Dataset Information

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

ABSTRACT:

Background

Endomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adult HTx recipients.

Methods

Plasma samples with contemporaneous EMBs were obtained from HTx recipients. A clinically available SNP-based massively multiplexed-PCR dd-cfDNA assay was used to measure dd-cfDNA fraction. dd-cfDNA fractions were compared with EMB-defined rejection status and test performance was assessed by constructing ROC curves and calculating accuracy measures.

Results

A total of 811 samples from 223 patients with dd-cfDNA testing and contemporaneous EMB were eligible for the study. dd-cfDNA fraction was significantly higher in AR (median 0.58%, IQR, 0.13%-1.68%) compared to non-AR (median 0.04%, IQR, 0.01%-0.11%, p_c < 0.001). ROC analysis produced an area under the curve (AUC-ROC) of 0.86 (95% CI, 0.77-0.96). Defining samples with dd-cfDNA fraction ≥0.15% as AR yielded 78.5% sensitivity (95% CI, 60.7%-96.3%) and 76.9% specificity (95% CI, 71.1%-82.7%). Positive and negative predictive values were 25.1% (95% CI, 18.8%-31.5%) and 97.3% (95% CI, 95.1%-99.5%) respectively, calculated using the cohort AR prevalence of 9.0% (95% CI, 5.3%-12.8%) with adjustment for repeat samples.

Conclusions

This novel dd-cfDNA test detects AR in HTx recipients with good accuracy and holds promise as a noninvasive test for AR in HTx recipients.

SUBMITTER: Kim PJ

PROVIDER: S-EPMC9670834 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

Kim Paul J PJ Olymbios Michael M Siu Alfonso A Wever Pinzon Omar O Adler Eric E Liang Nathan N Swenerton Ryan R Sternberg Jonathan J Kaur Navchetan N Ahmed Ebad E Chen Yen-An YA Fehringer Gordon G Demko Zachary P ZP Billings Paul R PR Stehlik Josef J

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20220410 7

<h4>Background</h4>Endomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adu ...[more]

PMID: 35577713

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Project description:BackgroundCellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge about donor immune cell types and functions in the setting of cardiac transplantation, and no current therapeutics exist for targeting these cell populations.MethodsUsing genetic lineage tracing, cell ablation, and conditional gene deletion, we examined donor mononuclear phagocyte diversity and macrophage function during acute cellular rejection of transplanted hearts in mice. We performed single-cell RNA sequencing on donor and recipient macrophages and monocytes at multiple time points after transplantation. On the basis of our imaging and single-cell RNA sequencing data, we evaluated the functional relevance of donor CCR2+ (C-C chemokine receptor 2) and CCR2- macrophages using selective cell ablation strategies in donor grafts before transplant. Last, we performed functional validation that donor macrophages signal through MYD88 (myeloid differentiation primary response protein 88) to facilitate cellular rejection.ResultsDonor macrophages persisted in the rejecting transplanted heart and coexisted with recipient monocyte-derived macrophages. Single-cell RNA sequencing identified donor CCR2+ and CCR2- macrophage populations and revealed remarkable diversity among recipient monocytes, macrophages, and dendritic cells. Temporal analysis demonstrated that donor CCR2+ and CCR2- macrophages were transcriptionally distinct, underwent significant morphologic changes, and displayed unique activation signatures after transplantation. Although selective depletion of donor CCR2- macrophages reduced allograft survival, depletion of donor CCR2+ macrophages prolonged allograft survival. Pathway analysis revealed that donor CCR2+ macrophages are activated through MYD88/nuclear factor kappa light chain enhancer of activated B cells signaling. Deletion of MYD88 in donor macrophages resulted in reduced antigen-presenting cell recruitment, reduced ability of antigen-presenting cells to present antigen to T cells, decreased emergence of allograft-reactive T cells, and extended allograft survival.ConclusionsDistinct populations of donor and recipient macrophages coexist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection, and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.

Project description:BackgroundThe quantification of rejection treatment efficacy has been insufficient using traditional markers due, in part, to the lagging response of serum creatinine and histologic alterations on biopsy specimens. Donor-derived cell-free DNA (dd-cfDNA) is a molecular marker of injury that may assess allograft injury after rejection.MethodsRetrospective review of the DART study identified 70 patients who had a clinically indicated biopsy, simultaneous dd-cfDNA measurement, and at least one follow-up dd-cfDNA within 3 months post-treatment. Thirty-five patients had no biopsy-proven rejection and no rejection treatment (NR), 16 patients had no biopsy-proven rejection but did receive rejection treatment (CR), 9 patients had diagnosis of ABMR/mixed rejection on biopsy and received rejection treatment (ABMR), and 10 patients had diagnosis of TCMR and received rejection treatment (TCMR). The CR, ABMR, and TCMR groups combined to form a rejection (R) group.ResultsIn the R group, median dd-cfDNA values at baseline and 1 month were 0.62% and 0.35% (n=21 pairs, p=0.34), and at baseline and 2-3 months were 0.77% and 0.21% (n=23 pairs, p=0.002). In TCMR, median dd-cfDNA values at baseline and 1 month were 1.13% and 0.37% (n=5 pairs, p=0.63), and at baseline and 2-3 months were 0.25% and 0.12% (n=9 pairs, p=0.004). In ABMR, median dd-cfDNA values at baseline and 1 month were 1.61% and 1.2 % (n=6 pairs, p>0.99), and at baseline and 2-3 months were 3.85% and 1.32% (n=6 pairs, p=0.09). In CR, median dd-cfDNA values at baseline and 1 month were 0.31% and 0.29% (n=10 pairs, p=0.38), and at baseline and 2-3 months were 0.38% and 0.17% (n=8 pairs, p=0.31). Lastly, in NR, median dd-cfDNA values at baseline and 1 month were 0.23% and 0.18% (n=21 pairs, p=0.10), and at baseline and 2-3 months were 0.33% and 0.17% (n=26 pairs, p=0.003). Changes in serum creatinine across 1 month and 2-3 months following rejection were similar.Conclusionsdd-cfDNA may be a useful dynamic biomarker to assess the health of the kidney allograft following rejection treatment.

Dataset Information

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

Background

Methods

Results

Conclusions

Publications

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

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