Urinary Extracellular Vesicles Reveal Distinct Biological Effects of Voclosporin in the Treatment of Lupus Nephritis
Bibliographic record
Abstract
Background: In the Phase 2 AURA-LV and Phase 3 AURORA 1 trials the novel calcineurin inhibitor voclosporin significantly increased complete renal response rates compared to placebo, both including mycophenolate mofetil and low-dose steroids. We further explore this treatment response by analyzing urinary extracellular vesicles (uEV), which are secreted by kidney cells and have the potential to provide a non-invasive readout of cellular processes. Methods: We isolated uEV from biobanked spot urine samples collected from patients with active lupus nephritis (LN) treated with voclosporin or placebo in AURORA 1 (n=60 per arm). uEVs were isolated at baseline and at the end of treatment using a differential ultracentrifugation protocol. Proteomes were quantified by tandem mass spectrometry on a Thermo Exploris480 with a data-independent acquisition strategy. Data was analyzed with Spectronaut and proteins with a log2-fold change >1 and q-value <0.05 considered significant. Pathway analysis was performed using the Reactome database. Results: We identified 3708 proteins in uEV. At baseline 545 proteins were different in patients who responded to voclosporin. Pathway analysis linked these proteins to neutrophil degranulation, selenoamino acid metabolism, and Robo-receptors. Previous work on Robo-signaling showed it controls leukocyte infiltration and podocyte function in kidney injury and is increased in LN, while selenoamino acids are key to cellular antioxidant defenses and control Akt signaling through calcineurin. 732 proteins significantly changed in the patients who responded to voclosporin. Pathway analysis for voclosporin-altered proteins showed enrichment of the complement C2 and C4 pathways, while Fc-gamma receptor phagocytosis and tyrosine kinase signaling changed in patients responding to placebo. Neutrophil degranulation was changed by both voclosporin (61 proteins) and placebo (52 proteins), but involved different proteins (15 shared). Conclusions: Using mass spectrometry of uEV we identified potential non-invasive biomarkers for treatment response to voclosporin in patients with LN. In addition, we were able to characterize the altered processes in the patients responding to voclosporin, which included complement and a specific change in neutrophil-associated proteins. Funding: Commercial Support - Aurinia Pharmaceuticals
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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) | 0.000 | 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 | 0.000 |
| 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".