Kidney Week

Abstract: TH-PO0173

Cyst-Type Epithelial Heterogeneity Shapes Therapeutic Responsiveness in ADPKD

Session Information

• ADPKD and Cystic Kidney Disease - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Roeles, Johannes, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Lower Saxony, Germany

Johannes Roeles, MD, DrMed

• Giesler, Axel, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Lower Saxony, Germany

Axel Giesler

• Schmitz, Jessica, Department of Pathology - Nephropathology Unit, Hannover Medical School, Hannover, Germany

Jessica Schmitz

• König, Johannes, Department of Pathology - Nephropathology Unit, Hannover Medical School, Hannover, Germany

Johannes König

• Friedersdorff, Frank, Department of Urology - Evangelisches Krankenhaus Königin Elisabeth Herzberge, Berlin, Germany

Frank Friedersdorff, DrMed

• Busch, Jonas, Department of Urology - Vivantes Klinikum Am Urban, Berlin, Germany

Jonas Busch, MD, PhD

• Greite, Robert, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Lower Saxony, Germany

Robert Greite, MD

• Krappitz, Matteus, University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States

Matteus Krappitz, DrMed

• Layne, Isabel A., University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States

Isabel A. Layne

• Kottgen, Michael, Department of Nephrology and Primary Care - University of Freiburg Faculty of Medicine, Freiburg, Baden-Wuerttemberg, Germany

Michael Kottgen, MD

• Kuehn, E. Wolfgang, Department of Nephrology and Primary Care - University of Freiburg Faculty of Medicine, Freiburg, Baden-Wuerttemberg, Germany

E. Wolfgang Kuehn, MD

• Schmid, Jessica Maria, Institute for Molecular and Cellular Anatomy - University of Regensburg, Regensburg, Bavaria, Germany

Jessica Maria Schmid

• Schmidt, Katharina Maria, Department of Surgery - University Hospital Regensburg, Regensburg, Bavaria, Germany

Katharina Maria Schmidt, MD

• Hoeft, Konrad, Division of Nephrology and Clinical Immunology - RWTH Aachen University, Aachen, North Rhine-Westphalia, Germany

Konrad Hoeft, DrMed

• Kramann, Rafael, Division of Nephrology and Clinical Immunology - RWTH Aachen University, Aachen, North Rhine-Westphalia, Germany

Rafael Kramann, MD, PhD, FASN

• Eckardt, Kai-Uwe, Department of Nephrology and Medical Intensive Care - Charité Universitätsmedizin Berlin, Berlin, Germany

Kai-Uwe Eckardt, MD

• Kocks, Christine, Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

Christine Kocks, PhD

• Braesen, Jan H., Department of Pathology - Nephropathology Unit, Hannover Medical School, Hannover, Germany

Jan H. Braesen, MD, PhD

• Halbritter, Jan, Department of Nephrology and Primary Care - University of Freiburg Faculty of Medicine, Freiburg, Baden-Wuerttemberg, Germany

Jan Halbritter, MD

• Schmitt, Roland, Department of Nephrology and Hypertension - University Hospital Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany

Roland Schmitt, MD, FASN

• Haerteis, Silke, Institute for Molecular and Cellular Anatomy - University of Regensburg, Regensburg, Bavaria, Germany

Silke Haerteis

• Hopp, Katharina, University of Colorado Anschutz Medical Campus Division of Renal Diseases and Hypertension, Aurora, Colorado, United States

Katharina Hopp, PhD

• Schmidt-Ott, Kai M., Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Lower Saxony, Germany

Kai M. Schmidt-Ott, MD, FASN

• Hinze, Christian, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Lower Saxony, Germany

Christian Hinze, MD, DrMed

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure. Substantial interpatient variability in disease progression and therapeutic response hinders targeted drug development and personalized patient care. The molecular and cellular mechanisms driving this inter-patient variability remain poorly defined.

Methods

A total of 15 cyst wall samples were obtained from 5 dialysis-dependent patients with ADPKD and tumor-adjacent normal kidney tissue was obtained from control patients. Specimens were analyzed using single-nucleus RNA sequencing (snRNA-seq) and immunofluorescence imaging, and cyst fluid electrolyte composition was measured. An independent validation cohort comprising over 1,800 cysts from 11 additional ADPKD patients was investigated using machine learning-based immunofluorescence image analysis. Findings were further assessed in an orthologous ADPKD mouse model (Pkd1^RC/RC).

Results

SnRNA-seq resolved three cyst types with different epithelial layers – proximal tubule-like, collecting duct-like, and mixed cysts – each characterized by distinct injury states, metabolic programs, and stromal microenvironments. In mixed cysts, proximal tubule-like and collecting duct-like epithelia were arranged in cell type patches, mosaic patterns or as single interposed cells. Furthermore, a mixed-cyst niche enriched for CCL2-associated inflammatory signaling was identified. Gene expression analysis of key molecular targets uncovered cell-type specific amenability to therapeutic strategies: CFTR was enriched in proximal-like epithelia, while the molecular target of tolvaptan – AVPR2 – was restricted to AQP2-positive collecting duct-like cells. Machine learning–based histological analysis revealed extensive inter-patient variability in cyst-type composition, suggesting differential responsiveness to therapy. In the Pkd1^RC/RCmouse model, the relative abundance of AQP2-positive cysts significantly correlated with therapeutic response to tolvaptan.

Conclusion

This study identifies cyst-type heterogeneity as a central determinant of molecular pathway activation and treatment response in ADPKD. Defining individual cyst-type compositions could inform the individual risk-benefit evaluation for the use of AVPR2 inhibitors and may be key to advancing personalized therapeutic strategies for patients with ADPKD.

Funding

• Government Support – Non-U.S.