Figure 916

Hypothetical model for cyst formation in autosomal-dominant polycystic kidney disease (ADPKD), relying on the "two-hit" mechanism as the primary event. The observation that only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors germinal PKD1 mutation, is best accounted for by the two-hit model. This model implies that, in addition to the germinal mutation, a somatic (acquired) mutation involving the normal PKD1

allele is required to trigger cyst formation (ie, a mechanism similar to that demonstrated for tumor suppressor genes in tuberous sclerosis complex and von Hippel-Lindau disease). The hypothesis is supported by both the clonality of most cysts and the finding of loss of heterozygosity in some of them [12].

Cell immaturity resulting from mutated polycystin would lead to uncontrolled growth, elaboration of abnormal extracellular matrix, and accumulation of fluid. Aberrant cell proliferation is demonstrated by the existence of micropolyps, identification of mitotic phases, and abnormal expression of proto-oncogenes. Abnormality of extracellular matrix is evidenced by thickening and lamination of the tubular basement membrane; involvement of extracellular matrix would explain the association of cerebral artery aneurysms with ADPKD. As most cysts are disconnected from their tubule of origin, they can expand only through net transepithelial fluid secretion, just the reverse of the physiologic tubular cell function [13]. Figure 9-17 summarizes our current knowledge of the mechanisms that may be involved in intracystic fluid accumulation.

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