Voclosporin ameliorates proteinuria in a model of non-inflammatory glomerular disease.

Abstract

BACKGROUND: Idiopathic nephrotic syndrome (INS) is among the most common glomerular diseases in children with standard first line treatment of glucocorticoids. However, there has been no definitive treatment that can completely cure disease with few side effects for steroid resistant INS patients. Voclosporin (VCS) is a second generation calcineurin inhibitor (CNI) approved in multiple countries for the treatment of adults with active lupus nephritis. VCS does not require therapeutic drug monitoring due to an improved pharmacokinetic profile compared to other CNIs. Based on this, we assessed the ability of VCS to ameliorate proteinuria and hypoalbuminemia in a non-inflammatory glomerular disease using an animal model of NS. METHODS: Rats received 50&#xa0;mg/kg puromycin aminonucleoside (PAN) IV to induce NS. Rats were gavaged BID with vehicle or VCS (4&#xa0;mg/kg/dose), a clinically relevant dose. Outcome measures included proteinuria, hypoalbuminemia, serum lipid profiles, glomerular podocyte injury, renal tubular injury, and hypercoagulopathy. Human podocytes were also treated with PAN +/- VCS and assessed for cell viability and stress using XTT and LDH release assays. RESULTS: VCS treatment significantly ameliorated PAN-induced proteinuria (61% median reduction; P&#x2009;<&#x2009;0.05) and tubular injury (P&#x2009;<&#x2009;0.05) in rats. VCS also numerically but insignificantly improved hypoalbuminemia (P&#x2009;=&#x2009;0.16), hypercoagulopathy (P&#x2009;=&#x2009;0.099), and glomerular podocyte injury (P&#x2009;=&#x2009;0.11). VCS did not exacerbate serum lipid profiles of rats with PAN-induced disease. In vitro, VCS significantly protected podocyte viability from PAN-induced toxicity and reduced PAN-induced stress, though not significantly. CONCLUSIONS: VCS significantly ameliorated proteinuria in a non-inflammatory model of glomerular disease, and compared favorably regarding improvements in hypoalbuminemia, hypercoagulopathy, dyslipidemia, and podocyte injury. These findings suggest that VCS could be clinically efficacious in patients with primary or secondary NS, without need for drug level testing and with decreased risk of exacerbation of known CNI-related dyslipidemia. CLINICAL TRIAL NUMBER: Not applicable.