In 85% to 90% of families, PKD1, on the short arm of chromosome 16, is the defective gene. This gene encodes a large (460-kDa) and complex cell membrane–associated protein called polycystin-1. The polycystin-1 protein has a large extracelluar domain and multiple transmembrane regions. The extracellular domains have regions that can bind to extracellular matrix. Polycystin-1 localizes to the primary cilium of tubular cells (as do nephrocystins linked to medullary cystic disease, discussed later), giving rise to the concept of renal cystic diseases as a type of ciliopathy. Cilia are hairlike organelles that project into the lumina from the apical surface of tubular cells, where they serve as mechanosensors of fluid flow. Current evidence suggests that polycystin mutations produce defects in mechanosensing (
Fig. 14.21 ). This, in turn, alters downstream signaling events involving calcium influx, leading to dysregulation of cell polarity, proliferation, and cell–cell and cell–matrix adhesion. The increase in intracellular calcium is thought to stimulate proliferation and secretion from the tubular epithelial cells, which together lead to the formation of cysts, which progressively enlarge over time. Mediators in cyst fluid derived from the epithelial cells can further enhance fluid secretion and induce inflammation. In addition, the calcium-induced signals alter the interaction of epithelial cells with extracellular matrix, and this too is thought to contribute to the cyst formation and interstitial fibrosis that are characteristic of progressive polycystic kidney disease. It is interesting to note that whereas germ-line mutations of the PKD1 gene are present in all renal tubular cells of affected individuals, cysts develop in only some tubules. This is most likely due to loss of both alleles of PKD1. Thus, as with tumor suppressor genes, a second “somatic hit” is required for cyst development.
The PKD2 gene, implicated in 10% to 15% of cases, resides on chromosome 4 and encodes polycystin-2, a smaller, 110-kDa protein. Polycystin-2 is thought to function as a calcium-permeable membrane channel, and is also localized to cilia. Although structurally distinct, polycystins 1 and 2 are believed to act together by forming heterodimers. Thus, mutation in either gene gives rise to essentially the same phenotype, although patients with
Mutations in polycystin 1, 2 or fibrocystin or nephrocystins Altered mechanosensation by tubular cilia Altered calcium flux Altered tubular epithelial growth and differentiation
Fig. 14.21 Possiblemechanismsofcystformationincystickidneydiseases(seetext).
Glomerular,
PKD2 mutations have a slower rate of disease progression compared to patients with PKD1 mutations.
MORPHOLOGYInautosomaldominantadultpolycystickidneydisease,thekidneymayreachenormoussize;weightsofupto4kgforeachkidneyhavebeenrecorded.Theseverylargekidneysarereadilypalpableabdominallyasmassesextendingintothepelvis.Ongrossexamination,thekidneyseemstobecomposedsolelyofcystsofupto3or4cmindiameterwithnointerveningparenchyma.Thecystsarefilledwithfluid,whichmaybeclear,turbid,orhemorrhagic(
Fig.14.22