Kidney Week

Abstract: SA-PO709

Voclosporin Ameliorates Proteinuria and Directly Protects Podocytes in a Model of Noninflammatory Glomerular Disease

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 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

• Kamigaki, Yu, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Yu Kamigaki, MD

• Dougherty, Julie, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Julie Dougherty, PhD

• Waller, Amanda P., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Amanda P. Waller, PhD

• Rehaume, Linda M., Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada

Linda M. Rehaume, PhD

• Biederman, Laura, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States

Laura Biederman, MD

• Kerlin, Bryce A., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Bryce A. Kerlin, MD

• Smoyer, William E., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

William E. Smoyer, MD

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 treatments. Voclosporin (VCS) is a second generation 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 investigated whether VCS could reduce proteinuria in a non-inflammatory animal model of NS.

Methods

Rats received 50 mg/kg puromycin aminonucleoside (PAN) or saline via tail vein injection and were gavaged twice daily with vehicle (VEH, vitamin E-TPGS, MCT oil, Tween 40, and 95% ethanol 4:2:2:1, by weight), VCS (4 mg/kg/dose), or cyclosporine (CsA, 10mg/kg/dose) as clinically relevant doses. Rats were euthanized on day 11, and proteinuria, lipid profile, glomerular cell injury, hypercoagulability, and histopathology were assessed. To validate the direct protective effect of VCS on podocytes, cultured human podocytes were also treated with PAN (5 µg/ml) + vehicle (DMSO), VCS (0.1 µg/ml), or CsA (0.1 µg/ml) for 72 hours and podocyte viability and actin stress fiber changes were analyzed.

Results

VCS improved proteinuria, hypercoagulopathy, lipid profile, and TUNEL positivity of glomerular podocytes. PAN + VCS rats exhibited a significantly decreased mean total tubular injury score (1.07 ± 0.23) compared with PAN + VEH (2.00 ± 0.37, P < 0.05), while PAN + CsA mean total injury score (1.75 ± 0.34, P = 0.66) was only slightly better than PAN + VEH. Cultured podocyte viability of the PAN + VCS group was significantly improved (100% ± 2.6%, P < 0.01) compared with PAN + DMSO (91% ± 2.5%), while PAN + CsA (94% ± 4.4%, P = 0.28) was mildly better than PAN +DMSO . Also, PAN + VCS cells had more intact actin-fiber cells and fewer actin-fiber-disrupted cells than PAN + DMSO and PAN + CsA .

Conclusion

Compared to CsA, a clinically relevant dose of VCS more effectively ameliorated PAN-induced proteinuria, hypercoagulopathy, NS-associated dyslipidemia, and tubular injury in rats, as well as cell viability and actin cytoskeleton of cultured podocytes.

Funding

• Commercial Support – Aurinia Pharmaceuticals Inc