A 45-year-old Indian man presents with hypertension (BP 160/100 mmHg) and flank pain. Renal ultrasound shows massively enlarged kidneys with multiple bilateral cysts. Genetic testing confirms mutations in the gene marked **A** in the diagram. Which of the following best explains why hypertension is often the FIRST clinical manifestation in this condition?

Explanation

## Why cyst-compressed nephrons activate the RAAS is right In ADPKD caused by PKD1 or PKD2 mutations (marked **A**), progressive cyst enlargement compresses and destroys functioning nephrons. This reduction in functional renal mass triggers activation of the renin-angiotensin-aldosterone system (RAAS) as the kidney senses reduced perfusion pressure. RAAS activation leads to sodium and water retention, volume expansion, and hypertension — which often precedes significant decline in GFR or overt renal insufficiency. This is the pathophysiologic mechanism for hypertension being the first clinical finding in ADPKD (Robbins 10e, Harrison 21e). ## Why each distractor is wrong - **Direct infiltration of the renal artery by cyst tissue causes mechanical stenosis**: While cysts can compress surrounding structures, they do not typically cause renal artery stenosis. The hypertension mechanism is functional (RAAS activation from reduced nephron mass), not mechanical stenosis. - **Polycystin-1 mutations directly impair sodium handling in the collecting duct, causing primary hyperaldosteronism**: Polycystin-1 and -2 are cilia-associated proteins that regulate tubular epithelial growth and differentiation. They do not directly regulate sodium transporters in the collecting duct. Hypertension is secondary to RAAS activation, not primary aldosteronism. - **Cyst rupture releases inflammatory mediators that cause acute vasculitis of the renal vasculature**: Cyst rupture can cause hematuria and flank pain, but vasculitis is not the mechanism of hypertension in ADPKD. Hypertension develops gradually from chronic RAAS activation, not from acute inflammatory events. **High-Yield:** In ADPKD, hypertension is the FIRST clinical sign (often before renal insufficiency) due to RAAS activation from cyst-compressed nephrons — treat aggressively with ACE-I/ARB and consider tolvaptan (V2 antagonist) in rapidly progressive disease. [cite: Robbins and Cotran Pathologic Basis of Disease, 10e, Ch 20; Harrison's Principles of Internal Medicine, 21e, Ch 318]