Julien Vionnet1, Rosa Miquel2, Juan G Abraldes3, Jurate Wall4, Elisavet Kodela4, Juan-Jose Lozano5, Pablo Ruiz6, Miguel Navasa6, Aileen Marshall7, Frederik Nevens8, Will Gelson9, Joanna Leithead9, Steven Masson10, Elmar Jaeckel11, Richard Taubert11, Phaedra Tachtatzis12, Dennis Eurich13, Kenneth J Simpson14, Eliano Bonaccorsi-Riani15, Sandy Feng16, John Bucuvalas17, James Ferguson18, Alberto Quaglia7, Julia Sidorova19, Maria Elstad20, Abdel Douiri20, Alberto Sánchez-Fueyo21. 1. Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom; Transplantation Center and Service of Gastroenterology and Hepatology, University Hospital of Lausanne, Lausanne, Switzerland. 2. Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom; Liver Histopathology Laboratory, King's College Hospital, London, United Kingdom. 3. Liver Unit, Division of Gastroenterology, Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Canada. 4. Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom. 5. Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Spain. 6. Hospital Clinic, Barcelona, Spain. 7. Royal Free Hospital, London, United Kingdom. 8. University Hospital KU Leuven, Leuven, Belgium. 9. Addenbrooke's Hospital, Cambridge, United Kingdom. 10. Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom. 11. Medizinische Hochschule Hannover, Hannover, Germany. 12. Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom. 13. Charité, Berlin, Germany. 14. Edinburgh Royal Infirmary, Edinburgh, United Kingdom. 15. Liver Transplant Unit, Cliniques Universitaires St-Luc, Brussels, Belgium. 16. Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. 17. Mount Sinai Kravis Children's Hospital and Recanati/Miller Transplantation Institute, Mount Sinai Health System, New York, NY, USA. 18. Queen Elizabeth Hospital, Birmingham, United Kingdom. 19. Instituto de Tecnología del Conocimiento (ITC), Campus Somosaguas, Universidad Complutense, Madrid, Spain. 20. School of Population Health and Environmental Sciences, King's College London, London, United Kingdom. 21. Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom. Electronic address: sanchez_fueyo@kcl.ac.uk.
Abstract
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.
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.