Dissecting a Subtle Endothelial Signal in Human Kidney Transplants With Antibody-Mediated Rejection.
Bibliographic record
Abstract
We aimed to describe the molecular changes most associated with ABMR in comparison to other events - IFNG effects, inflammasome activation, innate immunity, and complement inhibitors. In a set of 403 human kidney transplant indication biopsies, we used microarrays to compare ABMR to all other biopsies, including T cell-mediated rejection, acute kidney injury, polyomavirus nephropathy, and glomerulonephritis. Transcripts previously identified by a molecular classifier for ABMR - eg DARC, CDH13, FGFBP2 (Sellares et al. Am J Transplant 13(4):2013) - had the greatest association with ABMR (Figure 1, p-values as low as 10-14). Other transcripts with moderate associations with ABMR (p-values >10-8) included: inflammasome-related CASP1 and IL1B (which is activated by CASP1) and complement inhibitor transcripts CD55 (DAF) and CD59 (MAC-IP). Toll-like receptors 7/8/9; inflammasome-related IL18, CASP8 and CD95 (Fas); CD46 (complement regulatory protein); and the parenchyma (kidney solute carrier expression) changed little, unlike in TCMR.Figure: No Caption available.We analyzed the top 100 ABMR-associated transcripts (defined by the class comparison p-value) for overrepresentation in IPA Canonical Pathways: top pathways (p-values around 10-15) were associated with antigen presentation and contained HLA molecules (eg HLA-A/B/C, -DQ); and when the transcripts used in these pathways were purged and we and re-analyzed the remaining ABMR-associated transcripts - Step 2, Figure 2 - top pathways now were leukocyte Adhesion and Diapedesis (p-values around 10-9). Subsequent removal of these transcripts (eg CDH5, SELE, CX3CL1) left relatively weak associations (p>10-4) such as Nitric Oxide, Angiopoietin, and NK Cell Signaling - Step 3, Figure 2. ABMR-associated transcripts in these pathways included endothelial expressed GNG11, VEGFC, CAV1, TEK (angiopoeitin receptor) and NK expressed FCGR3A and CD94. Thus the transcripts most strongly associated with the ABMR phenotype reveal the endothelial injury, IFNG effects, and NK transcripts, but the more moderate association also suggest some of the molecular events in the microcirculation response to injury, including nitric oxide, angiopoietin, VEGF, caveolin, and complement inhibitors CD55 and CD59. DISCLOSURES:Halloran, P.: Speaker's Bureau, Astellas, Novartis, OneLamba.
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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".