Abstract: PO1678
Antiproteinuric and Podocytoprotective Effects of Direct Oral Anticoagulant Therapy in Glomerular Disease
Session Information
- Podocyte Injury in Human Disease: Pathomechanism, Diagnosis, and Therapy
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Waller, Amanda P., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Wolfgang, Katelyn, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Abdelghani, Eman, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Kerlin, Bryce A., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Podocyte injury is a key determinant of chronic kidney disease (CKD) progression toward end stage kidney disease. We and others have recently uncovered a putative podocytopathic role for intraglomerular thrombin during proteinuric glomerular disease. Direct oral anticoagulant (DOAC) therapies limit thrombin activity but their ability to improve podocyte health and potentially slow CKD progression remains unknown. Thus, the aim of this study is to determine if DOACs reduce thrombin-mediated podocytopathy during glomerular proteinuria. We hypothesized that DOACs would preserve podocyte health and function in a podocyte-specific model of proteinuric glomerular disease.
Methods
Diphtheria Toxin was used to induce proteinuria in transgenic rats expressing human diphtheria toxin receptor (DTR) in a podocyte-specific manner and was subsequently treated with 1) Dabigatran (20 mg/kg; Dabi), 2) Rivaroxaban (3 mg/kg; Riva), or 3) Sham (saline) and compared to healthy controls (n=7-9/group). Morning spot urine was collected on day 0 and 10 post-DT. Glomeruli were isolated from the kidney, dissociated into single-cell suspensions, and analyzed by flow cytometry after immunofluorescent synaptopodin antibody and TUNEL staining.
Results
Both Dabi and Riva significantly reduced proteinuria (Fig A) and terminal podocyte injury (TUNEL positive podocyte fraction; Fig B). In addition, there was a trend toward in situ podocyte preservation with both DOACs with a significant overall effect of DOAC therapy on podocyte survival (Fig C).
Conclusion
Both Dabi (a direct thrombin inhibitor) and Riva (a direct factor Xa inhibitor) reduce proteinuria and enhance podocyte health in a podocyte-specific model of proteinuric glomerular disease. These data suggest that DOACs may be repurposed as a novel approach to slow or halt proteinuric glomerular disease progression. Because thrombotic disease is a life-threatening co-morbidity of both glomerular disease and CKD, this approach may enable simultaneous thromboprophylaxis and glomerular disease therapy.
Funding
- NIDDK Support