Abstract
Objective: A systematic review and meta-analysis of diagnostic biomarkers for noninvasive diagnosis of acute allograft rejection following liver transplantation.Background: Noninvasive blood and urine markers have been widely explored in recent decades for diagnosing acute rejection after liver transplantation. However, none have been translated into routine clinical use so far due to uncertain diagnostic accuracy, and liver biopsy remains the gold standard.Methods: Systematic literature searches of Medline, Cochrane and Embase were conducted up to February 2019 to identify studies evaluating the use of noninvasive markers in diagnosing allograft rejection following liver transplantation. Meta-analysis was performed using a random effects model with DerSimonian–Laird weighting and the hierarchical summary receiver operating curve.Results: Of 560 identified studies, 15 studies (1,445 patients) met the inclusion criteria. The following markers were tested: acid labile nitroso-compounds (NOx), serum amyloid A protein, procalcitonin, peripheral blood eosinophil count, peripheral blood T-cell activation and interleukin 2 (IL-2) receptor, guanylate-binding protein-2 mRNA, graft-derived cell-free DNA, pi-glutathione S-transferase, alpha-glutathione S-transferase and serum HLA class I soluble antigens. Only eosinophil count was tested in multiple studies, and they demonstrated high heterogeneity (I2 = 72% [95% CI: 0.5–0.99]). IL-2 receptor demonstrated the highest sensitivity (89% [95% CI: 0.78–0.96]) and specificity (81% [95% CI: 0.69–0.89]).Conclusion: IL-2 receptor expression demonstrated the highest diagnostic accuracy, while the peripheral eosinophil count was the only marker tested in more than one study. Presently, liver biopsy remains superior to noninvasive diagnostic biomarkers as most studies exhibited inferior designs, hindering possible translation into clinical application.
Highlights
Liver transplantation (LT) exhibits 20-year survival rates of up to 50% (1) and is of great clinical importance
Wang et al had the highest positive likelihood ratio (LR) (3.67), followed by Barnes et al and Hughes et al Barnes et al demonstrated the highest specificity (% [95% confidence interval (CI): 0.81–0.94]) at an absolute eosinophil count (AEC) cut-off value of 0.145 × 109, but reported a very low sensitivity (32% [95% CI: 0.24–0.39])
Barnes et al found no significant difference in the AEC or the relative eosinophil count (REC) among those patients who subsequently improved, remained stable or deteriorated histopathologically following corticosteroid therapy; whereas, Rodriguez-Peralvarez et al discovered that the change in AEC between the first and second biopsies was closely correlated with the histological course of acute rejection (AR) (AUC 0.72 [95% CI: 0.66–0.78])
Summary
Liver transplantation (LT) exhibits 20-year survival rates of up to 50% (1) and is of great clinical importance. Within the first few weeks after transplantation, patients are at high risk of acute rejection (AR), with the incidence ranging from 50 to 70% (5), depending on the immunosuppressive regime selected. AR can be described as an immune response against donor tissues resulting from T-cell recognition of alloantigens. This overwhelming immune response compromises graft integrity and can lead to life-threatening graft loss. The early diagnosis of AR is crucial for successful anti-rejection therapy and maintenance of graft function/integrity. Noninvasive blood and urine markers have been widely explored in recent decades for diagnosing acute rejection after liver transplantation. None have been translated into routine clinical use so far due to uncertain diagnostic accuracy, and liver biopsy remains the gold standard
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