Autosomal dominant polycystic kidney disease

The most significant and notable feature of ADPKD is bilateral progressive dilation of the renal tubules, which could possibly lead to end stage renal disease (ESRD). Approximately 50% of patients with ADPKD have end-stage renal disease by age 60 years. ADPKD is, however, a systemic disease that can produce cysts in other organs such as the liver, seminal vesicles, pancreas, and arachnoid matter. Other non-cystic abnormalities such as intracranial aneuryisms, dolichoectasias, dilatation of the aortic root, dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias may occur. Although ADPKD is a systemic disease, it shows a focal expression because less than 5% of nephrons become cystic. Because the disease is caused mainly by truncating mutations in the PKD1 and PKD2 genes, inadequate levels of polycystin (haplo insufficiency) may cause ADPKD. The PKD1 gene is located at chromosomal locus 16p13.3-p13.1 and is the responsible gene in 95% of cases. In 5% of patients mutations in PKD2 chromosomal locus 4q21-q23 are causative. Cystogenesis can be explained by a model of dominant and/or negative function in which a mutated form of polycystin inactivates the normal polycystin produced by the normal allele; Also, the 2-hit hypothesis proposed by Knudson seems to be true for this disorder. The two hit hypothesis aka Knudson hypothesis is often used to explain the manifestation of polycystic kidney disease later in life even though the mutation is present at birth. This term is borrowed from cancer research stating that both copies of the gene present in the genome have to be "silenced" before cancer manifests itself (in Knudson's case the silenced gene was Rb1) . In ADPKD the original "hit" is congenital (in either the PKD1 or PKD2 genes) and the subsequent "hit" occurs later in life as the cells grow and divide. The two hit hypothesis as it related to PKD was originally purposed by Reeders in 1992. Support for this hypothesis comes from the fact that ARPKD patients develop disease at birth, and somatic mutations in the "normal" copy of PKD1 or PKD2 have been found in cyst-lining epithelia.

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