Description

• A group of monogenic disorders that results in renal cyst development
• The most frequent are two 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 to 69 years
  • More progressive disease in men than in women
  • Up to 90% of adults have cysts in the liver.
• ARPKD usually present 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

Incidence

• Mean age of ESKD: PKD1 mutation, 54.3 years versus PKD2 mutation, 74 years
• ARPKD affects 1/20,000 live births; carrier level is 1/70.
• ADPKD affects 1/400 to 1,000 live births.

Prevalence
As ESKD, ADPKD: 8.7/1 million in the United States; 7/1 million in Europe

Etiology and Pathophysiology

• ADPKD
  • PKD1 and PKD2 mutations, which encode for polycystin 1 (PC1) and polycystin 2 (PC2), disrupt the function of polycystins on the primary cilium, forming fluid-filled cysts that progressively increase in size, leading to gross enlargement of the kidney, and distortion of the renal architecture.
  • Glomerular hyperfiltration compensates for the progressive loss of healthy glomeruli, and therefore, by the time GFR decline becomes detectable, as much as ½ of the original functional glomeruli are irreversibly lost.
  • The majority of patients with ADPKD ultimately progress to ESKD (1).
• ARPKD
  • PKHD1 product fibrocystin is also located in cilia.
• ADPKD: Cysts arise from only 1% 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.

Genetics

• ADPKD
  • Autosomal dominant inheritance
  • 50% of children of an affected adult are affected.
  • 100% penetrance; genetic imprinting and genetic anticipation are seen as well.
  • Two genes isolated
    • PKD1 on chromosome 16p13.3 (85% of patients) encodes polycystin 1.
    • PKD2 on chromosome 4q21 (15% of patients) encodes polycystin 2.
• ARPKD
  • Autosomal recessive inheritance
  • Siblings have a 1:4 chance of being affected; gene PKHD1 on chromosome 6p21.1–p12 encodes fibrocystin.

Risk Factors

A more rapidly progressive clinical course is predicted by onset of ESKD at <55 years, development of stage III CKD at <40 years old, onset of HTN at <18 years, total kidney volume greater than the expected for a given age, or presence of multiple complications (gross hematuria, microalbuminuria) (1).

General Prevention

Genetic counseling

Commonly Associated Conditions

• ADPKD
  • Cysts in other organs
    • Polycystic liver disease in 58% of young age group to 94% of 45-year-olds
    • Pancreatic (5%); seminal (40%); arachnoid (8%)
  • Vascular manifestations
    • Intracerebral aneurysms in 6% of patients without family history and in 16% with family history
    • Aortic root dilation, dissections
  • Cardiac manifestations
    • Mitral valve prolapse (25%); left ventricular hypertrophy
  • Diverticular disease
• ARPKD: liver involvement: affected in inverse proportion to renal disease; congenital hepatic fibrosis with portal HTN