TY  - BOOK
AU  - Najjar, Samer S
AU  - Rodrigo, Maria
TI  - Cell-Free DNA to Detect Heart Allograft Acute Rejection
SN  - 0009-7322
PY  - 2021///
KW  - *Allografts/tr [Transplantation]
KW  - *Cell-Free Nucleic Acids/ge [Genetics]
KW  - *Graft Rejection/pp [Physiopathology]
KW  - Adult
KW  - Aged
KW  - Cohort Studies
KW  - Female
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Prospective Studies
KW  - Young Adult
KW  - MedStar Heart & Vascular Institute
KW  - Journal Article
N1  - Available online from MWHC library: 1950 - present, Available in print through MWHC library: 1999 - 2006
N2  - Background: After heart transplantation, Endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive and its conventional histologic interpretation has limitations. This is a validation study to assesses the performance of a sensitive blood biomarker- percent donor-derived cell-free DNA (%ddcfDNA) - for detection of AR in cardiac transplant recipients. Methods: This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data was collected to define AR, its two phenotypes (acute cellular rejection, ACR, and antibody-mediated rejection, AMR) and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range - IQR) for AR, AMR and ACR to controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis. Results: The study included 171 subjects with median post-transplant follow-up of 17.7 months (IQR: 12.1-23.6), with 1,392 EMBx, and 1,834 ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (0.03-0.21) by 28 days. %ddcfDNA increased again with AR compared to controls values (0.38, IQR=0.31-0.83, vs. 0.03, IQR=0.01-0.14 p<0.001). The rise was detected 0.5 and 3.2 months before histopathological diagnosis of ACR and AMR. The area-under-the- receiver-operator characteristics curve (AUROC) for AR was 0.92. A 0.25 %ddcfDNA threshold had a negative predictive value (NPV) for AR of 99% and would have safely eliminated 81% of EMBx. %ddcfDNA showed distinctive characteristics comparing AMR to ACR, included 5-fold higher levels (pAMR >=2 1.68, IQR=0.49-2.79 vs. ACR grade >=2R 0.34, IQR=0.28-0.72), higher AUROC (0.95 vs. 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments. Conclusions: %ddcfDNA detected AR with a high AUROC and NPV. Monitoring with ddcfDNA, demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in heart transplant patients and paves the way for a clinical utility study. Clinical Trial Registration: URL: http://clinicaltrials.gov Unique Identifier: NCT02423070
UR  - https://dx.doi.org/10.1161/CIRCULATIONAHA.120.049098
ER  -