Current Status of Biomarkers and Molecular Diagnostic Tools for Rejection in Liver Transplantation: Light at the End of the Tunnel?

Abstract

Strategies to minimize immune-suppressive medications after liver transplantation are limited by allograft rejection. Biopsy of liver is the current standard of care in diagnosing rejection. However, it adds to physical and economic burden to the patient and has diagnostic limitations. In this review, we aim to highlight the different biomarkers to predict and diagnose acute rejection. We also aim to explore recent advances in molecular diagnostics to improve the diagnostic yield of liver biopsies.

Keywords: 3BMBs, third bifurcation mucosal endo-bronchial biopsies; AMR, antibody mediated rejection; APC, antigen presenting cells; AR, Acute rejection; ATCMR, acute T-cell mediated rejection; ATG, Anti-thymoglobulin; AUC, area under curve; AUROC, area under receiver operating characteristic curve; B-HOT, Banff Human Organ Transplant; CNI, Calcineurin inhibitors; DSA, Donor specific antibodies; FDA, Food and drug administration; FFPE, formalin fixed paraffin embedded preparation; GLUT-4, glucose transport-4; HLA, human leukocyte antigens; HNMR, high nuclear magnetic resonance; ILTS, International liver transplantation society; LT, Liver transplantation; Liver transplantation; MDWG, molecular diagnostic work group; MFI, mean fluorescence intensity; MHC, major histo–compatibility complex; MMDX; MMDX, Molecular microscopic diagnostic system; MMF, Mycophenolate Mofetil; MToR, Mechanistic target of Rapamycin; NPV, Negative predictive value; PPV, Positive predictive value; RATs, rejection associated transcripts; TBB, trans-bronchial biopsies; UNOS, United network for organ sharing and procurement; biomarker; dd cfDNA, donor-derived cell-free DNA; donor-derived cell-free DNA; immune-suppression; mRNA, messenger RNA; miRNA, micro-RNA; micro-RNA; molecular diagnosis; nano-string; rejection.

Graphical abstract

Figure 1

Current and future strategies to adjust immune-suppression.

Figure 2

Allograft recognition pathways and immune effector pathways. 3 pathways has been identified; in direct pathway donor APCs, MHC class II molecules are recognized by recipient CD4⁺ T-cells as foreign and recipient CD8⁺ T-cells recognize MHC class I molecules on donor APCs. In indirect pathway, recipient APCs present graft antigen to recipient CD4⁺ T-cells, semi-indirect pathway combines both pathways as recipient APCs present exocytosis transferred donor MHC molecules to recipient CD4⁺ T-cells. Effector phase depends on hepatocyte cytotoxicity by activated CD8⁺ T-cell augmented by cytokines release from CD4⁺ T-cells.

Figure 3

Historic biomarkers of liver rejection.