Polycystic Kidney Disease

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Basics

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 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 half 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 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.

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

  • Large inter- and intrafamilial variability
  • 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 hypertension (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 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

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Basics

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 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 half 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 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.

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

  • Large inter- and intrafamilial variability
  • 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 hypertension (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 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

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