Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

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. Abbreviations ALP Alkaline phosphatase ALT Alanine transaminase AMR Antibody-mediated rejection AST Aspartate transaminase cAMR Possible chronic antibody-mediated rejection CK18 Cytokeratin-18 CI 95% Confidence interval CNI Calcineurin inhibitor CsA Cyclosporine A cTCMR Clinical T cell-mediated rejection DSA Donor-specific anti-human leukocyte antigen antibodies gGT Gamma-glutamyltransferase GH Graft hepatitis HCMini Histological criteria for minimization of immunosuppression HLA Anti-human leukocyte antigens IND Indeterminate histological findings LAF Liver allograft fibrosis

Non-invasive alloimmune risk stratification of long-term liver transplant recipients

“…The analysis of the LIFT liver biopsies confirm the findings from iWITH indicating that even in highly selected recipients with normal or minimally increased liver tests there is a high prevalence of subclinical damage 9 . Furthermore, our results corroborate the observations made by our group and others on the association between subclinical liver allograft damage, circulating class II DSA and increased intrahepatic TCMRrelated transcripts 8,9,[19][20][21][22][23][24] . Of note, while our study cannot establish causality, it clearly delineates the relationships existing between IS exposure, renal function and silent allograft damage.…”

“…Of note, while our study cannot establish causality, it clearly delineates the relationships existing between IS exposure, renal function and silent allograft damage. This is an important finding that illustrates the risk benefit balance of long-term maintenance IS in LT and which previous studies had failed to uncover 8,9,19,20,[22][23][24] .…”

Strategies for Liver Transplantation Tolerance

“…The predictive power of the liver-biopsy based gene signature was since confirmed in another separate adult LT cohort, however, a more recent pediatric LT trial could not predict the success of IS withdrawal using these iron metabolism genes [ 8 , 9 ]. Non-invasive biomarkers, such as the presence of DSA, can improve allograft health monitoring for subclinical injury, although their predictive capacity is currently limited and needs to be validated in independent studies [ 116 , 117 ]. Thus, there are currently no clinical or serological biomarkers that are considered predictive of operational tolerance [ 8 , 118 , 119 ].…”

Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies

“… 22 There are indications that acute unclear organ loss is associated with the presence of human leukocyte antigen antibodies, on the other hand, the presence of donor-specific antibodies against donor human leukocyte antigen may not be associated with any graft pathology. 23 , 24 …”

“…22 There are indications that acute unclear organ loss is associated with the presence of human leukocyte antigen antibodies, on the other hand, the presence of donor-specific antibodies against donor human leukocyte antigen may not be associated with any graft pathology. 23,24 The relevance of positive detection of donor-specific antibodies against donor human leukocyte antigen and practical consequences for clinical management are currently unclear. 25 Therefore, we have specifically collected and classified histological features of protocol liver biopsies and correlated them with donor-specific antibodies against donor human leukocyte antigen in order to determine the relevance of donor-specific antibodies against donor human leukocyte antigen and human leukocyte antigen antibodies on the biochemical, histological and clinical level including biliary complications.…”