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Purpose: Deferring bladder augmentation (BA) may be desirable in a pediatric neurogenic bladder (NGB) with worsening compliance, but prior studies have questioned whether onabotulinum toxin A (BTX) demonstrates durable improvement in compliance. We present our overall experience with BTX and its role in mitigating the "at‐risk" NGB, as determined by urodynamic characteristics. Methods: A retrospective single‐institution review of all BTX procedures performed during January 2010 to October 2018 was conducted. Patients with <12 months follow‐up after first BTX injection were excluded. Urodynamic studies (UDS) were reviewed to assign National Spina Bifida Patient Registry (NSBPR) as well as institutionally developed (LCH) risk classification groups. Patients were considered "at‐risk" for BA if they had any of the following: NSBPR risk grade of intermediate or hostile; LCH risk grades indicating end‐fill pressure >25 cmH2O or detrusor sphincter dyssynergia (DSD); upper tract changes including new hydronephrosis; new or worsening vesicoureteral reflux; or other signs of a hostile urinary tract (i.e., febrile UTIs). UDS risk grades pre and post‐first BTX injection were compared in this "at‐risk" group, when available. Results: Thirty‐nine patients underwent 162 injection procedures over a median follow‐up of 65 months interquartile range (IQR 49–81). Median age at first BTX was 10 years and the median number of BTX injections per patient was 4 (IQR 2–7; range 1–12) with a median time of 6 months between injections (IQR 4–10). Twenty‐six patients were deemed "at‐risk" at the time of first BTX injection, and of those, 16 (61.5%) proceeded to BA at a median of 36 months (IQR 22.5–42). A small number (four) had BA due to upper tract changes or worsening pressures on BTX, while nine patients (five with CKD) proceeded to BA given a lack of sufficient improvement to consider BTX a long‐term viable option. Post‐first BTX UDS demonstrated downgrading of risk group in 38% and 63% using NSBPR and LCH classifications, respectively. Conclusions: Encouraging improvements in the urodynamic risk group were noted in some patients. With careful counseling and follow‐up, BTX may safely extend the time to BA in some "at‐risk" patients. [ABSTRACT FROM AUTHOR]

Pediatric patients present unique challenges in the performance and interpretation of urodynamic studies. Interpretation of urodynamics to guide clinical management at an institutional level is accepted as reliable. Challenges arise however when multi-site collaborations incorporate urodynamics into study design to determine primary or secondary outcomes or to direct decision-making. Although standardized terminology has been established by ICCS, the application of this shared language to performance and interpretation of pediatric urodynamics to across multiple sites may not be intuitive or reliable. With a primary goal of defining the care necessary to protect future renal function, the UMPIRE protocol (Urologic Management to Preserve Initial REnal function) utilizes a urodynamics-based risk stratification to determine medical management for infants with myelomeningocele. Iterative changes in the protocol are based upon the clinical progress of the enrolled children. Despite a team experienced in subtleties of urodynamics and despite efforts to minimize variability across sites, the UMPIRE study group identified several areas in which the language of urodynamics required additional clarification or creation of more explicit definitions to standardize performance and interpretation across sites. This article reviews the foundations of current urodynamics practice, describes limitations and challenges unique to pediatric studies, and the shares the humble lessons learned by the UMPIRE study group on their journey toward standardized urodynamic language for management of infants and children with myelomeningocele. [ABSTRACT FROM AUTHOR]

Animal models that have been used to examine the regenerative capacity of cell-seeded scaffolds in a urinary bladder augmentation model have ultimately translated poorly in the clinical setting. This may be due to a number of factors including cell types used for regeneration and anatomical/physiological differences between lower primate species and their human counterparts. We postulated that mesenchymal stem cells (MSCs) could provide a cell source for partial bladder regeneration in a newly described nonhuman primate bladder (baboon) augmentation model. Cell-sorted CD105/CD73/CD34/CD45 baboon MSCs transduced with green fluorescent protein (GFP) were seeded onto small intestinal submucosa (SIS) scaffolds. Baboons underwent an approximate 40%-50% cystectomy followed by augmentation cystoplasty with the aforementioned scaffolds or controls and finally enveloped with omentum. Bladders from sham, unseeded SIS, and MSC/SIS scaffolds were subjected to trichrome, H&E, and immunofluorescent staining 10 weeks postaugmentation. Immunofluorescence staining for muscle markers combined with an anti-GFP antibody revealed that >90% of the cells were GFP/muscle marker and >70% were GFP/Ki-67 demonstrating grafted cells were present and actively proliferating within the grafted region. Trichrome staining of MSC/SIS-augmented bladders exhibited typical bladder architecture and quantitative morphometry analyses revealed an approximate 32% and 52% muscle to collagen ratio in unseeded versus seeded animals, respectively. H&E staining revealed a lack of infiltration of inflammatory cells in grafted animals and in corresponding kidneys and ureters. Simple cystometry indicated recovery between 28% and 40% of native bladder capacity. Data demonstrate MSC/SIS composites support regeneration of bladder tissue and validate this new bladder augmentation model. S C 2011;29:241-250 [ABSTRACT FROM AUTHOR]

Purpose: Autologous sources of bone marrow mesenchymal stem cells and endothelial progenitor cells are attractive alternatives to cells currently used for bladder tissue regeneration. To evaluate the potential use of these cells we determined whether mesenchymal stem cells have contractile protein profiles and physiological functions similar to those of normal bladder smooth muscle cells, and determined the angiogenic potential of endothelial progenitor cells. Materials and Methods: Mesenchymal stem cells and smooth muscle cells (Lonza, Gaithersburg, Maryland) underwent proliferation and Western blot analyses. Immunofluorescence imaging was performed using antibodies against smooth muscle cell epitopes. Contractility was assessed by intracellular Ca2+ release assays and confocal microscopy after carbachol stimulation. Endothelial progenitor cells were evaluated using a chicken chorioallantoic membrane model to determine neo-angiogenic potential. Results: Western blot and immunofluorescence data showed that mesenchymal stem cells endogenously expressed known smooth muscle cell contractile proteins at levels similar to those of smooth muscle cells. Ca2+ release assays revealed that smooth muscle cells and mesenchymal stem cells responded to carbachol treatment with a mean ± SD of 8.6 ± 2.5 and 5.8 ± 0.8 RFU, respectively, which was statistically indistinguishable. Proliferation trends of mesenchymal stem cells and control smooth muscle cells were also similar. Chorioallantoic membrane assay showed the growth of vasculature derived from endothelial progenitor cells. Conclusions: Data demonstrate that mesenchymal stem cells and smooth muscle cells express the same contractile proteins and can function similarly in vitro. Endothelial progenitor cells also have the ability to form vasculature in an in vivo chorioallantoic membrane model. These findings provide evidence that mesenchymal stem cells and endothelial progenitor cells have characteristics that may be applicable for bladder tissue regeneration. [Copyright &y& Elsevier]

Purpose: We compared the remission of pediatric primary nocturnal enuresis in groups of children who used a physician advised practice plan vs a parent chosen alternative. Materials and Methods: Between January 2004 and January 2006 there were 119 patients with primary nocturnal enuresis enrolled in this prospective, nonrandomized study. For this study primary nocturnal enuresis was defined as wetting at night during sleep during any 6-month interval without any known causative problem. A total of 76 children received the physician advised treatment plan and used an alarm, oxybutynin, desmopressin, an elimination diet and a bowel program, as indicated. A total of 43 children received a parent chosen alternative treatment plan, which consisted of any single or combination of treatments involving an alarm, oxybutynin, desmopressin and an elimination diet or bowel program. Parents from each group completed an intake survey that measured functional bladder capacity using a 3-day home diary and they identified demographic variables. Followup occurred at 2 weeks and then monthly for 12 weeks to study end. Results: We found that the probability of remission by the end of the study for the physician advised treatment group was significantly higher than that of the parent choice group (88% vs 29%, Kaplan-Meier curve p <0.0001). Conclusions: The group of children who followed physician advised treatment for primary nocturnal enuresis showed significantly earlier remission of primary nocturnal enuresis than children who followed the parent choice treatment (25th percentile 2 vs 10 weeks). [Copyright &y& Elsevier]

Purpose: Current practice at our institution is to recommend tethered cord release at diagnosis to prevent the onset or worsening of symptoms. Tethered cord release is frequently performed in children younger than 3 years who often have no urological manifestations. To our knowledge there are currently no long-term data on urological outcomes in this age group. Materials and Methods: We completed a retrospective review of 475 cases of tethered cord release performed at a single institution between 1995 and 2002. Of these surgeries 173 were performed in children younger than 3 years. Clinical outcomes, and preoperative and postoperative urodynamic and radiographic studies were evaluated. Results: A total of 79 patients met study criteria. Average age at surgery was 9.6 months and average followup was 5.2 years (range 6 months to 11.2 years). At followup 49 patients (62.1%) had no urological complaints and 30 (38%) had urological problems. A total of 20 children (25.3%) had minor problems (constipation, delayed toilet training or other) and 10 (12.7%) had major problems (need for clean intermittent catheterization, febrile urinary tract infection or reflux). Of 66 patients 30 (45.5%) had abnormal preoperative urodynamics. One of 31 patients (3.2%) had hydronephrosis on preoperative ultrasound. Statistical analysis revealed that abnormal preoperative urodynamics and ultrasound were not predictive of major urological problems. Lipomatous dysraphism and preoperative musculoskeletal symptoms positively correlated with major urological problems (p = 0.0076 and 0.0484, respectively). Conclusions: The majority of children did not experience urological problems following tethered cord release. Only a small set of children had major urological problems. Children with lipomatous dysraphism and musculoskeletal symptoms were more likely to experience poor urological outcomes. [Copyright &y& Elsevier]

OBJECTIVE To evaluate small intestinal submucosa (SIS), unseeded or seeded, as a possible augmentation material in a canine model of subtotal cystectomy. MATERIALS AND METHODS In all, 22 male dogs had a 90% partial cystectomy and were then divided into three groups. At 1 month after the initial cystectomy, dogs in group 1 (unseeded, six) and group 2 (seeded, six) received a bladder augmentation with a corresponding SIS graft. The dogs in group 3 (ten) received no further surgery and were considered the surgical control group. All dogs were evaluated before and after surgery with blood chemistry, urine culture, intravenous urography, cystograms and cystometrograms. After surgery (at 1, 5 and 9 months), the bladders were examined using routine histology and immunohistochemistry. RESULTS All 22 dogs survived the subtotal cystectomy, and 18 survived their intended survival period. One dog, in group 2 (seeded), was killed at 1 month after augmentation due to bladder perforation caused by a large piece of incompletely absorbed SIS. Three other dogs (group 1, two; and group 2, one) were killed within 2 months after augmentation due to bladder obstruction by stones. Group 1 and group 2 SIS grafts had moderate to heavy adhesion, graft shrinkage, and some had bone and calcification at the graft site. Histologically, there was limited bladder regeneration in both groups. Interestingly, dogs in group 3 at 1 month after cystectomy (when group 1 and 2 received their augmentations) had severely shrunken bladders and histologically had severe inflammation, fibroblast infiltration and muscle hypertrophy. These results verify the subtotal cystectomy model. CONCLUSIONS The use of seeded or unseeded SIS in a subtotal cystectomy model does not induce the same quality and quantity of bladder regeneration that is seen in the 40% non-inflammatory cystectomy model. This study provides important insights into the process of regeneration in a severely damaged bladder. The results led us to re-evaluate the critical elements required for a complete bladder replacement using tissue-engineering techniques. [ABSTRACT FROM AUTHOR]

ABSTRACT: Purpose:: The neuropathic bladder is characterized by increased muscle mass within the bladder wall and reduced functional capability. The exact cellular mechanisms that regulate these changes have yet to be elucidated. We determine the role of basic fibroblast growth factor (bFGF) in the increased smooth muscle cell (SMC) proliferation seen in the neuropathic bladder. Materials and Methods:: Primary human bladder SMC cultures were established from patients with either normal or neuropathic bladders (3 each). Expression of bFGF, smooth muscle markers and bFGF receptor-1 were quantified by immunohistochemistry and Western blot analysis. Cell proliferation was assayed by cell count after stimulation with recombinant bFGF in the presence and absence of a neutralizing anti-bFGF antibody. Results:: Neuropathic bladder SMC expressed higher levels of bFGF than normal bladder SMC. Functional studies using exogenous bFGF demonstrated a significant dose dependent increase in cell proliferation in normal and neuropathic bladder SMC. This stimulatory effect could be completely inhibited by simultaneous addition of anti-bFGF antibodies. Also, the higher rate of baseline cell proliferation in neuropathic bladder SMC could be brought down to normal levels after treatment with anti-bFGF antibodies. The addition of exogenous bFGF showed no effect on the expression of fibroblast growth factor receptor-1 or smooth muscle phenotypic markers, suggesting that bFGF induces cell proliferation in neuropathic bladders in an autocrine fashion. Conclusions:: These novel findings support the hypothesis that bFGF is over expressed in the neuropathic bladder and directly influences an increase in SMC proliferation. [Copyright &y& Elsevier]

ABSTRACT: Purpose:: The major goals of complete primary repair of exstrophy (CPRE) are the re-creation of normal anatomy which allows bladder cycling and to reduce the number of future procedures necessary to achieve continence. It is unclear whether CPRE is associated with a higher bladder neck fistula rate than the traditional staged repair. We review a multi-institutional experience with the CPRE technique to evaluate the rate of bladder neck fistula. Materials and Methods:: A retrospective review of 18 boys and 4 girls who underwent CPRE at 4 tertiary pediatric urology referral centers during the last 6 years was performed. All pertinent technical aspects were reviewed, including timing of procedure, whether osteotomies were performed, and number of layers used to reconstruct the bladder neck and urethra. Complications were noted, especially that of bladder neck fistula. Results:: Mean followup was 22.6 months. Of the patients 14 (64%) underwent primary closure within the first 48 hours of life and only 1 required osteotomies. The remaining 8 patients underwent closure between 5 days and 3 months of age (mean 24.6 days) and all required osteotomies. Bladder neck fistula occurred postoperatively at the pubic junction in 9 males (41%). Four cases had a 2 layer closure that was covered with a single layer small intestinal submucosa onlay (Surgisis®) and no patient had a fistula. Fistulas developed in 62.5% of patients with delayed closure vs 29% of those with immediate closure (p = 0.135). Two fistulas closed spontaneously and 7 required surgical closure at a mean of 7.5 months after the fistula occurred. Conclusions:: This multi-institutional study demonstrates that bladder neck fistulas occur in almost half of patients following CPRE by experienced pediatric urologists. While spontaneous closure is possible, most will eventually require repair. The long-term implications of this finding with regard to continence and the need for additional bladder neck procedures remain to be seen. We are encouraged by the preliminary results of small intestinal submucosa coverage and will continue to evaluate its use at the time of primary exstrophy closure. [Copyright &y& Elsevier]

ABSTRACT: Purpose:: Clean intermittent catheterization (CIC) has proven successful for bladder emptying in children without genital sensation with success rates of 94% to 100% in select groups. A subset of the pediatric population requires CIC for bladder dysfunction, yet has normal genital sensation. This study was designed to assess our experience with CIC in genitally sensate children and the health related (HR) quality of life (QOL) for them and their families. Materials and Methods:: A multimodality questionnaire on the usage, learning curve and degree of difficulty of CIC was developed. The PedsQL™ 4.0 Generic Core Scales, a reliable, validated HRQOL survey developed for pediatric patients with chronic disease, was used to assess patient and parental QOL. Children in our practice with normal genital sensation and bladder dysfunction requiring CIC were contacted to complete these questionnaires. When possible, QOL data were collected from the patient (self-report) and one or both of the parents (parent-proxy report). Results:: Data for 12 males and 8 females were collected, including 30 QOL questionnaires (12 self, 18 proxy). Of the patients 80% were able to learn CIC technique in 1 clinic visit with the help of a nurse. On a 10-point scale (1—not difficult, 10—very difficult) the mean degree of difficulty for learning the CIC technique was 3.25 for males and 4.00 for females (3.55 overall). On a 10-point scale (1—uncomfortable, 10—very comfortable) mean comfort level with the CIC technique was 9.12 for females and 9.46 for males (9.33 overall). On the PedsQL 100-point scale mean QOL was 83.24 for the self-report compared to 81.78 for the parent proxy report. The QOL for normal children has previously been shown as 83 (self) to 87.61 (proxy). Conclusions:: CIC was an easy technique for most sensate children to learn in 1 visit and master in a short time. Overall comfort with the technique was excellent and few problems were encountered. Their HRQOL was comparable to that of normal children. [Copyright &y& Elsevier]

Current attempts at tissue regeneration utilizing synthetic and decellularized biologic-based materials have typically been met in part by innate immune responses in the form of a robust inflammatory reaction at the site of implantation or grafting. This can ultimately lead to tissue fibrosis with direct negative impact on tissue growth, development, and function. In order to temper the innate inflammatory response, anti-inflammatory signals were incorporated through display on self-assembling peptide nanofibers to promote tissue healing and subsequent graft compliance throughout the regenerative process. Utilizing an established urinary bladder augmentation model, the highly pro-inflammatory biologic scaffold (decellularized small intestinal submucosa) was treated with anti-inflammatory peptide amphiphiles (AIF-PAs) or control peptide amphiphiles and used for augmentation. Significant regenerative advantages of the AIF-PAs were observed including potent angiogenic responses, limited tissue collagen accumulation, and the modulation of macrophage and neutrophil responses in regenerated bladder tissue. Upon further characterization, a reduction in the levels of M2 macrophages was observed, but not in M1 macrophages in control groups, while treatment groups exhibited decreased levels of M1 macrophages and stabilized levels of M2 macrophages. Pro-inflammatory cytokine production was decreased while anti-inflammatory cytokines were up-regulated in treatment groups. This resulted in far fewer incidences of tissue granuloma and bladder stone formation. Finally, functional urinary bladder testing revealed greater bladder compliance and similar capacities in groups treated with AIF-PAs. Data demonstrate that AIF-PAs can alleviate galvanic innate immune responses and provide a highly conducive regenerative milieu that may be applicable in a variety of clinical settings. [ABSTRACT FROM AUTHOR]