Elevated fractional donor‐derived cell‐free DNA during subclinical graft injury after liver transplantation

Abstract

Personalized immunosuppression (IS) promises to improve the balance of necessary control of alloreactivity and dose-dependent adverse effects of long-term IS such as kidney insufficiency, infections, and malignancies. The majority of liver transplantation (LT) recipients exhibit graft injuries (graft inflammation and/or fibrosis) that are not eligible for an IS reduction according to current Banff criteria, even when liver enzymes are normal or only marginally elevated. This cross-sectional study evaluated the noninvasive prediction of such subclinical graft injuries in surveillance liver biopsies via donor-derived cell-free DNA (dd-cfDNA). Absolute and fractional dd-cfDNA increased stepwise from patients without histological signs of rejection (n = 26) over subclinical graft injury (n = 61), including subclinical T cell-mediated rejection to clinical overt T cell-mediated rejection (n = 21). Thus, fractional plasma dd-cfDNA was significantly elevated paired to surveillance biopsies with relevant subclinical graft injury according to 2016 Banff criteria compared with those with minimal or absent histological graft injury. In contrast, the presence of donor-specific anti-human leukocyte antigen antibodies was not associated with the amount of dd-cfDNA. The sensitivity and specificity of fractional dd-cfDNA to noninvasively predict relevant subclinical graft injury was rather limited with 73% and 52% at the cutoff value of 2.1% fractional dd-cfDNA. The positive predictive value of fractional dd-cfDNA above 2.1% was 76% to noninvasively predict subclinical graft injury, calculated on the prevalence of graft injury in our prospective surveillance biopsy program, whereas the negative predictive values was not predictive (47%). In conclusion, dd-cfDNA has a

Serum CXCL8 Concentration Can Be Used as a Noninvasive Marker of Subclinical Rejection After Pediatric Liver Transplantation

“…CXCL8 is a noninvasive marker that is relatively effective in diagnosing SCR. In addition, plasma levels of donor-derived free DNA are significantly higher in recipients with subclinical rejection than in recipients with no histological evidence of rejection after LT. 19 However, because of its relatively low sensitivity and specificity in the diagnosis of SCR, the application value of CXCL8 was limited. A recent study found that miR-181a-5p and miR-155-5p in plasma could jointly predict the occurrence of SCR with sensitivity and specificity of up to 90%.…”

Donor-derived cell-free DNA as a diagnostic tool in transplantation

“…In a recent study, fractional dd-cfDNA was tested during subclinical graft injury after liver transplantation confirmed by surveillance biopsies (Baumann et al, 2022). The lower limit of quantification was 0.15% and the interassay CV ranged from 3% to 5.4%.…”

Immature and activated phenotype of blood NK cells is associated with acute rejection in adult liver transplant

“…In liver transplantation, the ddcfDNA is a powerful reference for the prediction and diagnosis of subclinical TCMR and overt TCMR and for the rapid diagnosis of graft-versus-host disease and monitoring of response to treatment. [48][49][50] However, as a product of allograft injury, the ddcfDNA is not rejection specific, its elevations can also be observed due to other causes, such as ischemia, trauma, and infection. [51] In renal transplantation, to achieve accurate detection of the alloresponse resulting in graft damage and benefit the individualized IS, the ddcfDNA is being tested in combination with other immunological strategies, including HLA epitope donor matching, T cell receptor sequencing, deep cytometric phenotyping of immune cell subsets, and routine DSA monitoring.…”