Polycystic Kidney Disease
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- A group of monogenic disorders that result in renal cyst development
- The most frequent are 2 genetically distinct conditions: Autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-recessive polycystic kidney disease (ARPKD).
- ADPKD is one of the most common human genetic disorders.
- ADPKD is generally late onset:
- Mean age of end-stage kidney disease (ESKD) 57–69 years
- More progressive disease in men than in women
- Up to 90% of adults have cysts in the liver.
- ARPKD usually presents in infants:
- A minority in older children and young adults may manifest as liver disease.
- Nonobstructive intrahepatic bile dilatation is sometimes seen.
- Found on all continents and in all races
- ADPKD: 8.7/1 million in the US; 7/1 million in Europe
- Mean age of ESRD: PKD1, 54.3 years vs. PKD2, 74 years
- ADPKD affects 1/400–1,000 live births.
- ARPKD affects 1/20,000 live births; carrier level is 1/70.
- Large inter- and intrafamilial variability
- A more rapidly progressive clinical course is predicted by onset of hypertension (HTN) <35 years, male gender in PKD2, diagnosis <30 years, hyperlipidemia, kidney size (1), increased glomerular filtration (2)
- Autosomal-dominant inheritance
- 50% of children of an affected adult are affected.
- 100% penetrance; genetic imprinting and genetic anticipation are seen as well.
- 2 genes isolated:
- PKD1 on chromosome 16p13.3 (85% of patients)
- PKD2 on chromosome 4q21 (15% of patients)
- Presumed PKD3 not yet identified
- Autosomal-recessive inheritance
- Siblings have a 1:4 chance of being affected; gene PKHD1 on chromosome 6p21.1–p12
- Protein product of PKD1: Polycystin-1 mechanosensor in cilia; detects changes in flow, interacts with surrounding matrix and cell membrane proteins, and influences Ca2+ influx through PKD2 product, polycystin-2 channel
- Intracellular Ca2+ is reduced in cyst-derived cells, decreasing the Ca2+ inhibition of adenyl cyclase and increasing the concentration of cAMP.
- cAMP stimulates cell proliferation and fluid secretion with cyst expansion.
- Abnormal extracellular matrix and cell–cell interactions cause cells to detach and form cysts.
- PKHD1 product fibrocystin is also located in cilia; might be a cell surface receptor implicated in protein–protein interactions and is capable of enhancing the channel function of polycystin-2.
- An alteration also occurs in intracellular calcium homeostasis.
- ADPKD: Cysts arise from only 5% of nephrons:
- Autosomal-dominant pattern of inheritance, but a molecularly recessive disease with the 2-hit hypothesis
- Requires genetic and environmental factors
- ARPKD: Mutations are scattered throughout the gene with genotype–phenotype correlation.
Commonly Associated Conditions
- Cysts in other organs:
- Polycystic liver disease in 58% of young age group to 94% of 45-year-olds
- Pancreatic cysts: 5%
- Seminal cysts: 40%
- Arachnoid cysts: 8%
- Vascular manifestations:
- Intracerebral aneurysms in 6% of patients without family history and in 16% with family history
- Aortic dissections
- Cardiac manifestations: Mitral valve prolapse: 25%
- Diverticular disease
- Cysts in other organs:
- ARPKD: Liver involvement: Affected in inverse proportion to renal disease; congenital hepatic fibrosis with portal HTN