximately 30%. Use of multidisciplinary therapy, guided by results from multi-institutional, randomized trials, has substantially improved overall survival to about 90%. Management of Wilms tumor differs substantially between Europe and the US. In Europe, the International Society of Pediatric Oncology protocols call for management of patients with presumptive Wilms tumor with neoadjuvant chemotherapy followed by nephrectomy and further chemotherapy. In the US, protocols developed by the National Wilms Tumor Study Group advise primary nephrectomy followed by a chemotherapy regimen tailored to the pathologic tumor stage. Despite these disparate strategies, overall survival is similar in patients managed according to European and US protocols. Patients with Wilms tumor now have excellent survival. Therefore, current goals aim to reduce the morbidity associated with therapy. Important complications of treatment for Wilms tumor include cardiomyopathy, renal failure, and increased risk of a secondary malignancy. Currently, the role of laparoscopic surgery in management of Wilms tumor remains extremely limited.

Magnetic resonance imaging detected renal volume reduction in refluxing and nonrefluxing kidneys.

PURPOSE: Renal parenchymal damage is a well recognized sequela of urinary tract infection in the setting of vesicoureteral reflux. We investigated renal magnetic resonance imaging as a quantitative modality to detect renal parenchymal damage in children with primary vesicoureteral reflux and urinary tract infection. MATERIALS AND METHODS: We retrospectively reviewed the medical records of children with primary vesicoureteral reflux and urinary tract infection who underwent renal magnetic resonance imaging evaluation. Those with other genitourinary pathology were excluded. Controls underwent magnetic resonance imaging for nongenitourinary pathologies. Kidneys were segregated among control, nonrefluxing, and low grade (I to III) and high grade (IV to V) reflux. Size plots (magnetic resonance imaging volume vs age) were drawn for comparison. Gross imaging abnormalities observed were renal scarring and small size. RESULTS: Magnetic resonance imaging was performed in 114 patients with vesicoureteral reflux (228 kidneys, patient age 0.5 to 17.8 years) and 21 controls (42, 0.5 to 12). Higher grades of reflux were associated with smaller volume, and smaller volume was noted in the refluxing and nonrefluxing kidneys of children with vesicoureteral reflux. Kidneys from patients with unilateral or bilateral reflux had significantly decreased renal volume compared to controls (p <0.0001). Kidneys in which vesicoureteral reflux spontaneously resolved had renal volumes similar to control kidneys (p = 0.23). CONCLUSIONS: Use of magnetic resonance imaging derived renal volume allows renal comparison and is helpful in evaluating patients with vesicoureteral reflux. In patients with a history of a febrile urinary tract infection and reflux the finding of measurably smaller kidneys appears to be more common than scarring. Whether these findings represent renal atrophy or hypoplasia needs further investigation.

New and developing diagnostic technologies for urinary tract infections.

Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs. Urine dipsticks are fast and amenable to point-of-care testing, but do not have adequate diagnostic accuracy or provide microbiological diagnosis. Urine culture with antimicrobial susceptibility testing takes 2-3 days and requires a clinical laboratory. The common use of empirical antibiotics has contributed to the rise of multidrug-resistant organisms, reducing treatment options and increasing costs. In addition to improved antimicrobial stewardship and the development of new antimicrobials, novel diagnostics are needed for timely microbial identification and determination of antimicrobial susceptibilities. New diagnostic platforms, including nucleic acid tests and mass spectrometry, have been approved for clinical use and have improved the speed and accuracy of pathogen identification from primary cultures. Optimization for direct urine testing would reduce the time to diagnosis, yet these technologies do not provide comprehensive information on antimicrobial susceptibility. Emerging technologies including biosensors, microfluidics, and other integrated platforms could improve UTI diagnosis via direct pathogen detection from urine samples, rapid antimicrobial susceptibility testing, and point-of-care testing. Successful development and implementation of these technologies has the potential to usher in an era of precision medicine to improve patient care and public health.

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-ß-catenin signaling. Constitutive activation of Wnt-ß-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

Pediatric urinary tract infections.

Pediatric urinary tract infections are common. These infections have been recognized as a source of acute morbidity and long-term medical consequences in adulthood. There are various risk factors and clinical presentations in children with urinary tract infections. The main objectives in management include prompt diagnosis, appropriate antimicrobial therapy, identification of anatomic anomalies, and, in select patients, long-term follow-up.