What is the pathophysiology of Autosomal Dominant Polycystic Kidney Disease (ADPKD)?

Pathophysiology of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is a genetically inherited disorder characterized by progressive development of bilateral kidney cysts caused by mutations in PKD1 or PKD2 genes, leading to kidney enlargement and eventual kidney failure in adulthood. 1

Genetic Basis

ADPKD is caused by mutations in one of two major genes:

• PKD1 gene (chromosome 16): Accounts for approximately 85% of cases

  • Encodes polycystin-1 (PC1), a large membrane receptor protein
  • Truncating mutations (~48% of families) cause more severe disease with kidney failure typically in the 50s
  • Non-truncating mutations (~19% of families) cause variable disease severity 1

• PKD2 gene (chromosome 4): Accounts for approximately 15% of cases

  • Encodes polycystin-2 (PC2), a non-selective cation channel permeable to Ca²⁺
  • Generally milder disease with kidney failure typically in the 70s 1, 2

• Minor genes: Several minor genes (IFT140, ALG5, ALG9, GANAB, DNAJB11, NEK8) account for a small percentage (<5%) of ADPKD cases with variable phenotypes 1

Molecular Mechanisms of Cyst Formation

1. Polycystin Complex Dysfunction:

   • PC1 and PC2 form a functional complex in the primary cilium of renal tubular cells
   • This complex acts as a mechanosensor that detects fluid flow and mediates calcium signaling
   • Mutations disrupt this sensory function 2

2. Intracellular Calcium Dysregulation:

   • Defective polycystin complex leads to impaired intracellular Ca²⁺ homeostasis
   • Reduced intracellular calcium results in increased cAMP levels 2

3. cAMP Accumulation:

   • Elevated cAMP levels promote both fluid secretion and cell proliferation
   • In normal cells, cAMP inhibits cell proliferation, but in ADPKD cells, it paradoxically stimulates proliferation 2, 3

4. Two-Hit/Three-Hit Model:

   • Individuals inherit one mutated allele (germline mutation)
   • A "second hit" (somatic mutation) in the normal allele triggers cyst formation
   • Early gene inactivation leads to rapid and diffuse cyst development
   • Inactivation in adult life leads to focal and late cyst formation
   • Renal injury (ischemia/reperfusion) can serve as a "third hit," accelerating cyst formation 2

Cellular Abnormalities in ADPKD

1. Increased Cell Proliferation:

   • Cyst-lining epithelial cells show increased proliferation rates
   • Activation of mitogenic signaling pathways, including MAPK/ERK 2, 4

2. Fluid Secretion:

   • Reversal of normal absorptive function to secretory phenotype
   • Chloride and fluid secretion into cyst lumen driven by cAMP 2, 5

3. Extracellular Matrix Abnormalities:

   • Thickened and altered basement membrane composition
   • Increased matrix metalloproteinase activity 2

4. Defective Planar Cell Polarity:

   • Disruption of normal tubular architecture
   • Misoriented cell division leading to tubular dilation 2

5. mTOR Pathway Activation:

   • Increased activity of mammalian target of rapamycin (mTOR)
   • Promotes cell growth and proliferation 2, 4

6. DNA Damage and Repair Defects:

   • Increased DNA damage in cystic epithelial cells
   • Altered DNA damage response pathways 6

Cyst Formation and Progression

1. Initiation Phase:

   • Focal cyst formation in approximately 1-2% of nephrons
   • Requires both germline and somatic mutations in PKD genes

2. Expansion Phase:

   • Increased cell proliferation and fluid secretion
   • Progressive enlargement of existing cysts
   • Compression of surrounding normal tissue

3. Progression to Kidney Failure:

   • Cyst growth leads to kidney enlargement
   • Progressive fibrosis and inflammation in non-cystic tissue
   • Gradual decline in kidney function 1, 2

Clinical Manifestations Related to Pathophysiology

1. Kidney Manifestations:

   • Bilateral kidney enlargement with multiple cysts
   • Hypertension (due to renin-angiotensin system activation)
   • Progressive decline in kidney function
   • Kidney pain (due to cyst hemorrhage, infection, or kidney stones) 1

2. Extrarenal Manifestations:

   • Liver cysts (most common extrarenal manifestation)
   • Intracranial aneurysms
   • Cardiac valve abnormalities 1

Phenotypic Variability

Disease severity varies based on:

1. Genotype:

   • PKD1 mutations generally cause more severe disease than PKD2
   • Truncating PKD1 mutations typically cause more severe disease than non-truncating mutations 1

2. Sex:

   • Males generally progress more rapidly than females 1

3. Environmental Factors:

   • Obesity and high salt intake may accelerate disease progression 1

Therapeutic Targets Based on Pathophysiology

Current and potential therapeutic approaches target specific pathophysiologic mechanisms:

1. Vasopressin V2 Receptor Antagonists (e.g., tolvaptan):

   • Reduce cAMP levels in collecting duct cells
   • Decrease fluid secretion and cell proliferation 3, 4

2. PPAR-γ Agonists (e.g., pioglitazone):

   • Target epithelial cells of renal collecting tubules
   • May reduce cystic burden through multiple mechanisms 4

Understanding the complex pathophysiology of ADPKD has led to the development of targeted therapies, with tolvaptan being the first FDA-approved treatment specifically for ADPKD 3, 4.