Donor-derived cell-free DNA levels predict graft injury in liver transplant recipients

Abstract

Donor‐derived cell‐free DNA (dd‐cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd‐cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd‐cfDNA. Phenotypes of treated biopsy‐proven acute rejection (AR, N = 57), normal function (TX, N = 94), and acute dysfunction no rejection (ADNR; N = 68) were divided into training and test sets. In the training set, dd‐cfDNA was significantly different between AR versus TX (AUC 0.95, 5.3% cutoff) and AR versus ADNR (AUC 0.71, 20.4% cutoff). Using these cutoffs in the test set, the accuracy and NPV were 87% and 100% (AR vs. TX) and 66.7% and 87.8% (AR vs. ADNR). Blood samples collected serially from LTR demonstrated incremental elevations in dd‐cfDNA prior to the onset of graft dysfunction (AR > ADNR), but not in TX. Dd‐cfDNA also decreased following treatment of rejection. In conclusion, the serial elevation of dd‐cfDNA identifies pre‐clinical graft injury in the context of normal liver function tests and is greatest in rejection. This biomarker may help detect early signs of graft injury and rejection to inform LTR management strategies.

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“…Patients were initially divided into three groups: transplant excellent (TX representing IQ and healthy graft function; n = 25), acute dysfunction no rejection (ADNR, representing nonrejection causes of graft injury; n = 25), and AR ( n = 25). The AR and ADNR phenotypes were diagnosed by needle biopsy, and TX by clinical and laboratory criteria, as previously described ( 31 – 34 ). The absence of biopsies in TX was a limitation; however, transplant centers do not generally perform surveillance biopsies in LTR with healthy graft function.…”

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“…Based on these results, it is expected that ctDNA will also be introduced as an efficacy indicator for ICI used before and after liver transplantation for HCC. Similar to kidney transplant acute rejection, dd-cfDNA can also be used to evaluate allograft tolerance in liver transplant recipients [ 74 , 75 ]. Levitsky et al [ 75 ] reported that the area under the curve of dd-cfDNA in the acute rejection group (n=57) compared to the normal function group (n=94) was as high as 0.95, and dd-cfDNA decreased alongside normalization after treatment for acute rejection.…”

“…Similar to kidney transplant acute rejection, dd-cfDNA can also be used to evaluate allograft tolerance in liver transplant recipients [ 74 , 75 ]. Levitsky et al [ 75 ] reported that the area under the curve of dd-cfDNA in the acute rejection group (n=57) compared to the normal function group (n=94) was as high as 0.95, and dd-cfDNA decreased alongside normalization after treatment for acute rejection. Therefore, dd-cfDNA may become a biomarker for evaluating rejection in liver transplant patients who receive ICI treatment.…”

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“…The over-arching hypothesis is that dd-cfDNA levels above baseline may indicate graft injury; they have been associated with elevated liver enzymes in the setting of acute rejection. Longitudinal trajectories of rising dd-cfDNA levels have been linked to graft injury, and a dd-cfDNA threshold has been suggested to differentiate allo-immune attack from other mechanisms of graft injury [3]. Imaging modalities including ultrasound elastography, acoustic radiation impulse frequency imaging, or magnetic resonance elastography can be used to measure liver stiffness, which varies with the degree of inflammation, edema, and/ or fibrosis.…”