Chronic Dosing of Voclosporin at Clinically Relevant Exposure Levels Does Not Induce Renal Fibrosis Markers in Rats
Bibliographic record
Abstract
Background: Although prognosis of lupus nephritis (LN) has improved, the long-term outcome is still poor, with many patients progressing to end-stage renal disease. Calcineurin inhibitors (CNIs) like cyclosporine A (CsA) and tacrolimus have demonstrated benefit in LN; however, prolonged use is associated with renal fibrosis. CsA-induced fibrosis has largely been in the context of high doses required for immunosuppression in transplant patients. Voclosporin (VCS), a potent, novel CNI with a predictable PK/PD profile, is approved for treatment of LN. This study tested the hypothesis that the clinically effective dose of VCS used in LN patients, would not induce fibrosis markers in the chronic dosing rat model compared to CsA and vehicle controls. Methods: Sprague Dawley rats (n=10/ group) on a low sodium (0.05%) diet were treated by oral gavage (QD) with VCS (4 mg/kg), cyclosporine A control (10 mg/kg) or vehicle control (5 mL/kg) for 3 or 6 weeks. Clinical chemistry was performed on serum and overnight urine. Gene expression (RT-qPCR) and histology were performed on kidneys. Data were analyzed as change from baseline. Results: There were no significant differences in clinical measures of renal or liver function. There were no significant changes in urine protein/creatinine or fractional excretion. Serum total bilirubin and cholesterol were significantly increased in the CsA treated group compared to vehicle and VCS. At 3 weeks, there was a significant decrease in expression of Tgfb1 and the epithelial-mesenchymal transition (EMT) marker Cdh2 (N-cadherin) in VCS treated animals compared to vehicle and CsA, and significant decreases in expression of the EMT regulators, Snai1 (SNAIL) and Snai2 (SLUG), and the extracellular matrix components (ECM) Col1a1, Col3a1 and Vim in the VCS treated group. At 6 weeks, trends between groups remained, and there were significant decreases in Tgfb2 and Col3a1 in the VCS treated group. At 6 weeks, there were no differences in renal histopathology. Conclusions: This study shows that the clinically relevant dose of voclosporin does not induce renal fibrosis markers in rats, in contrast to the CsA control. Additionally, voclosporin may protect against renal EMT and ECM deposition, which are associated with CsA. Collection of data from a two-year continuation renal biopsy sub-study of AURORA-1 is ongoing. 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 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".