Kidney Week

Abstract: TH-PO437

Patient Cyst Type Composition Predicts Responsiveness to Therapeutic Intervention in Autosomal Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | 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: Cystic

Authors

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

Johannes Roeles, MD

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

Axel Giesler

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

Jan H. Braesen, MD, PhD

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

Jessica Schmitz

• Friedersdorff, Frank, Charité Universitätsmedizin Berlin, Department of Urology, Berlin, Germany

Frank Friedersdorff, DrMed

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

Michael Kottgen, MD

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

E. Wolfgang Kuehn, MD

• Schmitt, Roland, Hannover Medical School, Department of Nephrology and Hypertension, Hannover, Germany

Roland Schmitt, MD, FASN

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

Kai M. Schmidt-Ott, MD, DrMed

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

Christian Hinze, DrMed, MD

Group or Team Name

• Hinze Lab.

Background

Autosomal polycystic kidney disease (ADPKD) is the main genetic cause of end stage renal disease. High variability of disease progression and inability of current models to accurately predict clinical efficacy hamper drug development and individualized patient care.

Methods

We analyzed 15 cyst wall samples from 5 ADPKD patients and 3 samples of tumor adjacent normal kidney tissue from 3 patients using single nucleus RNA sequencing (snRNA-seq) and immunofluorescence (IF) imaging. For cysts, the composition of cyst fluids was measured. An additional cohort of ca. 370 cyst from 9 patients was analyzed using machine learning aided IF image analysis to validate results.

Results

Integrated snRNA-seq analysis enabled clear identification of all major kidney cell types. Based on the expression of megalin (LRP2) or aquaporin 2 (AQP2) in the cyst epithelium, cysts could be categorized into proximal tubule-like (LRP2⁺) and collecting duct-like (AQP2⁺) cysts. Moreover, multiple cysts contained LRP2⁺and AQP2⁺ populations within the same cyst (mixed cysts). Our gene expression analysis strongly suggests a differential responsiveness of cyst types to therapeutic interventions, including diet modifications, preclinical compounds, and drugs tested in clinical trials. The mechanistic amenability to drugs targeting epithelial injury and inflammation (MCP-1 inhibitors, Bardoxolone) depended mainly on pure versus mixed cyst identity. By contrast, expression of molecular targets for modulating solute-water transport (Vaptans, CFTR inhibitors) was cell type-specific. Importantly, the analysis of ca. 370 cysts from 9 additional patients revealed highly variable ratios of LRP2⁺ to AQP2⁺ to mixed cysts between patients.

Conclusion

Our study reveals an intra- and inter-individual heterogeneity of cyst types, which predicts the differential responsiveness of patients to treatment. The frequent detection of proximal tubule and mixed cysts calls for critical re-evaluation of current disease models and drug development efforts, which focus mainly on the collecting duct. Future strategies determining the individual cyst type composition are warranted to significantly improve treatment of patients with ADPKD.