A 52-year-old man with a 10-year history of hypertension presents with flank pain and gross hematuria. On examination, both kidneys are palpable as firm, enlarged masses. Imaging shows bilateral kidneys with multiple cysts of varying sizes throughout the cortex and medulla, with progressive loss of normal parenchyma. The structure marked **A** in the diagram represents cortical cysts arising from renal tubules. Which of the following best explains the pathophysiology of cyst formation in this patient's condition?

Explanation

## Why "Defective ciliary mechanosensing leading to abnormal tubular epithelial proliferation and cyst formation" is right The cortical cysts marked **A** in autosomal dominant polycystic kidney disease (ADPKD) arise from defective function of polycystin-1 and polycystin-2 complexes located on the primary cilia of renal tubular cells. These proteins normally sense fluid flow and mechanical stress within the tubule; when defective (due to PKD1 or PKD2 mutations), mechanosensing fails, leading to aberrant intracellular calcium signaling, increased cAMP, and uncontrolled tubular epithelial proliferation with progressive cyst formation. This mechanism classifies ADPKD as a ciliopathy (Robbins 10e Ch 20; Harrison 21e Ch 318). ## Why each distractor is wrong - **Loss of glomerular filtration barrier integrity causing fluid accumulation in Bowman's space**: This describes nephrotic syndrome or glomerular disease, not the tubular origin of cysts in ADPKD. The cysts in ADPKD arise from the tubular epithelium itself, not from glomerular pathology. - **Obstruction of the collecting duct by calculi resulting in post-obstructive cyst formation**: While kidney stones can occur in ADPKD patients (and may contribute to symptoms), they are not the primary mechanism of cyst formation. The cysts form de novo from tubular epithelial proliferation, not secondarily from obstruction. - **Chronic pyelonephritis causing abscess formation and secondary cyst development**: Recurrent UTIs and pyelonephritis are complications of ADPKD (due to cyst-related stasis and hematuria), not the cause of cyst formation. Infection is a consequence, not the initiating pathophysiology. **High-Yield:** ADPKD is a ciliopathy—polycystin-1/2 defects impair primary ciliary mechanosensing on renal tubules, driving uncontrolled epithelial proliferation and cyst formation; hypertension is often the first clinical sign due to RAAS activation from cyst-compressed nephrons. [cite: Robbins 10e Ch 20; Harrison 21e Ch 318]