Polycystic kidney disease

Abstract

A number of inherited disorders result in renal cyst development. The most common form, autosomal dominant polycystic kidney disease (ADPKD), is a disorder most often diagnosed in adults and caused by mutation in PKD1 or PKD2. The PKD1 protein, polycystin-1, is a large receptor-like protein, whereas polycystin-2 is a transient receptor potential channel. The polycystin complex localizes to primary cilia and may act as a mechanosensor essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract. Elucidation of defective cellular processes has highlighted potential therapies, some of which are now being tested in clinical trials. ARPKD is the neonatal form of PKD and is associated with enlarged kidneys and biliary dysgenesis. The disease phenotype is highly variable, ranging from neonatal death to later presentation with minimal kidney disease. ARPKD is caused by mutation in PKHD1, and two truncating mutations are associated with neonatal lethality. The ARPKD protein, fibrocystin, is localized to cilia/basal body and complexes with polycystin-2. Rare, syndromic forms of PKD also include defects of the eye, central nervous system, digits, and/or neural tube and highlight the role of cilia and pathways such as Wnt and Hh in their pathogenesis.

Figure 1

Structures of the ADPKD proteins polycystin-1 and -2 and the ARPKD protein, fibrocystin. Details of domains found in these proteins are shown in the key. Arrows indicate places where the proteins are thought to be cleaved.

Figure 2

Cellular changes associated with polycystic kidney disease (PKD). Components and pathways that are downregulated and upregulated in PKD are indicated. Potential treatments that target these defective pathways are shown in red.

Figure 3

Genes and phenotypic abnormalities associated with syndromic forms of PKD. Diseases are listed in the center; genes associated with them are shown on the left (gray). On the right are phenotypes found in these different disorders (yellow). Note the high degree of overlap in genes and phenotypes between the different disorders.