William A. Kennedy

THE MODERN ENDOSCOPIC APPROACH TO URETEROCELE

PURPOSE During the last 20 years the surgical approach to ureterocele has evolved from major open surgery to minimally invasive endoscopic puncture. We believe that the endoscopic approach decreases the need for open surgical procedures. We identified specific factors that predict the need for repeat surgery. MATERIALS AND METHODS We reviewed the charts of 60 new patients with ureterocele treated with primary endoscopic incision between 1991 and 1995. Followup ranged from 4 to 62 months (mean 20). Mode of presentation, ureterocele location, associated vesicoureteral reflux and association of the ureterocele with a duplex system were evaluated. Ureterocele wall thickness was assessed subjectively via radiographic and cystoscopic methods, and categorized as thin, intermediate and thick. RESULTS All 9 patients with a single system ureterocele had an intravesical ureterocele. No patient had associated reflux nor did any require a secondary open procedure. In 3 cases new onset ipsilateral reflux into the ureterocele spontaneously resolved. Of the 51 patients with a duplex system and associated ureterocele 19 (37%) required a secondary open procedure. The ureterocele was intravesical and ectopic in 22 (43%) and 29 (57%) cases, respectively. Reflux was associated with the ureterocele in 27 patients (53%), and 12 (44%) required a secondary open procedure. A total of 11 patients underwent ureteral reimplantation of 15 refluxing renal units and only 2 renal units required ureteral tapering. Reflux is no longer present in 14 of the 15 renal units (93%). Patients with a thick walled ureterocele required repeat puncture more frequently than those with a nonthick ureterocele. CONCLUSIONS With the use of modern endoscopic techniques children with intravesical and single system ureteroceles require secondary open surgery less frequently than those with ectopic and duplex system ureteroceles. The mode of presentation does not predict the need for a repeat open procedure. Thick walled ureteroceles require repeat endoscopic puncture more frequently than thin and intermediate walled ureteroceles.

Epidermal growth factor suppresses renal tubular apoptosis following ureteral obstruction

OBJECTIVES Acute unilateral ureteral obstruction (UUO) results in ipsilateral hydronephrosis characterized by a decrease in epidermal growth factor (EGF) mRNA expression and EGF protein levels in the distal renal tubules. UUO results in programmed cell death with increases in the characteristic markers of apoptosis. To suppress the apoptotic response during UUO, recombinant EGF was administered during renal obstruction and the ensuing molecular and histologic changes were studied. METHODS Mature Sprague-Dawley rats underwent left ureteral obstruction and the kidneys were harvested at 24, 48, and 72 hours. Markers of apoptosis included DNA laddering pattern on agarose gel electrophoresis, in situ gap labeling of fragmented DNA for quantitative apoptotic body determination, polyadenylated mRNA expression of SGP-2, and in situ hybridization for sulfated glycoprotein-2 (SGP-2) mRNA. Studies were repeated in rats following administration of 10, 20, and 40 micrograms of subcutaneous recombinant EGF on a daily basis after UUO. RESULTS Subcutaneous injection of EGF into unilaterally obstructed rats promotes renal tubular epithelial cell regeneration, as demonstrated by increased cortical mitotic activity. Systemic EGF supplementation in these unilaterally obstructed rats also resulted in a decrease in the intensity of the DNA laddering pattern associated with renal tubular apoptosis. An in situ labeling procedure to identify apoptotic nuclei in the ureterally obstructed kidneys revealed a 50% reduction in apoptosis after EGF administration. Northern blot analysis and in situ hybridization for SGP-2 mRNA or clustering gene product also revealed a decreased expression in the obstructed and EGF-treated renal parenchyma. CONCLUSIONS These data suggest that EGF, apart from its known role as a mitogenic substance for renal tubular epithelial cells, is also a critical in vivo renal cell survival factor for the developmentally mature kidney.

Renal Tubular Apoptosis after Partial Ureteral Obstruction

Partial ureteral obstruction in the weanling rat leads to hydronephrosis of the ipsilateral kidney and renal cell deletion through the process of programmed cell death known as apoptosis. The apoptotic response following partial ureteral obstruction in weanling Sprague-Dawley rats was studied using the traditional markers of apoptosis, including deoxyribonucleic acid (DNA) laddering pattern on agarose gel electrophoresis, in situ gap labeling of fragmented DNA for quantitative apoptotic body determination, polyadenylated messenger ribonucleic acid (mRNA) expression of sulfated glycoprotein-2, and polyadenylated mRNA expression of epidermal growth factor and transforming growth factor-beta. Partial ureteral obstruction resulted in a progressive increase in the intensity of DNA fragmentation associated with apoptosis during the initial 3 weeks. Quantitative apoptotic body counting revealed a 3-fold increase by week 3 of partial obstruction. This increase represented a level of apoptosis, which is 65% of that observed in complete ureteral obstruction. By week 2 of partial obstruction there was a 13-fold increase in the expression of sulfated glycoprotein-2 mRNA, as well as changes in the growth factor environment characterized by a decline in the constitutive expression of epidermal growth factor mRNA and an increase in the expression of transforming growth factor-beta mRNA. These altered levels represent changes in expression comparable to those observed during the apoptotic response following complete ureteral obstruction, although the time course is delayed by 2 to 3 weeks.

Persistent and recurrent postsurgical varicoceles: venographic anatomy and treatment with N-butyl cyanoacrylate embolization.

PURPOSE To elucidate the mechanism of persistence or recurrence of varicoceles after surgical repair by examining the venographic anatomy, and to review the efficacy of treatment of these patients with n-butyl cyanoacrylate (NBCA) embolization. MATERIALS AND METHODS From 2001 to 2007, 17 patients with persistent or recurrent varicoceles were studied by retrograde venography 4 months to 18 years after open surgical repair. All patients were then treated with NBCA glue embolization of the entire gonadal vein and the venographically identified duplications and collateral vessels, with three patients undergoing bilateral procedures. Venographic anatomy and clinical success were retrospectively analyzed. RESULTS The majority of patients (65%) exhibited duplications draining into a single left gonadal vein. Duplications were most frequently found to be confined to the pelvis and inguinal canal. Communication with other retroperitoneal veins, including the renal hilar, lumbar, iliac, and circumaortic renal vein, was relatively uncommon. NBCA embolization effectively treated the main gonadal vein as well as the duplications and communications, with only one patient developing thrombophlebitic complications. CONCLUSIONS Duplication of the gonadal vein in the pelvic or inguinal region with apparent incomplete ligation or resection is a common finding in patients with persistence or recurrence of varicocele after surgery. NBCA embolization effectively treats these duplicated vessels, resulting in a high rate of clinical success on short-term follow-up.

EVALUATION OF SONOGRAPHIC RENAL PARENCHYMAL AREA IN THE MANAGEMENT OF HYDRONEPHROSIS

PURPOSE We used quantitative parameters of renal sonography to differentiate children with significant obstruction requiring surgical intervention from those without significant obstruction who were followed conservatively. MATERIALS AND METHODS We retrospectively reviewed the records of children who underwent evaluation for hydronephrosis. Those with a history of vesicoureteral reflux, anatomical abnormalities or neurogenic bladder were excluded from study. Patients were divided according to hydronephrosis grade into groups 1-grades III and IV followed conservatively, 2-grades III and IV requiring surgical intervention, 3-unilateral grade II and 4-bilateral. All images were scanned into a computer. Renal parenchymal and pelvic area was determined using National Institutes of Health image software. Parenchymal-to-pelvic area ratios were calculated from all images. We evaluated the ability of these measurements to determine the likelihood of surgical intervention. RESULTS The records of 81 children were available for analysis. Deterioration in parenchymal area growth was a predictor of surgical intervention. Such patients had catch-up growth of the affected kidney after pyeloplasty. A parenchymal-to-pelvic area ratio of greater than 1.6 on the initial ultrasound study after birth predicted cases that would need pyeloplasty in the future (p <0.05). No patient with grade II hydronephrosis required surgical intervention. CONCLUSIONS Following serial parenchymal area on serial ultrasound is useful for evaluating children with hydronephrosis. Those with a parenchymal area below the nomogram for growth usually require pyeloplasty. A parenchymal-to-pelvic area ratio of less than 1.6 on the initial ultrasound study after birth in patients with prenatally diagnosed ureteropelvic junction obstruction or on initial ultrasound in those diagnosed postnatally indicated the need for surgical intervention in this limited series.

Bladder Neck Closure in Association with Continent Urinary Diversion

Bladder neck closure is not a standard part of continent urinary diversion. When bladder augmentation and continent urinary diversion are done simultaneously, it is frequently convenient and advantageous to leave the native bladder neck intact as long as there is a reasonable degree of intrinsic continence. Even in patients with marginal control the effect of lowering intravesical pressure and increasing intravesical volume will often produce acceptable continence. At times, particularly in patients who have undergone multiple surgical procedures involving the bladder neck, there is poor intrinsic resistance. To provide acceptable continence in these cases bladder neck closure is a necessary part of continent diversion. Between 1990 and 1993 we treated 6 male and 7 female patients, most of whom underwent simultaneous bladder augmentation and continent urinary diversion, and they had poor intrinsic outlet resistance. Patient age ranged from 8 to 22 years. Underlying diagnoses included thoracic myelomeningocele in 5 patients, bladder exstrophy in 5, bladder leiomyosarcoma in 1 and extensive pelvic trauma in 1 as well as 1 previously separated conjoined twin. Three patients had artificial urinary sphincter failure and 3 had failure of urethral sling procedures. A clean intermittent catheterization program had failed in 12 patients and all 13 had diurnal incontinence. Bladder neck and urethral resistance was evaluated using voiding cystourethrography and urodynamics to measure leak point pressure and bladder capacity. Reliable bladder neck closure is historically difficult to achieve and is best done at the time of diversion. We have had initial success in 12 of our 13 cases and subsequently in all 13 using a technique of bladder neck division, 2-layer closure and omental interposition between the bladder neck closure and urethra.

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.

Clinical Presentation and Urachal Remnant Pathology: Implications for Treatment

PURPOSE Symptomatic pediatric urachal remnants are frequently excised but to our knowledge it is unknown whether incidentally identified urachal remnants require removal. Urachal remnant excision in childhood is advocated to avoid future malignancy. Urachal anomalies that contain fibrostromal tissue without epithelium may have lower malignant potential and not require excision. In contrast, lesions with epithelium may have increased potential to undergo malignant transformation. We examined whether incidentally identified urachal remnants would be less likely to contain epithelial elements and not require removal. MATERIALS AND METHODS At our institution 29 patients underwent surgical excision of a urachal anomaly from 1999 to 2008. We retrospectively investigated the presentation mode, radiographic findings, associated genitourinary abnormalities, operative approach, tissue pathology, complications and followup in each patient. RESULTS The male-to-female ratio was 1.2:1. Patient presentation was incidental (5) or symptomatic (24). Symptomatic presentations included umbilical discharge without omphalitis in 13 cases, umbilical discharge with omphalitis in 7, omphalitis without umbilical discharge in 3 and urinary tract infection in 1. The epithelial types identified were transitional, gastrointestinal, squamous, metaplastic and mixed. Epithelium was present on pathological analysis in 3 of 5 patients who presented incidentally and in 17 of 24 who presented symptomatically. Statistical analysis showed no association between presentation mode and pathology (p = 0.63). Five patients 4 weeks to 2.5 months old had vesicoureteral reflux on voiding cystourethrogram for urachal remnant evaluation. CONCLUSIONS Analysis of 29 patients with urachal anomalies showed no association between incidental presentation and fibrostromal pathology. Patients presenting without symptoms were as likely to have epithelial elements in the urachal remnant as those presenting with symptoms. We could not define treatment recommendations for incidentally identified urachal remnants based on predicting the histopathological composition.

SERIAL FOLLOWUP OF THE CONTRALATERAL RENAL SIZE IN CHILDREN WITH MULTICYSTIC DYSPLASTIC KIDNEY

PURPOSE Multicystic dysplastic kidneys have negligible renal function and the contralateral kidney (solitary kidney) frequently exhibits abnormalities that may affect growth. We previously showed that nomograms related to renal size constructed from digitalized ultrasonographic measurements of renal parenchymal area are a sensitive measure of renal growth and correlate with functional mass. We assess the age-dependent characteristics of compensatory renal growth in infants and children with multicystic dysplastic kidneys by construction of a growth curve for the contralateral kidney, assess these characteristics in comparison to normal renal growth of right and left kidneys, analyze the extent of compensatory renal growth and evaluate abnormal growth in solitary kidneys in infants and children. MATERIALS AND METHODS From 1988 to 2000 we reviewed 152 serial sonograms from 48 patients with a diagnosis of multicystic dysplastic kidneys. We also reviewed 209 renal sonograms in patients whose studies, done for other purposes, showed normal bilateral kidneys. Using computer planimetry, parenchymal area and pelvicaliceal area were determined after digitalization of ultrasound images. Parenchymal area was calculated by parenchymal area minus pelvicaliceal area and expressed as a mean of 3 measurements. A parenchymal area growth curve was generated for the contralateral kidney in the multicystic dysplastic kidney group from birth to 216 months, and for right and left normal kidneys from birth to 338 months. Data were plotted as mean parenchymal area +/- 2 SD on a nomogram generated by linear regression. Differences in parenchymal area between normal right and left kidneys, between normal kidneys and the contralateral to multicystic dysplastic kidney were analyzed by unpaired Student t test. RESULTS Of the 48 patients with multicystic dysplastic kidneys 36 had contralateral normal kidneys and 12 (25%) had a contralateral abnormality. Of the 12 cases 4 and an additional 5 without an identified abnormality (9 of 48) or 18.7% had solitary kidneys 2 SD below the normal growth curve for total parenchymal area, indicating a smaller than expected increase in compensatory renal growth. Conversely, 8 of 12 including 1 with grade V reflux into a solitary kidney exhibited normative compensatory renal growth. Left normal kidneys demonstrated a small but statistically significantly larger parenchymal area throughout growth. Solitary kidneys did not demonstrate growth differences associated with side. Solitary kidneys showed accelerated growth from 0 to 22 months while normal kidneys showed accelerated growth from 0 to 15 months. CONCLUSIONS Nomograms constructed from ultrasonographic measurements of renal parenchymal area may be useful for assessing abnormal renal growth in solitary kidneys. Patients with solitary kidneys identified by conventional ultrasonographic measurement as normal may not exhibit expected growth. Clinical decision making may be improved by identification of solitary kidneys at risk for poor growth.

Results of a 2-Year Multicenter Trial of Endoscopic Treatment of Vesicoureteral Reflux With Synthetic Calcium Hydroxyapatite

PURPOSE With no FDA approved material available for endoscopic treatment of vesicoureteral reflux, in 2001 we began a prospective multicenter trial of synthetic calcium hydroxyapatite as a subureteral bulking agent in children with traditional indications for surgical repair. MATERIALS AND METHODS A total of 98 patients (155 ureters) with grades II to IV reflux were enrolled at 10 sites in the United States to obtain 86 patients with completed protocol end points at 3 months. Of the 86 patients 74 underwent renal and bladder ultrasonography, blood count and serum chemistry analysis, and VCUG at 1 year. A total of 46 patients (47%) completed 2-year study end points, including VCUG. RESULTS At 1 and 2 years 24 of the 74 patients (32%) were cured. Ureteral cure rates were 46% and 40% at 1 and 2 years, respectively. With 35 patients treated and 85% compliance with the required 2-year VCUG the primary center achieved 2-year cure rates of 66% of patients and 72% of ureters. CONCLUSIONS Synthetic calcium hydroxyapatite is a safe, durable and effective material for endoscopic treatment of VUR. Increased experience with the injection of synthetic calcium hydroxyapatite yields improved results.