Correlation of Donor-Derived Cell-Free DNA With Histology and Molecular Diagnoses of T-Cell Mediated Rejection in Kidney Transplant Biopsies
Bibliographic record
Abstract
Background: We reported correlation of donor-derived cell-free DNA (dd-cfDNA) with histologic and molecular diagnosis (MMDx) of kidney transplant biopsies (Gupta et al, Transplantation 2021). Here we build on that initial cohort with a larger TCMR sample size and provide data on therapy and outcomes. Methods: We identified biopsies classified as TCMR by histology and/or MMDx. Those with viral/bacterial nephritis/mixed rejection were excluded. Prior to therapy fractional dd-cfDNA (%; Allosure) was measured. 37 such biopsies were divided into two groups, H+M+ (concomitant TCMR; N=18) and H+M- (discordant TCMR; N=19). Results: Median dd-cfDNA was lower (p=0.02) in H+M- (0.32%; IQR: 0.15-0.43) compared to H+M+ group (1.03%; IQR: 0.38-1.8). In histologic findings interstitial and tubular inflammation (i+t) (4.8±1.5 vs 3.3±1.2, p=0.002) was worse for H+M+ vs H+M-. A graded dose-response was seen between i+t and dd-cfDNA for H+M+ and not seen in H+M- (Figure 1a). Borderline/1A TCMR was seen frequently in the H+M- (16/19, 84%) while TCMR ≥1B was seen in the H+M+ group (12/18, 67%). MMDx scores for TCMR (0.50±0.29 vs 0.02±0.02, p<0.0001) and inflammation (4.6±2.1 vs -0.55±1.5, p<0.0001) were higher in the H+M+ vs H+M- group. eGFR at biopsy was worse in the H+M+ group (27±19ml/min) compared to the H+M- (40±23ml/min; p=0.06). A majority of H+M+ were treated (16/18; 89%; 14 rATG and 2 steroids only) and a minority of H+M- received steroids only (7/19; 37%). Despite this discrepancy, there was improvement in eGFR in both groups. At median follow-up of 14.7 months eGFR improved to 34±24ml/min in the H+M+ and 49.2±26ml/min in the H+M- group (Figure 1b). All 4 graft losses and one patient death was in the H+M+ group (p=0.02). Conclusions: We confirm our findings in patients with histologic TCMR absent on molecular gene expression is associated with low dd-cfDNA. Majority of patients had improvement in kidney function without targeted therapy. This may indicate low-grade TCMR is a ‘response to wounding’, rather than cognate allo-recognition.
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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 | 0.003 |
| 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) | 0.002 | 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".