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

¹ Pulmonary, Allergy, and Critical Care Division, ² Department of Biostatistics and Epidemiology, ³ Penn Cardiovascular Institute, and ¹¹ Department of Anesthesia and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ⁴ Division of Pulmonary, Allergy, and Critical Care Medicine, and ⁵ Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York; ⁶ Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Raleigh-Durham, North Carolina; ⁷ Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama; ⁸ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; ⁹ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Johns Hopkins University Hospital, Baltimore, Maryland; ¹⁰ Division of Pulmonary and Critical Care Medicine, Stanford University, Palo Alto, California; and ¹² Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Jason D. Christie, M.D., M.S., Assistant Professor of Medicine and Epidemiology, Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 423 Guardian Drive, 719 Blockley Hall, Philadelphia, PA 19104. E-mail: jchristi{at}mail.med.upenn.edu

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_O2/FI_O2 < 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 = 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 = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 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.

Key Words: primary graft dysfunction • reperfusion injury • lung transplantation • receptor for advanced glycation end products • acute lung injury

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Soluble receptor for advanced glycation end products (sRAGE) is a novel marker of alveolar epithelial injury, and RAGE blockade attenuates experimental lung ischemia reperfusion injury. The role of sRAGE in clinical primary graft dysfunction is incompletely understood. What This Study Adds to the Field This multicenter cohort study demonstrates that sRAGE is elevated in primary graft dysfunction, suggesting that RAGE blockade may be a useful future therapy. In addition, sRAGE was elevated with use of cardiopulmonary bypass and red cell transfusion.

 

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