Autosomal dominant polycystic kidney disease: clinical and genetic aspects

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease caused by at least three different genes. The renal and extrarenal clinical manifestations, and the systemic complications due to cystic and non-cystic abnormalities in ADPKD patients have been widely investigated. Cellular and molecular aspects of cystogenetic mechanisms concern epithelial tubular cell proliferation, remodelling of extracellular matrix, fluid secretion and accumulation, and relations between cell proliferation and apoptosis. In vitro studies on cystogenesis suggest a key role of cell-to-cell or cell-to-matrix interactions. Surface proteins mediating cell-to-cell contact, such as E-cadherin (polycystin?), integrin interactions, growth factors, receptor expression, are involved in the process of differentiation of the cellular condition and of the extracellular matrix. Blocking any one of these complex mechanisms should influence the orientation and polarization of epithelial tubular cells and should mediate the inversion of fluid secretion which ends in renal cystogenesis. ADPKD comprises at least three phenotypically indistinguishable but genetically distinct entities, caused by mutations in three autosomal genes: PKD1 (chromosome 16p13.3) is present in about 85% of patients; PKD2 (chromosome 4q13q23) in 10%; PKD3 (unknown chromosome) in a few families. PCR-based mutation detection methods, automated DNA sequencing, and other "functional" methods are used to screen and analyse ADPKD patients. It is not yet known whether the mutations identified so far in PKD1 and PKD2 inactivate the genes or generate an aberrant product. The products of PKD1 and PKD2 genes have been called polycystin 1 and 2. Polycystins are members of a family of interactive proteins involved in complex adhesive cell-cell, cell-matrix, protein-protein, and protein-carbohydrate interactions in the extracellular compartment, and are involved in the same pathway (ion channel regulator? ion channel? pore?) where mutations in only one of the simple genes (PKD3 too?) may cause the ADPKD phenotype. Genotype-phenotype correlations, in terms of disease severity and/or progression to end-stage renal disease, probably depend on other factors, both genetic and environmental (for instance: DD genotype of the ACE gene in ADPKD hypertensive patients), that might influence the clinical course and progression of ADPKD. The hypothesis of the "two hits" has been proposed to explain at the molecular level the focal nature of cyst formation.