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Janciauskiene S, Royer PJ, Fuge J, Wrenger S, Chorostowska-Wynimko J, Falk C, Welte T, Reynaud-Gaubert M, Roux A, Tissot A, Magnan A. Plasma Acute Phase Proteins as Predictors of Chronic Lung Allograft Dysfunction in Lung Transplant Recipients. J Inflamm Res 2020; 13:1021-1028. [PMID: 33299339 PMCID: PMC7721309 DOI: 10.2147/jir.s272662] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/22/2020] [Indexed: 11/23/2022] Open
Abstract
Cumulating reports suggest that acute phase proteins (APPs) have diagnostic and prognostic value in different clinical conditions. Among others, APPs are proposed to serve as markers that help to control the outcome of transplant recipients. Here, we questioned whether plasma concentrations of APPs mirror the development of chronic lung allograft dysfunction (CLAD). We performed blinded analysis of serial plasma samples retrospectively collected from 35 lung transplanted patients, of whom 25 developed CLAD and 10 remained stable during the follow-up period of 3 to 4.5 years. Albumin (ALB), alpha1-antitrypsin (AAT), high sensitivity C-reactive protein (CRPH), antithrombin-3 (AT3), ceruloplasmin (CER), and alpha2-macroglobulin (A2MG) were measured by the nephelometric method. We found that within the first six months post-transplantation, levels of A2MG, CER and AAT were higher in stable patients relative to those who later developed CLAD. Moreover, in stable patient’s plasma CRPH levels decreased during the follow-up period whereas opposite, in those developing CLAD, the CRPH gradually increased. The ALB levels became significantly lower at the end of the follow-up period in CLAD relative to a stable group. A logistic regression model based on A2MG, CER and AT3 at cut-offs levels of ≥175.5 mg/dL, ≥37.8 mg/dL and ≥27.35 mg/dL enabled to discriminate between stable and CLAD patients with a sensitivity of 87.5%, 100% and 62.5%, and specificity of 65.9%, 72.7% and 79.5%, respectively. We identified A2MG (below 175.5 mg/dL) as an independent predictor of CLAD (hazard ratio 11.5, 95% CI (1.5–91.3), p<0.021). Our findings suggest that profiles of certain APPs may help to predict the development of lung dysfunction at the very early stages after transplantation.
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Affiliation(s)
- Sabina Janciauskiene
- Department of Pulmonary and Infectious Diseases, BREATH German Center for Lung Research (DZL) Hannover University School, Hannover, Germany.,Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
| | - Pierre-Joseph Royer
- CHU de Nantes, Centre National De Référence Mucoviscidose Nantes-Roscoff, Nantes, France
| | - Jan Fuge
- Department of Pulmonary and Infectious Diseases, BREATH German Center for Lung Research (DZL) Hannover University School, Hannover, Germany
| | - Sabine Wrenger
- Department of Pulmonary and Infectious Diseases, BREATH German Center for Lung Research (DZL) Hannover University School, Hannover, Germany
| | - Joanna Chorostowska-Wynimko
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
| | - Christine Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research DZIF Hannover Braunschweig Site, TTU-IICH, Hannover, Germany
| | - Tobias Welte
- Department of Pulmonary and Infectious Diseases, BREATH German Center for Lung Research (DZL) Hannover University School, Hannover, Germany
| | - Martine Reynaud-Gaubert
- Department ofPulmonary Diseases and Lung Transplantation, CHU Nord de Marseille; IHU - Méditerranée Infection, Aix Marseille Université, Marseille, France
| | - Antoine Roux
- Hôpital Foch, Suresnes, France.,Université Versailles Saint-Quentin- en-Yvelines, Versailles, France.,l'Institut du Thorax, Université de Nantes, Nantes, France
| | - Adrien Tissot
- CHU de Nantes, Centre National De Référence Mucoviscidose Nantes-Roscoff, Nantes, France
| | - Antoine Magnan
- CHU de Nantes, Centre National De Référence Mucoviscidose Nantes-Roscoff, Nantes, France
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2
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Graves KL, Vigerust DJ. Hp: an inflammatory indicator in cardiovascular disease. Future Cardiol 2016; 12:471-81. [DOI: 10.2217/fca-2016-0008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Over the past decade significant advancement has occurred in the biological and pathological role that Hp has in cardiovascular disease. Hp is an acute-phase protein with a role in the neutralization and clearance of free heme. Iron has tremendous potential for initiating vascular oxidation, inflammation and exacerbating coronary atherosclerosis. Hp genotype has been linked as a prognostic biomarker of acute myocardial infarction, heart failure, restenosis and cardiac transplant rejection. The increased understanding of Hp as a biomarker has provided new insights into the mechanisms of inflammation after cardiac injury and support the concept that Hp is not only an important antioxidant in vascular inflammation and atherosclerosis, but also an enhancer of inflammation in cardiac transplant.
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Affiliation(s)
| | - David J Vigerust
- Vanderbilt University School of Medicine, Nashville, TN 37212, USA
- MyGenetx Clinical Laboratories, Franklin, TN 37067, USA
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3
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Towards cytoprotection in the peritransplant period. Semin Immunol 2011; 23:209-13. [DOI: 10.1016/j.smim.2011.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 07/10/2011] [Indexed: 01/26/2023]
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Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 as a Marker of Acute Rejection in Pancreas Allotransplantation in Pigs. Transplant Proc 2010; 42:3063-9. [DOI: 10.1016/j.transproceed.2010.08.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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5
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O'Riordan E, Orlova TN, Podust VN, Chander PN, Yanagi S, Nakazato M, Hu R, Butt K, Delaney V, Goligorsky MS. Characterization of urinary peptide biomarkers of acute rejection in renal allografts. Am J Transplant 2007; 7:930-40. [PMID: 17331118 DOI: 10.1111/j.1600-6143.2007.01733.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We previously demonstrated that 4.7 kDa and 4.4 kDa peptides are useful in diagnosing acute rejection in renal transplant recipients. The aim of this study was to characterize these polypeptides and assess their potential as biomarkers. The polypeptides were identified as human beta-Defensin-1 (4.7 kDa) and alpha-1-antichymotrypsin (4.4 kDa), by tandem mass spectrometry and ProteinChip immunoassay. The urinary abundance of both polypeptides, assessed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), revealed a reduction in beta-Defensin-1 while alpha-1-antichymotrypsin increased in patients with rejection (p < 0.05) compared with clinically stable transplants. The area under the curve (AUC) for the receiver operator characteristic (ROC) curve for the diagnosis of rejection for the ratio of both peptides combined was 0.912. Longitudinal analysis confirmed a reduction in beta-Defensin-1 with a reciprocal increase in alpha-1-antichymotrypsin as rejection developed. The difference in urinary beta-Defensin-1 levels quantified by radioimmunoassay was 176.8 +/- 122.3 pg/mL in stable patients compared with 83.2 +/- 52.2 pg/mL in patients with acute rejection, with an ROC AUC of 0.749 (p < 0.01). Immunohistochemistry (IHC) confirmed reduced beta-Defensin-1 expression in the renal parenchyma of patients experiencing acute rejection. In conclusion, the ratio of beta-Defensin-1 and alpha-1-antichymotrypsin excretion in the urine is a novel, potentially useful candidate biomarkers of acute rejection.
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Affiliation(s)
- E O'Riordan
- Renal Institute, New York Medical College, Valhalla, New York, USA.
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6
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Fallsehr C, Zapletal C, Kremer M, Demir R, von Knebel Doeberitz M, Klar E. Identification of differentially expressed genes after partial rat liver ischemia/reperfusion by suppression subtractive hybridization. World J Gastroenterol 2005; 11:1303-16. [PMID: 15761968 PMCID: PMC4250677 DOI: 10.3748/wjg.v11.i9.1303] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify potential diagnostic target genes in early reperfusion periods following warm liver ischemia before irreversible liver damage occurs.
METHODS: We used two strategies (SSH suppression subtractive hybridization and hybridization of cDNA arrays) to determine early changes in gene expression profiles in a rat model of partial WI/R, comparing postischemic and adjacent nonischemic liver lobes. Differential gene expression was verified (WI/R; 1 h/2 h) and analyzed in more detail after warm ischemia (1 h) in a reperfusion time kinetics (0, 1, 2 and 6 h) and compared to untreated livers by Northern blot hybridizations. Protein expression was examined on Western blots and by immunohistochemistry for four differentially expressed target genes (Hsp70, Hsp27, Gadd45a and IL-1rI).
RESULTS: Thirty-two individual WI/R target genes showing altered RNA levels after confirmation by Northern blot analyzes were identified. Among them, six functionally uncharacteristic expressed sequences and 26 known genes (12 induced in postischemic liver lobes, 14 with higher transcriptional expression in adjacent nonischemic liver lobes). Functional categories of the verified marker genes indicate on the one hand cellular stress and tissue damage but otherwise activation of protective cellular reactions (AP-1 transcription factors, apoptosis related genes, heat shock genes). In order to assign the transcriptional status to the biological relevant protein level we demonstrated that Hsp70, Hsp27, Gadd45a and IL-1rI were clearly up-regulated comparing postischemic and untreated rat livers, suggesting their involvement in the WI/R context.
CONCLUSION: This study unveils a WI/R response gene set that will help to explore molecular pathways involved in the tissue damage after WI/R. In addition, these genes especially Hsp70 and Gadd45a might represent promising new candidates indicating WI/R liver damage.
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Affiliation(s)
- Christine Fallsehr
- Institute of Molecular Pathology, University of Heidelberg, Heidelberg, Germany
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Raguso CA, Genton L, Dupertuis YM, Pichard C. Assessment of nutritional status in organ transplant: is transthyretin a reliable indicator? Clin Chem Lab Med 2002; 40:1325-8. [PMID: 12553438 DOI: 10.1515/cclm.2002.228] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Transthyretin has been proposed as a nutritional index to screen for malnutrition and monitor the metabolic response to dietary intervention. In the presence of inflammation, circulating transthyretin levels drop regardless of optimal caloric intake. In this case, due to its rapid turnover, the pattern of transthyretin, monitored by means of repeated measures, could indicate the metabolic status (catabolism vs. anabolism). The aim of this review is to investigate the possible role of transthyretin as a nutritional parameter in organ transplantation. The literature on nutritional assessment in transplantation was reviewed and all the data regarding circulating transthyretin levels were analyzed. It appears that, on the one hand, the transthyretin level reflects closely dietary manipulations; on the other hand, it is affected by the inflammatory status. Consequently, interpretation could be difficult during the acute phase immediately after the transplant. Moreover, the role of transthyretin in monitoring the hepatic synthetic function in liver transplant is discussed. In conclusion, transthyretin is a reliable indicator of nutritional status in transplant candidates and potentially useful in the post-transplant phase if the inflammatory status is taken into account.
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Affiliation(s)
- Comasia A Raguso
- Division of Clinical Nutrition, University Hospital, Geneva, Switzerland
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Schütz E, Luy-Kaltefleiter M, Kaltefleiter M, Burdelski M, Ringe B, Armstrong VW, Oellerich M. The value of serial determination of MEGX and hyaluronic acid early after orthotopic liver transplantation. Eur J Clin Invest 1996; 26:907-16. [PMID: 8911865 DOI: 10.1111/j.1365-2362.1996.tb02137.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Post-transplant assessment of early graft function has become an essential part of monitoring, especially when deciding on retransplantation. If primary non-function is indicated, retransplantation is inevitable; early graft dysfunction may be related to subsequent complications. In a prospective study in 84 patients after orthotopic liver transplantation (OLT) we measured aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), bilirubin (BIL), prothrombin time, MEGX formation, hyaluronic acid (HA) and soluble interleukin-2 receptor (sIL-2R) concentrations during the first 2 postoperative weeks; graft outcome was followed over 4 months. The aim of this study was to determine whether graft survival could be predicted by such variables early after OLT. Compared with patients with stable graft function (n = 25), patients with post-transplant icteric cholestasis (n = 30) exhibited no difference in graft survival, despite a decrease in MEGX formation to a nadir median of 12 micrograms L-1 on day 10. Patients with rejection (n = 8) and septicaemia (n = 6) showed a marked decrease in MEGX values and an increase in HA and sIL-2R concentrations between postoperative days 3 and 7. Patients with primary non-function (PNF; n = 5) were characterized by strongly reduced MEGX formation (median 4 micrograms L) and increased HA values (median 2300 micrograms L-1) on day 3 after OLT. A total of 24/84 grafts were lost within 120 days. In a survival analysis using the Cox proportional hazards regression, HA and MEGX values on day 1 were the only independent variables entering the model that showed an adequate prognostic sensitivity. At cut-off points of 22 micrograms L-1 (MEGX) and 730 micrograms L-1 (HA) the combined use of these parameters in a parallel approach yielded a sensitivity of 58% with a corresponding specificity of 95% for 120-day graft survival. These findings suggest that the inclusion of MEGX and HA in postoperative monitoring of OLT patients may be helpful in the early prediction of graft survival.
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Affiliation(s)
- E Schütz
- Abteilung Klinische Chemie, Zentrum Innere Medizin, Georg-August-Universität, Göttingen, Germany
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9
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Izumi S, Hughes RD, Langley PG, Pernambuco JRB, Williams R. Acute phase response after liver transplantation for fulminant hepatic failure and cirrhosis. Transpl Int 1995. [DOI: 10.1007/bf00337164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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10
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Izumi S, Hughes RD, Langley PG, Pernambuco JRB, Williams R. Acute phase response after liver transplantation for fulminant hepatic failure and cirrhosis. Transpl Int 1995. [DOI: 10.1111/j.1432-2277.1995.tb01533.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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11
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Uguccioni M, Meliconi R, Lalli E, Nesci S, Delfini C, Lucarelli G, Gasbarrini G, Facchini A. Serum amyloid A protein concentration in bone marrow transplantation for beta thalassaemia. J Clin Pathol 1992; 45:348-351. [PMID: 1577974 PMCID: PMC495278 DOI: 10.1136/jcp.45.4.348] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
AIMS To investigate whether serum amyloid A protein (SAA) and C-reactive protein (CRP) concentrations could be used in the management of beta thalassaemic patients undergoing bone marrow transplantation (BMT). METHODS Serum SAA and CRP concentrations were determined in paired samples from 66 patients with beta thalassaemia before and after BMT. Serum SAA concentrations were determined by an enzyme linked immunoassay (EIA); serum CRP concentrations were determined by a nephelometric assay. RESULTS Serum SAA concentrations before transplantation were significantly higher in the group that subsequently rejected the transplant than the group without complications. SAA concentrations increased after BMT in acute graft versus host disease (GvHD) and rejection. No significant increase in SAA or CRP was found in chronic GvHD. Increases in serum in SAA and CRP concentrations were not related to concomitant infection episodes. CONCLUSIONS The different acute phase response in acute GvHD and rejection compared with chronic GvHD suggests that different immunopathogenic mechanisms are responsible.
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Affiliation(s)
- M Uguccioni
- Laboratorio di Immunologia e Genetica, Istituto di Ricerca Codivilla-Putti, Bologna, Italy
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13
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Abstract
We have reviewed the literature to determine the value of C-reactive protein (CRP) measurements in the diagnosis and management of a wide range of conditions. CRP levels are of value in 6 clinical situations: (a) monitoring the response to antibiotic treatment in patients with known bacterial infections, (b) in obstetric patients with premature rupture of membranes, a rise in CRP can give early warning of intrauterine infections, (c) differentiation between active disease and infections in patients with systemic lupus and ulcerative colitis where the level of response to active disease has been previously established, (d) as a measure of disease activity and response to disease-modifying drugs in rheumatoid arthritis, (e) early detection of complications in postoperative patients, (f) in differentiating between infection and graft-versus-host-disease in bone marrow transplant patients. CRP levels have been used in an attempt to differentiate between bacterial and viral infections in various clinical situations, however the published literature does not support this role.
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Affiliation(s)
- B Young
- Discipline of Pathology, University of Newcastle, NSW
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14
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Affiliation(s)
- G Paintaud
- Department of Hepatology, Hôpital Jean Minjoz, Besançon, France
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15
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Affiliation(s)
- K Höckerstedt
- IV Dept. of Surgery, Helsinki University Central Hospital, Finland
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16
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Tredger JM, Williams R. Drug-binding proteins after liver transplantation: are they significant? Hepatology 1989; 10:390-2. [PMID: 2668151 DOI: 10.1002/hep.1840100326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- J M Tredger
- Kings College School of Medicine & Dentistry, London, Great Britain
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