Three clonal types of urothelium with different capacities for replication.

OBJECTIVES: Similar to other epithelia, urothelium in vivo has a hierarchal organization of cells each with specific gradients of differentiation. While distinct cell types have been described as important in bladder cancer in vitro, clonal and proliferative capacities of normal urothelial cells have not been characterized. MATERIALS AND METHODS: Three cell types and colony types were identified from primary porcine urothelial culture. Proliferative activity, patterns of apoptosis and differentiation, colony forming efficiency and ability to change phenotype with passage were determined and compared. RESULTS: Small, T-I colonies with large flattened (type-1) cells had low levels of proliferation and high levels of apoptosis. Large T-III colonies had a central area of small (type-3) cells surrounded by type-1 and type-2 cells. Proliferation and apoptosis were asymmetrically distributed in the periphery of T-II and T-III colonies. T-III colonies proved to be significantly more clonogenic and proliferative. With appropriate induction, type-1 cells were able to proliferate upon passage and form type-3 cells, yet long-term culture demonstrated that progeny of type-1 cells appeared to have inherited a clonogenic handicap. CONCLUSIONS: Type-3 cells in the centre of T-III colonies appear to harbour stem-like qualities with a relatively low proliferative and apoptotic index at homeostasis and the ability to become highly proliferative upon passage. This study demonstrates that distinct urothelial cell types with differing clonal capacities can be isolated from the bladder and these cells may have implications for tissue engineering and carcinogenesis.

Urothelial progenitor cells: regional differences in the rat bladder.

OBJECTIVES: Because the trigone is a unique region in the caudal bladder with a higher risk of neoplasia, we hypothesized that this area would have a high proportion of progenitor cells. As yet there is no marker nor methodology to specifically isolate urothelial stem cells, and thus demonstrate multi-potential differentiation and self-renewal. Here, our goal was to evaluate the distribution of progenitor cells that carry two general major attributes of stem cells: clonogenicity and proliferative capacity. MATERIALS AND METHODS: The bladders of Fisher rats were divided into caudal and cephalic segments and primary cultures were established from the harvested urothelial cells. RESULTS: We found that colony-forming efficiency was almost 2-fold higher for cells from the caudal bladder compared to the cephalic bladder. Doubling time was significantly faster for cells harvested from the caudal bladder at initial plating. This suggested that the caudal bladder harbours a higher density of urothelial progenitor cells. With passage to p4, the differences between the upper and lower bladder were lost, suggesting selection of proliferative cells with serial passage. Based on Ki-67 staining, there was no geographical difference in cell proliferation under normal homeostatic in vivo conditions. CONCLUSIONS: These results demonstrate geographical sequestration of urothelial progenitor cells to the area of the bladder that encompasses the bladder neck and trigone, which may be a factor in pathological disparities between the trigone and remaining bladder.

Clinical utility of ureteral jets: disparate opinions.

BACKGROUND AND PURPOSE: Many renal/bladder ultrasound scans at our institution include evaluation of ureteral jets, often regardless of the indication for the study. Such jets often are absent in normal volunteers. Because these jets are of unclear clinical significance, we sought to determine if urologists and radiologists nationally agree on the clinical utility of ureteral jets. MATERIALS AND METHODS: A three-item survey was mailed electronically to a randomly selected group of urologists and radiologists asking about the physician's practice pattern and opinion of the clinical relevance of ureteral jets by percentage and on the Likert scale. Using the unpaired Student's t-test, the responses of the groups were compared. RESULTS: Responses were available from 177 physicians. Statistically significant differences were noted between urologists and radiologists for all three questions. Radiologists reported that 50% of ultrasonograms evaluate ureteral jets, compared with 29% for urologists (P < 0.01). Whereas radiologists "somewhat agreed" (2.01) that ureteral jets were clinically relevant, urologists were "indifferent" (2.77) to their clinical relevance (P < 0.01). The two groups also differed on the question of whether a routine ultrasound study should include evaluation of ureteral jets. CONCLUSIONS: Urologists and radiologists disagreed on both the necessity for evaluating ureteral jets and their clinical relevance. On the basis of jet frequency and a review of the literature, accurate evaluation of jets requires a minimum of 10 minutes. The cost of this time should be considered in light of the requesting physician's opinion of the clinical relevance of the results. Until further evidence supports their value, evaluation of jets should be excluded from routine renal/bladder sonography.

Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma.

PURPOSE: We evaluated the long-term urological complications in survivors of infant advanced stage abdominal neuroblastoma. MATERIALS AND METHODS: The records of patients who presented during an 8-year period with surgical problems related to the kidney and who had survived advanced stage (IV and IV-S) neuroblastoma were reviewed. RESULTS: Of 7 patients identified 3 had complications of obstruction from retroperitoneal fibrosis and 4 had renal cell carcinoma. In the renal cell carcinoma group 3 patients had synchronous, multifocal, bilateral tumors and 1 had a tumor in a solitary kidney. Pathological examination of renal cell carcinoma revealed oncocytoidy with solid and papillary patterns. One patient underwent bilateral nephrectomy but in the remaining 3 renal preservation surgery was performed. All 7 patients have no progression of secondary complications 2 to 8 years after initial presentation. CONCLUSIONS: Survivors of advanced stage abdominal neuroblastoma may be predisposed to long-term urological complications well after initial diagnosis. Because of the risk of renal damage from obstruction secondary to retroperitoneal fibrosis, and the propensity to have renal cell carcinoma, close long-term followup using abdominal imaging is recommended.

Urethral development in the fetal rabbit and induction of hypospadias: a model for human development.

PURPOSE: To determine whether the development of the rabbit phallus would be an appropriate model of human phallic development, we evaluated the formation of the fetal rabbit phallus and attempted to induce hypospadias pharmacologically. MATERIALS AND METHODS: New Zealand rabbit fetuses were obtained on gestational days 20 to 24, 26, 28 and 31. Sex was determined by gonadal morphology, and 6 fetuses were obtained at each age. The perineum was dissected, fixed, sectioned and stained with hematoxylin and eosin, and monoclonal antibodies against neuronal specific enolase. Two pregnant rabbits were treated with 10 mg./kg. finasteride orally daily between gestational days 19 and 28. The development of the external genitalia was compared in treated and untreated control rabbits. RESULTS: The rabbit phallus contains 2 corpora cavernosa and dorsolateral nerves similar to the human. In male and female fetuses fusion of the urethral folds progressed in a proximal to distal sequence forming a seam at the point of ventromedial fusion. In male fetuses urethral fold and ventral preputial fusion continued more distally toward the glans compared to females. Thus, in mature males the urethral meatus and ventral prepuce extended to the tip of the phallus, whereas in females the urethral meatus opened on the proximal phallus and the prepuce was deficient ventrally forming a dorsal hood. Male offspring had a significantly larger anogenital distance postnatally than female offspring. In male fetuses exposed to finasteride urethral fusion did not extend distally and the prepuce was deficient ventrally. Also, male offspring exposed to finasteride in utero had a significantly shorter anogenital distance than females and untreated control males at all ages (p <0.05). CONCLUSIONS: Fetal development of the rabbit phallus and urethra is homologous to the human. Although the gestational period is significantly shorter, the temporospatial pattern of external genitalia development is analogous in these species. Feminization of the rabbit urethra, hypospadias, can be induced by inhibiting 5alpha-reductase. Use of this animal model will allow further study of molecular mechanisms involved in urethral fusion and the evaluation of the pathophysiological processes of hypospadias.

Right intrathoracic renal ectopia: a case report and review of the literature.

We report a case of right intrathoracic renal ectopia associated with a previously unreported congenital anomaly (trisomy 21) and review of the literature.

Epithelial-mesenchymal interactions in development of the mouse fetal genital tubercle.

Epithelial-mesenchymal interactions play a central role in the development of urogenital organs. We hypothesized that normal development of the external genitalia depends upon proper mesenchymal-epithelial signaling. The mesenchyme of the adult mouse penis consists of a corpus cavernosum and proximal and distal bones. The differentiation of penile mesenchyme into bone and cartilage begins after birth and can be accelerated by androgens. After determining the sex, genital tubercles of fetal mice at gestational day 15 were removed. The genital tubercles were trypsinized and microdissected to remove the epidermis and urethra from the mesenchyme. Recombinant specimens were created by combining genital tubercle mesenchyme with genital tubercle epithelium, bladder epithelium or tail epidermis. Tissues were grafted under the renal capsule of male athymic mice. After 3 weeks of growth, grafts were removed from the kidney, weighed and stained with hematoxylin and eosin, Alcian blue and peanut agglutinin. Male and female grafts showed no difference in growth or differentiation. Intact grafts and recombinant grafts, irrespective of the epithelial source, grew significantly more than grafts of the mesenchyme only. Recombinant grafts demonstrated a significantly higher prevalence of cartilage formation and mesenchymal differentiation compared to grafts of the mesenchyme without epithelium. Since heterologous epithelium is able to induce equivalent growth and differentiation of phallic mesenchyme, epithelium carries a permissive, but critical, role in genital mesenchyme development.

Ontogeny of the male urethra: theory of endodermal differentiation.

The most widely accepted mechanism of male urethral development proposes that the urethral plate is elevated by urethral folds which fuse ventrally in a proximal-to-distal sequence. Unlike its proximal counterpart, the urethra which forms within the glans is lined by a stratified squamous epithelium and has a more controversial development. One theory supports the idea that fusion of the urethral folds extends all the way to the tip of the glans. Another theory suggests that a solid ectodermal in-growth of epidermis canalizes the glandar urethra. We hypothesized that the use of immunohistochemical staining and tissue recombinant grafting would delineate the epithelia involved and lend clues to their origin. Thirty-six human fetal phallic specimens of gestational ages 5-22 weeks were sectioned and stained immunohistochemically with antibodies raised against different cytokeratins. Evaluation of the sections showed that the urethral plate, an extension of the urogenital sinus, extended to the tip of the phallus and maintained patency and continuity throughout the process of urethral development. The entire urethra, including the glans portion, was formed by dorsal extension and disintegration of the urethral plate combined with ventral growth and fusion of the urethral folds. Sections of the distal glandar urethra showed no evidence of a solid ectodermal ingrowth. Rather, immunostaining results at different ages suggested differentiation of the endodermal urethral plate into a stratified squamous epithelium. To determine whether urothelium could be induced to express a stratified squamous phenotype, mouse fetal bladder epithelium was combined with rat fetal genital tubercle mesenchyme and grown under the renal capsule of athymic mice. The bladder epithelium differentiated into a stratified squamous epithelium. Thus, proper mesenchymal signaling may induce differentiation of urothelium into a stratified squamous phenotype, such as during development of the urethra of the glans penis.

Gastrocystoplasty: long-term followup.

PURPOSE: Gastrocystoplasty is no longer favored at many institutions due to complications, including the hematuria-dysuria syndrome and metabolic alkalosis. We reviewed our experience to determine the advantages and disadvantages of bladder augmentation using stomach body wall. MATERIALS AND METHODS: We retrospectively reviewed the medical records, urodynamic studies, x-rays and laboratory evaluations of 47 children who underwent gastrocystoplasty at our institution between 1986 and June 1997. Parents and patients were contacted by telephone for detailed interviews to validate the medical record and determine whether there had been any changes since the last visit. Followup ranged from 9 months to 11 years (mean 4.4 years). Bladder dysfunction was secondary to spinal dysraphism in 38 children. Other diagnoses included cloacal and bladder exstrophy, posterior urethral valves, a persistent urogenital sinus and bilateral ectopic ureters. RESULTS: Preoperative and postoperative ultrasound studies available for 79 renal units demonstrated a stable or improved upper tract in 75 (95%). Preoperative and postoperative serum sodium, potassium and creatinine levels showed no significant changes. Mean serum chloride decreased 2.7 mEq./l. and bicarbonate increased 3.3 mEq./l. In the 3 patients with renal insufficiency serum bicarbonate increased 8 mEq./l. Mean pressure specific bladder volume at less than 20 cm. water increased 177 cc and mean maximum bladder pressure decreased from 35 to 13 cm. water. Two-thirds of the patients had bacilluria and a fourth reported a symptomatic bladder infection. No patients had bothersome mucus or required routine bladder irrigation. Symptoms consistent with the hematuria-dysuria syndrome were present in 27% of the patients. No patients had symptoms more than once weekly. Symptoms occurred in 75% of the patients without a neurogenic bladder, such as exstrophy or posterior urethral valves, and in 14% of those with neurogenic bladder dysfunction. In 1 case a bladder stone developed 8 years after surgery. Five patients required reoperation for complications related to gastrocystoplasty. No patient had perforation. CONCLUSIONS: Our data show that even after a mean of 4.4 years gastrocystoplasty has significant advantages over intestinal augmentation, including decreased chloride reabsorption, mucous production and urinary infection, and an extremely low incidence of stones and perforation. The gastric patch is associated with metabolic alkalosis and the hematuria-dysuria syndrome, which may be avoided and medically treated with proper patient selection and close followup. The procedure should be avoided in sensate patients with sufficient bowel.

Gastrocystoplasty: is there a consensus?

The problems encountered with ileal and colocystoplasty have led to the use of the stomach for bladder augmentation, termed gastrocystoplasty. The advantages of gastrocystoplasty over intestinal segment augmentation include reduced chloride reabsorption, decreased mucus production, decreased urinary infection in the presence of acid urine, extremely low incidence of stones, and avoidance of complications from short bowel syndrome. The gastric patch provides comparable improvements in bladder volume, pressure, and continence. The thick muscular wall of the stomach facilitates ureteric reimplantation as compared with the small intestine, but the rate of stenosis and reflux may not be superior. The disadvantages of the gastric patch include complications of severe systemic alkalosis, which is usually manifest in dehydrated, renal compromised patients, and the hematuria-dysuria syndrome (HDS), which is more prevalent in patients with renal insufficiency, normal pelvic sensation, and urinary incontinence. The postoperative complication rate of gastrocystoplasty is comparable with that of other augmentation procedures and similarly warrants proper selection and close follow-up of patients. In this report we review the literature and present the results, including a discussion of the technique and the pathophysiology of its complications.

Renal deterioration in myelodysplastic children: urodynamic evaluation and clinical correlates.

PURPOSE: We determined which factors portend a higher risk of renal deterioration in the myelodysplastic child, and evaluated the sensitivity and predictive value. MATERIALS AND METHODS: We retrospectively reviewed the medical history, imaging studies and urodynamics of 90 children with spinal dysraphism. Median patient age at initial evaluation was 3 months and average followup ranged between 2 and 25 years (average 11). We evaluated the relation of urodynamic parameters and sex to upper tract changes and the resolution of these changes. RESULTS: Statistically significant relationships were identified between the urodynamic parameters of leak point pressure, compliance and detrusor-sphincter dyssynergia, and renal deterioration but not with resolution of deterioration. Boys and girls did not demonstrate a significant difference among urodynamic parameters. Female patients had a higher incidence of reflux and parenchymal loss. CONCLUSIONS: With knowledge of the inherent sensitivity, specificity and predictive value of urodynamic parameters, selective use of urodynamics will assist in identifying patients at risk of renal deterioration. Female patients with reflux are at greatest risk of parenchymal loss. We advocate early institution of intermittent catheterization in patients identified as high risk for deterioration by urodynamics.

Endoscopic treatment of pediatric urolithiasis.

Children have been slow to benefit from the improvements in stone therapy. Despite the success of less invasive techniques, open surgery for pediatric urolithiasis is still commonly practiced. The authors' goal was to evaluate the indications, efficacy, and complications of endourologic surgery in the treatment of pediatric urolithiasis. They reviewed the treatment of 53 children who had upper tract calculi. Open nephro- and ureterolithotomy were avoided in all cases. The management of 25 children whose stones were not amenable to extracorporeal shock wave lithotriopsy is presented. Seventeen children (19 stones) were treated with miniature ureteroscopes and lasertripsy. Only one (6%) of the patients required ureteral dilation, and only five (29%) needed a postoperative internal stent. Eight children with large renal calculi were treated percutaneously, without transfusion, complication, or evidence of persistent renal damage. All 25 patients were rendered stone-free. The hospital stay was shorter and secondary procedures were less common in comparison to other series of endoscopic lithotripsy. With significant experience in adult endourology and proper instrumentation, one can apply the same techniques to children and achieve equal if not greater benefit. Nephrolithiasis in children is uncommon and should be managed in an institution where endourologists and multiple treatment modalities are available.

Bladder wall pedicle wraparound sling for neurogenic urinary incontinence in children.

PURPOSE: To improve the results of current bladder neck reconstruction a modification was developed to provide tapering, circumferential compression and suspension of the bladder neck. MATERIALS AND METHODS: Nine female and 15 male patients with spinal dysraphism and incontinence, despite intermittent catheterization and pharmacotherapy, and low outlet resistance underwent surgery. The procedure involves wrapping a pedicle strip of anterior bladder wall around the bladder neck and suspending it to the pubic symphysis. RESULTS: All 9 girls are completely continent, whereas 10 boys are dry and 5 have stress incontinence after 9 to 14 months of followup. Subjective symptoms correlate with changes in leak point pressure. CONCLUSIONS: This technique is an efficacious addition to bladder augmentation in female patients with poor compliance and low outlet resistance.

Fluorourodynamic and clinical evaluation in males following construction of a Kock ileal-urethral reservoir.

OBJECTIVES: Since 1986, we have offered the option of lower urinary tract reconstruction with the Kock ileal-urethral reservoir in selected male patients requiring diversion. This study provides insight into the functional characteristics of the Kock ileal-urethral reservoir and its effect on continence. METHODS: Twenty-four of the initial 225 male patients undergoing this procedure at our institution were evaluated by fluorourodynamics within 2 years of neobladder construction. Information regarding continence was also obtained by means of a patient interview and questionnaire. RESULTS: The average resting neobladder pressure was 8.5 cm H2O (range, 0 to 18). Reservoir capacity averaged 741 cc (range, 225 to 1400). Afferent nipple failure with bilateral grade II vesicoureteral reflux was noted in 1 patient (4%). Unsatisfactory daytime continence was seen in 2 patients (8%). Unsatisfactory nighttime continence was seen in 6 patients (25%). Patient satisfaction was high with an average rating of 8.6 on a scale of 1 to 10. CONCLUSIONS: Fluorourdynamic data demonstrate a low-pressure, high-capacity reservoir with a low incidence of reflux. The rate of continence is acceptable and patient satisfaction is excellent. The Kock ilealurethral reservoir is an excellent alternative to standard diversion for the male patient undergoing cystectomy.