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• The PKD1 gene encodes a large (460-kDa) integral membrane protein named polycystin-1, which has
a large extracellular region, multiple transmembrane domains, and a short cytoplasmic tail.It has been
localized to tubular epithelial cells, particularly those of the distal nephron . it involved in cell-cell
and cell-matrix interactions.
• The PKD2 gene product polycystin-2 is an integral membrane protein.[15] It has been localized to all
segments of the renal tubules and is also expressed in many extrarenal tissues. Recent evidence
indicates that polycystin-2 may act as a Ca2+-permeable cation channel and that a basic defect in
ADPKD is a disruption in the regulation of intracellular Ca2+ levels.Another leading possibility is that
polycystin-2 may also occupy a plasma membrane position, where it may form a complex with
polycystin-1.[17]
• focused on links between the polycystins and cell-cell and cell-matrix interactions important in
tubular epithelial cell growth and differentiation.
• epithelial cells lining the cysts of ADPKD have a high proliferation rate, and that the
nonproliferating cells in cysts exhibit abnormally simplified structure, with a relatively immature
phenotype.
• Cysts are frequently detached from adjacent tubules and enlarge by active fluid secretion from the
lining epithelial cells.
• the extracellular matrix (ECM) produced by cyst-lining cells is abnormal.
• cysts develop as a result of an abnormality in cell differentiation, associated with sustained cellular
proliferation and some degree of increased apoptosis, transepithelial fluid secretion, and
remodeling of the ECM.[10]
• The increase in cells caused by abnormal proliferation, and the expanding volume of intraluminal
fluid caused by abnormal secretion from epithelial cells lining the cysts, result in progressive cyst
enlargement.
• cyst fluids harbor mediators, derived from epithelial cells, that enhance fluid secretion and induce
inflammation contribute to further enlargement of cysts and the interstitial fibrosis
characteristic of progressive polycystic kidney disease.[11]
• PKD1 gene serves a suppressor function: its loss leads to hyperplasia of epithelial cells.[
• polycystin-1 and polycystin-2 form components of a polycystin complex acts to regulate
intracellular Ca
• The extracellular region of polycystin-1 may be the binding site for one or more ligands that
modulate the activity of the channel.
• Mutation of either of these genes lead to loss of the polycystin complex or the formation of an
aberrant complex.
• The consequent disruption of normal polycystin activity may lead to changes in intracellular Ca2+
levels and, given the second messenger effects of Ca2+, to changes in cellular proliferation,
abnormal extracellular matrix, and the secretory function of the epithelia that together result in the
characteristic features of ADPKD.
Morphology.
In gross appearance : the kidneys are usually bilaterally enlarged and may achieve
enormous sizes;
weights up to 4 kg for each kidney
The external surface appears to be composed solely of a mass of
cysts, up to 3 to 4 cm in diameter, with no intervening
parenchyma .
microscopic examination: reveals functioning nephrons dispersed between the cysts.
cysts may be filled with a clear, serous fluid or, more usually,
with turbid, red to brown, sometimes hemorrhagic fluid.
As these cysts enlarge, they may encroach on the calyces and
pelvis to produce pressure defects.
cysts arise from the tubules throughout the nephron and therefore have
variable lining epithelia.
papillary epithelial formations and polyps project into the lumen.
Bowman capsules are occasionally involved in cyst formation, and
glomerular tufts may be seen within the cystic space.
Clinical Features.
remain asymptomatic until indications of renal insufficiency announce the presence of the underlying
kidney disease.
In others, hemorrhage or progressive dilation of cysts may produce pain.
Excretion of blood clots causes renal colic.
The larger masses, usually apparent on abdominal palpation, may induce a dragging sensation.
occasionally begins with the insidious onset of hematuria, followed by other features of progressive
chronic renal disease, such as proteinuria (rarely more than 2 gm/day), polyuria, and hypertension.
Patients with PKD2 mutations tend to have an older age at onset and later development of renal failure.
Progression is accelerated in blacks (largely correlated with sickle cell trait), in males compared with
females, and in the presence of hypertension.
Tend to have extrarenal congenital anomalies.
About 40% have one to several cysts in the liver (polycystic liver disease) that are usually
asymptomatic. The cysts are derived from biliary epithelium.
occur much less frequently in the spleen, pancreas, and lungs. Intracranial berry aneurysms,
presumably from altered expression of polycystin in vascular smooth muscle, arise in the circle of
Willis, and subarachnoid hemorrhages from these[21] account for death in about 4% to 10% of patients
with polycystic kidney disease.
Mitral valve prolapse and other cardiac valvular anomalies occur in 20% to 25% of patients, but most
are asymptomatic.
The clinical diagnosis is made by radiologic imaging techniques.
Morphology.