What is the mechanism of elevated blood pressure in ADPKD?

Mechanism of Elevated Blood Pressure in ADPKD

Hypertension in ADPKD results from a complex interplay of mechanisms including activation of the renin-angiotensin-aldosterone system (RAAS) due to intrarenal ischemia from cyst expansion, polycystin deficiency causing endothelial dysfunction with reduced nitric oxide production, and altered vascular structure and function—all occurring before significant loss of kidney function. 1

Primary Pathophysiologic Mechanisms

Polycystin Deficiency and Vascular Dysfunction

• Polycystin 1 and 2 are highly expressed in major vessels, endothelial cell cilia, and vascular smooth muscle cells 1
• Decreased or absent polycystin expression causes:
  • Reduced nitric oxide (NO) levels 1
  • Altered endothelial response to shear stress with attenuated vascular relaxation 1
  • Abnormal vascular structure and function independent of kidney damage 1
• This polycystin deficiency contributes directly to hypertension through its role in regulating vascular tone 2

RAAS Activation

• RAAS activation occurs through two mechanisms:
  1. Decreased NO production from polycystin deficiency 1
  2. Bilateral cyst expansion causing intrarenal ischemia 1
• As cyst size increases, further RAAS activation occurs, creating a vicious cycle: elevated blood pressure → enhanced cyst growth → more RAAS activation → worsening hypertension → progression to ESRD 1

Kidney Volume and Structural Changes

• Progressive kidney enlargement directly correlates with hypertension development 1
• Increased total kidney volume is associated with elevated blood pressure even before renal insufficiency 2
• Cyst volume and total kidney volume correlate with current hypertension status and predict future hypertension development 3

Temporal Sequence and Clinical Manifestations

Early Onset Before Renal Dysfunction

• Hypertension occurs in 10-20% of ADPKD children 1
• The majority of adults develop hypertension before any loss of kidney function 1
• Blood pressure elevation is common even with estimated GFR >60 mL/min/1.73m² 4

Cardiac Changes Precede Hypertension

• Left ventricular hypertrophy and carotid intimal wall thickening are present before the development of hypertension in ADPKD 1
• This suggests that vascular and cardiac abnormalities from polycystin deficiency occur independently of blood pressure elevation 1

Clinical Implications

Why This Mechanism Matters

• Hypertension is an independent risk factor for progression to ESRD in ADPKD 1
• Cardiovascular complications are the major cause of death in ADPKD patients 2
• Understanding the RAAS-driven mechanism explains why renin-angiotensin system inhibitors (ACE inhibitors or ARBs) are first-line treatment 3, 5

The Vicious Cycle

The mechanism creates a self-perpetuating cycle:

1. Polycystin deficiency → reduced NO → RAAS activation
2. Cyst expansion → intrarenal ischemia → more RAAS activation
3. Elevated BP → accelerated cyst growth
4. Larger cysts → worse ischemia → higher BP
5. Progressive kidney damage → ESRD 1

Common Pitfall

Do not assume hypertension in ADPKD is simply due to reduced kidney function—the mechanism is fundamentally different from other forms of CKD, with vascular dysfunction and RAAS activation occurring independently of and prior to significant nephron loss 1. This explains why hypertension appears so early in the disease course, often in childhood or young adulthood with normal GFR 3, 1.