Kidney Week

Abstract: FR-PO0686

Molecular and Cyst-Type Composition Heterogeneity in Human ADPKD

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  November 07, 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

• Roeles, Johannes, Medizinische Hochschule Hannover, Hanover, NDS, Germany

Johannes Roeles, MD, DrMed

• Giesler, Axel, Medizinische Hochschule Hannover, Hanover, NDS, Germany

Axel Giesler

• Schmitz, Jessica, Medizinische Hochschule Hannover, Hanover, NDS, Germany

Jessica Schmitz

• König, Johannes, Medizinische Hochschule Hannover, Hanover, NDS, Germany

Johannes König

• Friedersdorff, Frank, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany

Frank Friedersdorff, DrMed

• Busch, Jonas, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany

Jonas Busch, MD, PhD

• Greite, Robert, Medizinische Hochschule Hannover, Hanover, NDS, Germany

Robert Greite, MD

• Kottgen, Michael, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, BW, Germany

Michael Kottgen, MD

• Kuehn, E. Wolfgang, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, BW, Germany

E. Wolfgang Kuehn, MD

• Halbritter, Jan, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany

Jan Halbritter, MD

• Eckardt, Kai-Uwe, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany

Kai-Uwe Eckardt, MD

• Kocks, Christine, Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, BE, Germany

Christine Kocks, PhD

• Braesen, Jan H., Medizinische Hochschule Hannover, Hanover, NDS, Germany

Jan H. Braesen, MD, PhD

• Schmitt, Roland, Universitatsklinikum Schleswig-Holstein, Kiel, SH, Germany

Roland Schmitt, MD, FASN

• Schmidt-Ott, Kai M., Medizinische Hochschule Hannover, Hanover, NDS, Germany

Kai M. Schmidt-Ott, MD, DrMed, FASN

• Hinze, Christian, Medizinische Hochschule Hannover, Hanover, NDS, Germany

Christian Hinze, MD, DrMed

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage kidney disease. Current treatment options are limited to the vasopressin V2 receptor (AVPR2) antagonist tolvaptan and risk factor management, such as blood pressure control. However, patient-specific differences in disease progression and therapeutic response suggest underlying biological heterogeneity.

Methods

To investigate cyst heterogeneity, we performed single-nucleus RNA sequencing (snRNA-seq) on 15 cysts from five ADPKD patients and developed a machine learning–based imaging pipeline to analyze 1815 cysts from 11 additional individuals.

Results

Our integrated transcriptomic and imaging analysis classified most cysts as either megalin-positive (LRP2⁺) or aquaporin-2–positive (AQP2⁺), with a subset of mixed cysts containing both cell types. Molecular profiling revealed cyst-type-specific expression of therapeutic targets: AVPR2 was confined to AQP2⁺ cells, while the chloride channel CFTR was predominantly expressed in LRP2⁺ cells. Mixed cysts were associated with elevated oxidative stress and MCP-1–driven inflammation. These findings indicate cyst subtype–specific drug susceptibilities, with potential implications for tolvaptan, CFTR inhibitors, and MCP-1–targeting therapies. Image-based analysis across patients revealed striking variability in cyst-type composition, with LRP2⁺/AQP2⁺ ratios differing by up to 28-fold.

Conclusion

We uncover substantial molecular and compositional heterogeneity among renal cysts in human ADPKD, including a significant fraction of mixed cysts. These differences may contribute to the variability in disease progression and treatment response.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025qf15qev5