Genetics · MU Sofia

36. Monogenic Kidney Diseases: Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease

Covers the two main monogenic polycystic kidney diseases, autosomal dominant and autosomal recessive, taking each in turn through genetic basis, pathophysiology, clinical features, diagnosis and management. The dominant form is traced through PKD1 and PKD2 and their polycystin proteins, with extra-renal features such as liver cysts and intracranial aneurysms. The recessive form is traced through PKHD1 and fibrocystin, with prenatal presentation and congenital hepatic fibrosis. A comparison table of the two diseases closes the note.

Inside: 3 sections · 6 labelled pictures · 1 table · 14 flashcards · 4 min

Topic 36 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 3 sections, about 569 words (4 min of reading), with 14 flashcards.

In this note

  1. Monogenic Kidney Diseases: Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease
  2. I. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)
  3. II. AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD)

Monogenic Kidney Diseases: Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease

Polycystic kidney diseases (PKD) are inherited disorders characterized by the development of multiple fluid-filled cysts in the kidneys, leading to progressive enlargement, loss of normal renal architecture, and eventual renal insufficiency. They arise from mutations in genes involved in tubular epithelial cell function, ciliary signaling, and cell–cell interactions.

The two major monogenic forms are:

  • Autosomal Dominant Polycystic Kidney Disease (ADPKD)
  • Autosomal Recessive Polycystic Kidney Disease (ARPKD)

I. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

ADPKD is a late-onset inherited kidney disorder characterized by bilateral renal cysts that progressively enlarge and destroy normal renal parenchyma. It is the most common inherited kidney disease and a frequent genetic cause of end-stage renal disease (ESRD) in adults.

Genetic and Molecular Basis

  • Inheritance: Autosomal dominant
  • Genes involved:
  • PKD1 (chromosome 16p13.3) → polycystin-1 (~85% of cases)
  • PKD2 (chromosome 4q21) → polycystin-2 (~15% of cases)
  • Proteins involved:
  • Polycystin-1: cell-cell and cell-matrix interactions
  • Polycystin-2: calcium-permeable ion channel

These proteins are located in primary cilia of renal tubular epithelial cells.

Pathophysiology

  1. 1. Mutation in PKD1 or PKD2 → defective polycystin signaling in primary cilia.
  2. 2. Impaired calcium signaling within tubular epithelial cells.
  3. 3. Increased intracellular cAMP → abnormal cell proliferation and fluid secretion.
  4. 4. Progressive formation of multiple cysts from different nephron segments.
  5. 5. Cysts enlarge, compress surrounding parenchyma → ischemia and fibrosis.
  6. 6. Gradual loss of renal function → chronic kidney disease and ESRD.

Clinical Features

ADPKD is often asymptomatic in childhood, with manifestations appearing in adulthood.

Renal Manifestations

  • Bilaterally enlarged kidneys
  • Flank or abdominal pain
  • Hematuria (microscopic or gross)
  • Recurrent urinary tract infections
  • Nephrolithiasis
  • Progressive renal insufficiency

Extra-renal Manifestations

  • Liver cysts (most common extrarenal feature)
  • Pancreatic and splenic cysts
  • Intracranial (berry) aneurysms → risk of subarachnoid hemorrhage
  • Mitral valve prolapse, aortic regurgitation
  • Colonic diverticulosis, abdominal hernias

Diagnosis

  • Ultrasound: first-line (age-dependent cyst number criteria).
  • CT / MRI: more sensitive, especially in early disease.
  • Genetic testing: confirms diagnosis, useful in equivocal cases or family screening.
  • Renal function tests: initially normal, later declining GFR.

Management

  • Blood pressure control (ACE inhibitors / ARBs).
  • Management of UTIs and nephrolithiasis.
  • Tolvaptan (vasopressin V2 receptor antagonist) slows cyst growth in selected patients.
  • Dialysis or renal transplantation in ESRD.
  • Screening for intracranial aneurysms in high-risk individuals.

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