Kidney Week

Abstract: FR-PO800

Podocyte Exopher Formation as a Novel Pathomechanism in Membranous Nephropathy

Session Information

• Glomerular Diseases: Inflammation and Immunology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Meyer-Schwesinger, Catherine, Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Catherine Meyer-Schwesinger, MD

• Lahme, Karen, Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Karen Lahme

• Sachs, Wiebke, Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Wiebke Sachs, PhD

• Froembling, Sarah, Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Sarah Froembling, MSc

• Surmann, Kristin, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

Kristin Surmann, PhD

• Thuenauer, Roland, Technology Platform Microscopy and Image Analysis (TP MIA), Leibniz Institute of Virology, Hamburg, Germany

Roland Thuenauer, PhD

• Zielinski, Stephanie, Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Stephanie Zielinski

• Brand, Johannes, Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Johannes Brand

• Michalik, Stephan, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

Stephan Michalik, PhD

• Zimmermann, Marina, Institute of Medical Systems Biology, Center for Biomedical AI, Center for Molecular Neurobiology, Hamburg, Germany

Marina Zimmermann, PhD

• Wiech, Thorsten, Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Thorsten Wiech, DrMed

• Meyer, Tobias N., Nephrology, Asklepios Klinikum Barmbek, Hamburg, Germany

Tobias N. Meyer, MD

• Fester, Lars, Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany

Lars Fester, PhD

Background

Membranous nephropathy (MN) is caused by autoantibody binding to podocyte foot process antigens such as THSD7A and PLA₂R1. The mechanisms of the glomerular antigen/autoantibody deposition and clearance are unknown.

Methods

We explore the origin and significance of glomerular accumulations in (1) diagnostic and follow-up biospecimens from THSD7A⁺ and PLA₂R1⁺-MN patients compared to nephrotic non-MN patients, and (2) in experimental models of THSD7A⁺-MN.

Results

We discovered podocyte exophers as correlates of histological antigen/autoantibody aggregates found in the glomerular urinary space of MN patients. Exopher vesicle formation represents a novel form of toxic protein aggregate removal in Caenorhabditis elegans neurons. In MN patients, podocytes released exophers to the urine. Enrichment of exophers from MN patient urines established them as a glomerular exit route for antigens and bound autoantibody. Exophers also carried disease-associated proteins such as complement and provided a molecular imprint of podocyte injury pathways. In experimental THSD7A⁺-MN, exophers were formed from podocyte processes and cell body. Their formation involved the translocation of antigen/autoantibody from the subepithelial to the urinary side of podocyte plasma membranes. Urinary exopher-release correlated with lower albuminuria and lower glomerular antigen/autoantibody burden. In MN patients the prospective monitoring of urinary exopher abundance and of exopher-bound autoantibodies was additive in the assessment of immunologic MN activity.

Conclusion

Exopher-formation and release is a novel pathomechanism in MN to remove antigen/autoantibody aggregates from the podocyte. Tracking exopher-release will add a non-invasive diagnostic tool with prognostic potential to clinical diagnostics and follow-up of MN patients.