Early Plasma Soluble Receptor for Advanced Glycation End-Product Levels Are Associated With Bronchiolitis Obliterans Syndrome

Shah, Rosita M.; Bellamy, Scarlett L.; Lee, Jc C.; Cantu, Edward; Diamond, J.M.; Mangalmurti, N.; Kawut, S.M.; Ware, L.B.; Christie, Jason D.

doi:10.1111/ajt.12062

Cited by 16 publications

(14 citation statements)

References 31 publications

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“…Soluble RAGE (sRAGE) is detectable in plasma but data are conflicting regarding its correlation with cardiovascular disease (35)(36)(37). Recently, sRAGE levels were correlated with BOS development in patients following LTx (38). This supports the hypothesis that glycation is a mechanism by which DM may cause lung pathology and supports our finding that BOS may be accelerated in the presence of hyperglycemia.…”

Section: Discussionsupporting

confidence: 83%

Diabetes Is a Major Risk Factor for Mortality After Lung Transplantation

Hackman

Bailey

Snell

et al. 2014

American Journal of Transplantation

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Survival following lung transplant (LTx) remains significantly lower than after other solid organ transplants. Diabetes mellitus (DM) is a mortality risk factor not comprehensively studied in LTx recipients. Notably, neither the relation of time of DM onset to survival nor the actual causes of DM-associated excess mortality have been described. We determined DM status, DM diagnosis date and all-cause mortality in 386 consecutive adults who underwent LTx at our institution from January 1, 2001 to July 31, 2010. The relationship of DM to survival both as a categorical and time-dependent variable was studied. Fifty-three percent of patients had DM. Overall median survival was 5.2 (95% CI 3.8-6.6) years. At study end, 52% of patients had died, of whom 64% had DM. Estimated median survival was 10 years in patients without DM,) years in patients with DM pre-and post-LTx and 4.3 (3.1-5.5) years in patients with new onset DM. As a timedependent covariate, DM was the strongest risk factor for mortality, hazard ratio 3.96 (2.85-5.51). Bronchiolitis obliterans syndrome was the main cause of death in all patients surviving >90 days, but its incidence was not increased in patients with DM. Further studies are warranted to determine whether improved glycemic control could improve outcomes in LTx recipients.

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Section: Discussionsupporting

confidence: 83%

Diabetes Is a Major Risk Factor for Mortality After Lung Transplantation

Hackman

Bailey

Snell

et al. 2014

American Journal of Transplantation

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“…Elevated levels represent lung injury and are associated with impaired alveolar fluid clearance and increased risk of pulmonary oedema . Normal values are ≤ 2 pg.ml −1 , and, therefore, all of our values were elevated, with a peak and statistically significant difference at 4 h. A correlation between elevated sRAGE levels and worsening primary graft dysfunction grade has been reported . Our study demonstrated higher levels of sRAGE in the alveolar recruitment group between 1 h and 4 h after first lung reperfusion.…”

Section: Discussionsupporting

confidence: 50%

Intra‐operative protective mechanical ventilation in lung transplantation: a randomised, controlled trial

et al. 2017

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Primary graft dysfunction occurs in up to 25% of patients after lung transplantation. Contributing factors include ventilator-induced lung injury, cardiopulmonary bypass, ischaemia-reperfusion injury and excessive fluid administration. We evaluated the feasibility, safety and efficacy of an open-lung protective ventilation strategy aimed at reducing ventilator-induced lung injury. We enrolled adult patients scheduled to undergo bilateral sequential lung transplantation, and randomly assigned them to either a control group (volume-controlled ventilation with 5 cmH O, positive end-expiratory pressure, low tidal volumes (two-lung ventilation 6 ml.kg , one-lung ventilation 4 ml.kg )) or an alveolar recruitment group (regular step-wise positive end-expiratory pressure-based alveolar recruitment manoeuvres, pressure-controlled ventilation set at 16 cmH O with 10 cmH O positive end-expiratory pressure). Ventilation strategies were commenced from reperfusion of the first lung allograft and continued for the duration of surgery. Regular PaO /F O ratios were calculated and venous blood samples collected for inflammatory marker evaluation during the procedure and for the first 24 h of intensive care stay. The primary end-point was the PaO /F O ratio at 24 h after first lung reperfusion. Thirty adult patients were studied. The primary outcome was not different between groups (mean (SD) PaO /F O ratio control group 340 (111) vs. alveolar recruitment group 404 (153); adjusted p = 0.26). Patients in the control group had poorer mean (SD) PaO /F O ratios at the end of the surgical procedure and a longer median (IQR [range]) time to tracheal extubation compared with the alveolar recruitment group (308 (144) vs. 402 (154) (p = 0.03) and 18 (10-27 [5-468]) h vs. 15 (11-36 [5-115]) h (p = 0.01), respectively). An open-lung protective ventilation strategy during surgery for lung transplantation is feasible, safe and achieves favourable ventilation parameters.

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“…Increased plasma levels of sRAGE were associated with primary graft dysfunction at six and 24 hours after lung transplantation [59]. Elevated plasma sRAGE measured 24 hours postoperatively was associated with the development of bronchiolitis obliterans syndrome [60]. No data exist on RAGE and lung transplantation for iPAH.…”

Section: Discussionmentioning

confidence: 99%

Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH

et al. 2014

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ObjectiveThe 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.MethodsWe 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).ResultsIn 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.ConclusionsOur 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.

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Early Plasma Soluble Receptor for Advanced Glycation End-Product Levels Are Associated With Bronchiolitis Obliterans Syndrome

Cited by 16 publications

References 31 publications

Diabetes Is a Major Risk Factor for Mortality After Lung Transplantation

Diabetes Is a Major Risk Factor for Mortality After Lung Transplantation

Intra‐operative protective mechanical ventilation in lung transplantation: a randomised, controlled trial

Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH

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