Voclosporin Ameliorates Both Proteinuria and Dyslipidemia in a Model of Noninflammatory Glomerular Disease
Bibliographic record
Abstract
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. Conclusions: 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".