Andrea Fernandez Valledor,Cathrine M Moeller,Daniel Oren,Julia Baranowska,Salwa Rahman,Adi Hertz,Afsana Rahman,Carolyn Hennecken,Gal Rubinstein,Boaz Elad,Ilan Richter,Dor Lotan,Matthew Regan,Brian LaBarre,Adil Yunis,Justin Fried,Ersilia M DeFilippis,Paolo C Colombo,Melana Yuzefpolskaya,Jayant Raihkelkar,Farhana Latif,Kevin D Clerkin,David T Majure,Gabriel T Sayer,Nir Uriel
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引用次数: 0
Abstract
INTRODUCTION
The introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope (MMDx) is changing how we diagnose rejection following heart transplantation (HT). This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance.
METHODS
Single-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a Receiver Operator Curve (ROC) to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated dependent samples when appropriate.
RESULTS
247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. Elevated dd-cfDNA levels were associated with a fourfold increase in rejection rates by MMDx, mainly driven by a fivefold increase in ABMR detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (AUC of 0.77; optimal cut-off dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further, (AUC of 0.89; optimal cut-off value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64. The correlation between dd-cfDNA levels and MMDx rejection scores was moderate (r=0.51; p<0.001).
CONCLUSIONS
In a for-cause biopsy population, elevated dd-cfDNA levels were more predictive of rejection on MMDx than on histology, suggesting that molecular techniques may detect rejection at earlier stages than traditional histological methods. A dd-cfDNA cutoff of 0.26% provided the highest predictive accuracy for rejection by MMDx when applied within a mixed-effects model for repeated measures.