Description

• 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.

Epidemiology

• 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.

Risk Factors

• 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)

• ADPKD:
  • 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
• ARPKD:
  • Autosomal-recessive inheritance
  • Siblings have a 1:4 chance of being affected; gene PKHD1 on chromosome 6p21.1–p12

General Prevention

Genetic counseling

Pathophysiology

• ADPKD:
  • 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.
• ARPKD:
  • 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.

Etiology

• 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

• ADPKD:
  • 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
• ARPKD: Liver involvement: Affected in inverse proportion to renal disease; congenital hepatic fibrosis with portal HTN