1. Low Levels of Hepatocyte‐Specific Methylation in Cell‐Free DNA Are a Strong Negative Predictor for Acute T Cell–Mediated Rejection Requiring Treatment Following Liver Transplantation
- Author
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Daniel R. A. Cox, Nicholas Low, Su Kah Goh, Eunice Lee, Angela Vago, Louise Jackett, Julie Lokan, Sabine Braat, Robert Jones, Adam Testro, Alexander Dobrovic, and Vijayaragavan Muralidharan
- Subjects
Graft Rejection ,Transplantation ,Hepatology ,T-Lymphocytes ,Methylation ,Tissue Donors ,Liver Transplantation ,Cross-Sectional Studies ,Hepatocytes ,Humans ,Surgery ,Prospective Studies ,Cell-Free Nucleic Acids ,Biomarkers - Abstract
Graft-derived cell-free DNA (gdcfDNA) quantification is a promising, minimally invasive tool for detecting acute T cell-mediated rejection (ATCMR) following liver transplantation (LT). We investigated the utility of measuring hepatocyte-specific methylation in cfDNA (HS-cfDNA) to quantify gdcfDNA, examining its accuracy in detecting ATCMR in a prospective, cross-sectional study. Blood was collected from LT recipients immediately prior to graft biopsy for suspected rejection. HS-cfDNA was quantified using droplet-digital polymerase chain reaction. Prebiopsy liver function tests (LFTs) and HS-cfDNA levels were correlated with biopsy results and the primary outcome of treated biopsy-proven acute rejection (tBPAR). A total of 51 patients were recruited; 37 had evidence of rejection on biopsy and 20 required treatment. As much as 11 patients needed inpatient treatment for rejection. HS-cfDNA significantly outperformed LFTs in identifying patients with tBPAR, particularly those needing inpatient treatment (area under the curve, 73.0%; 95% confidence interval, 55.4%-90.6%; P = 0.01). At a threshold of33.5% of the total cfDNA fraction, HS-cfDNA had a specificity of 97%, correctly excluding tBPAR in 30/31 patients. Quantifying graft-specific methylation in cfDNA has a major advantage over previous gdcfDNA techniques: it does not require genotyping/sequencing, lending it greater feasibility for translation into transplantation care. Low levels of HS-cfDNA were a strong negative predictor for tBPAR (negative predictive value, 86%) and may have a future role in triaging patients prior to invasive graft biopsies.
- Published
- 2022