Prospective Evaluation of Noninvasive Cell Death Marker and Donor Specific Antibodies as Predictors of Subclinical Graft Inflammation and Graft Fibrosis

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IntroductionThe majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. The commonest findings are subclinical inflammation and fibrosis, which are suspected to contribute to allograft failure. The identification of non-invasive biomarkers of subclinical graft injury might help to facilitate individualization of the immunosuppressivion.Material and MethodsThe cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA; MFI>1000) were measured in 301 blood samples paired to liver biopsies in our prospective liver biopsy program. 118 liver biopsies were obtained from patients with completely normal, 77 from patients with marginally elevated (<2x upper limit of normal (ULN)) and 106 from patients with relevantly elevated (>2 ULN) liver enzymes (ALT, AST, AP, gGT).Results and DiscussionThe M65 marker correlated with liver enzyme levels (AST: Spearman rho (SR)=0.625 p<0.001; ALT: SR=0.607 p<0.001; AP: SR=0.546 p<0.001; gGT: SR=0.654 p<0.001) and with histological scores for rejection, hepatitis activity and fibrosis (maximum SR=0.393 p<0.001 for hepatitis activity index (HAI); maximum SR=0.328 p<0.001 for liver allograft fibrosis score) in the total cohort. However, in liver biopsies from patients with completely normal liver enzymes M65 only correlated marginally with lobular inflammation (SR=0.251 p=0.008) and not with liver fibrosis.Next, we tested whether M65 or liver enzyme levels could predict the absence of inflammation (AoI) or the histological criteria for immunosuppression weaning (CIW), as outlined in the Banff 2016 consensus document, in protocol liver biopsies with normal liver enzymes. M65, ALT, AST and gGT levels were not significantly associated with AoI or CIW. AP was only weakly associated with both biopsy findings (CIW: AUC=0.672 p=0.011; AoI: AUC=0.744 p=0.047).Liver biopsies from patients with serum DSA had significantly higher scores for hepatitis activity and fibrosis, when all patients were included. In the cohort with normal liver enzymes, DSA positivity was still significantly associated with more hepatitis activity (Odds ratio (OR) lobular inflammation score ≥2: 8.4 (1.7-42.0); OR portal inflammation score ≥2:12.5 (3.7-42.8); OR HAI≥3: 11.2 (3.5-35.8) and slightly more perisinusoidal fibrosis (OR sinusoidal LAF score≥1: 13.5 (3.0-61.3)). Although 0/7 of liver biopsies with AoI and only 1/25 biopsies with CIW were DSA positive in the cohort with normal liver enzymes, these associations of DSA with AoI (p=0.586) and CIW (p=0.063) were not significant.ConclusionAlthough DSA positivity may help to identify patients with more subclinical inflammation and fibrosis, reliable noninvasive serum markers for subclinical inflammation are still missing. Therefore, protocol biopsies are currently the only way to exclude subclinical inflammation for the individualization of immunosuppression in patients with normal liver enzymes.

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