TY - JOUR
T1 - Non-invasive alloimmune risk stratification of long-term liver transplant recipients
AU - Vionnet, Julien
AU - Miquel, Rosa
AU - Abraldes, Juan G.
AU - Wall, Jurate
AU - Kodela, Elisavet
AU - Lozano, Juan Jose
AU - Ruiz, Pablo
AU - Navasa, Miguel
AU - Marshall, Aileen
AU - Nevens, Frederik
AU - Gelson, Will
AU - Leithead, Joanna
AU - Masson, Steven
AU - Jaeckel, Elmar
AU - Taubert, Richard
AU - Tachtatzis, Phaedra
AU - Eurich, Dennis
AU - Simpson, Kenneth J.
AU - Bonaccorsi-Riani, Eliano
AU - Feng, Sandy
AU - Bucuvalas, John
AU - Ferguson, James
AU - Quaglia, Alberto
AU - Sidorova, Julia
AU - Elstad, Maria
AU - Douiri, Abdel
AU - Sánchez-Fueyo, Alberto
N1 - Publisher Copyright:
© 2021
PY - 2021/12
Y1 - 2021/12
N2 - Background & Aims: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. Methods: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). Results: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. Conclusion: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. Lay summary: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.
AB - Background & Aims: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. Methods: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). Results: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. Conclusion: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. Lay summary: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.
KW - DSA
KW - FibroScan
KW - HLA epitope mismatch
KW - LT
KW - PIRCHE-II score
KW - T cell-mediated rejection
KW - biomarkers
KW - fibrosis
KW - gene-expression profiling
KW - immunosuppression minimisation
KW - non-invasive
KW - tolerance
UR - http://www.scopus.com/inward/record.url?scp=85116224955&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2021.08.007
DO - 10.1016/j.jhep.2021.08.007
M3 - Article
C2 - 34437910
AN - SCOPUS:85116224955
SN - 0168-8278
VL - 75
SP - 1409
EP - 1419
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -