Cyst-type epithelial heterogeneity shapes therapeutic responsiveness in ADPKD

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) exhibits substantial interpatient variability in disease course and therapeutic response, but the cellular basis for this variability remains poorly understood. Here, we combine single-nucleus RNA sequencing of human cyst epithelia with machine learning-based histological analysis of >1,800 cysts to resolve three epithelial cyst types--proximal tubule-like, collecting duct-like, and mixed. These cyst types display distinct injury states, metabolic programs, and stromal microenvironments, including a mixed-cyst niche enriched for CCL2-associated inflammatory signaling. Expression of key therapeutic targets was highly cell-type specific with CFTR enriched in proximal-like epithelia, whereas AVPR2 expression was confined to AQP2-positive collecting duct-like cells. Cyst-type composition varied widely across patients and in an orthologous mouse model (Pkd1RC/RC) in which the burden of AQP2-positive cysts correlated with responsiveness to tolvaptan. These findings identify cyst-type heterogeneity as a major determinant of molecular pathway activation and predictability of therapeutic response in ADPKD.