Wouter F.J. Feitz

Hypospadias: risk factor patterns and different phenotypes.

Study Type – Aetiologic (case‐referent)
Level of Evidence 2a

A rabbit model to tissue engineer the bladder.

A rabbit model was used for the evaluation of a collagen-based biomatrix of small intestinal submucosa (SIS, COOK) in comparison to a biochemically reconstructed biomatrix for bladder tissue regeneration. Rabbits underwent partial cystectomy and cystoplasty with SIS patch graft or with a biochemically defined collagen biomatrix. The grafts of the regenerated bladder wall were harvested at different intervals and tissue regeneration was evaluated. The results of the SIS and biochemically defined biomatrix grafts were comparable. At harvesting, we found five bladder stones and encrustation of the biomatrix in 21/56 animals. No stone formation was observed in the control group. The results of the molecularly defined biomatrix are thus far comparable to SIS. Both matrices show good epithelialization and ingrowth of smooth muscle cells. Both biomatrices show considerable encrustation, which appears to disappear in time. The rabbit model is suitable for bladder tissue engineering studies as it is an easy model to use. In this model, besides tissue regeneration, also some of the clinical problems are seen such as encrustation of foreign body material in the bladder. These aspects are subject for further pre-clinical studies in this animal model.

Outcome Analysis Of The Psychosexual And Socioeconomical Development Of Adult Patients Born With Bladder Exstrophy

Since sonographic evaluation of the fetus became routine, prenatally established diagnosis of multiple or severe malformations raises the question of whether a pregnancy should be terminated. To answer this question properly, all aspects concerning the life of a child born with a serious malformation, such as exstrophy of the bladder, must be considered. Therefore, more than ever an evaluation of the quality of life of these patients is necessary to be able to make a solid based decision. We studied the psychosexual and socioeconomic development of 22 adult exstrophy patients (11 men and 11 women) by a standardized personal interview, evaluation of a standard performance test SCL-90 (symptom checklist 1990) and an adapted personality score test. The latter 2 tests are well established and provide reproducible results. Based on several large scale investigations, standard scores are available. Nine women (82%) and 10 men (91%) scored better or in accordance with the standard scores. Exstrophy of the bladder does influence the psychosexual and socioeconomic development. The quality of life is hardly ever considered so poor that termination of pregnancy is a realistic alternative.

Localization and Functional Characterization of Glycosaminoglycan Domains in the Normal Human Kidney as Revealed by Phage Display-Derived Single Chain Antibodies

Glycosaminoglycans (GAG) play an important role in renal homeostasis. They are strongly negatively charged polysaccharides that bind and modulate a myriad of proteins, including growth factors, cytokines, and enzymes. With the aid of specific phage display-derived antibodies, the distribution of heparan sulfate (HS) and chondroitin sulfate (CS) domains in the normal human kidney was studied. HS domains were specifically located in basement membranes and/or surfaces of renal cells and displayed a characteristic distribution over the nephron. A characteristic location in specific parts of the tubular system was also observed. CS showed mainly an interstitial location. Immunoelectron microscopy indicated specific ultrastructural location of domains. Only partial overlap with any of seven different proteoglycan core proteins was observed. Two HS domains, one highly sulfated (defined by antibody HS4C3) and one low sulfated (defined by antibody RB4Ea12), were studied for their cell biologic relevance with respect to the proliferative effect of FGF-2 on human mesangial cells in vitro. Fibroblast growth factor 2 (FGF-2) binding was HS dependent. Addition of purified HS4C3 antibody but not of the RB4Ea12 antibody counteracted the binding and the proliferative effect of FGF-2, indicating that the HS4C3 domain is involved in FGF-2 handling by mesangial cells. In conclusion, specific GAG domains are differentially distributed in the normal human kidney and are likely involved in binding of effector molecules such as FGF-2. The availability of tools to identify and study relevant GAG structures allows the development of glycomimetica to halt, for instance, mesangial proliferation and matrix production as seen in diabetic nephropathy.

Urological Complications in Pediatric Renal Transplantation

Objective: In this study, we evaluated the urological complications and their consequences after renal transplantation in children. Materials and Methods: A retrospective study was performed concerning urological complications after kidney transplantation in children at the University Medical Center St Radboud Nijmegen from August 1977 until July 1999. The mean age of the cadaver kidney donors was 23.2 (range 1–74.3) years. Results: In this period 146 children received 183 renal allografts. Twenty–four urological complications (13.1%) were noted in 23 patients. Urinary leakage was seen in 8 cases (4.4%) and a ureteral stenosis was present in 7 cases (3.8%), 5 patients developed stones (2.7%) and 4 severe lymph leakage needing surgical treatment (2.2%). In 3 patients the urological complication induced graft loss. In cadaver kidneys from donors younger than 5 years there was no significantly increased complication rate in comparison to older cadaver kidneys [2/32 (6.3%) versus 16/125 (12.2%)]. In a subgroup of 24 patients treated for severe posterior urethral valves the complication rate was not significantly increased in comparison to the others (8.3% in the group with posterior urethral valves against 13.7% in the group without). Conclusions: Urological complications are a small threat for graft function and the results are comparable with earlier studies. Routine ultrasound can be important for early detection of problems in the postoperative period. A close observation in the postoperative care and good collaboration between pediatric nephrologist and urologist is mandatory. Sometimes, early intervention can be undertaken with the possibility of saving graft function and reducing morbidity.

Risk factors for undescended testis.

OBJECTIVE To contribute to the understanding of the etiology of undescended testis (UDT), by exploring a wide range of potential risk factors in a case-referent study. PATIENTS AND METHODS Cases and referents were recruited at five hospitals and included 200 boys with surgically corrected UDT and 629 boys with persistent middle ear effusion. Risk factor data were obtained by postal questionnaires to both parents. Clinical data were collected from medical files. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression. RESULTS The main findings include associations between UDT and familial occurrence of the disorder: OR 3.1 (95%CI 1.9-4.9), low birth weight: 2.2 (1.1-4.3), twinning: 2.2 (0.9-5.4), gestational preeclampsia: 1.9 (0.8-4.4), use of oral contraceptives after conception: 3.6 (1.0-12.5), in vitro fertilization/intracytoplasmic sperm injection treatment: 2.2 (0.8-6.0), paternal subfertility: 1.8 (0.8-4.1), and maternal occupational exposure to cosmetics: 3.0 (0.9-10.0). Subgroup analyses indicated differences in ORs for several factors between cases with (n = 92) and without (n = 103) inguinal hernia or hydrocele. CONCLUSION The findings point towards a role for genetic predisposition, placental insufficiency, and possibly exposure to specific endocrine disrupting substances in the etiology of UDT. Further research should take into account potential etiologic differences between subgroups of cases with UDT.

Genes in the Ureteric Budding Pathway: Association Study on Vesico-Ureteral Reflux Patients

Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p<0.005 were included in a follow-up study in 202 cases and 892 controls. Of the total cohort, ∼50% showed a clear-cut primary VUR phenotype and ∼25% had both a duplex collecting system and VUR. We also looked for association in these two extreme phenotype groups. None of the SNPs reached a significant p-value. Common genetic variants in four genes (GREM1, EYA1, ROBO2 and UPK3A) show a trend towards association with the development of primary VUR (GREM1, EYA1, ROBO2) or duplex collecting system (EYA1 and UPK3A). SNPs in three genes (TGFB1, GNB3 and VEGFA) have been shown to be associated with VUR in other populations. Only the result of rs1800469 in TGFB1 hinted at association in our study. This is the first extensive study of common variants in the genes of the ureteric budding pathway and the genetic susceptibility to primary VUR.

Lower urinary tract symptoms after renal transplantation in children.

PURPOSE We investigated the prevalence and nature of LUTS after renal Tx in children. The focus of the study was the presence of LUTS in children without a history of urological symptoms. We also studied the relationship between the characteristics of these patients and the occurrence of LUTS. MATERIALS AND METHODS Data were gathered using a written questionnaire, frequency volume chart, free uroflowmetry, transabdominal ultrasonography and medical records. The study group (30 patients) consisted of 9 children (30%) undergoing renal transplantation with an underlying urological disease and 21 (70%) with an underlying nephrological disease. RESULTS In the nephrological group the incidence of high capacity bladder was 75%, residual urine 50%, UTI 43%, hesitancy 38%, intermittent flow 33%, bladder pain 33%, nighttime incontinence 29%, nocturia 24%, feeling of incomplete emptying 15%, daytime incontinence 14%, straining 14%, urgency 10%, burning sensation 10% and intermittency 5%. No substantial difference in the occurrence of LUTS, UTI or high bladder capacity after Tx was found between children with an underlying urological disease and those with an underlying nephrological disease. On average, patients in both groups suffered from 3 different LUTS. CONCLUSIONS After renal Tx children with a nephrological disease demonstrated a high incidence of LUTS. The occurrence of LUTS combined with UTI and increased bladder capacity indicates that these children are at risk for development of myogenic failure. This finding emphasizes the importance of close urological followup after Tx in children with urological and nephrological disease.

Bladder augmentation: Review of the literature and recent advances.

Bladder augmentation is an important tool in the management of children requiring reconstructions for urinary incontinence or preserving of the upper urinary tract in congenital malformations. We reviewed the literature and evaluated the long-term results of enterocystoplasty in the pediatric age group and summarized techniques, experimental options and future perspectives for the treatment of these patients. For this purpose, a directed Medline literature review for the assessment of enterocystoplasty was performed. Information gained from these data was reviewed and new perspectives were summarized. The ideal gastrointestinal (GI) segment for enterocystoplasty remains controversial. The use of GI segments for enterocystoplasty is associated with different short and long-term complications. The results of different centers reported in the literature concerning urological complications after enterocystoplasty are difficult to compare because of the non-comparable aspects and different items included by different authors. On the other hand, there are more and more case reports about cancer arising from bowel segments used for bladder augmentation in recent publications. Although bladder reconstruction with GI segments can be associated with multiple complications, such as metabolic disorders, calculus formation, mucus production, enteric fistulas and potential for malignancy, enterocystoplasty is unfortunately still the gold standard. However, there is an urgent need for the development of alternative tissues for bladder augmentation.

Endoscopic intrauterine fetal therapy: a monkey model

OBJECTIVES Prenatal ultrasonographic investigations have led to an increasing number of prenatally detected abnormalities, of which a large number involves the urogenital tract. This study was performed to evaluate if endoscopic intra-amniotic access is possible in primates. METHODS In 10 midtrimester rhesus monkeys (Macaca mulatta), endoscopic intrauterine fetoscopy was performed with three access cannulas. Using a Seldinger technique, a vascular access system, and a pediatric laparoscopy set, intra-amniotic inspection was attempted. Fetal growth throughout pregnancy was monitored by ultrasonographic measurements of fetal biometry. RESULTS Intrauterine access could successfully be achieved in 10 rhesus monkeys with three cannulas. After partial amniotic fluid exchange, adequate fetoscopy was always possible. Two monkeys aborted on the second and sixth postoperative days. Serial ultrasonographic investigations for fetal biometry showed no disturbance of the intrauterine growth patterns in the remaining 8 monkeys. CONCLUSIONS We currently conclude that the rhesus monkey model for experimental intrauterine endoscopic surgery may be suitable for study of the developmental abnormalities of the genitourinary tract.