Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

Abstract

Rationale:The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. Objectives: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study. Methods: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa O 2 /FI O 2 , 200 with alveolar infiltrates) within the first 72 hours after transplantation. Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P 5 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P , 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P 5 0.003) and 24 hours (P , 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's r 5 0.39, P 5 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P 5 0.02). Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

Humoral Immunity and the Development of Obliterative Bronchiolitis after Lung Transplantation

“…The presence of autoimmunity immediately after lung transplantation in this group of patients is most likely representative of developing autoimmunity before lung transplantation, secondary to underlying lung disease. These observations are consistent with recent studies showing that interstitial lung diseases (among which idiopathic pulmonary fibrosis makes up the vast majority) pose a major risk factor for PGD (37). Reports from a number of investigators, including our group, have shown the presence of autoimmunity in the pathophysiology of idiopathic pulmonary fibrosis (38,39).…”

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

“…A variety of clinical risk factors for PGD have been identified with contributions from the donor (3)(4)(5)(6)(7), the recipient (3)(4)(5)(7)(8)(9)(10), and operative variables (4,5,8,11). In addition, a number of biomarkers have been associated with increased risk of PGD, including markers of innate and adaptive immune activation, epithelial and endothelial injury, coagulation, vascular permeability, and lipid peroxidation (2,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Despite identification of these clinical and biomarker predictors of PGD, the mechanisms leading to PGD are not well understood, and there are no specific therapeutic interventions for PGD.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Similarly, recent reports suggest a predominant role of RAGE and its ligand HMGB1 in the initiation of lung IR injury (Sternberg, et al, 2008). In a multi-center study, Christie et al reported that an elevated plasma level of soluble RAGE (a truncated form of RAGE) was associated with primary graft dysfunction in patients undergoing lung transplantation (Christie, et al, 2009). An in depth characterization of the role of HMGB1, TLRs and RAGE remains to be elucidated in pulmonary injury after IR and transplantation.…”