Abstract: SA-PO975
Voclosporin Ameliorates Both Proteinuria and Dyslipidemia in a Model of Noninflammatory Glomerular Disease
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
Authors
- Kamigaki, Yu, Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
- Dougherty, Julie, Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
- Waller, Amanda P., Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
- Rehaume, Linda M., Aurinia Pharmaceuticals Inc, Edmonton, Alberta, Canada
- Wolfgang, Katelyn, Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
- Abdelghani, Eman, Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
- Kerlin, Bryce A., Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
- Smoyer, William E., Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, Ohio, United States
Background
Idiopathic nephrotic syndrome (INS) is one of the most frequent glomerular diseases in children. There is a critical need for the development of more effective and less toxic INS treatments. Voclosporin (VCS) is a novel calcineurin inhibitor (CNI) approved in the USA, EU, Great Britain and Switzerland on a background of immunosuppressive therapy for the treatment of adults with active lupus nephritis. VCS does not require therapeutic drug monitoring due to an improved pharmacokinetic profile. We thus investigated whether VCS could reduce proteinuria in non-inflammatory glomerular disease using an animal model of nephrotic syndrome (NS).
Methods
Male Wistar rats received 50 mg/kg puromycin aminonucleoside (PAN) or saline via tail vein injection on day 0. Rats were gavaged twice daily with vehicle (VEH), VCS (4 mg/kg/dose), or cyclosporine (CsA, 10mg/kg/dose) at clinically relevant doses. Rats were euthanized on Day 11 and proteinuria, lipid profile, glomerular cell injury (TUNEL), and hypercoagulability (TGA) were measured.
Results
PAN induced proteinuria in all disease groups. VCS ameliorated proteinuria more effectively vs. CsA (mean reduction vs. disease control was 81% vs. 17%, respectively). Mean triglyceride (TG) levels increased by 74% vs. controls in the PAN + VEH group vs. 22% in the PAN + CsA group vs. -26% in the PAN + VCS group. Similarly, PAN induced increases in all other lipid levels vs. controls, while VCS reduced these lipid levels. Flow cytometry TUNEL positivity of isolated glomeruli revealed injury of 2.1% in control podocytes vs. 5.3% in PAN + VEH cells (152% increase) vs. 8.5% in PAN + CsA cells (305% increase) vs. 4.1% in PAN + VCS cells (95% increase). TGA assays revealed that VCS effectively improved PAN-induced hypercoagulopathy.
Conclusion
A clinically relevant dose of VCS ameliorated PAN-induced proteinuria, hypercoagulopathy, and in situ glomerular injury in a model of non-inflammatory glomerular disease, without apparent exacerbation of NS-associated dyslipidemia. Compared to CsA, VCS more effectively ameliorated proteinuria, hypercoagulopathy, and glomerular injury and led to a better lipid profile.
Funding
- Commercial Support – Aurinia Pharmaceuticals Inc.