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Novel Treatment Ameliorates Proteinuria and Dyslipidemia in a Model of Noninflammatory Glomerular Disease

Novel Treatment Ameliorates Proteinuria and Dyslipidemia in a Model of Noninflammatory Glomerular Disease 150 150 Lauren Dembeck

Idiopathic nephrotic syndrome — characterized by proteinuria, hypoalbuminemia, dyslipidemia, and edema — is one of the most common pediatric glomerular diseases. Glucocorticoids are first-line treatment, followed by calcineurin inhibitors for steroid-resistant disease; however, currently available calcineurin inhibitors can have numerous side effects, including dyslipidemia, and require frequent monitoring of drug levels in the blood. Since many patients have a clinical course complicated by frequent relapses or steroid resistance, development of more effective and less toxic treatment options is a high priority.

At the 2023 annual meeting of the American Society of Nephrology, researchers from Nationwide Children’s Hospital presented preclinical data demonstrating that the novel calcineurin inhibitor voclosporin ameliorated podocyte toxin-induced proteinuria, hypercoagulopathy, and in situ glomerular injury in an animal model of nephrotic syndrome, a non-inflammatory glomerular disease.

“Voclosporin is currently approved only in the treatment of adult patients with active lupus nephritis, where it has been found to be effective despite having fewer side effects than other calcineurin inhibitors,” says Yu Kamigaki, MD, postdoctoral research fellow in the laboratory of William E. Smoyer, MD, in Center for Clinical and Translational Research at Nationwide Children’s, who presented the findings. “Another benefit is that voclosporin does not require monitoring of drug levels in the blood due to an improved pharmacokinetic profile. Thus, we believe that patients would benefit from an expanded indication for this drug.”

The investigators evaluated whether voclosporin could reduce proteinuria in a non-inflammatory glomerular disease using a rat model of puromycin aminonucleoside (PAN)- induced nephrotic syndrome.

Following induction of glomerular disease, rats were administered a clinically relevant dose of voclosporin (VCS), or an older calcineurin inhibitor, cyclosporine A (CsA), or vehicle control (disease control) twice daily for 10 days. On day 11, the team assessed proteinuria, blood lipid profiles, glomerular cell injury, and hypercoagulability in the different treatment groups.

The study showed that VCS ameliorated proteinuria more effectively than CsA (median reduction vs. disease control was 71% vs. 26%, respectively). Overall, VCS appeared to have less exacerbation of dyslipidemia than CsA in PAN-treated animals.

“The drug already has an indication in an inflammatory glomerular disease, so we had some expectations for positive results, but I think we were pleasantly surprised that voclosporin worked as well as it did in this animal model,” says research scientist Julie Dougherty, PhD, who co-led the research with Dr. Kamigaki.

Analysis of podocytes, the target cell of injury in nephrotic syndrome, showed that VCS protected cells from death induced by PAN (38% decrease vs. PAN + vehicle), whereas CsA in disease animals exacerbated podocyte injury (19% increase vs. PAN + vehicle). Additionally, hypercoagulopathy changes seen in nephrotic syndrome and the PAN-nephrotic syndrome model were better improved with VCS than CsA.

“Our study suggests that voclosporin may not only be effective for lupus nephritis but could also potentially be expanded to non-inflammatory glomerular diseases with severe proteinuria, for example, steroid-resistant nephrotic syndrome and other types of secondary nephrotic syndrome in children,” says Dr. Smoyer, principal investigator of the study and Director of the Center for Clinical and Translational Research at Nationwide Children’s.

Disclosure: This research was supported by Aurinia Pharmaceuticals Inc.

 

Reference

Kamigaki, Yu; Dougherty, Julie; Waller, Amanda P.; Rehaume, Linda M.; Wolfgang, Katelyn; Abdelghani, Eman; Kerlin, Bryce A.; Smoyer, William E. Voclosporin Ameliorates Both Proteinuria and Dyslipidemia in a Model of Noninflammatory Glomerular Disease. Presented at the American Society of Nephrology Kidney Week 2023. Philadelphia, Pennsylvania. November 1-5, 2023.

 

About the author

Lauren Dembeck, PhD, is a freelance science and medical writer based in New York City. She completed her BS in biology and BA in foreign languages at West Virginia University. Dr. Dembeck studied the genetic basis of natural variation in complex traits for her doctorate in genetics at North Carolina State University. She then conducted postdoctoral research on the formation and regulation of neuronal circuits at the Okinawa Institute of Science and Technology in Japan.

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