Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These condition are phenottypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheles, overlap between diseases and challenges in clinical diagnois complicate studies attemping to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanepric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these stategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still reperesents a challenge, both for the clinicians who attempt a precise diagnosisand for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goals to be feasible with the large multicentric collaborative groups that share the same objectives and resources.
Congenital abnormalities of the kidney and urinary tract are frequently observed in the first year of life, when they collectively represent a significant cause of morbidity and mortality. Data from birth defect registries Metropolitan Atlanta Congenital Defect Program and California Birth Defects Monitoring Program indicate an overall frequency from three to six per 1000 births, and the abnormalities impact life expectancy. Human urinary tract abnormalities are phenotypically variable and may affect several segments simultaneously, often aggregating to form complex phenotypes. Hence, clinical classification and diagnosis may be difficult. As a consequence of the overlap between anatomical defects, many investigators have opted to group renal and urologic malformations under the single label of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). This broad classification is supported by the fact that a mutation in single gene can have pleiotropic effects on the development of the urogenital tract. For example, mutation in the PAX2 gene cause the renal-coloboma syndrome, but the clinical features of the trait vary significantly between affected individuals, ranging from renal agenesis/hypoplasia to vesicoureteral reflux (VUR) and secondary obstruction. Conversely, mutation in different genes can result in similar renal phenotypes, e.g., EYA1 and PAX2 mutation both can cause the development of hypoplastic kidney. Hence, improved classification of urinary tract malformations may require understanding of primary molecular defects. A broad but clinically useful diagnostic scheme consistof classifying malformations depending on whether the kidney, the collecting system, or both are affected. This scheme stems from the fact that the upper tract (glomeruli and tubules) is derived from the metanephric mesenchyme (MM), and the lower urinary tract (collecting duct, renal pelvis, ureter)is derived from the ureteric bud. Even if this is in contrast with more recent data about the reciprocal interaction between the ureteric bud and metanephric mesenchyme, this classification can be clinically useful to partition patients with different types of urinary tract abnormalities.
Bilateral renal agenesis is a rare and fatal event, usually associated with severe oligohydramnions, which produces a characteristic clinical pattern with facial compression and pulmonary hypoplasia (potter syndrome). An estimate of the incidenceof bilateral agenesisis 0.1/1000 births. Unilateral renal agenesis is more common, although the frequencyis difficult to estimate, as it is usually clinically silent and is commonly detected as a chance observation by autopsy or by prenatal ultrasound.