Monitoring of miR-181a-5p and miR-155-5p Plasmatic Expression as Prognostic Biomarkers for Acute and Subclinical Rejection in de novo Adult Liver Transplant Recipients

Abstract

Background and Aims: News strategies for the accurate assessment of the state of immunosuppression (IS) in liver transplant recipients are needed to prevent rejection and minimize drug-related side effects. miRNAs can potentially be used as diagnostic or prognostic biomarkers in transplant patients. This study evaluated the capacity of a plasmatic miRNA panel (miR-155-5p, miR-122-5p, miR-181a-5p, and miR148-3p) as an early non-invasive prognostic and diagnostic biomarker for T cell-mediated acute rejection (TCMAR) and subclinical rejection (SCR) in adult liver recipients. Methods: A total of 145 liver recipients were included. All patients received a calcineurin inhibitor with or without mycophenolate mofetil and methylprednisolone. Plasmatic miRNA expression was assessed by qPCR before and at different time-points after liver transplantation. Results: Seventeen patients experienced TCMAR, and eight were diagnosed with SCR during the protocol biopsy at the 3rd month post-transplantation. Pre-transplantation, miR-155-5p expression was significantly higher in TCMAR patients and in SCR patients than in non-rejectors, and miR-181a-5p expression was also significantly higher in SCR patients than in non-rejectors. Post-transplantation, before transaminase-level modification, significantly increased miR-181a-5p, miR-155-5p, and miR-122-5p expression was observed in TCMAR and SCR patients. Binary logistic regression analyses showed, post-transplantation, that TCMAR risk was better predicted by individual expression of miR-181a-5p (LOGIT = −6.35 + 3.87 * miR-181a-5p), and SCR risk was better predicted by the combination of miR-181a-5p and miR-155-5p expression (LOGIT = −5.18 + 2.27 * miR-181a-5p+1.74 * miR-155-5p). Conclusions: Pre-transplantation plasmatic miR-155-5p expression may be useful for stratifying low-immunologic-risk patients, and post-transplantation miR-181a-5p and miR-155-5p may be candidates for inclusion in early, non-invasive prognostic biomarker panels to prevent TCMAR or SCR and better identify patient candidates for IS minimization. Large prospective randomized multicenter trials are needed to refine the cut-off values and algorithms and validate the clinical usefulness of these biomarkers.

Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients

“…Statistical differences between groups were assessed with the Mann‐Whitney test, and correlations between NFAT‐RGE, intralymphocytary cytokines and clinical events were assessed with Spearman's Rho test. We used a receiver operating characteristic (ROC) curve analysis to define the optimal cut‐off values for differentiating between patient groups with and without TCMAR or SCR following the same criteria that we applied in our previous publication . All analyses were performed using SPSS 23.0 software (SPSS, Inc), and all data are presented as the median ± standard deviation (SD).…”

“…Triple therapy with CNi with reduced target trough levels (5‐8 ng/mL for Tac and 75‐150 ng/mL for CsA) with mycophenolate mofetil (MMF), corticosteroids and induction therapy with a single dose of basiliximab was given to Child‐Pugh B or C patients, retransplanted patients and to those transplanted because of acute liver failure. In both cases, the corticosteroids were tapered and withdrawn earlier than 6 months after LT …”

“…We used a receiver operating characteristic (ROC) curve analysis to define the optimal cut-off values for differentiating between patient groups with and without TCMAR or SCR following the same criteria that we applied in our previous publication. 29 All analyses were performed using SPSS 23.0 software (SPSS, Inc), and all data are presented as the median ± standard deviation (SD). A value of P ≤ .05 was considered statistically significant.…”

MicroRNAs 155‐5p, 122‐5p, and 181a‐5p Identify Patients With Graft Dysfunction Due to T Cell–Mediated Rejection After Liver Transplantation

“…(12) miRNAs can be detected in plasma and have been proposed as potential biomarkers under certain conditions. (13) In LT, although previous studies have suggested the differential plasmatic expression of certain miRNAs both before and during TCMR, (14)(15)(16) the evidence regarding their clinical use is still scarce. Thus, we aimed to assess the performance of a panel of 4 miR-NAs (155-5p, 122-5p, 181a-5p, and 148-3p) in diagnosing TCMR in a prospective cohort of LT patients with GD who underwent LB and to compare its diagnostic accuracy with that of other noninvasive tests.…”

Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application

“…miRNAs, which are ~20–22 nucleotide single-stranded RNA species, and play a central role in the regulation of protein-coding genes, are also emerging as robust biomarkers for assessing allograft status. Millán et al have reported that plasma miRNAs can serve as early non-invasive prognostic and diagnostic biomarkers for T-cell mediated acute rejection in LT recipients, that is, miR-155-5p regulates the differentiation of CD4 + T cells into Th cells and IFN-γ production in human T and NK cells, and miR-181a levels modulate T cell receptor sensitivity and intensity of signaling ( 140 ). Hence, the plasma levels of miR-155-5p and miR-181a-5p after LT potentially help identify patients for IS minimization.…”