000			04286nam a22005177a 4500
008			210217s20212021 xxu||||| |||| 00| 0 eng d
022			_a0009-7322
024			_a10.1161/CIRCULATIONAHA.120.049098 [doi]
040			_aOvid MEDLINE(R)
099			_a33435695
245			_aCell-Free DNA to Detect Heart Allograft Acute Rejection.
251			_aCirculation. 143(12):1184-1197, 2021 03 23.
252			_aCirculation. 143(12):1184-1197, 2021 03 23.
252			_zCirculation. 2021 Jan 13
252			_zCirculation. 143(12):1184-1197, 2021 03 23.
253			_aCirculation
260			_c2021
260			_fFY2021
265			_sppublish
266			_d2021-02-17
268			_aCirculation. 2021 Jan 13
268			_aCirculation. 143(12):1184-1197, 2021 03 23.
269			_fFY2021
501			_aAvailable online from MWHC library: 1950 - present, Available in print through MWHC library: 1999 - 2006
520			_aBackground: 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.
546			_aEnglish
650			_a*Allografts/tr [Transplantation]
650			_a*Cell-Free Nucleic Acids/ge [Genetics]
650			_a*Graft Rejection/pp [Physiopathology]
650			_aAdult
650			_aAged
650			_aCohort Studies
650			_aFemale
650			_aHumans
650			_aMale
650			_aMiddle Aged
650			_aProspective Studies
650			_aYoung Adult
651			_aMedStar Heart & Vascular Institute
657			_aJournal Article
700			_aNajjar, Samer S
700			_aRodrigo, Maria
790			_aAgbor-Enoh S, Berry GJ, Bhatti K, Bikineyeva A, Feller E, Fideli U, GRAfT Investigators, Hsu S, Jang MK, Kong H, Marboe C, Marishta A, Mutebi C, Najjar SS, Pirooznia M, Rodrigo ME, Russell S, Shah K, Shah P, Tunc I, Valantine HA, Yang Y, Yu K
856			_uhttps://dx.doi.org/10.1161/CIRCULATIONAHA.120.049098 _zhttps://dx.doi.org/10.1161/CIRCULATIONAHA.120.049098
942			_cART _dArticle
999			_c6058 _d6058