Unbiased Proteomics Distinguishes Chronic and Acute Antibody-Mediated Rejection in Donor-Specific Antibody-Positive Kidney Transplant Recipients
Bibliographic record
Abstract
Background: Nearly a million North Americans have end-stage renal disease, for which transplantation of a new kidney is the best treatment; however, >50% of grafts fail by 10 years due mainly to antibody-mediated rejection (ABMR), where recipient donor-specific antibodies (DSA) can drive tissue injury. Unfortunately, presence of DSA alone cannot predict ABMR, as 30-60% of DSA+ patients do not develop rejection. We aim to identify factors regulating kidney protein expression in DSA+ kidney transplant recipients with and without ABMR. Methods: Kidney biopsies were obtained from DSA+ kidney transplant recipients with no rejection (NR; n=45) or ABMR (acute, n=25; chronic, n=25; mixed ABMR/cellular rejection, n=25). Glomeruli (glom) and tubulointerstitium (TI) extracted from kidney biopsies using laser capture microdissection were digested to peptides and analyzed by liquid chromatography mass spectrometry. MaxQuant and Perseus software were used for protein identification and differential expression. Differentially expressed proteins (ANOVA, p<0.05) were mapped to signaling pathways using pathDIP (FDR: BH, q<0.05). Results: 180 glomerular and 325 tubulointerstitial proteins were significantly differentially expressed between DSA+ patients with NR or with a subtype of ABMR (Fig 1). Proteins upregulated in acute or mixed ABMR mapped significantly to pathways for MHC and interferon (IFN) signaling in TI (MHC pathway, q=5.5e-12; IFN signaling, q=3.3e-8). In contrast, proteins upregulated in chronic ABMR mapped to the complement cascade (glom, q=2.9e-3; TI, q=6.8e-11) and extracellular matrix organization (glom, q=2.1e-7; TI, q=2.5e-4) in both compartments. DSA+ patients with any ABMR subtype showed significant downregulation of proteins linked to pyruvate metabolism in both compartments compared to NR (glom, q=2.7e-4; TI, q=6.9e-14). Conclusion: Our results suggest that while both acute and chronic ABMR in DSA+ kidney transplant patients involve altered metabolism, distinct immune-mediated mechanisms may drive tissue damage in the individual subtypes. Funding: Government Support – Non-U.S.
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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 | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".