Early Graft Injury Measured by Donor-Derived Cell-Free DNA Predicts Early Mortality in Lung Transplant Recipients

Agbor-Enoh, S.; Tunc, Ilker; Vlaminck, Iwijn De; Davis, Andrew A.; Gorham, S.; Cuttin, Karen; Fideli, U.; Marishta, A.; Wylie, Jennifer; Luikart, Helen; Khush, Kiran K.; Valantine, Hannah A.

doi:10.1016/j.healun.2017.01.159

Cited by 3 publications

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“…Compared to the NHP with sustained normal xenograft function, baseline %xdcfDNA was seven times higher in NHPs that subsequently developed clinical rejection and progressive xenograft failure. In lung transplant recipients higher donor-derived cfDNA levels after the initial transplant decay are correlated with increased rates of allograft loss [16]. These data from our xenograft model provide further evidence that cfDNA is a marker of persistent graft injury that partains poor outcomes.…”

Section: Discussionsupporting

confidence: 52%

“…To verify this analysis, we also extracted the sequences from position 0 to 25 of the properly aligned sequence reads, performed similar analysis and compared the nucleotide composition to the previous analysis. We performed similar length distribution and nucleotide composition analyses using previously analyzed cfDNA sequence data from allotransplant recipients [7, 9, 11, 16].…”

Section: Methodsmentioning

confidence: 99%

“…To compare technological characteristics of cfDNA analyses, we obtained sequencing and computation data from previously analyzed plasma cfDNA of cardiac allotransplantation recipients [7, 9, 11, 16] and compared the characteristics to the xenograft cfDNA assayed in current study. The xdcfDNA and troponin values showed a skewed distribution, thus non-parametric methods were used to compare rejection from non-rejection time-points.…”

Section: Methodsmentioning

confidence: 99%

“…Achieving this goal requires diagnostic tools for early detection of tissue injury (due to AHXR) to prompt initiation of therapy before irreversible damage occurs. Previous studies have demonstrated the use of donor-derived cfDNA as a marker for allograft injury [7, 9, 11, 12], immunosuppressive drug efficacy [15], or long term outcomes [16]. Quantification of xenograft-derived cfDNA (xdcfDNA) may allow us to detect xenograft injury earlier and with greater accuracy than currently available methods – manual palpation, echocardiography and serum troponin assay.…”

Section: Introductionmentioning

confidence: 99%

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Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model

Agbor‐Enoh

Chan

Singh

et al. 2018

The Journal of Heart and Lung Transplantation

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Section: Discussionsupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model

Agbor‐Enoh

Chan

Singh

et al. 2018

The Journal of Heart and Lung Transplantation

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Donor-specific Cell-free DNA as a Biomarker in Solid Organ Transplantation. A Systematic Review

2019

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Cell-Free DNA to Detect Heart Allograft Acute Rejection

et al. 2021

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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

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Early Graft Injury Measured by Donor-Derived Cell-Free DNA Predicts Early Mortality in Lung Transplant Recipients

Cited by 3 publications

References 0 publications

Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model

Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model

Donor-specific Cell-free DNA as a Biomarker in Solid Organ Transplantation. A Systematic Review

Cell-Free DNA to Detect Heart Allograft Acute Rejection

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