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 PGD for translational research. Methods Biomarkers reflecting lung epithelial injury (sRAGE and SP-D), coagulation cascade (PAI-1 and Protein C), and cell adhesion (ICAM-1) were measured in the plasma of 315 subjects derived from the LTOG cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in two 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 86/315 subjects (27%) developed PGD. 23 subjects (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 (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 of 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 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 mortality, and may provide an alternative outcome useful in future research.

Inhaled nitric oxide in cardiac surgery: Evidence or tradition?

“…Lung injury and primary graft dysfunction in this setting is considered a pulmonary inflammatory response to the microvascular endothelium and alveolar epithelium, with inflammatory activation of alveolar cells, circulating and resident leukocytes, proinflammatory cytokine imbalance and increased oxidative stress (43,44). Furthermore, reperfusion sets into motion programmed cell death cascades with up to 30% lung cells exhibiting signs of apoptosis prior to chest closure (45).…”

Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP

“…Stage 1 consisted of 297 subjects enrolled between May 2002 and October 2006, in whom PAI-1 protein levels were measured as part of a previous study of biomarker discrimination. [10] Stage 2 consisted mostly of LTOG subjects enrolled in a subsequent era between November 2006 and December 2010; however 38 subjects with DNA samples not included in Stage 1 due to insufficient plasma for protein analyses dating from March 2003 were also included in Stage 2. Clinical data were collected prospectively as previously described.…”

“…[10] PAI-1 is an acute phase reactant and an endogenous inhibitor of tissue plasminogen activator that is increased in non-transplant acute lung injury (ALI) [11] with increased circulating levels being associated with mortality. [12] For these reasons, PAI-1 was selected for study as a PGD quantitative trait.…”

Early Use of Surfactant-BL after Lung Transplantation

“…Сравнительно недавно было предложено использовать определение концен трации SP D в плазме в качестве прогностического критерия у лиц с ОРДС [26,27]. Их появление в кро Т р а н с п л а н т а ц и я л е г к и х ви может использоваться как маркер повреждения легочной ткани при достаточно разнообразной пато логии нижних дыхательных путей [28,29].…”