Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial
Bibliographic record
Abstract
BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR. We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison with clinical indication biopsy. METHODS: In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate ≥20 mL/min/1.73 m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-month period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9 and 12 months. In the intervention group, dd-cfDNA >50 copies/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR. RESULTS: Thirty-nine of 40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group [median 2.8 months, interquartile range (IQR) 1.7-5.3 vs median 14.5 months, IQR 13.3-16.7, P = .003]. Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR. CONCLUSIONS: Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04897438.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| 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".