Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease worldwide. It is characterized by progressive development of kidney cysts. ADPKD is the fourth leading cause of kidney failure worldwide.
Most patients are diagnosed between the ages of 27 and 42 years. In addition to kidney cysts, 70-80% of patients have hypertension, 90% have liver cysts, and 9% to 14% develop intracranial aneurysms. Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age.
ADPKD is caused by a single pathogenic genetic variant in PKD1 (78%), PKD2 (15%), or one of several minor genes including IFT140, GANAB, DNAJB11, ALG9, ALG8, ALG5, and NEK8. PKD1 and PKD2 code for the proteins polycystin-1 and polycystin-2. These proteins are necessary for normal cilia function.
Loss of polycystin function leads to reduced intracellular calcium, increased cyclic adenosine monophosphate (cAMP) signaling, and activation of protein kinase A. These cellular changes cause proliferation of cyst cells and cyst fluid secretion. The latter cause interstitial inflammation and fibrosis. Eventually, these alterations lead to multiple cyst formation, destruction of adjacent kidney parenchyma, and kidney failure. Enlarging cysts compress the renal vasculature, causing ischemia and chronic activation of the renin-angiotensin-aldosterone system, resulting in hypertension.
Patients with PKD1 gene variants develop kidney failure at an earlier age than those with PKD2 gene variants or other pathogenic gene variants associated with ADPKD.
The diagnosis of ADPKD is usually made by evaluation of kidney imaging, often in consultation with a nephrologist Bilaterally enlarged kidneys (>13 cm) with more than 10 cysts per kidney are diagnostic of likely ADPKD.
Individuals with incidentally detected multiple kidney cysts who have atypical imaging findings benefit from genetic testing to obtain a definitive diagnosis. Genetic testing can be accomplished with a targeted polycystic kidney disease or kidney gene panel. Alternatively the causative mutations can be detected by whole exome or whole genome sequencing.
References
Chebib FT, et al. Autosomal Dominant Polycystic Kidney Disease: A Review. JAMA Network, published online March 24, 2025. doi:10.1001/jama.2025.0310
Franceschini N, Feldman DL, Berg JS, et al; NKF Genetic Testing Working Group. Advancing genetic testing in kidney diseases: report from a National Kidney Foundation Working Group. Am J Kidney Dis. 2024;84(6):751-766
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