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  The International Liver Congress™
EASL - European Association for the
Study of the Liver
June 23-26 2021
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Noninvasive Tools Can Spot Liver Transplant Patients With No Alloimmune Damage
  EASL International Liver Congress, June 23-26, 2021
Mark Mascolini
Standard noninvasive measures-like ALT and FibroScan-can identify liver transplant recipients with no underlying alloimmune damage, according to a LIFT trial analysis of 190 adults at 12 centers across Europe [1]. The prediction model could help pinpoint candidates for withdrawal of potentially hazardous immunosuppressive therapy.
Liver transplant recipients may need immunosuppressive therapy for the rest of their lives, a daunting prospect because of the long-term side effect risk with immunosuppression. Immunosuppressive therapy for transplant recipients requires "impeccable management" to succeed without causing further harm [2]. Too much immunosuppression, the LIFT researchers noted, can promote chronic kidney disease, malignancies, infections, and cardiovascular and metabolic complications. But too little immunosuppression may lead to overt rejection of the transplanted organ or subclinical liver allograft damage.
Complete withdrawal of immunosuppression may be possible in about 20% of transplant recipients [3]. Accurately predicting who can safely stop immunosuppressive therapy would be a boon to this population. Right now, the LIFT team observed, that calculation depends on a mix of noninvasive and invasive measures: liver function tests, clinical parameters, immunosuppressive trough levels, and liver biopsy plus transcriptional profiling. They planned this study to build noninvasive prediction models that will stratify stable long-term liver transplant recipients based on risk of underlying alloimmune damage. (Alloimmunity generates an immune response against antigens from members of the same species, as in the response to transplanted tissues caused by graft rejection [4]).
People participating in this analysis were having a liver biopsy to assess eligibility for an immunosuppression withdrawal trial. These 190 adults from 12 European centers had a liver transplant 3 to 6 years ago, had an alanine aminotransferase (ALT) below 60 U/L, and did not have an autoimmune or replicative viral disease. Researchers collected relevant demographic, clinical, biochemical, and histologic data from all participants; 125 people had liver stiffness measurements, and 184 had assessment of transcript levels of an 11-gene T cell-mediated rejection (TCMR) biomarker via the NanoString platform.
Median age at enrollment stood at 61 years, median time from liver transplant to enrollment measured 8 years, and two thirds of participants were men. While 60 participants (32%) needed liver transplantation because of hepatitis B- or C-related cirrhosis, 49 (26%) needed a transplant for alcohol-related cirrhosis. Most people, 87%, received tacrolimus for immunosuppression.
Of these 190 people with biopsies, the 122 (64%) who met 2016 Banff criteria for immunotherapy withdrawal made up group 1 (normal). Of the 68 people (36%) with biopsies showing damage, 26 (14% of 190) were assigned to group 2 (mild) and 42 (22%) to group 3 (moderate to severe).
Severity of subclinical liver allograft damage was significantly associated with kidney function (measured by AST, ALT, creatinine, and estimated glomerular filtration rate, eGFR); greater liver stiffness (4.5 kPa group 1, 4.8 kPa group 2, 7.3 kPa group 3); and lower tacrolimus trough (4.1 ug/L group 1, 3.0 ug/L group 2, 3.3 ug/L group 3). Class II donor-specific antibodies could be detected in 13.1% of group 1, 17.4% of group 2, and 30.6% of group 3 (P = 0.018 for group 1 vs group 3). Cumulative mean fluorescence intensity (MFI) of class II donor-specific antibodies was lowest in group 1 (1779 cumulative MFI), higher in group 2 (3876 cumulative MFI), and highest in group 3 (6388 cumulative MFI) (P = 0.012 for group 1 vs group 3).
The researchers assigned a TCMR probability to each of 184 baseline liver biopsies based on transcript levels of the 11-gene classifier [5]. Stratifying liver biopsies on the basis of TCMR-related gene transcript levels determined that 16.8% of participants overall had above-threshold levels, including 7.2% in group 1, 29.2% in group 2, 42.5% in group 3, and 88.9% with acute TCMR. Modeling determined that liver stiffness measurements, class II donor-specific antibodies, and ALT levels could be useful noninvasive tools for detecting silent alloimmune damage.
Next the researchers conducted two classification and regression tree (CART) analyses [6] to predict alloimmune damage. Active alloimmune damage affected 46% of participants with an ALT above 35 U/L, 17% with an ALT of 15 to 35 U/L, and 0% with an ALT at or below 15 U/L. Active alloimmune damage affected 11% of people with a FibroScan at or below 8.4 kPa and 63% with a FibroScan above 8.4 kPa. In a separate CART analysis, active alloimmune liver damage affected 67% of participants with an ALT above 39 U/L, 19% with an ALT of 13 to 39 U/L, and 0% with an ALT at or below 13 U/L. In this group 15% with class II donor-specific antibody cumulative MFI at or below 10,000 had active alloimmune liver damage, compared with 43% with class II donor-specific antibody cumulative MFI above 10,000.
The investigators validated this ALT/DSA (donor-specific antigen) prediction model in a separate cohort of children with liver transplantation in the iWITH trial of complete immunosuppression withdrawal [7]. The 157 children came from 12 centers across North America and had their transplant more than 4 years before the trial. Active alloimmune liver damage affected 44% of children with an ALT above 39 U/L, 29% with an ALT of 13 to 39 U/L, and 14% with an ALT at or below 13 U/L. In these children 16% with class II donor-specific antibody cumulative MFI at or below 10,000 had active alloimmune liver damage, compared with 47% with class II donor-specific antibody cumulative MFI above 10,000. A calibration plot of the ALT/DSA model in iWITH with the formula derived from LIFT showed tight correlation between the predicted probability and observed frequency of alloimmune damage.
The LIFT trial researchers concluded that their analysis confirms previous findings that about one third of stable long-term liver transplant recipients have abnormal histology, and about half have a molecular signature of rejection. But unlike previous studies, the LIFT team found a "clear link between immunosuppressive exposure, renal function and alloimmunity" and an association between immunogenicity (assessed by HLA molecular mismatch) and active alloimmunity.
The LIFT investigators believe their findings mean "it is possible to accurately identify patients with no underlying alloimmune damage with simple and readily available measurements (such as ALT, class II donor-specific antibodies, [and] FibroScan)."
1. Vionnet J, Miquel R, Abraldes JG, et al. Immunological risk stratification of stable long-term liver transplant recipients employing non-invasive tools. EASL International Liver Congress, June 23-26, 2021. Abstract OS-213.
2. Feng S, Bucuvalas J. Tolerance after liver transplantation: Where are we? Liver Transpl. 2017;23:1601-1614. doi: 10.1002/lt.24845.
3. Londono MC, Rimola A, O'Grady J, Sanchez-Fueyo A. Immunosuppression minimization vs. complete drug withdrawal in liver transplantation. J Hepatol. 2013;59:872-879. doi: 10.1016/j.jhep.2013.04.003.
4. Biology Online. Alloimmunity. https://www.biologyonline.com/dictionary/alloimmunity
5. Bonaccorsi-Riani E, Pennycuick A, Londono MC, et al. Molecular characterization of acute cellular rejection occurring during intentional immunosuppression withdrawal in liver transplantation. Am J Transplant. 2016;16:484-496. doi: 10.1111/ajt.13488.
6. United States Environmental Protection Agency. CADDIS Volume 4. Basic Analyses. Additional Information on Classification and Regression Tree (CART) Analysis. https://www.epa.gov/caddis-vol4/caddis-volume-4-data-analysis-classification-and-regression-tree-cart-analysis "CART analysis is used in data exploration to classify systems that differ due to natural causes. CART analysis may be used to determine the relative importance of different variables for identifying homogeneous groups within the data set."
7. Feng S, Bucuvalas J, Demetris A, et al. Primary outcome of iWITH: a multi-center clinical trial of complete immunosuppression withdrawal (ISW) in stable pediatric liver transplant (LT) recipients. 2016 American Transplant Congress. Abstract 185.1. https://atcmeetingabstracts.com/abstract/primary-outcome-of-iwith-a-multi-center-clinical-trial-of-complete-immunosuppression-withdrawal-isw-in-stable-pediatric-liver-transplant-lt-recipients/