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Background: Sacral agenesis (SA) is a rare congenital condition that refers to the absence of part or all of two or more lower sacral vertebral bodies. It can be associated with neurogenic bladder dysfunction that does not necessarily correlate with the level of spinal or skeletal defect. Patients with SA should undergo urodynamic studies (UDS) to guide lower urinary tract (LUT) management., Objective: This review aimed to update the present institutional experience since 1981 of this rare patient population with detailed, long-term follow-up of bladder and kidney function., Study Design: A single institution, retrospective, IRB-approved review was performed on patients born after January 1, 1981 with an isolated diagnosis of sacral agenesis without spina bifida, and followed with urologic involvement at Boston Children's Hospital. Records were reviewed for demographics, radiologic imaging, UDS including cystometrogram (CMG) and electromyography (EMG), surgery, and blood chemistries. Comparisons were made between groups of patients based on age at diagnosis, with specific focus on renal function and stability of neurogenic bladder lesion., Results: Forty-three patients were identified: 23 female and 20 male. Thirty-seven children (86%) had a known age of diagnosis. Nineteen were diagnosed before 2 months old, including five who were diagnosed prenatally, 11 were diagnosed between 2 and 18 months, and seven were diagnosed after 18 months. All 43 had UDS, with 24 (55.8%) studied at the time of diagnosis (Summary Table). Twenty had serial full UDS, with 30% demonstrating neurourologic instability. None developed end-stage renal disease (ESRD) or required spinal cord detethering., Discussion: Many children with SA appeared to be diagnosed prenatally or early in life; SA was mostly identified during evaluation of associated anomalies. Though UDS aid in urologic management, testing was not routinely utilized at the time of diagnosis., Conclusions: This review of long-term follow-up in SA patients showed stable LUT and renal function, with minimal risk of progression to ESRD., (Copyright © 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Purpose: Augmentation cystoplasty using gastrointestinal segments in children/adolescents with medically refractory neurogenic bladder is associated with significant complications. We evaluated an autologous cell seeded biodegradable scaffold (Tengion®) for bladder augmentation as an alternative to traditional enterocystoplasty in this population., Materials and Methods: A phase II prospective study was performed in children with neurogenic bladder due to spina bifida requiring enterocystoplasty for detrusor pressure 40 cm H2O or greater despite maximum antimuscarinic medication. Following open bladder biopsy, urothelial and smooth muscle cells were grown ex vivo and seeded onto a biodegradable scaffold to form a regenerative augment as the foundation for bladder tissue regeneration. Bladder neck sling was the only concomitant surgical procedure permitted. Bladders were cycled postoperatively to promote regeneration. Primary and secondary outcomes at 12 months included change in bladder compliance, bladder capacity and safety. Long-term assessment was done with similar outcomes at 36 months., Results: Compliance improved in 4 patients at 12 months and in 5 patients at 36 months, although the difference was not clinically or statistically significant. There was no clinical or statistical improvement in bladder capacity at 12 or 36 months in any patient. Adverse events occurred in all patients, and most were easily treated. Two patients had low cell growth following bladder biopsy, of whom 1 withdrew from the study and 1 underwent a second biopsy. Serious adverse events of bowel obstruction and/or bladder rupture occurred in 4 patients., Conclusions: Our autologous cell seeded biodegradable scaffold did not improve bladder compliance or capacity, and our serious adverse events surpassed an acceptable safety standard., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Concern in patients with bladder exstrophy after reconstruction regarding potential injury to pelvic neurourological anatomy and a resultant functional deficit prompted combined (simultaneous) cystometrography and electromyography after complete primary repair of bladder exstrophy. We determined whether complete primary repair of bladder exstrophy would adversely affect the innervation controlling bladder and external urethral sphincter function., Materials and Methods: Complete primary repair of bladder exstrophy was performed via a modified Mitchell technique in newborns without osteotomy. Postoperative evaluation included combined cystometrography and needle electrode electromyography via the perineum, approximating the external urethral sphincter muscle complex. Electromyography was done to evaluate the external urethral sphincter response to sacral reflex stimulation and during voiding., Results: Nine boys and 4 girls underwent combined cystometrography/electromyography after complete primary repair of bladder exstrophy. Age at study and time after complete primary repair of bladder exstrophy was 3 months to 10 years (median 11.5 months). Cystometrography revealed absent detrusor overactivity and the presence of a sustained detrusor voiding contraction in all cases. Electromyography showed universally normal individual motor unit action potentials of biphasic pattern, amplitude and duration. The external urethral sphincter sacral reflex response was intact with a normal caliber with respect to Valsalva, Credé, bulbocavernosus and anocutaneous (bilateral) stimulation. Synergy was documented by abrupt silencing of external urethral sphincter electromyography activity during voiding., Conclusions: After complete primary repair of bladder exstrophy combined cystometrography/electromyography in patients with bladder exstrophy showed normal neurourological findings, including sacral reflex responses, sustained detrusor voiding contraction and synergic voiding, in all patients postoperatively. These findings confirm the safety of complete primary repair of bladder exstrophy. Based on our results we have discontinued routine electromyography in these patients., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Augmentation cystoplasty is the mainstay of surgical treatment for medically refractory neurogenic bladder in patients with spina bifida. Concerns regarding an increased risk of malignancy have prompted many centers to consider routine postoperative screening. We examine the potential cost-effectiveness of such screening., Materials and Methods: A Markov model was used to compare 2 screening strategies among patients with spina bifida after cystoplasty, namely annual screening cystoscopy and cytology and usual care. Model parameters were informed via a systematic review of post-augmentation malignancy and cost estimates from published reports or government sources., Results: In a hypothetical cohort the individual increase in life expectancy for the entire cohort was 2.3 months with an average lifetime cost of $55,200 per capita, for an incremental cost-effectiveness ratio of $273,718 per life-year gained. One-way and two-way sensitivity analyses suggest the screening strategy could be cost effective if the annual rate of cancer development were more than 0.26% (12.8% lifetime risk) or there were a greater than 50% increase in screening effectiveness and cancer risk after augmentation. After adjusting for multiple levels of uncertainty the screening strategy had only an 11% chance of being cost effective at a $100,000 per life-year threshold or a less than 3% chance of being cost effective at $100,000 per quality adjusted life-year., Conclusions: Annual screening for malignancy among patients with spina bifida with cystoplasty using cystoscopy and cytology is unlikely to be cost effective at commonly accepted willingness to pay thresholds. This conclusion is sensitive to a higher than expected risk of malignancy and to highly optimistic estimates of screening effectiveness., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: A major goal of bladder exstrophy management is urinary continence, often using bladder neck reconstruction. We report our experience with bladder neck reconstruction after complete primary repair of exstrophy., Materials and Methods: Patient history, ultrasound, voiding cystourethrogram, examination using anesthesia and urodynamics were performed during a prospective evaluation. Continence was assessed using the International Children's Continence Society classification and the dry interval. Bladder capacity was measured by examination using anesthesia, voiding cystourethrogram and/or urodynamics. Urodynamics were also done to assess bladder compliance and detrusor muscle function., Results: From 1994 to 2010 we treated 31 male and 15 female patients with bladder exstrophy after complete primary repair of exstrophy. Of patients 5 years old or older bladder neck reconstruction was performed after complete primary repair in 9 of 21 males (43%) and in 3 of 11 females (27%) at a mean age of 6.3 and 8.1 years, respectively. By the International Children's Continence Society classification 6 of 12 patients (50%) were continent less than 1.5 years after bladder neck reconstruction and 2 of 9 (23%) were evaluable 1.5 years or greater after reconstruction. Median bladder capacity was 100 ml before, 50 ml less than 1.5 years after and 123 ml 1.5 years or greater after bladder neck reconstruction. Three males and 2 females emptied via an appendicovesicostomy. Two boys underwent augmentation., Conclusions: In our experience most patients with bladder exstrophy require bladder neck reconstruction after complete primary repair of exstrophy. The need for reconstruction is more common in males. Our rates of bladder neck reconstruction after complete primary repair of exstrophy and of continence after bladder neck reconstruction are similar to those in other reports., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated associated urodynamic abnormalities in toilet trained children with vesicoureteral reflux., Materials and Methods: A total of 298 toilet trained children with primary vesicoureteral reflux underwent urodynamic evaluation. Urodynamic parameters were reviewed and correlated with age, gender, presence of lower urinary tract symptoms and reflux severity., Results: Symptomatic lower urinary tract symptoms were present in 111 children (37.2%, group 1). Children with lower urinary tract symptoms had significantly decreased severity of vesicoureteral reflux compared to children without these symptoms (187 patients, group 2). The majority of the patients had normal early bladder compliance regardless of presence of lower urinary tract symptoms or reflux grade. On the other hand, decreased late bladder compliance was more common in group 1 vs group 2. Ratio of cystometric bladder capacity to expected bladder capacity was higher in group 2. Detrusor overactivity was observed in 28.5% of the children, and the incidence was significantly higher in group 1 vs group 2, and in mild vs moderate or severe reflux. Dysfunctional voiding from bladder sphincter dyscoordination was seen in 32% of children 2.5 to 4 years old with vesicoureteral reflux and lower urinary tract symptoms, compared to 8% in children 5 to 16 years old., Conclusions: The presence of lower urinary tract symptoms in children with vesicoureteral reflux correlated well with some urodynamic findings suggestive of overactive bladder and negatively correlated with reflux severity. In contrast, dysfunctional voiding was more common in younger children with reflux and lower urinary tract symptoms. These findings suggest that treatment of voiding dysfunction should be directed toward the specific type of abnormality in children with vesicoureteral reflux., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

A major goal of bladder exstrophy (BE) management is achieving urinary continence, most commonly with surgical bladder neck reconstruction (BNR). This is a report of outcome of BNR after complete primary repair of exstrophy (CPRE). At our institution, patient history, ultrasound, cystogram (VCUG) and urodynamic study (UDS) were performed during a prospective evaluation of patients with BE. Dry interval of >3 hours was used as the definition of continence and dry interval <1-hour incontinence. Bladder capacity was measured at VCUG and/or UDS. UDS was also used to assess bladder compliance. From 1994 to 2010, we cared for 47 BE patients (31 male, 15 female) after CPRE. For patients ≥3 years after CPRE, BNR was performed in 9 of 22 (41%) male and 3 of 11 (27%) female patients. Mean age at BNR was 6.3 and 5.9 years for male and female patients, respectively. The mean (±SD) bladder capacity pre-BNR was 104.8 (±20.4 mL). There was a significant increase in capacity from pre-BNR to ≥1.5 years post-BNR (P = 0.013) and from <1.5 and ≥1.5 years post-BNR (P = 0.002). In conclusion, most patients with BE require BNR after CPRE. The need for BNR is more common in male patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The new technique of complete primary repair of bladder exstrophy has offered the promise of improved bladder functional outcomes and yet longitudinal followup in patients with exstrophy who have undergone this form of closure is sparse. We present our median 5-year data on patients who have undergone complete primary repair of bladder exstrophy., Materials and Methods: The records of patients who underwent complete primary repair of bladder exstrophy were analyzed retrospectively. Patients were followed prospectively using case report forms, radiological and clinical data, and semistructured parental and patient interviews. We reviewed parameters including clinical events, scarring on renal scan, vesicoureteral reflux, surgical procedures, urodynamic studies, urinary and fecal continence status, and episodes of urinary tract infection., Results: From 1994 to 2007 complete primary repair of bladder exstrophy was performed in 32 patients. Of these patients 28 underwent closure within 72 hours of life, including 20 males and 8 females, and 4 underwent it after 72 hours at ages 7 days to 12 months. One patient underwent complete primary repair of bladder exstrophy elsewhere. Median followup was 5 years (range 1 to 13). In 32 patients a total of 193 surgical procedures were done, of which 40% were minor endoscopic cases. Six of 23 males (26%) underwent bladder neck reconstruction at a median age of 4.5 years (range 4 to 10). Two boys and 1 girl received Deflux injection to the bladder neck at ages 3 to 5 years. To date no patient has undergone bladder augmentation. Nine patients (28%) had 1 to 4 episodes of pyelonephritis and 6 had cortical defects on renal scan. A total of 30 patients were voiding or incontinent via the urethra. One patient performed clean intermittent catheterization via the urethra and 1 performed it via appendicovesicostomy. All 4 children who were at least 6 months from bladder neck reconstruction after complete primary repair of bladder exstrophy had urinary continence periods of 2 to 3 hours or greater. Parents did not report any fecal incontinence or soiling in children older than 4 years. Relative to males the females had better urinary continence and a decreased need for bladder neck reconstruction., Conclusions: Complete primary repair of bladder exstrophy has been shown to be safe and efficacious. Prospective followup in this small number of evaluable patients reveals that continence periods of more than 2 hours are possible in patients after bladder neck reconstruction. Long-term followup in patients after complete primary repair of bladder exstrophy continues to be necessary to establish the long-term effects of this procedure.

Background: With open surgery, it is difficult to access structures posterior to the bladder. The advent of laparoscopy provides a more direct approach to these structures. In this study, we report on our experience in treating these structures using minimally invasive techniques., Methods: Between 1998 and 2006, 11 patients underwent conventional or robotic-assisted laparoscopic (RAL) surgeries to treat various anomalies posterior to the bladder; 5/11 procedures were performed with conventional laparoscopy and the others utilized robotic-assistance., Results: There were no complications. Average EBL was 49.1 ml. Mean operative time was 233.3 min. Median total i.v. analgesic use was 0.9 mg/kg MSO(4). Median hospital stay was 2.0 days., Conclusions: Our study confirms the safety and feasibility of conventional and RAL surgery posterior to the urinary bladder. This minimally invasive procedure allows the retrovesical structures to be approach more directly, allows for excellent visualization of these structures and avoids the morbidity associated with open surgery., ((c) 2008 John Wiley & Sons, Ltd.)

Purpose: We compared urodynamic findings in patients who underwent prenatal closure of myelomeningocele with those of patients who underwent postnatal closure, and equivalent lower urinary tract evaluations., Materials and Methods: Urodynamic studies of 5 patients (2 boys, 3 girls) who underwent prenatal closure of myelomeningocele were compared to those of 88 patients with similar level lesions who underwent repair postnatally between 1979 and 2002., Results: All 5 patients in the prenatally treated cohort had lower lumbosacral lesions on neurological examination. These patients displayed no evidence of electromyographic activity, indicating complete denervation of the external sphincter. In comparison 34 of the 88 patients in the postnatal cohort (39%) lacked sphincter activity at newborn examination, with similar findings noted at 1-year evaluation. In terms of bladder function all 5 patients in the prenatal cohort exhibited detrusor overactivity, compared to 33 of the 88 patients (38%) in the postnatal cohort at the newborn examination, with similar findings at 1-year evaluation., Conclusions: Fetal closure of myelomeningocele is associated with a higher incidence of complete denervation of the external urethral sphincter and detrusor overactivity compared to postnatal closure. Patients who undergo this novel procedure should undergo urodynamic studies in the immediate newborn period and should be under close postnatal surveillance to document possible tethering of the spinal cord, urinary incontinence and increased detrusor pressures.

Purpose: We assessed bladder growth and dynamics following complete primary repair of bladder exstrophy (CPRE) compared to the staged approach., Materials and Methods: We reviewed the records of 16 boys and 7 girls who underwent CPRE within 3 days of life from 1996 to 2004 and compared them to the records of 8 boys and 6 girls treated with a staged repair from 1979 to 1996. Screening methods included voiding cystourethrogram, radionuclide cystogram and urodynamic study. We estimated growth curves for bladder capacity following repair in each group, and compared percent predicted bladder capacity (PPBC), compliance and detrusor overactivity between the CPRE and staged repair groups following bladder neck reconstruction., Results: Bladder capacity in the staged repair group was 69.8 ml (95% CI 46.7-104.4) immediately after bladder neck reconstruction and increased by 15.0% per year thereafter (95% CI 6.2-24.5, p = 0.002). In the CPRE group bladder capacity was 29.0 ml (95% CI 21.3-39.5) initially and increased by 28.9% per year thereafter (95% CI 17.4-41.5, p <0.001). PPBC started at 45.6% (95% CI 35.7-55.5) and increased 1.2% per year (95% CI -1.1-3.5, p = 0.29) following repair for all genders and surgery groups. Compliance was 124.4% (95% CI 22.6-310.7, p = 0.01) greater in the CPRE group at all times following repair. Detrusor overactivity was present in 0 of 19 patients in the CPRE group and 6 of 13 (46%) in the staged group (exact p = 0.002)., Conclusions: Within the CPRE group bladder stability was universal, and sphincter electromyography was normal suggesting no neuromuscular compromise of the pelvic floor. At early followup, our results suggest that PPBC is equivalent irrespective of gender or management. Further objective evaluation is needed in both groups.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an activating ligand for the epidermal growth factor receptor (ErbB1) tyrosine kinase and at least one isoform of the ErbB4 receptor tyrosine kinase, is synthesized by the smooth muscle of the human bladder wall. In this study we tested the hypothesis that HB-EGF plays a role in the bladder-wall thickening that occurs in response to obstructive syndromes affecting the lower urinary tract, possibly by acting as an autocrine smooth muscle cell (SMC) growth factor. HB-EGF was mitogenic for primary culture human bladder SMC, and cell growth in serum-containing medium was inhibited more than 70% by [Glu52]-diphtheria toxin/CRM197, a specific HB-EGF inhibitor, consistent with a physiologic role for HB-EGF as an autocrine bladder SMC mitogen. Human and mouse bladder SMC in vivo and cultured human bladder SMC expressed the primary HB-EGF receptor, ErbB1, but not mRNA for the secondary HB-EGF receptor, ErbB4, thereby identifying ErbB1 as the cognate HB-EGF receptor in the bladder wall. Reverse transcription-polymerase chain reaction analysis also demonstrated ErbB2 and ErbB3 expression in human bladder muscle tissue, suggesting the possibility of receptor cross-talk after ErbB1 activation. Urethral ligation in mice resulted in an increase in steady-state HB-EGF mRNA expression up to 24 hours in whole bladder tissue in comparison with ErbB1 and glyceraldehyde 3-phosphate dehydrogenase mRNA levels, which did not change in a demonstrable pattern. HB-EGF protein increased coordinately with HB-EGF mRNA levels. Dissection of bladder tissue into muscle and mucosal layers demonstrated that the increase in HB-EGF mRNA occurred predominantly in the muscle layer, with peak levels (13-fold higher than sham controls) occurring 12 hours after obstruction. These data support a physiologic role for HB-EGF as a mediator of hypertrophic bladder tissue growth.

Cultured rat bladder smooth muscle cells (SMC) were grown on collagen-coated silicone membranes and subjected to continuous cycles of stretch-relaxation. Semiquantitative RT-PCR analysis revealed a time-dependent increase in heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) mRNA levels after stretch, with maximal levels appearing after 4 h. Immunostaining for proHB-EGF revealed higher levels of HB-EGF protein in the stretched than in the nonstretched SMC. The ANG II receptor type 1 antagonist losartan markedly suppressed stretch-activated HB-EGF expression. ANG II levels were 3.3-fold higher in the stretch- than in the non-stretch-conditioned media. Stretch stimulation of bladder SMC that had been transiently transfected with an HB-EGF promoter-luciferase expression construct resulted in an 11-fold increase in reporter activity. Mechanical stretch induced a 4.7-fold increase in tritiated thymidine incorporation rate, and this was reduced by 25% in the presence of losartan. We conclude that mechanical stretch activates HB-EGF gene expression in bladder SMC and that this is mediated in part by autocrine ANG II secretion.