Antoine E. Khoury

Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children

PURPOSE The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to children with diagnosed reflux including those young or older than 1 year without evidence of bladder and bowel dysfunction and those older than 1 year with evidence of bladder and bowel dysfunction. From this evidence clinical practice guidelines were developed to manage the clinical scenarios insofar as the data permit. MATERIALS AND METHODS The Panel searched the MEDLINE(R) database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children with vesicoureteral reflux and a defined care program that permitted identification of cohort specific clinical outcomes. The reporting of meta-analysis of observational studies elaborated by the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) group was followed. The extracted data were analyzed and formulated into evidence-based recommendations. RESULTS A total of 2,028 articles were reviewed and data were extracted from 131 articles. Data from 17,972 patients were included in this analysis. This systematic meta-analysis identified increasing frequency of urinary tract infection, increasing grade of vesicoureteral reflux and presence of bladder and bowel dysfunction as unique risk factors for renal cortical scarring. The efficacy of continuous antibiotic prophylaxis could not be established with current data. However, its purported lack of efficacy, as reported in selected prospective clinical trials, also is unproven owing to significant limitations in these studies. Reflux resolution and endoscopic surgical success rates are dependent upon bladder and bowel dysfunction. The Panel then structured guidelines for clinical vesicoureteral reflux management based on the goals of minimizing the risk of acute infection and renal injury, while minimizing the morbidity of testing and management. These guidelines are specific to children based on age as well as the presence of bladder and bowel dysfunction. Recommendations for long-term followup based on risk level are also included. CONCLUSIONS Using a structured, formal meta-analytic technique with rigorous data selection, conditioning and quality assessment, we attempted to structure clinically relevant guidelines for managing vesicoureteral reflux in children. The lack of robust prospective randomized controlled trials limits the strength of these guidelines but they can serve to provide a framework for practice and set boundaries for safe and effective practice. As new data emerge, these guidelines will necessarily evolve.

THE DYSFUNCTIONAL VOIDING SCORING SYSTEM: QUANTITATIVE STANDARDIZATION OF DYSFUNCTIONAL VOIDING SYMPTOMS IN CHILDREN

PURPOSE Academic research on pediatric nonneurogenic voiding dysfunction has long been hampered by the lack of a standardized reporting system for voiding symptoms. We evaluated the performance of a newly devised, objective instrument to quantify or grade the severity of abnormal voiding behaviors of children. MATERIALS AND METHODS There were 10 voiding dysfunction parameters that were assigned scores of 0 to 3 according to prevalence, and possible total scores ranged from 0 to 30. The Dysfunctional Voiding Symptom Score was completed by 2 groups of patients. Group 1 consisted of patients 3 to 10 years old presenting to the pediatric urology clinic with a history of diurnal urinary incontinence, urinary tract infections or abnormal voiding habits. Group 2 consisted of an age matched cohort with no history of urological complaints presenting to hospital clinics outside of urology. Patients diagnosed with organic or anatomical disease, such as posterior urethral valves or meningomyelocele, were excluded from our analysis. RESULTS Group 1 consisted of 104 patients (female-to-male ratio 4:1) with a median symptom score of 14 and group 2 consisted of 54 patients (female-to-male ratio 1.3:1) with a median score of 4. The dysfunctional voiding odds ratio was 2.93 for females compared to that of males. Using receiver operating characteristics the optimum cutoff score was 6.026 (sensitivity 92.77% and specificity 87.09%) for females and 9.02 (sensitivity of 80.95% and specificity of 91. 30%) for males. In addition, we found certain questions to be more reflective than others of dysfunctional voiding symptoms in our population. CONCLUSIONS The Dysfunctional Voiding Symptom Score appears to provide accurate and objective, that is, numerical, grading of voiding behaviors of children. Comparative research studies of dysfunctional voiding diagnosis and response to therapy as well as objective measurements of treatment efficacy and outcomes analysis should be aided greatly by this system.

Ureteral Bladder Augmentation

Virtually all segments of the gastrointestinal tract have been used successfully in augmentation cystoplasty. The complications inherent in enterocystoplasty are well described. Megaureters subtending effete kidneys (poorly or nonfunctioning) provide a novel and excellent source of augmentation material with urothelium and muscular backing, free of the electrolyte and acid base disturbances, and mucus production that plague enterocystoplasty. Augmentation cystoplasty using detubularized, reconfigured, otherwise disposable megaureter, with or without ipsilateral total or partial nephrectomy, was performed in 16 patients (mean age 8.8 years, range 1 to 25) with inadequate and dysfunctional bladders. Postoperative followup varied between 8 and 38 months (mean 22). The overall renal function and radiographic appearance of the remaining upper tracts have remained stable or improved in all patients. Of the 16 patients 15 require intermittent catheterization and 1 voids spontaneously. Ten patients are continent day and night, 5 have improved continence (4 damp at night and 1 stress incontinence) and 1 has failed to gain continence despite good capacity and compliance. Complete postoperative urodynamic evaluations in 12 of 13 patients show good capacity, low pressure bladders with no instability. Complications occurred in 5 patients, including transient urine extravasation in 2, contralateral ureterovesical obstruction in 2 and Mitrofanoff stomal stenosis in 1. Augmentation ureterocystoplasty combines the benefits common to all enterocystoplasties without adding any of the untoward complications or risks associated with nonurothelial augmentations.

22 week assessment of bladder acellular matrix as a bladder augmentation material in a porcine model.

Previous studies on the reconstruction of porcine bladder using bladder acellular matrix allograft (BAMA) have indicated positive preliminary results with respect to graft shrinkage and cellular repopulation. The current study was conducted to investigate the feasibility of using BAMA in a similar model of bladder reconstruction out to longer time frames (22 weeks). At predetermined time points, the macroscopic, histological and mechanical properties of explanted native and BAMA tissues were evaluated and compared. Macroscopically, contracture of the BAMA was observed. The peripheral regions of the grafts experienced extensive cellular repopulation. Towards the centre however, all grafts were consistently devoid of organized smooth muscle bundles and a well-developed urothelium. An alteration in both the amount and organization of collagen was also observed within this region. Significant differences (p < 0.05) in the rupture strain and the elastic modulus of the BAMA compared to native bladder tissue appear to correlate with macroscopic graft contracture as well as the fibroproliferative tissue response of the matrix.

REGENERATION OF FUNCTIONAL BLADDER SUBSTITUTES USING LARGE SEGMENT ACELLULAR MATRIX ALLOGRAFTS IN A PORCINE MODEL

PURPOSE We previously reported on the short-term (4 weeks) morphometric analysis of a large bladder acellular matrix allograft used as a bladder bioprosthesis (average size 24 cm.2). We demonstrated cellular repopulation through the entire thickness of the graft. We now present the long-term (12 weeks) morphometric results of graft regenerated porcine bladders using segments measuring an average of 40 cm.2. MATERIALS AND METHODS Bladders harvested from pigs were subjected to detergent and enzymatic extractions to render them acellular. Partial cystectomy was performed in 21 pigs and the defect was repaired with a bladder acellular matrix allograft (average size 40.52 cm.2). Of the animals 8 were sacrificed at 1, 2 and 4 weeks and 13 were sacrificed at 8 and 12 weeks. To evaluate cellular repopulation and matrix reorganization the native bladder and graft were analyzed using standard histological and immunofluorescent techniques. To evaluate for calcium deposits in the grafts a radiological evaluation of the graft was performed after explantation. RESULTS All animals survived the surgical procedure and there were no significant urinary leaks. No stones were noted in any of the bladders. At 1 week there was a diffuse infiltration with acute inflammatory cells. At 2 weeks the luminal surface of the graft was lined with a single layer of urothelium, and there was stromal infiltration with unorganized smooth muscle cells and angiogenesis. At 4 weeks the urothelium was multilayered with organizing groups of smooth muscle cells and angiogenesis. At 8 and 12 weeks there was repopulation throughout the bladder acellular matrix allograft implant with all native cellular components participating. CONCLUSIONS We present evidence that large patch bladder acellular matrix allograft implantation is technically feasible and may prove to be a viable surgical alternative to bladder augmentation with intestinal segments. Its advantages may include the potential for complete and functional regeneration of a bladder substitute.

Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis

PURPOSE The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to screening of siblings and offspring of index patients with vesicoureteral reflux and infants with prenatal hydronephrosis. From this evidence clinical practice guidelines are developed to manage the clinical scenarios insofar as the data permit. MATERIALS AND METHODS The Panel searched the MEDLINE(R) database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children, clearly stating the number of children undergoing screening for vesicoureteral reflux. Vesicoureteral reflux should have been diagnosed with a cystogram and renal outcomes assessed by nuclear scintigraphy. The screening articles were extracted into data tables developed to evaluate epidemiological factors, patient and renal outcomes, and results of treatment. The reporting of meta-analysis of observational studies elaborated by the MOOSE group was followed. The extracted data were analyzed and formulated into evidence-based recommendations regarding the screening of siblings and offspring in index cases with vesicoureteral reflux and infants with prenatal hydronephrosis. RESULTS In screened populations the prevalence of vesicoureteral reflux is 27.4% in siblings and 35.7% in offspring. Prevalence decreases at a rate of 1 screened person every 3 months of age. The prevalence is the same in males and females. Bilateral reflux prevalence is similar to unilateral reflux. Grade I-II reflux is estimated to be present in 16.7% and grade III-V reflux in 9.8% of screened patients. The estimate for renal cortical abnormalities overall is 19.3%, with 27.8% having renal damage in cohorts of symptomatic and asymptomatic children combined. In asymptomatic siblings only the rate of renal damage is 14.4%. There are presently no randomized, controlled trials of treated vs untreated screened siblings with vesicoureteral reflux to evaluate health outcomes as spontaneous resolution, decreased rates of urinary infection, pyelonephritis or renal scarring. In screened populations with prenatal hydronephrosis the prevalence of vesicoureteral reflux is 16.2%. Reflux in the contralateral nondilated kidney accounted for a mean of 25.2% of detected cases for a mean prevalence of 4.1%. In patients with a normal postnatal renal ultrasound the prevalence of reflux is 17%. The prenatal anteroposterior renal pelvic diameter was not predictive of reflux prevalence. A diameter of 4 mm is associated with a 10% to 20% prevalence of vesicoureteral reflux. The prevalence of reflux is statistically significantly greater in females (23%) than males (16%) (p=0.022). Reflux grade distribution is approximately a third each for grades I-II, III and IV-V. The estimate of renal damage in screened infants without infection is 21.8%. When stratified by reflux grade renal damage was estimated to be present in 6.2% grade I-III and 47.9% grade IV-V (p <0.0001). The risk of urinary tract infection in patients with and without prenatal hydronephrosis and vesicoureteral reflux could not be determined. The incidence of reported urinary tract infection in patients with reflux was 4.2%. CONCLUSIONS The meta-analysis provided meaningful information regarding screening for vesicoureteral reflux. However, the lack of randomized clinical trials for screened patients to assess clinical health outcomes has made evidence-based guideline recommendations difficult. Consequently, screening guidelines are based on present practice, risk assessment, meta-analysis results and Panel consensus.

A liposomal hydrogel for the prevention of bacterial adhesion to catheters

The adhesion of bacteria to medical implants and the subsequent development of a biofilm frequently results in the infection of surrounding tissue and may require removal of the device. We have developed a liposomal hydrogel system that significantly reduces bacterial adhesion to silicone catheter material. The system consists of a poly (ethylene glycol)-gelatin hydrogel in which liposomes containing the antibiotic ciprofloxacin are sequestered. A poly (ethylene glycol)-gelatin-liposome mixture was applied to a silicone surface that had been pre-treated with phenylazido-modified gelatin. Hydrogel cross-linking and attachment to surface-immobilized gelatin was accomplished through the formation of urethane bonds between gelatin and nitrophenyl carbonate-activated poly (ethylene glycol). Liposomal hydrogel-coated catheters were shown to have an initial ciprofloxacin content of 185+/-16 microg cm(-2). Ciprofloxacin was released over seven days with an average release rate of 1.9+/-0.2 microg cm(-2) h(-1) for the first 94 h. In vitro assays using a clinical isolate of Pseudomonas aeruginosa established the antimicrobial efficacy of the liposomal hydrogel. A modified Kirby-Bauer assay produced growth-inhibition zone diameters of 39+/-1 mm, while bacterial adhesion was completely inhibited on catheter surfaces throughout a seven-day in vitro adhesion assay. This new antimicrobial coating shows promise as a prophylactic and/or treatment for catheter-related infection.

Occult Spinal Dysraphism: Clinical and Urodynamic Outcome after Division of the Filum Terminale

A highly select group of 31 patients presenting with urinary incontinence failed to respond to conservative management and were found to have unstable bladders and spina bifida occulta. After thorough evaluation they were suspected of having neurogenic bladder dysfunction possibly due to a tethered cord. Following division of the filum terminale daytime incontinence resolved in 72%, urodynamic detrusor hyperreflexia disappeared in 59% and bladder compliance improved in 66% of the patients. The operation was well tolerated and did not result in any neurological complications. The clinical, radiological and urodynamic characteristics of these patients before and after treatment are reported.

Loss of Elasticity in Dysfunctional Bladders: Urodynamic and Histochemical Correlation

To store adequate volumes of urine at low safe pressures an elastic bladder wall is required. We developed 2 new techniques to measure this ability in our urodynamic laboratory: pressure specific bladder volume, which measures the bladder capacity at a given pressure, and dynamic analysis of bladder compliance. Recently, morphometric and histochemical techniques have been used to determine the relative volume of connective tissue in the bladder wall and to measure the 2 major types (I and III) of collagen within the bladder wall. These methods quantitate 3 parameters of bladder ultrastructure: 1) relative volume of per cent connective tissue, 2) ratio of connective tissue to smooth muscle and 3) ratio of type III to type I collagen. These parameters have been shown to be abnormally elevated in patients with dysfunctional bladders compared to normals. The purpose of the study was to describe the ultrastructural changes that occur in the wall of dysfunctional bladders and to determine the ability of these new urodynamic techniques to detect reliably the clinical effect of these histological changes. The study included 29 consecutive patients with dysfunctional bladders necessitating bladder augmentation. All patients had upper tract changes and/or were incontinent despite treatment with clean intermittent catheterization and pharmacotherapy. Preoperative urodynamic evaluation included measurement of the total bladder capacity, pressure specific bladder volume and dynamic analysis of bladder compliance. Full thickness bladder biopsies were obtained from the dome of the bladders during augmentation. The per cent connective tissue and the ratio of connective tissue to smooth muscle were determined for all patients, and 4 unselected patients from this group had the ratio of type III to type I collagen determined. These histological results were compared to previously established normal values. All 29 patients had a decreased pressure specific bladder volume and dynamic analysis of bladder compliance, whereas 9 had a normal total bladder capacity. The per cent connective tissue was 35.19 +/- 2.84 and ratio of connective tissue to smooth muscle was 0.60 +/- 0.08 compared to normal values of 10.6 +/- 0.020 and 0.131 +/- 0.021, respectively (p < 0.05). Ratio of type III to type I collagen was also significantly elevated in the 4 samples analyzed (30.53 +/- 1.37 versus 24.00 +/- 2.50, p < 0.05). We conclude that poor storage function of poorly compliant bladders is secondary to an alteration in the connective tissue content of the bladder wall. Furthermore, these pathological ultrastructural changes are universally reflected by an abnormally low pressure specific bladder volume and dynamic analysis of bladder compliance. This strong association validates the use of these parameters and suggests that they are urodynamic indicators of a loss of elasticity in bladder wall.

Acellular bladder matrix allografts in the regeneration of functional bladders : evaluation of large-segment (> 24 cm2) substitution in a porcine model

Objectives To evaluate the use of a large‐segment (> 24 cm2) bladder substitution with porcine bladder acellular matrix allograft (BAMA) in a large animal model.