Innervation pattern of the unclosed detrusor muscle in classic bladder exstrophy: a study of patients with urothelial overexpression of nerve growth factor.

PURPOSE: An overexpression of nerve growth factor (NGF) in the urothelium is discussed to lead to neuronal hyperinnervation of the bladder detrusor. The aim was to assess the sensory and sympathetic innervation of the detrusor in unclosed exstrophic bladders patients with known overexpression of NGF in the urothelium. METHODS: Full-thickness bladder biopsies were prospectively obtained from 34 infants at delayed primary bladder closure between 01/2015 and 04/2020. The bladder biopsies were immunohistochemically stained with antibodies against S100, calcitonin gene-related peptide (anti-CGRP), Neurofilament 200 (anti-NF200), and tyrosine-hydroxylase (anti-TH). Specimens from 6 children with congenital vesicoureterorenal reflux (VUR) served as controls. RESULTS: There was no statistically significant difference in nerve fiber density in any of the immunohistochemical assessments (anti-S100 [p = 0.210], anti-CGRP [p = 0.897], anti-NF200 [p = 0.897]), and anti-TH [p = 0.956]) between patients with BE and patients with VUR. However, we observed a trend toward lower nerve fiber densities in exstrophic detrusor. CONCLUSION: Overall our results showed an unharmed innervation pattern in this cohort but a lower density of nerve fibers in the detrusor compared to controls. Further studies in patients after successful primary closure are needed to clarify the potential impact of the urothelial overexpression of NGF modulating the innervation pattern in exstrophic bladders.

Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates LZTR1 in Disease Formation.

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well. METHODS: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2. RESULTS: The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants (NR1H2, GKAP1), four candidate genes with autosomal-recessive biallelic variants (AKR1B10, CLSTN3, NDST4, PLEKHB1) and one candidate gene with suggestive uniparental disomy (SVEP1). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in LZTR1 (c.978_985del, p.Ser327fster6) and in SLC7A4 (c.1087delC, p.Arg363fster68). CONCLUSIONS: According to previous studies, our study further implicates LZTR1 in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.

Ureterocystoplasty in Boys with Valve Bladder Syndrome-Is This Method Still up to Date?

Boys with valve bladder syndrome (PUV) require adequate treatment of the lower urinary tract to preserve renal function and improve long-term outcomes. In some patients, further surgery may be necessary to improve bladder capacity and function. Ureterocytoplasty (UCP) is usually carried out with a small segment of intestine or, alternatively, with a dilated ureter. Our aim was to evaluate the long-term outcomes after UCP in boys with PUV. UCP had been performed in 10 boys with PUV at our hospital (2004-2019). Pre- and postoperative data were evaluated in relation to kidney and bladder function, the SWRD score, additional surgery, complications, and long-term follow-up. The mean time between primary valve ablation and UCP was 3.5 years (SD ± 2.0). The median follow-up time was 64.5 months (IQR 36.0-97.25). The mean increase in age-adjusted bladder capacity was 25% (from 77% (SD ± 0.28) to 102% (SD ± 0.46)). Eight boys micturated spontaneously. Ultrasounds showed no severe hydronephrosis (grade 3-4). The SWRD score showed a median decrease from 4.5 (range 2-7) to 3.0 (range 1-5). No conversion of augmentation was required. UCP is a safe and effective approach to improve bladder capacity in boys with PUV. In addition, the possibility of micturating naturally is still maintained.

Open Pyeloplasty in Infants under 1 Year-Proven or Meaningless?

The use of minimally invasive surgery (MIS) to treat ureteropelvic junction obstruction (UPJO) in children has significantly increased. Nowadays, open pyeloplasty (OP) seems to lose importance. The aim of this study is to evaluate the safety and efficacy of OP in infants < 1 year. Medical records of patients < 1 year with UPJO who had undergone retroperitoneal OP (January 2008-February 2022) at our institution were retrospectively analyzed. Included patients were operated on according to a modified Anderson-Hynes technique. All clinical, operative, and postoperative (1 month-5 years' follow-up) data were collected. Additionally, a nonvalidated questionnaire was sent to the patients/parents. A total of 162 infants (124 boys) met the inclusion criteria. The median age at surgery was 3 months (range: 0-11 months). The median operation time was 106 min (range: 63-198 min). None of the patients had severe surgical complication (Clavien-Dindo > 3). The nonvalidated questionnaire showed a high impact of quality of life. Follow-up was in median 30.5 months (0-162 months). OP is still a reliable procedure with good long-term results especially in infants < 1 year of age, which can be performed in a variety of centers.

[Between wish and reality: more efficiency through increased outpatient procedures in paediatric urology]. / Zwischen Wunsch und Wirklichkeit: Mehr Effizienz durch Ambulantisierung von Eingriffen in der Kinderurologie.

The "outpatientisation" of procedures is gaining more and more interest. According to a report published by the German research institute IGES, more than 2000 procedures will be included in the catalogue for outpatient surgery in the future. This also means a significant increase in the number of procedures that can be performed on an outpatient basis in the field of (paediatric) urology. However, the feasibility, especially in paediatric urology, depends on many specific personnel, organisational and structural conditions.

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy.

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.

Is Vesicostomy Still a Contemporary Method of Managing Posterior Urethral Valves?

In boys with posterior urethral valves (PUVs) the main treatment aim is to preserve long-term bladder and renal function. To determine the effectiveness of secondary vesicostomy in boys with PUVs, the medical records of 21 patients with PUV (2010-2019), divided into two groups (group I: valve ablation; group II: secondary vesicostomy), were reviewed regarding the course of serum creatinine, renal ultrasound, voiding cystourethrogram, urodynamics, postoperative complications, need of further surgery, and long-term solution. The median age of all patients at first follow-up was 11 (9-13) months and at last follow-up 64.5 (39.5-102.5) months. Despite a significant difference of the SWDR score (shape, wall, reflux, and diverticula) (p = 0.014), both groups showed no significant differences preoperatively. Postoperatively, serum creatinine (p = 0.024), grade of vesicoureteral reflux (p = 0.003), side of upper tract dilatation (p = 0.006), side of megaureter (p = 0.004), and SWDR score (p = 0.002) were significantly decreased in group II. Postoperative urodynamic measurements showed comparable results in both groups. Stoma complications were found in three (20%) patients (group II). Eight (53.3%) patients already received a closure of the vesicostomy. Seven out of eight (87.5%) patients were able to micturate spontaneously. Vesicostomy remains a reliable treatment option for boys with PUV to improve bladder function and avoid further damage to the urinary tract.

Delayed primary closure of bladder exstrophy without osteotomy: 12 year experience in a safe and gentle alternative to neonatal surgery.

BACKGROUND: Successful primary closure of bladder exstrophy is of utmost importance for bladder capacity and urinary continence. We evaluated our concept of delayed primary closure that challenges the role of neonatal surgery, pelvic osteotomy, and perioperative pain management. MATERIAL AND METHODS: We reviewed the medical records of patients with classic bladder exstrophy (CBE) who had undergone delayed primary closure without osteotomy at our institution between January 2008 and May 2020. Data to be analyzed included patient demographics, intraoperative pelvic laxity, blood transfusion, postoperative ventilation time, requirement of pain medication, time to full feeds, length of ICU stay, postoperative complications, and total hospital stay. RESULTS: 66 patients (44 boys) met the inclusion criteria. Mean age at surgery was 64.8 days (SD±24.7). Pelvic approximation < 5 mm was possible in 66 (100%) patients. Blood transfusion was required by 31 (47%) patients. 14 (21.2%) patients needed postoperative ventilation for a mean time of 2.7 h. 45 (68.2%) children required intravenous opioids in addition to an epidural catheter. Oral feeding started on average 17.6 h after surgery. Mean ICU stay was 1.3 day. The initial success rate of delayed closure was 93.9%. None of the patients had bladder dehiscence. Girls developed more often minor postoperative complications than boys (m/f: 12 [27.3%] vs. 8 [36.4%]. Mean overall time of hospitalization was 19 days (13-34 d). CONCLUSION: Delayed primary closure of CBE without osteotomy but with continuous epidural blockage is a safe and promising procedure that has crucial advantages in the pre- and postoperative management of CBE. LEVEL OF EVIDENCE: Level III.

Congenital Heart Defects in Patients with Classic Bladder Exstrophy: A Hitherto Neglected Association?

INTRODUCTION: Classic bladder exstrophy (BE) is regarded as an isolated malformation without any further anomalies, but some studies have indicated a higher incidence of cardiac anomalies. This cross-sectional study is planned to evaluate the prevalence of congenital heart defects (CHDs) and the clinical relevance for patients with BE admitted for primary closure. MATERIALS AND METHODS: Patients were prospectively recruited between March 2012 and January 2019. Patients' profiles including demographic data, results of transthoracic echocardiography (TTE), as well as essential peri- and postoperative data were assessed. RESULTS: Thirty-nine (25 boys and 14 girls) patients with BE (median age 61 days) underwent delayed primary bladder closure. Thirty-seven (24 boys and 13 girls) patients had received TTE 1 day before surgery. CHD was detected in 7 (18.9%) out of the 39 patients, but no clinical differences between patients with and without CHD were observed peri- or postoperatively. DISCUSSION AND CONCLUSION: This prospective systematic evaluation shows an even higher rate of CHD in patients with BE than assumed previously. Although peri- and postoperative outcome did not differ between patients with and without CHD, we consider TTE an important additional method for ensuring a safe peri- and postoperative courses and a short- and long-term care for patients with CHD.

Persistent urothelial differentiation changes in the reconstructed exstrophic bladder: Congenital or acquired dysfunction of the epithelial barrier?

BACKGROUND: We have previously characterised the urothelium from infants with classic bladder exstrophy (CBE) for the expression of urothelial differentiation-associated markers. We found abnormal expression patterns of uroplakin 3a, cytokeratin 13, cytokeratin 20 and claudin 4 in the majority of bladder biopsies taken at the time of primary bladder closure. Abnormal urothelial differentiation results in a compromised urothelial barrier with potential implications on bladder development and the success of reconstructive surgery. OBJECTIVE: To investigate whether the urothelial differentiation changes observed in the unclosed exstrophic bladder persist after successful primary exstrophy repair. DESIGN, SETTING AND PARTICIPANTS: From 2005 to 2018 bladder biopsies from 115 children with CBE obtained at the time of primary bladder closure (n = 67, median age: 8.1 weeks) and during secondary procedures aimed at achieving continence (n = 48, median age: 6.8 years) were prospectively collected. Following histological assessment immunohistochemistry was used to investigate the expression of uroplakin 3a, cytokeratin 13 and 20 and claudin 4, well-characterized markers associated with the terminally-differentiated, fully functional urothelial phenotype. The urothelium from 16 children with VUR and with non-refluxing disorders of the urinary tract served as controls. RESULTS: Tissue specimen from 100 children were included in the analysis. Only 32% of bladder specimens from children having undergone successful primary bladder closure in early infancy displayed a fully differentiated urothelial phenotype with regular expression of all 4 markers. The remaining bladders revealed irregular or absent marker expression suggesting abnormal urothelial differentiation. 86% of the samples had inflammatory, proliferative or metaplastic histological changes. CONCLUSION: Our results suggest persisting urothelial differentiation changes in two-thirds of exstrophic bladders following successful bladder closure in early infancy. Despite some limitations, the findings provide a platform for translational studies into the role of the urothelium for the developmental potential of the exstrophic bladder and the success of reconstructive surgery.

Evaluation of Undescended Testes in Newborns: It Is Really Simple, Just Not Easy.

INTRODUCTION: The evaluation of the testicular position in newborns is important to ensure timely initiation of therapy. The aim of our study was to assess the reliability of a routinely performed screening examination. PATIENTS AND METHODS: Newborns were examined by a pediatrician between 48 and 72 h after birth. Boys with suspected cryptorchidism were double-checked by a pediatric urologist within 24 h. RESULTS: 1,181/2,353 children included in the study between June 2015 and December 2017 were male. Eight hundred sixty-one boys could be included in this analysis; 5.8% (n = 50) were diagnosed with undescended testis (UDT) by the pediatrician. 30/50 boys were double-checked at the Department of Pediatric Urology. Forty percent (20/50) were lost to follow-up. In 43% (13/30), the diagnosis could be confirmed. Three former studies had shown a relevant discrepancy in the results of the diagnosis of UDT made by health care providers and urologists/pediatric surgeons. To our knowledge, this is the first study evaluating the testicular position in male newborns in such a large prospective birth cohort study by physicians with ranging expertise within 1 day. CONCLUSION: Further treatment for UDT is based on clinical examination. Ours and previous studies can clearly show the various findings in boys suspected having UDT. Therefore, it is essential that the diagnosis is confirmed by a specialist before a therapy is initiated.

[Juvenile granulosa cell tumor-Testicular tumor of the very young : Report of three cases and contemporary recommendations]. / Der juvenile Granulosazelltumor ­ der Hodentumor der Kleinsten : Aktuelle Handlungsempfehlungen anhand von drei Kasuistiken.

Juvenile granulosa cell tumor of the testis is a relevant differential diagnosis regarding testicular neoplasia of the very young. This benign lesion requires surgical treatment. Metastases or recurrences have not been described in literature. We present three different cases and give recommendations for diagnosis and treatment.

SLC20A1 Is Involved in Urinary Tract and Urorectal Development.

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.

Treatment Strategies and Outcome of the Exstrophy-Epispadias Complex in Germany: Data From the German CURE-Net.

Introduction: To evaluate the impact of reconstructive strategies and post-operative management on short- and long-term surgical outcome and complications of classical bladder exstrophy (CBE) patients' comprehensive data of the multicenter German-wide Network for Congenital Uro-Rectal malformations (CURE-Net) were analyzed. Methods: Descriptive analyses were performed between 34 prospectively collected CBE patients born since 2009, median 3 months old [interquartile range (IQR), 2-4 months], and 113 cross-sectional patients, median 12 years old (IQR, 6-21 years). Results: The majority of included individuals were males (67%). Sixty-eight percent of the prospectively observed and 53% of the cross-sectional patients were reconstructed using a staged approach (p = 0.17). Although prospectively observed patients were operated on at a younger age, the post-operative management did not significantly change in the years before and after 2009. Solely, in prospectively observed patients, peridural catheters were used significantly more often (p = 0.017). Blood transfusions were significantly more frequent in males (p = 0.002). Only half of all CBE individuals underwent inguinal hernia repair. Cross-sectional patients after single-stage reconstructions showed more direct post-operative complications such as upper urinary tract dilatations (p = 0.0021) or urinary tract infections (p = 0.023), but not more frequent renal function impairment compared to patients after the staged approach (p = 0.42). Continence outcomes were not significantly different between the concepts (p = 0.51). Self-reported continence data showed that the majority of the included CBE patients was intermittent or continuous incontinent. Furthermore, subsequent consecutive augmentations and catheterizable stomata did not significantly differ between the two operative approaches. Urinary diversions were only reported after the staged concept. Conclusions: In this German multicenter study, a trend toward the staged concept was observed. While single-stage approaches tended to have initially more complications such as renal dilatation or urinary tract infections, additional surgery such as augmentations and stomata appeared to be similar after staged and single-stage reconstructions in the long term.

[Anti-reflux surgery in infancy: contra]. / Antireflux-Operation im ersten Lebensjahr, wenn ja, wann und wie? Kontra OP.

The current management of vesicoureteral reflux (VUR) in infants remains controversial. Parameters such as high spontaneous resolution rates even in high-grade reflux in up to 45 %, associated renal hypo-/dysplasia in boys in up to 30 % and immature bladder function characterise the condition in early life. In this context, the reflux per se has become less important. This makes it all the more surprising that endoscopic treatment is recommended in recent papers to eliminate or downgrade the reflux in infants as an alternative to conservative treatment regimes. Compared with antibiotic prophylaxis, there is no difference in outcomes regarding new episodes of urinary tract infections or renal scarring. On the other hand, the necessity of anaesthesia, considerable reflux recurrence rates and the risk of obstruction in the short and long-term follow-up must be taken into consideration. Minimally-invasive anti-reflux surgery techniques are feasible also in infants. However, in due consideration of the high spontaneous resolution rates of reflux during the first 12 to 15 months of life and the fact that bladder function is still immature at that age, they should not be used as routine interventions.

Ureteroureterostomy in patients with duplex malformations: does a large diameter of the donor ureter affect the outcome?

INTRODUCTION: Ureteroureterostomy is a commonly adopted, minimally invasive approach in the management of duplex anomalies requiring diversion, e.g., ectopic upper pole ureters. OBJECTIVE: The authors hypothesized that a large diameter of the donor ureter could affect the outcome of this procedure. STUDY DESIGN: Forty-two patients from two centers were retrospectively reviewed. To compare patients with small (group 1) vs large donor ureters (group 2), they were split at the median of the sonographically measured diameter at the level of the future anastomosis (n = 20 < 1.2 cm, mean 0.71 cm vs n = 22 ≥ 1.2 cm, mean 1.75 cm; P < 0.001) Figure. Ureteroureterostomy was performed in an end-to-side fashion with the donor ureter being tapered if required. RESULTS: There was no significant difference in operation time (127 vs 121 min; P = 0.59) or duration of hospital stay (4.15 vs 4.09 days; P = 0.89) or number of postoperative complications (3 febrile urinary tract infections [fUTIs] in group 1 and one fUTI in group 2, P = 0.33). Reoperations during follow-up (1 stump resection and 2 endoscopic vesicoureteral reflux procedures) occurred exclusively in group 1 (P = 0.22). The mean pre-operative hydronephrosis grade of the affected moiety was higher in group 2 compared with group 1 (mean 2.73 Society for Fetal Urology classification [SFU] vs 1.65, P < 0.001). During follow-up, the mean hydronephrosis grade in group 2 improved from 2.73 to 1.36 SFU (P = 0.0011). In patients from group 1, the mean hydronephrosis grade remained relatively unchanged, from 1.65 to 1.35 SFU (P = 0.4). DISCUSSION: After its first description in 1928, it took almost 40 years for ipsilateral ureteroureterostomy to become a widely adopted technique in the management of duplex malformations, especially for obstructive or ectopic upper pole moieties. Whereas it has been recently shown that the upper pole function does not seem to matter, there are still only narrative reports about the influence of the donor ureter diameter contributing to potential complications such as a de novo hydronephrosis of the receiving ureter with potential damage of the healthy moiety or the persistence of a pre-operatively marked hydronephrosis. While the study data are retrospective, the authors could demonstrate that a ureteral diameter of ≥1.2 cm is not factoring adversely into the occurrence of postoperative complications. CONCLUSION: A donor ureter diameter ≥1.2 cm in ureteroureterostomy was not associated with a higher complication rate or worse outcome considering further fUTIs or reoperations. The postoperative reduction in hydronephrosis grade was more pronounced in patients with large donor ureters with disappearance of the pre-operative significant difference between the two groups.