Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: A proteomic signature validated by enzyme‐linked immunosorbent assay
The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpl...
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Published in | Liver transplantation Vol. 17; no. 6; pp. 723 - 732 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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01.06.2011
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Abstract | The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpler and faster enzyme‐linked immunosorbent assay (ELISA)‐based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high‐abundance protein depletion and isobaric tag for relative and absolute quantitation liquid chromatography–tandem mass spectrometry to characterize the serum proteome in serum samples of patients with or without ACR. Seven of the 41 proteins identified as differentially abundant [serum amyloid A, complement component 4 (C4), fibrinogen, complement component 1q (C1q), complement component 3, heat shock protein 60 (HSP60), and HSP70] could be measured with ELISA‐based assays in a validation cohort consisting of patients with ACR (n = 25) and patients without ACR (n = 21). The mean alanine aminotransferase (ALT) levels in patients with ACR and in patients without ACR were 198 ± 27 and 153 ± 34 U/L, respectively. Among the 7 proteins for which ELISA assays were available, C4 and C1q were both independent predictors of ACR. C4 had the greatest predictivity for differentiating patients with or without ACR. A C4 level ≤ 0.31 g/L had a sensitivity of 97%, a specificity of 62%, a positive predictive value of 74%, and a negative predictive value of 94%. A C4 level ≤ 0.31 g/L and an ALT level ≥ 70 IU/mL together had a sensitivity of 96%, a specificity of 81%, a positive predictive value of 86%, and a negative predictive value of 94%. In summary, in this exploratory analysis, serum C4 and ALT levels were highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, and diverse population is needed. Liver Transpl 17:723‐732, 2011. © 2011 AASLD. |
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AbstractList | The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpler and faster enzyme-linked immunosorbent assay (ELISA)-based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high-abundance protein depletion and isobaric tag for relative and absolute quantitation liquid chromatography-tandem mass spectrometry to characterize the serum proteome in serum samples of patients with or without ACR. Seven of the 41 proteins identified as differentially abundant [serum amyloid A, complement component 4 (C4), fibrinogen, complement component 1q (C1q), complement component 3, heat shock protein 60 (HSP60), and HSP70] could be measured with ELISA-based assays in a validation cohort consisting of patients with ACR (n = 25) and patients without ACR (n = 21). The mean alanine aminotransferase (ALT) levels in patients with ACR and in patients without ACR were 198 ± 27 and 153 ± 34 U/L, respectively. Among the 7 proteins for which ELISA assays were available, C4 and C1q were both independent predictors of ACR. C4 had the greatest predictivity for differentiating patients with or without ACR. A C4 level ≤ 0.31 g/L had a sensitivity of 97%, a specificity of 62%, a positive predictive value of 74%, and a negative predictive value of 94%. A C4 level ≤ 0.31 g/L and an ALT level ≥ 70 IU/mL together had a sensitivity of 96%, a specificity of 81%, a positive predictive value of 86%, and a negative predictive value of 94%. In summary, in this exploratory analysis, serum C4 and ALT levels were highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, and diverse population is needed. The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpler and faster enzyme‐linked immunosorbent assay (ELISA)‐based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high‐abundance protein depletion and isobaric tag for relative and absolute quantitation liquid chromatography–tandem mass spectrometry to characterize the serum proteome in serum samples of patients with or without ACR. Seven of the 41 proteins identified as differentially abundant [serum amyloid A, complement component 4 (C4), fibrinogen, complement component 1q (C1q), complement component 3, heat shock protein 60 (HSP60), and HSP70] could be measured with ELISA‐based assays in a validation cohort consisting of patients with ACR (n = 25) and patients without ACR (n = 21). The mean alanine aminotransferase (ALT) levels in patients with ACR and in patients without ACR were 198 ± 27 and 153 ± 34 U/L, respectively. Among the 7 proteins for which ELISA assays were available, C4 and C1q were both independent predictors of ACR. C4 had the greatest predictivity for differentiating patients with or without ACR. A C4 level ≤ 0.31 g/L had a sensitivity of 97%, a specificity of 62%, a positive predictive value of 74%, and a negative predictive value of 94%. A C4 level ≤ 0.31 g/L and an ALT level ≥ 70 IU/mL together had a sensitivity of 96%, a specificity of 81%, a positive predictive value of 86%, and a negative predictive value of 94%. In summary, in this exploratory analysis, serum C4 and ALT levels were highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, and diverse population is needed. Liver Transpl 17:723‐732, 2011. © 2011 AASLD. |
Author | Viker, Kimberly Sanchez, William Charlton, Michael Massoud, Omar Wiesner, Russell Krishnan, Anuradha Poterucha, John Watt, Kymberly Heimbach, Julie |
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Copyright | Copyright © 2011 American Association for the Study of Liver Diseases Copyright © 2011 American Association for the Study of Liver Diseases. |
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Notes | Telephone: 507‐266‐7054; FAX: 507‐266‐1856 This work was supported by the Public Health Service (National Institute of Diabetes and Digestive and Kidney Diseases grant RO1 DK069757‐01 and General Clinical Research Center grant RR00585). ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
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SubjectTerms | Adult Alanine Transaminase - blood Biomarkers - blood Biopsy Complement C4 - metabolism Enzyme-Linked Immunosorbent Assay - methods Female Graft Rejection - blood Graft Rejection - diagnosis Graft Rejection - pathology Hepatitis C - surgery Humans Liver - metabolism Liver - pathology Liver Transplantation Male Middle Aged Predictive Value of Tests Proteomics Sensitivity and Specificity Transplantation |
Title | Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: A proteomic signature validated by enzyme‐linked immunosorbent assay |
URI | https://onlinelibrary.wiley.com/doi/abs/10.1002%2Flt.22266 https://www.ncbi.nlm.nih.gov/pubmed/21618694 https://www.proquest.com/docview/868997979/abstract/ |
Volume | 17 |
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