Abstract
Congenital anomalies of the kidney and urinary tract, as well as primary vesico-ureteric reflux (VUR) and associated renal dysplasia, are the most relevant causes of end-stage renal failure in the pediatric population. In vivo and in vitro experimental studies have allowed the identification of several genes involved both in ureteric bud branching, ureteric elongation and insertion into the bladder, and in nephrogenesis. It has been proposed that both renal and ureteral abnormalities, as well as the associated renal hypo-dysplasia, may derive from a common mechanism as the result of a dysregulation of the normal developmental program. The large homologies between mice and the human genome suggest that the same genes could be involved both in rodent and human VUR. Furthermore, epidemiological observations suggest that not only syndromic but also isolated VUR is an inherited trait. Linkage analysis for homologous mouse genes in humans, genome-wide linkage studies in multigenerational families and association studies by polymorphisms support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. The present teaching paper is an overview of the embryology and genetics of primary VUR and associated congenital reflux nephropathy.
Highlights
Primary vesico-ureteric reflux (VUR) is a congenital defect of the urinary tract that causes urine to flow retrogradely from the bladder to the kidneys and it is not associated with any underlying neuromuscular or obstructive phenomenon [1]
The different phenotypes of renal and ureteric malformations may depend on the stage of nephrogenesis at which the alteration of the developmental program occurs: renal agenesis should be the result of the complete lack of metanephric induction by the ureteric bud; different degrees of dysplasia associated with urinary tract anomalies, such as VUR, should originate from the disruption of the normal ureteral branching and elongation, and the epithelial differentiation processes
Animal and human studies suggest that VUR and the associated renal dysplasia may result from a dysregulation of the complex gene network that regulates the normal developmental program of the kidneys and urinary tract
Summary
Primary vesico-ureteric reflux (VUR) is a congenital defect of the urinary tract that causes urine to flow retrogradely from the bladder to the kidneys and it is not associated with any underlying neuromuscular or obstructive phenomenon [1]. 2. The different phenotypes of renal and ureteric malformations may depend on the stage of nephrogenesis at which the alteration of the developmental program occurs: renal agenesis should be the result of the complete lack of metanephric induction by the ureteric bud; different degrees of dysplasia associated with urinary tract anomalies, such as VUR, should originate from the disruption of the normal ureteral branching and elongation, and the epithelial differentiation processes. Other authors identified a 13q deletion in several children affected by VUR and reported congenital anomalies of kidney and urinary tract (CAKUT)-associated locus on 13q12–22 These authors very recently described the results of cyto- and molecular genetic studies to identify a second region on chromosome 13 that is located on 13q33– 34 and is associated with CAKUT such as severe VUR and reflux nephropathy [24]. This suggests that missense changes of UP genes cannot play a dominant role in causing VUR in humans, they may be weak risk factors contributing to complex polygenic disease
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