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A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation.

ABSTRACT: BACKGROUND:We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research. METHODS:Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality. RESULTS:PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each). CONCLUSIONS:Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.

SUBMITTER: Shah RJ

PROVIDER: S-EPMC3418416 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation.

Shah Rupal J RJ Bellamy Scarlett L SL Localio A Russell AR Wickersham Nancy N Diamond Joshua M JM Weinacker Ann A Lama Vibha N VN Bhorade Sangeeta S Belperio John A JA Crespo Maria M Demissie Ejigayehu E Kawut Steven M SM Wille Keith M KM Lederer David J DJ Lee James C JC Palmer Scott M SM Orens Jonathan J Reynolds John J Shah Ashish A Wilkes David S DS Ware Lorraine B LB Christie Jason D JD

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20120612 9

<h4>Background</h4>We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research.<h4>Methods</h4>Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals ...[more]

PMID: 22694851

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Project description:The clinical use of circulating biomarkers for primary graft dysfunction (PGD) after lung transplantation has been limited. In a prospective single-center cohort, we examined the use of plasma protein biomarkers as indicators of PGD severity and duration after lung transplantation. The study comprised 40 consecutive lung transplant patients who consented to blood sample collection immediately pretransplant and at 6, 24, 48, and 72 h after lung transplant. An expert grader determined the severity and duration of PGD and scored PGD at T0 (6 h after reperfusion), T24, T48, and T72 h post-reperfusion using the 2016 ISHLT consensus guidelines. A bead-based multiplex assay was used to measure 27 plasma proteins including cytokines, growth factors, and chemokines. Enzyme-linked immunoassay was used to measure cell injury markers including M30, M65, soluble receptor of advanced glycation end-products (sRAGE), and plasminogen activator inhibitor-1 (PAI-1). A pairwise comparisons analysis was used to assess differences in protein levels between PGD severity scores (1, 2, and 3) at T0, T24, T48, and T72 h. Sensitivity and temporal analyses were used to explore the association of protein expression patterns and PGD3 at T48-72 h (the most severe, persistent form of PGD). We used the Benjamini-Hochberg method to adjust for multiple testing. Of the 40 patients, 22 (55%) had PGD3 at some point post-transplant from T0 to T72 h; 12 (30%) had PGD3 at T48-72 h. In the pairwise comparison, we identified a robust plasma protein expression signature for PGD severity. In the sensitivity analysis, using a linear model for microarray data, we found that differential perioperative expression of IP-10, MIP1B, RANTES, IL-8, IL-1Ra, G-CSF, and PDGF-BB correlated with PGD3 development at T48-72 h (FDR < 0.1 and p < 0.05). In the temporal analysis, using linear mixed modeling with overlap weighting, we identified unique protein patterns in patients who did or did not develop PGD3 at T48-72 h. Our findings suggest that unique inflammatory protein expression patterns may be informative of PGD severity and duration. PGD biomarker panels may improve early detection of PGD, predict its clinical course, and help monitor treatment efficacy in the current era of lung transplantation.

Dataset Information

A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation.

Publications

A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation.

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