Advances in the cell biology and genetics of human kidney malformations.

In recent years there have been advances in the biology of renal malformations. Our focus is on human disease, but we will use animal paradigms when relevant. The mammalian kidney derives from two metanephric components (1-5): ureteric bud, which forms collecting ducts and uroepithelium, and renal mesenchyme, which forms nephrons. The human metanephros appears at 5 wk gestation, and glomeruli first form by 9 wk (Figure 1). Nephrons are generated until approximately 34 wk, with maturation continuing postnatally. Murine metanephroi arise 1 1 to I 2 d after fertilization, and nephrogenesis continues 2 wk postnatally. The term “kidney malformation” describes diverse anomalies (4-5). In “renal agenesis” the kidney is absent. In “renal dysplasia,” poorly branched ducts terminate in cysts and are surrounded by undifferentiated cells and metaplastic cartilage. An “aplastic” kidney is a tiny dysplastic rudiment, and the “multicystic dysplastic kidney” is distended by cysts. “Cystic dysplastic kidney” refers to a dysplastic organ with some functioning nephrons. In “renal hypoplasia” the organ is small with fewer nephrons than normal; when nephrons are large the condition is called “oligomeganephronia” (6). Lower urinary tract malformations include calyceal distortions and hypoplasia, as well as hydronephrosis and hydroureter associated with obstruction or vesicoureteric reflux. The definition of renal malformation can be extended to microscopic abnormalities such as “tubular dysgenesis,” in which proximal tubules form abnormally (7). Although polycystic diseases may present as malformations, they are disorders of terminal epithelial differentiation (8-10) and will not be discussed further in this report. Renal malformations may occur sporadically or be familial, appearing in isolation or as part of a multiorgan syndrome commonly affecting central nervous, cardiovascular, and skeletal systems (4, 1 1 ); accompanying lung hypoplasia is often secondary to oligohydramnios. Ascertainment of the occurrence of renal malformations is subject to bias: Some surveys exclude neonatal deaths; unilateral disease is often clinically silent ( 12); there is rarely access to tissue for histology; in