Stacy T. Tanaka

Pediatric Ureteroscopic Management of Intrarenal Calculi

PURPOSE Data addressing ureteroscopic management of intrarenal calculi in prepubertal children are limited. We reviewed our experience from January 2002 through December 2007. MATERIALS AND METHODS We retrospectively reviewed ureteroscopic procedures for intrarenal calculi in children younger than 14 years. Stone-free status was determined with postoperative imaging. Multiple logistic regression analysis was used to assess the influence of preoperative factors on initial stone-free status and the need for additional procedures. RESULTS Intrarenal calculi were managed ureteroscopically in 52 kidneys in 50 children with a mean age of 7.9 years (range 1.2 to 13.6). Mean stone size was 8 mm (range 1 to 16). Stone-free rate after a single ureteroscopic procedure was 50% (25 of 50 patients) on initial postoperative imaging and 58% (29 of 50) with extended followup. Initial stone-free status was dependent on preoperative stone size (p = 0.005) but not stone location. Additional stone procedures were required in 18 upper tracts. Younger patient age (p = 0.04) and larger preoperative stone size (p = 0.002) were associated with the need for additional procedures. Additional procedures were required in more than half of the stones 6 mm or larger but in no stone smaller than 6 mm. CONCLUSIONS Ureteroscopy is a safe method for the treatment of intrarenal calculi in the prepubertal population. Our ureteroscopic stone-free rate for intrarenal stones is lower than that reported for ureteral stones. Parents should be informed that additional procedures will likely be required, especially in younger patients and those with stones larger than 6 mm.

A Comparison of Open vs Laparoscopic Pediatric Pyeloplasty Using the Pediatric Health Information System Database— Do Benefits of Laparoscopic Approach Recede at Younger Ages?

PURPOSE The potential benefits of laparoscopic pyeloplasty may recede in younger age groups. We used a multi-institutional database to address the effect of laparoscopic approach on length of stay and postoperative parenteral narcotic use in specific pediatric age groups. MATERIALS AND METHODS We performed a retrospective study of 5,261 children with an ICD-9 procedure code for correction of ureteropelvic junction obstruction from the Pediatric Health Information System, a database of freestanding pediatric hospitals. Discharge dates from January 1, 2002 to June 30, 2007 were included. Laparoscopic cases were identified by ICD-9 procedure codes and hospital equipment charges. We used multivariate linear regression to investigate the effect of laparoscopic approach on length of stay and parenteral narcotic use in several age categories, including infant (1 month to less than 2 years old), preschool (2 to less than 6 years), grade school (6 to less than 10 years), preadolescent (10 to less than 13 years) and adolescent (13 to less than 19 years). RESULTS Laparoscopic approach decreased length of stay and number of parenteral narcotic pharmacy charges in the preadolescent (p = 0.03 and p = 0.005, respectively) and adolescent (p = 0.03 and p = 0.006, respectively) groups but not in any of the younger groups. CONCLUSIONS Laparoscopic approach was associated with a shorter hospital stay and decreased parenteral narcotic use in patients older than 10 years. Evolving technique may reveal less morbidity in younger patients. Future comparisons to open pyeloplasty should address specific pediatric age groups and outpatient convalescence.

Mesenchymal Stem Cell Recruitment and Improved Bladder Function After Bladder Outlet Obstruction: Preliminary Data

PURPOSE Mesenchymal stem cells have various therapeutic benefits in various organ injury models. Bladder outlet obstruction causes smooth muscle hypertrophy and fibrosis, leading to lowered compliance, increased storage pressures and renal injury. Decreased blood flow and hypoxia may contribute to obstruction related bladder decompensation. We used a mouse model to determine whether mesenchymal stem cell recruitment occurred after bladder outlet obstruction and whether this was associated with changes in bladder hypoxia, histology and function. We also identified potential chemokines involved in mesenchymal stem cell recruitment. MATERIALS AND METHODS A total of 20 female mice underwent bladder outlet obstruction. Three days later 2 million green fluorescent protein labeled mesenchymal stem cells were intravenously administered. After 4 weeks urodynamic and histological evaluation was performed. Quantitative reverse transcriptase-polymerase chain reaction was done to determine relative expression of the chemokines CCL2, CCL20, CCL25, CXCL9 and CXCL16. We simultaneously studied mice with bladder outlet obstruction only without mesenchymal stem cell injection and a control group. RESULTS In 10 of 15 surviving mesenchymal stem cell injected mice mesenchymal stem cells were identified in the detrusor, and decreased hypoxia, hypertrophy and fibrosis was seen. Nine of 10 mice with mesenchymal stem cell engraftment had improved compliance compared to those without engraftment (mean±SD 9.6±5.1 vs 3.9±2.6 μl/cm H2O, p=0.012). Polymerase chain reaction revealed a 2-fold increase in CCL2 expression but there were no significant changes in other chemokine levels. CONCLUSIONS Mesenchymal stem cell recruitment to the bladder after bladder outlet obstruction appears to be associated with increased blood flow and decreased tissue hypoxia, which may contribute to improvement in histopathological and functional parameters. Mesenchymal stem cell recruitment may be related to CCL2 over expression. Additional studies in larger samples are needed but these initial results suggest a potential role for mesenchymal stem cell based therapy for bladder outlet obstruction related bladder injury.

Endodermal Origin of Bladder Trigone Inferred From Mesenchymal-Epithelial Interaction

PURPOSE In the classic view of bladder development the trigone originates from the mesoderm derived wolffian ducts while the remainder of the bladder originates from the endoderm derived urogenital sinus. Recent molecular developmental studies have questioned the veracity of this received wisdom, suggesting an endodermal origin for the trigone. To shed further light on this issue we observed mesenchymal-epithelial interactions between trigone epithelium and fetal urogenital sinus mesenchyma to infer the trigonal germ layer of origin. MATERIALS AND METHODS Mouse trigone epithelium was recombined with fetal rat urogenital sinus mesenchyma in tissue recombinant grafts that were placed beneath the renal capsule of athymic mouse hosts. Grafts were harvested at 4 weeks. Control grafts with bladder dome and ureteral epithelium were also examined. Tissues were evaluated with hematoxylin and eosin, and Hoechst dye 33258 to confirm cell species origin. Immunohistochemistry was done with androgen receptor, broad spectrum uroplakin, dorsolateral prostate secretions and seminal vesicle secretions to differentiate prostatic and seminal vesicle differentiation. RESULTS Grafts of mouse trigone epithelium with fetal rat urogenital sinus mesenchyma yielded epithelial tissue that stained for dorsolateral prostate secretions but not for seminal vesicle secretions. Control grafts of bladder dome epithelium yielded the expected endodermal prostate differentiation. Control grafts of ureteral epithelium yielded the expected mesodermal seminal vesicle differentiation. CONCLUSIONS The consistent finding of prostatic epithelium in tissue recombinants of trigone epithelium and fetal urogenital sinus mesenchyma reinforces the hypothesis that the trigone is derived from the endoderm and not from the mesoderm, as commonly accepted.

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.

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.

Recruitment of Bone Marrow Derived Cells to the Bladder After Bladder Outlet Obstruction

PURPOSE Bladder fibrosis is an undesired end point of partial bladder outlet obstruction. In fibrotic disease of the lung, kidney, skin and heart chemokines recruit bone marrow derived cells to injured tissue. Blockade of chemokines like CCL2 results in decreased fibrosis in other organs. To our knowledge we present the first report of bone marrow derived cell recruitment to the bladder in a murine bladder outlet obstruction model. MATERIALS AND METHODS We lethally irradiated WT female mice and reconstituted their bone marrow using fetal liver cells from transgenic mice ubiquitously expressing green fluorescent protein. Periurethral collagen injection was used for bladder outlet obstruction. Obstruction was assessed by urodynamics, and bladder and kidney histological changes. Bladders were harvested 1 to 12 weeks after bladder outlet obstruction and compared to those in nonobstructed controls. The chemokine CCL2 was compared between obstructed and nonobstructed mice with reverse transcriptase-polymerase chain reaction. Green fluorescent protein expressing bone marrow derived cells were identified with immunohistochemistry and fluorescence activated cell sorting. RESULTS Bladders showed histological and urodynamic changes consistent with obstruction. CCL2 induction increased after obstruction compared to that in controls. After obstruction bone marrow derived cells were present in the urothelial and stromal layers. Activated epidermal growth factor receptor was found in cells associated with bone marrow derived cells. CONCLUSIONS Bone marrow derived cells are recruited to the bladder by bladder outlet obstruction and are present in the urothelial and stromal layers. Stromal bone marrow derived cells may have a role in hypertrophy and fibrosis. Further study of the recruitment and function of bone marrow derived cells in the bladder may provide potential targets for antifibrotic therapy.

Bladder Stromal Loss of Transforming Growth Factor Receptor II Decreases Fibrosis After Bladder Obstruction

PURPOSE Transforming growth factor-beta is a potent stimulator of extracellular matrix production. Several studies show that loss of transforming growth factor-beta signaling decreases kidney, liver and lung fibrosis. However, the role of transforming growth factor-beta signaling in bladder fibrosis is not entirely understood. We investigated the effect of stromal loss of such signaling in mice after partial bladder outlet obstruction. MATERIALS AND METHODS We performed partial bladder outlet obstruction by urethral ligation in 5-week-old female Tgfbr2(colTKO) mice. These mice were compared to WT mice with partial bladder outlet obstruction and to WT nonobstructed controls. After 4 weeks and before sacrifice urodynamics were performed. Bladder tissue was harvested, and p-Smad2 and collagen (Massons trichrome) staining were performed. RESULTS Bladder compliance was increased in partially obstructed Tgfbr2(colTKO) mice and decreased in partially obstructed WT mice. The latter had increased smooth muscle hypertrophy and increased collagen deposition between smooth muscle bundles compared to those in Tgfbr2(colTKO) mice and nonobstructed controls. Transforming growth factor-beta responsive collagen promoter activity was significantly decreased in Tgfbr2 knockout bladder stromal cells vs WT stromal cells. CONCLUSIONS Stromal loss of transforming growth factor-beta signaling decreased collagen deposition after partial bladder outlet obstruction. In contrast to collagen production by recruited macrophages, stromal transforming growth factor-beta signaling appears to be the primary source of fibrosis after partial bladder outlet obstruction. These findings further support the hypothesis that manipulating transforming growth factor-beta signaling in bladder stromal cells would provide a future avenue for neuropathic bladder and bladder fibrosis treatment.

Febrile Urinary Tract Infection After Ureteroneocystostomy: A Contemporary Assessment at a Single Institution

PURPOSE Febrile urinary tract infection represents significant morbidity in patients with vesicoureteral reflux, especially following open surgical or endoscopic treatment. The reported incidence of febrile urinary tract infection after ureteroneocystostomy varies from 10% to 24%. We investigated the incidence of febrile urinary tract infection following ureteroneocystostomy in a contemporary, single institution series. MATERIALS AND METHODS We retrospectively reviewed medical records of 395 consecutive patients undergoing ureteroneocystostomy for primary vesicoureteral reflux at our institution between 2002 and 2007. We examined demographic, diagnostic and operative data, including presence of postoperative febrile urinary tract infection. A Cox proportional hazards model was performed to assess predictors of febrile urinary tract infection following ureteroneocystostomy. RESULTS Ureteroneocystostomy was performed in 395 patients (673 ureters) at a mean age of 58 months. The most common reflux grade was III (41%). The incidence of postoperative febrile urinary tract infection was 4.6% at a mean followup of 15 months. Postoperative dysfunctional elimination syndrome was a significant predictor of febrile urinary tract infection (HR 3.8, 95% CI 1.2-12, p = 0.02), and was identified in 58 of 340 toilet trained children (15% overall). Age at diagnosis, initial presentation, age at surgery, indication for surgery, reflux grade, laterality, surgical technique and preoperative dysfunctional elimination syndrome were not predictive of postoperative febrile urinary tract infection. CONCLUSIONS The incidence of febrile urinary tract infection following ureteroneocystostomy may be lower than previously reported. The presence of postoperative dysfunctional elimination syndrome is a significant predictor of postoperative febrile urinary tract infection.

Orchiopexy for Intra-Abdominal Testes: Factors Predicting Success

PURPOSE Intra-abdominal testes can be treated with several surgical procedures. We evaluated factors influencing the outcome of orchiopexy for intra-abdominal testis. MATERIALS AND METHODS We retrospectively reviewed 156 consecutive orchiopexies performed for intra-abdominal testis, defined as a nonpalpable testis on examination and located in the abdomen at surgery. All surgical approaches were included in the study. Primary outcome was the overall success rate and secondary outcomes were success based on surgical approach, age and a patent processus vaginalis. Success was considered a testis with normal texture and size compared to the contralateral testis at followup. Multivariate analysis was performed to determine factors predictive of success. RESULTS The overall success rate of all orchiopexies was 79.5%. Median patient age at orchiopexy was 12 months and mean followup was 16 months. Of the patients 117 had a patent processus vaginalis at surgery. One-stage abdominal orchiopexy was performed in 92 testes with 89.1% success. Of these cases 32 were performed laparoscopically with 96.9% success. One-stage Fowler-Stephens orchiopexy was performed in 27 testes and 2-stage Fowler-Stephens orchiopexy was performed in 37 with success in 63.0% and 67.6%, respectively. Multivariate analysis revealed that 1-stage orchiopexy without vessel division had more successful outcomes than 1 and 2-stage Fowler-Stephens orchiopexy (OR 0.24, p = 0.007 and 0.29, p = 0.19, respectively). Neither age at surgery nor an open internal ring was significant (p = 0.49 and 0.12, respectively). CONCLUSIONS The overall success of orchiopexy for intra-abdominal testis is 79.5%. While patient selection remains a critical factor, 1-stage orchiopexy without vessel division was significantly more successful and a laparoscopic approach was associated with the fewest failures for intra-abdominal testes.