Abstract: SA-PO0595
Modelling Phenotype Severity in ADPKD Using Patient-Derived Kidney Organoids: Comparative Analysis of Mild and Severe Genotypes
Session Information
- Cystic Kidney Diseases: Clinical Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Knezevic, Sara, University College Dublin, Dublin, Ireland
- Davis, Jessica, University College Dublin, Dublin, Ireland
- Clince, Michelle, Beaumont Hospital, Dublin, Ireland
- Cavalleri, Gianpiero, Royal College of Surgeons in Ireland, Dublin, Ireland
- Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
- Crean, John, University College Dublin, Dublin, Ireland
Background
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetically heterogeneous disorder characterised by cyst formation and progressive renal dysfunction. Patient-specific induced pluripotent stem cells (iPSCs) are used as valuable models to replicate disease phenotypes in vitro. In this study, we compared kidney organoid phenotypes derived from two genetically distinct ADPKD patients - one with a mild and the second with a severe clinical presentation.
Methods
Patients were recruited from the Inherited Kidney Disease Clinic at Beaumont Hospital (Ireland) based on their genetic risk profiles. Fresh urine samples were collected and urinary epithelial cells (URECs) were isolated. URECs were reprogrammed to iPSCs using non-integrating OSKM episomal plasmids. Patient-derived iPSCs were characterised by immunocytochemistry, trilineage assay and karyotyping. Kidney organoids were generated from both patients and a healthy control, characterised by RT-qPCR, immunocytochemistry and assessed for tubular swelling by bright-field microscopy. Transcriptional changes between mild and severe ADPKD were characterised by Single-cell RNA sequencing (scRNA-seq).
Results
The mild patient is a 77-year-old female with a PKD1 missense variant (c.7300C>T:p.R2434W), a history of hypertension and reduced estimated glomerular filtration rate (eGFR, 35 mL/min). Imaging revealed enlarged cystic kidneys and liver cysts indicative of ADPKD. The severe patient is a 33-year-old male harbouring a PKD1 nonsense variant (c.8056C>T; p.Q2686X) with end-stage renal disease (eGFR <10 mL/min), enlarged cystic kidneys and a history of nephrectomy. Organoids from the mild patient developed moderate tubular dilatation, while those generated from the severe patient showed a more pronounced cystic phenotype. scRNA-seq analysis revealed cell-type-specific responses and transcriptional differences.
Conclusion
This study modelled phenotypic variability in ADPKD using kidney organoids derived from autologous urine-derived iPSCs. Cellular and molecular drivers of disease progression were identified through comparison of organoid morphology and transcriptomic profiles from patients with mild and severe disease. This approach may advance our understanding of ADPKD pathogenesis and inform personalised therapeutic strategies.