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Hypospadias is a congenital defect of the penis, which occurs in one out of 200-300 newborn boys. The meatus of the urethra is not positioned at the top of the glans, but somewhere between the glans and the scrotum. Surgical correction of hypospadias is performed around their first birthday, sometimes combined with a correction of a penile curvature. The goals of treatment are a forward, straight urinary stream, a straight penis in erection and a normal penile appearance. However, puberty can cause complications due to penile growth and sexual interest is increasing during this phase. Therefore, the final outcomes of surgical corrections can only be assessed after puberty. In this thesis boys with hypospadias, operated between 1987-1993, were evaluated at the age of 18 years old to assess their long-term micturition, sexual and cosmetic outcomes in hypospadias. In general, hypospadias patients had satisfying outcomes, but more severe hypospadias - those with ameatus near the scrotum at first - have a higher chance of complications, sexual outcomes and cosmetic outcomes. Subanalysis of the group was done, revealing no negative outcomes of preoperative stimulation of the penis with testosterone, the foreskin could be preserved in mild hypospadias patients and severe hypospadias patiënt can be treated with a single-stage surgical technique (Duckett tube) with fairly good results.

Lower urinary tract dysfunction in children can have many faces. It can present with incontinenece for urine, urinary tract infections or even constipation or loosing stools. All kinds of factors influencing the function of the pelvic floor muscle tension can have an impact on the lower urinary tract functions. The recognition of these factors and the following therapy are described in some studies in this thesis. Home flow biofeedback as therapy, treatment of meatal deformaties, instructions on pelvicfloor use, colonic washout treatment for constipation are therapeutic options being discussed. Ultrasound for detection of constipation and urethral length measurement are diagnostic options being discussed against the background of urodynamic investigation in children.

Spinal dysraphism (SD) is a common name for a group of heterogeneous congenital conditions of the central nervous system, of which myelomeningocele is the most well-known form. SD has a wide spectrum of symptoms, mainly caused by neurological deficits. The bladder and pelvic floor are also affected often and problems with bladder and pelvic floor may give rise to renal damage or even failure. SD is mostly readily apparent at birth and are followed-up intensly during childhood. After the age of 18, however, many SD-patients disappear from regular follow-up. Literature on adult SD-patients is rare and it is relatively unknown what the long-term outcomes of treatments initiated during childhood are. Moreover, it is also unknown of which modalities follow-up of these patients should exist (although some recommendations are made in existing Guidelines, these are hardly being followed and are not evidence based). This thesis studies 1) what is known in the literature about upper and urinary tract outcomes in SD-patients, 2) what outcomes of treatments from the childhood period are; 3) what the outcomes with regard to bladder- and kidney dysfunction are in various subgroups of SD-patients, as well as of other organ systems; 4); with which modalities urological follow-up should be organized. The studies were done using patient data from a prospectively made dataset, retrospective cohort studies and interviews with patients and caregivers.

The first chapters of this thesis focus on the prenatal development of the kidney, with a particular focus on the development of a CSFK. We aim to unravel the process of compensatory enlargement in a CSFK. In Chapter 2, a prospective longitudinal study of normal human fetuses is described, focussing on size and growth of the fetal kidney, renal pelvis and adrenal gland. We constructed size charts with multilevel statistical analysis. In Chapter 3, we examinined timing and extent of compensatory enlargement in human fetuses with a CSFK without any other anomaly by comparing CSFK size with charts of normal kidney size. In Chapter 4, we determined glomerular size and volume of pigs with a CSFK with a 3-dimensional stereologic technique and compared this to the nephron volume and size of pigs with two kidneys. Currently, protocol biopsies or crude surrogate markers like longitudinal measurements of the glomerular filtration rate are the only clinical tools available to detect early signs of chronic allograft injury. Therefore, in Chapter 5, we studied the association between urinary CCN-2 levels and renal allograft fibrosis during the first 2 years after transplantation. Histological and biochemical data were collected from 315 kidney transplant recipients enrolled in a protocol biopsy-based clinical program. Emerging evidence also indicates a role for CCN-2 in the pathogenesis of cardiovascular disease. While being expressed only minimally in healthy tissue, CCN-2 is strongly upregulated in atherosclerotic plaques, in cardiac tissue after myocardial infarction, in cardiac fibrosis and in vascular and cardiac tissues in experimental hypertension. In Chapter 6, we investigated the association of plasma CCN-2 with cardiovascular risk and mortality in a high-risk population of patients with manifest atherosclerotic vascular disease. In Chapter 7, we administered microspheres loaded with the mTOR inhibitor rapamycin under the renal capsule and compared this with systemic delivery of rapamycin. In a wide variety of animal models, mTOR inhibitors inhibit interstitial inflammation, fibrosis, and loss of renal function associated with CKD. Although rapamycin has great potential, the use of rapamycin and other mTOR inhibitors is associated with many systemic effects. We hypothesise that a local dose of rapamycin leads to a local therapeutic dose with little systemic consequences and explored the therapeutic potential of this local drug delivery system.

Chronic renal failure and end stage renal disease (ESRD) can be life-threatening conditions. In a significant number of cases with ESRD the primary cause l is a congenital anomaly of the kidney and/or urinary tract (CAKUT). Vesico-ureteral reflux (VUR) is the most common of the CAKUT spectrum. The studies in this thesis focus on isolated VUR. Although most children grow out of VUR without serious morbidity, a subset has associated complications. Together these account for 15% of ESRD in Dutch children. An autosomal dominant inheritance pattern with reduced penetrance is seen in some VUR families. Other segregation patterns have also been described, but for most cases a multifactorial etiology is most likely. Disruption of ureter budding in mouse embryos has been shown to lead to CAKUT. Genes involved in this budding process are therefore considered to be candidate genes for VUR susceptibility. The studies in this thesis were aimed at identifying genetic risk factors for VUR and/or CAKUT. Chapter 2 presents a literature study regarding the relationship between prenatally detected hydronephrosis (PNH) and postnatal VUR. In 15% of the patients with PNH primary VUR was detected, approximately 35% had other urogenital anomalies and in 50% postnatal examinations were normal. To explore whether we could provide clinical evidence for a new hypothesis on a contributory constitutional factor to VUR predisposition, and therefore on VUR genetics, we evaluated joint hypermobility in 50 VUR patients (chapter 3). The results of this study suggest that patients with hypermobile joints may have underlying systemic laxity that might in turn contribute to VUR. In chapters 4, 5 and 6 we investigated candidate genes in the ureter budding process for their role in VUR development with varied genetic approaches. We studied a syndromal patient with severe VUR who had a complex chromosomal aberration disturbing the ROBO2 gene. ROBO2 is a protein known to have a role in the ureter budding pathway. This led us to search for mutations in this gene in 124 VUR patients. Indeed mutations were detected in two familial cases. In four families we performed a linkage study, that focused on a subset of genes in the ureter budding process and other candidate regions. We could significantly exclude a role for the majority of genes under investigation. We performed an association study of common SNPs in 44 genes in the ureter budding pathway in > 400 Dutch VUR cases and > 1400 controls. None of the SNPs were significantly associated to VUR. Common SNPs in four ureter budding genes (GREM1, EYA1, ROBO2 and UPK3A) did show a trend towards association. In a subset of VUR patients with duplex collecting systems we identified 3 patients with mutations in UPK3A that possibly contribute to their phenotype. In chapter 7 we investigated patients with renal adysplasia, another part of the CAKUT spectrum. We investigated a gene known to be involved in renal adysplasia in other populations (UPK3A) and a new candidate gene (FGF7). We studied 19 patients and identified the first known stop-mutation in UPK3A.