Plasma Receptor for Advanced Glycation End-products Predicts Duration of ICU Stay and Mechanical Ventilation in Patients After Lung Transplantation

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, California 94143-0130, USA.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation (Impact Factor: 6.65). 08/2007; 26(7):675-80. DOI: 10.1016/j.healun.2007.04.002
Source: PubMed


Primary graft dysfunction, formerly termed reperfusion pulmonary edema, is the leading cause of short-term complications after lung transplantation. New evidence shows that alveolar type I epithelial cells play an active role in alveolar fluid transport and are therefore presumed to be critical in the absorption of pulmonary edema. We tested the potential relevance of a novel marker of alveolar type I cell injury, the receptor for advanced glycation end-products (RAGE), to short-term outcomes of lung transplantation.
The study was a prospective, observational cohort study of 20 patients undergoing single lung, bilateral lung or combined heart-lung transplantation. Plasma biomarkers were measured 4 hours after allograft reperfusion.
Higher plasma RAGE levels were associated with a longer duration of mechanical ventilation and longer intensive care unit length of stay, in contrast to markers of alveolar type II cell injury, endothelial injury and acute inflammation. Specifically, for every doubling in plasma RAGE levels, the duration of mechanical ventilation increased on average by 26 hours, adjusting for ischemia time (95% confidence interval [CI] 7.4 to 44.7 hours, p = 0.01). Likewise, for every doubling of plasma RAGE levels, intensive care unit length of stay increased on average by 1.8 days, again adjusting for ischemia time (95% CI 0.13 to 3.45 days p = 0.04). In contrast, the clinical diagnosis of primary graft dysfunction was not as predictive of these short-term outcomes.
Higher levels of plasma RAGE measured shortly after reperfusion predicted poor short-term outcomes from lung transplantation. Elevated plasma RAGE levels may have both pathogenetic and prognostic value in patients after lung transplantation.

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    • "Glial fibrillary acidic protein (GFAP) Yes/Yes Highly selective for CNS injury [11] [19] [132] Brain Spectrin breakdown products Yes/Yes Can indicate mechanism of cell death [25] [26] [132] Intercellular adhesion molecule-1 (ICAM1) Yes/Yes Not a specific indicator of lung injury [133] [134] von Willebrand factor No/Yes Can predict lung injury after sepsis [134] Surfactant protein D Yes/Yes Correlated with poor outcome and death [134] [135] Soluble receptor for advanced glycation end-products (sRAGE) Yes/Yes Admittance levels correlate with outcome [136] [137] Lung High mobility group box protein -1 (HMGB-1) Yes/Yes Correlates with trauma severity and poor outcome [38] Alanine and aspartate aminotransferases Yes/Yes Indicators of liver function [41] [138] [139] Alkaline phosphatase Yes/Yes Indicator of liver function [41] [138] Gamma glutamyl transferase No/Yes Indicator of liver function [41] Bilirubin Yes/Yes Presence in urine indicates liver damage [42] [43] [140] Cytokeratin-18 No/No Caspase-mediated breakdown indicates liver damage [141] [142] Liver Arginosuccinate synthetase, Sulfotransferase 2A1, "
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    ABSTRACT: A molecular biomarker is an entity whose release, abundance and/or modification state is altered as a result of injury or disease, and can be used to aid diagnosis. The concentrations of injury biomarkers are typically highest within the injured organ, but may be measurable in body fluids. Injuries such as trauma often result in damage to multiple organs, requiring biomarkers that can specifically identify the organs that are injured. Biomarkers such as glial fibrillary acidic protein for brain injury, kidney injury marker-1 for kidney injury, cardiac troponin for heart damage, intestinal-type fatty acid binding protein for gut injury, and d-dimer for coagulopathy have been shown to have clinical diagnostic utility to detect injury to individual organs. The long-term objective of injury-associated biomarker research is to identify and validate a panel of biomarkers to diagnose (or exclude) injury to various organs and/or predict ensuing symptoms/outcome. Unfortunately, such a panel is not currently available. This review will critically assess the current status and related patents of individual biomarkers being investigated for the diagnosis of injury to specific organs, and discuss the feasibility of generating a panel of biomarkers that can be used to diagnose injury to multiple organs.
    12/2014; 4(2). DOI:10.2174/2210309004666140616232339
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    • "In lung transplant recipients elevated plasma sRAGE concentrations measured four hours after reperfusion of the lung allograft were associated with longer duration of mechanical ventilation and longer intensive care unit length of stay [58]. Increased plasma levels of sRAGE were associated with primary graft dysfunction at six and 24 hours after lung transplantation [59]. "
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    ABSTRACT: Objective The molecular determinants of chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) remain poorly understood. The receptor for advanced glycation endproducts (RAGE) and its ligands: HMGB1 and S100A9 are involved in inflammatory disorders. We sought to investigate the role of the RAGE axis in patients with CTEPH undergoing pulmonary endarterectomy (PEA), iPAH undergoing lung transplantation (LuTX). The high pulmonary vascular resistance in CTEPH/iPAH results in pressure overload of the right ventricle. We compared sRAGE measurements to that of patients with aortic valve stenosis (AVS) – pressure overload of the left ventricle. Methods We enrolled patients with CTEPH(26), iPAH(15), AVS(15) and volunteers(33). Immunohistochemistry with antibodies to RAGE and HMGB1 was performed on PEA specimens and lung tissues. We employed enzyme-linked immunosorbent assays to determine the concentrations of sRAGE, esRAGE, HMGB1 and S100A9 in serum of volunteers and patients with CTEPH, iPAH, AVS before and after PEA, LuTX and aortic valve replacement (AVR). Results In endarterectomised tissues from patients with CTEPH RAGE and HMGB1 were identified in myofibroblasts (α-SMA+vimentin+CD34−), recanalizing vessel-like structures of distal myofibrotic tissues and endothelium of neointima. RAGE was differentially expressed in prototypical Heath Edwards lesions in iPAH. We found significantly increased serum concentrations of sRAGE, esRAGE and HMGB1 in CTEPH. In iPAH, sRAGE and esRAGE were significantly higher than in controls. Serum concentrations of sRAGE were significantly elevated in iPAH(p<0.001) and CTEPH(p = 0.001) compared to AVS. Serum sRAGE was significantly higher in iPAH compared to CTEPH(p = 0.042) and significantly reduced in AVS compared to controls(p = 0.001). There were no significant differences in sRAGE serum concentrations before and after surgical therapy for CTEPH, iPAH or AVS. Conclusions Our data suggest a role for the RAGE pathway in the pathophysiology of CTEPH and iPAH. PEA improves the local control of disease but may not influence the systemic inflammatory mechanisms in CTEPH patients through the RAGE pathway.
    PLoS ONE 09/2014; 9(9):e106440. DOI:10.1371/journal.pone.0106440 · 3.23 Impact Factor
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    • "Sharma et al. showed that TNF-α production by alveolar macrophages mediates alveolar type II epithelial cell activation and KC production in an in vitro hypoxiareoxygenation model (Sharma, et al., 2007). Recent studies also implicate alveolar type I cellreleased mediators such as soluble receptor for advanced glycation end products (sRAGE) as a potential biomarker and indicator of lung injury after lung transplantation (Calfee, et al., 2007). This new marker may be useful given the recent discovery of the role of alveolar type I cells in alveolar fluid clearance (Johnson, et al., 2006). "

    Topics in Thoracic Surgery, 02/2012; , ISBN: 978-953-51-0010-2
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