The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation · 2025
Correlation between donor-derived cell-free DNA and tissue gene expression in heart transplant patients undergoing for-cause endomyocardial biopsies.
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Valledor Andrea Fernandez, Moeller Cathrine M, Oren Daniel, Baranowska Julia, Rahman Salwa, Hertz Adi, Rahman Afsana, Hennecken Carolyn, Rubinstein Gal, Elad Boaz, Richter Ilan, Lotan Dor, Regan Matthew, LaBarre Brian, Yunis Adil, Fried Justin, DeFilippis Ersilia M, Colombo Paolo C, Yuzefpolskaya Melana, Raihkelkar Jayant, Latif Farhana, Clerkin Kevin D, Majure David T, Sayer Gabriel T, Uriel Nir
Аннотация
BACKGROUND: The introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope Diagnostic System (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 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 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 4-fold increase in rejection rates by MMDx, mainly driven by a 5-fold increase in antibody-mediated rejection detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (area under the curve [AUC] of 0.77; optimal cutoff dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further (AUC of 0.89; optimal cutoff value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64.
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.
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 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 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 4-fold increase in rejection rates by MMDx, mainly driven by a 5-fold increase in antibody-mediated rejection detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (area under the curve [AUC] of 0.77; optimal cutoff dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further (AUC of 0.89; optimal cutoff value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64.
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.