FP761NON-HLA AGONISTIC ANTI-ANGIOTENSIN II TYPE 1 RECEPTOR ANTIBODIES INDUCE A DISTINCTIVE PHENOTYPE OF REJECTION IN KIDNEY TRANSPLANT RECIPIENTS: AN OBSERVATIONAL COHORT STUDY
Bibliographic record
Abstract
INTRODUCTION: The implementation of the HLA system in clinical practice was a breakthrough in transplant medicine. However, half of transplants fail within 15 years. We aimed to determine whether non-HLA anti-angiotensin II type 1 receptor (AT1R) antibodies might identify kidney recipients at risk of allograft rejection and loss. METHODS: We prospectively enrolled 1845 kidney recipients transplanted in two centers. Patients underwent allograft evaluation within the first year after transplantation, including allograft function, proteinuria, blood pressure, anti-HLA donor-specific antibodies (DSAs), AT1R antibodies (using quantitative ELISA) and allograft biopsy to assess rejection phenotype using histology, immunochemistry and gene expression in allografts based on microarray. RESULTS: Overall, 371 (20.1%) patients had AT1R antibodies (>10 U/mL), 334 (18.1%) had anti-HLA DSAs and 133 (7.2%) had both antibodies. The presence of AT1R antibodies was associated with an increased risk of allograft loss: adjusted HR, 1.49 (95%CI, 1.07-2.06) for AT1R antibodies alone and 2.26 (95%CI, 1.52-3.36) for AT1R antibodies and anti-HLA DSAs. Higher levels of circulating anti-AT1R antibodies were associated with increasing incidence of allograft loss in penalized spline modeling (p<0.001). Patients with AT1R antibodies showed a higher incidence of active antibody-mediated rejection (AMR) compared with patients without AT1R antibodies (n=126/504 (25.0%) vs. n=173/1341 (12.9%); p<0.001). AT1R antibodies identified 51/77 (66.2%) patients as having AMR among patients with histological features of active AMR without evidence of anti-HLA DSAs. Compared to patients with prototypical anti-HLA DSA-mediated rejection, patients with AT1R antibody-associated rejection had more frequently hypertension, increased prevalence of vascular rejection with arterial inflammation and lack of complement deposition in allograft capillaries. Based on gene expression analysis, patients with AT1R antibody-associated rejection showed higher levels of endothelial-associated transcripts demonstrating the interaction of AT1R antibodies with the vascular endothelium (p=0.013) and lower levels of gamma interferon-induced transcripts (p=0.010) compared with those with prototypical anti-HLA DSA-mediated rejection. CONCLUSIONS: Non-HLA AT1R antibodies identify kidney recipients at high risk of allograft rejection and loss, independent of HLA system. Recognition of complement-independent AT1R antibody-mediated vascular rejection could lead to the development of new treatment strategies targeting circulating antibodies and AT1Rs, such as the use of sartans, to improve kidney allograft survival.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".