Patient-derived kidney organoids recapitulate ADPKD and facilitate the identification of Rho pathway inhibitors as candidate therapeutics.

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) remains refractory to curative therapy partly due to the lack of human models that recapitulate its adult-onset nature, genetic context, and multi-segment origin. Here, we established expandable, multi-lineage adult renal organoids (MAROs) directly from surgical specimens of ADPKD patients and healthy donors, creating a three-dimensional (3D) high-content screening platform. Patient-derived MAROs faithfully reproduced hallmark cystogenic features, including elongated primary cilia, polarity disruption, and elevated Rho GTPase/planar cell polarity (PCP) signaling. Single-cell transcriptomics of PKD1/PKD2-mutant organoids revealed genotype-specific alterations. Genetic ablation of IFT88 disrupted cilia and selectively attenuated Rho/PCP activity in mutant backgrounds, supporting a cilia-dependent cyst-activating (CDCA) mechanism in cystogenesis. Microfluidic perfusion accelerated cyst expansion and amplified Rho/PCP signaling. A high-throughput drug screen identified Rho GTPase inhibitors, including ML141, as effective cyst-reducing agents across genotypes without compromising viability. Our findings establish a patient-derived organoid platform that captures ADPKD pathology and nominates Rho pathway modulation as a therapeutic strategy.