ADPKD as a Temporally Dynamic Disease: Implications for Biomarkers, Trial Design, and Therapeutic Targeting

Autosomal dominant polycystic kidney disease (ADPKD) has traditionally been conceptualized as a structurally progressive disease, with cyst growth driving loss of kidney function. This view has led to the widespread use of total kidney volume for risk stratification and clinical trial design. However, longitudinal human studies and experimental models indicate that the relationship between structure, function, and underlying biology changes over the disease course. Earlier disease is characterized by prominent cystic, proliferative, and metabolic activity together with early inflammatory responses; inflammatory and injury-repair processes become increasingly prominent during intermediate disease, whereas fibrosis and loss of functional parenchyma assume a greater role later as kidney function declines. These processes overlap rather than define discrete stages, and their timing and relative contributions likely vary among individuals. This review proposes that ADPKD be considered as a temporally dynamic disease and examines the implications of this framework for biomarker development, clinical trial design, and therapeutic targeting. Such a framework emphasizes the need to complement structural measures with biomarkers of evolving biology, to identify biological transitions prospectively, and to align therapeutic targets and end points with the processes contributing meaningfully to progression in the population being studied.