Identification of Novel and Noninvasive Biomarkers of Acute Cellular Rejection After Liver Transplantation by Protein Microarray

Okubo, Keita; Wada, Hiroshi; Tanaka, Atsushi; Eguchi, Hidetoshi; Hamaguchi, Masahide; Tomokuni, Akira; Tomimaru, Yoshito; Asaoka, Tadafumi; Hama, Naoki; Kikuchi, Kôichi; Kobayashi, Shogo; Marubashi, Shigeru; Nagano, Hiroaki; Sakaguchi, Noriko; Nishikawa, Hiroyoshi; Doki, Yuichiro; Mori, Masaki; Sakaguchi, Shimon

doi:10.1097/txd.0000000000000630

Cited by 6 publications

(9 citation statements)

References 42 publications

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“…Many studies have evaluated the role of noninvasive biomarkers of TCMR among serum parameters of inflammation or mediators of T‐cell activation . Unfortunately, none of these biomarkers has been implemented hitherto because of their complexity, lack of reproducibility/validation, inaccuracy, or costs .…”

Section: Discussionmentioning

confidence: 99%

“…Although previous studies have identified some clinical predictors of TCMR, such as younger age, low MELD score, underlying autoimmune liver disease, elevated blood eosinophils count, and vitamin D deficiency, they are not sufficiently validated to guide clinical decisions. Biomarkers and immune function assays have been proposed, but again results are contradictory and they are not widely available …”

Section: Introductionmentioning

confidence: 99%

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An objective definition for clinical suspicion of T‐cell‐mediated rejection after liver transplantation

Rodríguez‐Perálvarez

Luca

Crespo

et al. 2017

Clinical Transplantation

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A uniform definition of clinical suspicion of T‐cell‐mediated rejection (TCMR) in liver transplantation (LT) is needed to homogenize clinical decisions, especially within randomized trials. This multicenter study included a total of 470 primary LT recipients. The derivation cohort consisted of 142 patients who had clinically driven liver biopsies at any time after LT. The external validation cohort included 328 patients who underwent protocol biopsies at day 7‐10 after LT. The rates of moderate‐severe histological TCMR were 33.8% in the derivation cohort and 43.6% in the validation cohort. Independent predictors (ie, risk factors) of moderate‐severe TCMR in the derivation cohort were as follows: serum bilirubin >4 mg/dL (OR=5.83; P<.001), rising bilirubin within the 4 days prior to liver biopsy (OR=4.57; P=.003), and blood eosinophils count >0.1×109/L (OR=3.81; P=.004). In the validation cohort, the number of risk factors was an independent predictor of moderate‐severe TCMR (OR=1.74; P=.001), after controlling for hepatitis C status. The number of risk factors paralleled the rates of moderate‐severe TCMR in the derivation and validation cohorts (P<.001 in both comparisons). In conclusion, increased serum bilirubin, rising bilirubin and eosinophilia are validated risk factors for moderate‐severe histological TCMR and could be used as objective criteria to select candidates for liver biopsy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An objective definition for clinical suspicion of T‐cell‐mediated rejection after liver transplantation

Rodríguez‐Perálvarez

Luca

Crespo

et al. 2017

Clinical Transplantation

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“…Many major rejection and injury features initially described in kidney transplants 31,44,45 are shared with heart 33,46‐48 and lung transplants, 35,49 indicating that rejection changes are not organ specific and are likely shared by liver transplants. Existing studies have established the potential utility of molecular assessment of liver biopsies 1,24‐25,50‐56 …”

Section: Introductionmentioning

confidence: 99%

The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study

Madill‐Thomsen

Abouljoud

Bhati

et al. 2020

American Journal of Transplantation

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Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1 normal " (N = 129), T cell-mediated rejection (TCMR) "R2 TCMR " (N = 37), early injury "R3 injury " (N = 61), and fibrosis "R4 late " (N = 8). Groups differed in median time posttransplant, for example, R3 injury 99 days vs R4 late 3117 days. R2 TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3 injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4 late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2 TCMR correlated with histologic rejection although with many discrepancies, and R4 late with fibrosis. R2 TCMR , R3 injury , and R4 late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2 TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, | 2157 MADILL-THOMSEN ET AL. 1 | INTRODUC TI ON Diagnosis of rejection in liver transplantation remains an important issue in clinical management. 1-4 The current standard-of-care (SOC) for liver biopsy diagnoses is histology, generally following Banff guidelines. 5 Histology is based on pattern recognition by experts, and assessments differ between observers. 6-11 Reported kappa values for pathology related to T cell-mediated rejection (TCMR) are low to moderate (0.15-0.62 12) especially when comorbidities are present, 7 leaving an unmet need for improvement in precision. Moreover, the diagnosis and prevalence of antibody-mediated rejection (ABMR) in liver transplants remain controversial. 5,13-15 Liver transplants present unique challenges because of their tolerogenic properties, inviting clinicians to consider reducing immunosuppression. 16-20 However, this practice requires a precise and accurate system for diagnosing rejection. 21-25 Liver function test abnormalities are associated with rejection but cannot distinguish TCMR from other diseases such as steatohepatitis. 26,27 Molecular measurement of gene expression using microarrays coupled with machine learning has the potential to improve the assessment of transplant biopsies by overcoming the limitations of conventional diagnostics. 28 We previously developed the Molecular Microscope ® Diagnostic System (MMDx) for kidney, 29-32 heart, 33,34 and lung transplants. 35-37 A number of factors argue that MMDx testing is more accurate than histology 29 : for example, use of continuous quantitative measurements, 29 low samplin...

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“…The study by Massoud et al (24) identified the following seven markers: serum amyloid A protein (SAA), complement 4 (C4), fibrinogen, complement 1q (C1q), complement 3, heat shock protein 60, and heat shock protein 70. The study by Okubo et al (20) identified autoantibodies in sera by fold change and intensity to charge one of the following markers: multivesicular body protein 2B, potassium channel tetramerization domain containing 14, voltage-gated subfamily A regulatory beta subunit 3, and triosephosphate isomerase 1.…”

Section: Resultsmentioning

confidence: 99%

“…Studies of Okubo et al (20) (20 AR cases, 80 samples) and Massoud et al (24) (33 AR cases, 62 samples) were similarly designed. The authors used proteomics and ELISA to test blood samples to discover possible markers of AR.…”

Section: Resultsmentioning

confidence: 99%

Diagnostic Biomarkers to Diagnose Acute Allograft Rejection After Liver Transplantation: Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies

et al. 2019

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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 ( I 2 = 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.

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Identification of Novel and Noninvasive Biomarkers of Acute Cellular Rejection After Liver Transplantation by Protein Microarray

Cited by 6 publications

References 42 publications

An objective definition for clinical suspicion of T‐cell‐mediated rejection after liver transplantation

An objective definition for clinical suspicion of T‐cell‐mediated rejection after liver transplantation

The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study

Diagnostic Biomarkers to Diagnose Acute Allograft Rejection After Liver Transplantation: Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies

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