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.

2022-06

Cox, Daniel R A

Low, Nicholas

Goh, Su Kah

Lee, Eunice

Vago, Angela

Jackett, Louise A

Lokan, Julie

Braat, Sabine

Jones, Robert M

Testro, Adam G

Dobrovic, Alexander

Muralidharan, Vijayaragavan

Journal Article

https://orcid.org/0000-0002-5092-4370

https://orcid.org/0000-0002-6684-2521

https://orcid.org/0000-0003-1997-3999

https://orcid.org/0000-0002-8415-5565

https://orcid.org/0000-0001-6776-3115

https://orcid.org/0000-0003-3414-112X

https://orcid.org/0000-0001-8247-8937

https://orcid.org/0000-0003-2792-6199

https://orcid.org/0000-0002-1333-4734

10.1002/lt.26388

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 of <33.5% 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.

link

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2022; 28(6): 1024-1038

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society