Non-invasive Screening for Subclinical Liver Graft Injury in Adults Via Donor-specific Anti-HLA Antibodies

Overview

Journal Sci Rep

Specialty Science

Date 2020 Aug 30

PMID 32859929

Citations 11

Authors

Anne Hofer

Danny Jonigk

Bjorn Hartleben

Murielle Verboom

Michael Hallensleben

Michael P Manns

Elmar Jaeckel

Richard Taubert

Affiliations

Soon will be listed here.

Abstract

The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87-89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92-97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury.

Citing Articles

Elevated Plasma CXCL8 Concentrations in Significant Fibrosis but Not in Subclinical Rejection After Adult Liver Transplantation.

Campos-Murguia A, Hupa-Breier K, Hartleben B, Wedemeyer H, Taubert R, Engel B Transplant Direct. 2025; 10(3):e1592.

PMID: 39877649 PMC: 11774564. DOI: 10.1097/TXD.0000000000001592.

Impact of steroid withdrawal on subclinical graft injury after liver transplantation: A propensity score-matched cohort analysis.

Campos-Murguia A, Bosselmann E, Hartleben B, Wedemeyer H, Engel B, Taubert R Front Transplant. 2024; 2:1124551.

PMID: 38993902 PMC: 11235343. DOI: 10.3389/frtra.2023.1124551.

Prospective comparison of liver stiffness measurement methods in surveillance biopsies after liver transplantation.

Bosselmann E, Engel B, Hartleben B, Wedemeyer H, Jaeckel E, Maasoumy B Front Transplant. 2024; 2:1148195.

PMID: 38993851 PMC: 11235307. DOI: 10.3389/frtra.2023.1148195.

Combination of everolimus and low-dose tacrolimus controls histological liver allograft injury as sufficiently as high-dose tacrolimus.

Bosselmann E, Dranicki F, Campos-Murguia A, Hartleben B, Wedemeyer H, Jaeckel E Front Transplant. 2024; 2:1168163.

PMID: 38993848 PMC: 11235273. DOI: 10.3389/frtra.2023.1168163.

A Comprehensive Review of Liver Allograft Fibrosis and Steatosis: From Cause to Diagnosis.

Rabindranath M, Zaya R, Prayitno K, Orchanian-Cheff A, Patel K, Jaeckel E Transplant Direct. 2023; 9(11):e1547.

PMID: 37854023 PMC: 10581596. DOI: 10.1097/TXD.0000000000001547.

References

Hubscher S . What is the long-term outcome of the liver allograft?. J Hepatol. 2011; 55(3):702-717. DOI: 10.1016/j.jhep.2011.03.005. View

Londono M, Souza L, Lozano J, Miquel R, Abraldes J, Llovet L . Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients. J Hepatol. 2018; 69(3):626-634. DOI: 10.1016/j.jhep.2018.04.012. View

Jia Y, Li C, Yang X, Dong Z, Huang K, Luo Y . CT Enterography score: a potential predictor for severity assessment of active ulcerative colitis. BMC Gastroenterol. 2018; 18(1):173. PMC: 6230286. DOI: 10.1186/s12876-018-0890-z. View

Benitez C, Londono M, Miquel R, Manzia T, Abraldes J, Lozano J . Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology. 2013; 58(5):1824-35. DOI: 10.1002/hep.26426. View

Feng S, Ekong U, Lobritto S, Demetris A, Roberts J, Rosenthal P . Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012; 307(3):283-93. DOI: 10.1001/jama.2011.2014. View

Joka D, Wahl K, Moeller S, Schlue J, Vaske B, Bahr M . Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis. Hepatology. 2011; 55(2):455-64. DOI: 10.1002/hep.24734. View

Sekiguchi T, Umemura T, Fujimori N, Shibata S, Ichikawa Y, Kimura T . Serum cell death biomarkers for prediction of liver fibrosis and poor prognosis in primary biliary cirrhosis. PLoS One. 2015; 10(6):e0131658. PMC: 4482393. DOI: 10.1371/journal.pone.0131658. View

Bechmann L, Jochum C, Kocabayoglu P, Sowa J, Kassalik M, Gieseler R . Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol. 2010; 53(4):639-47. DOI: 10.1016/j.jhep.2010.04.029. View

Del Bello A, Congy-Jolivet N, Danjoux M, Muscari F, Lavayssiere L, Esposito L . De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients. Transpl Int. 2015; 28(12):1371-82. DOI: 10.1111/tri.12654. View

10.

Iacob S, Cicinnati V, Lindemann M, Heinemann F, Radtke A, Kaiser G . Donor-Specific Anti-HLA Antibodies and Endothelial C4d Deposition-Association With Chronic Liver Allograft Failure. Transplantation. 2015; 99(9):1869-75. DOI: 10.1097/TP.0000000000000613. View

11.

Vandevoorde K, Ducreux S, Bosch A, Guillaud O, Hervieu V, Chambon-Augoyard C . Prevalence, Risk Factors, and Impact of Donor-Specific Alloantibodies After Adult Liver Transplantation. Liver Transpl. 2018; 24(8):1091-1100. DOI: 10.1002/lt.25177. View

12.

Wozniak L, Hickey M, Venick R, Vargas J, Farmer D, Busuttil R . Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation. Transplantation. 2015; 99(7):1416-22. PMC: 5283576. DOI: 10.1097/TP.0000000000000796. View

13.

Ohe H, Uchida Y, Yoshizawa A, Hirao H, Taniguchi M, Maruya E . Association of anti-human leukocyte antigen and anti-angiotensin II type 1 receptor antibodies with liver allograft fibrosis after immunosuppression withdrawal. Transplantation. 2014; 98(10):1105-11. DOI: 10.1097/TP.0000000000000185. View

14.

Hofer A, Jonigk D, Hartleben B, Verboom M, Hallensleben M, Hubscher S . DSA Are Associated With More Graft Injury, More Fibrosis, and Upregulation of Rejection-associated Transcripts in Subclinical Rejection. Transplantation. 2019; 104(3):551-561. DOI: 10.1097/TP.0000000000003034. View

15.

Varma S, Ambroise J, Komuta M, Latinne D, Baldin P, Reding R . Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients. EBioMedicine. 2016; 9:346-355. PMC: 4972529. DOI: 10.1016/j.ebiom.2016.05.040. View

16.

Feng S, Demetris A, Spain K, Kanaparthi S, Burrell B, Ekong U . Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R. Hepatology. 2016; 65(2):647-660. PMC: 5159322. DOI: 10.1002/hep.28681. View

17.

Jucaud V, Shaked A, DesMarais M, Sayre P, Feng S, Levitsky J . Prevalence and Impact of De Novo Donor-Specific Antibodies During a Multicenter Immunosuppression Withdrawal Trial in Adult Liver Transplant Recipients. Hepatology. 2018; 69(3):1273-1286. DOI: 10.1002/hep.30281. View

18.

Reis H, Wohlschlager J, Hagemann S, Wenzel P, Bechmann L, Suttorp A . (Cleaved) CK18 serum and tissue expression levels differentiate acute HCV reinfection from acute rejection in liver allografts. Liver Int. 2014; 35(3):905-13. DOI: 10.1111/liv.12572. View

19.

Baumann A, Schlue J, Noyan F, Hardtke-Wolenski M, Lehner F, Barg-Hock H . Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts. Liver Transpl. 2016; 22(7):943-55. DOI: 10.1002/lt.24427. View

20.

Couchonnal E, Rivet C, Ducreux S, Dumortier J, Bosch A, Boillot O . Deleterious impact of C3d-binding donor-specific anti-HLA antibodies after pediatric liver transplantation. Transpl Immunol. 2017; 45:8-14. DOI: 10.1016/j.trim.2017.08.001. View