Voclosporin Ameliorates Proteinuria and Directly Protects Podocytes 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 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
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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".