Effects of Atrasentan on Kidney Gene Transcription, Mesangial Cell Proliferation, and Proteinuria in IgA Nephropathy
Bibliographic record
Abstract
KEY POINTS: In human renal mesangial cells stimulated with endothelin-1, atrasentan reduced mesangial cell proliferation and matrix expansion. Atrasentan reduced kidney injury in two preclinical models of IgA nephropathy. These findings support the therapeutic potential of atrasentan to treat IgA nephropathy; clinical studies of atrasentan are ongoing. BACKGROUND: IgA nephropathy (IgAN) is the leading cause of primary GN and carries a high risk of progression to ESKD. Endothelin-1 type A (ET A ) receptor activation may be a key driver of proteinuria, inflammation, and fibrosis in patients with kidney diseases. Atrasentan, a highly potent and highly selective antagonist of the ET A receptor, demonstrated a statistically significant and clinically meaningful proteinuria reduction of 36.1% (95% confidence interval, 26.4% to 44.6%; P < 0.001) relative to placebo, at week 36 in the ongoing Atrasentan in Patients With IgA Nephropathy (ALIGN) phase 3 trial. Based on these data, atrasentan is indicated to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression. METHODS: We explored the biologic effects and changes in gene transcription with atrasentan in cultured human renal mesangial cells, grouped ddY mouse model of IgAN, and Wistar rats injected with anti-Thy1.1 (CD90) antibody to induce mesangial injury and mesangioproliferative GN. The effect of atrasentan on proteinuria and kidney gene transcriptome was evaluated in both animal models, and histologic and morphometric assessments of rat kidneys were conducted. RESULTS: In separate transcriptomics analyses of all three models, atrasentan reversed gene expression changes related to cell proliferation, proinflammatory, and profibrotic signatures. In human renal mesangial cells stimulated with endothelin-1, atrasentan reduced mesangial cell proliferation and matrix expansion. After 7 days, atrasentan treatment in the mesangioproliferative GN rat model diminished renal mesangial hypercellularity and matrix expansion, decreased glomerular and tubulointerstitial structural alterations, and significantly reduced proteinuria. In grouped ddY mice, atrasentan treatment for 4 days significantly reduced mean albuminuria by >60%. CONCLUSIONS: The acute mechanistic effects of atrasentan demonstrated in vitro and in vivo support the therapeutic potential of atrasentan in IgAN. The ongoing Atrasentan in Patients With Proteinuric Glomerular Diseases (AFFINITY) and Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy (ASSIST) phase 2 trials, and the ALIGN phase 3 trial in patients with IgAN will further evaluate the translation of these mechanistic effects to the clinical efficacy and safety of atrasentan.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".