Chloride and fluid secretion in polycystic kidney disease.

One of the more remarkable sights in the practice of nephrology is the end-stage kidney in polycystic kidney disease (PKD). Grossly enlarged to four to eight times the size of a normal kidney, its surface is covered with multiple dark and clear cysts ranging in size from microscopic to >6 cm in diameter and containing more than 250 ml of fluid. Sectioning of the kidney reveals that these cysts arise throughout the parenchyma. In fact, fluid trapped within the cysts may constitute more than 75% of the volume of the organ. Despite the spectacular appearance of the kidney and the fact that autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, potentially lethal genetic diseases known, little systematic research on the cellular mechanisms of the disease was earned out until the past two decades. However, in that period of time, the growth of knowledge of this disease has been almost exponential. Two of the genes involved, PKD1 and PKD2, have been identified and cloned (1-5). Mutations of these genes account for more than 95% of the patient population. The structures of the proteins that the two genes encode have been established, and work to determine their functions is under way (1-5). The accumulation of fluid within the cysts has been shown to be due in large measure to fluid secretion, and the major mechanism driving that secretion, transepithelial chloride secretion, has been identified. Ironically, this contrasts with cystic fibrosis, another genetic disease involving chloride and fluid transport. In the latter disease, chloride secretion is diminished by malfunction of the membrane protein, known as cystic fibrosis transmembrane conductance regulator (CFTR) (6). In contrast, that same protein functions all too well in ADPKD, and the epithelial cells lining the cysts have reversed their dominant function from absorption of solute and fluid to secretion. The work that has documented this mechanism of fluid secretion by the cystic epithelium is the subject of this review.