Receptor for Advanced Glycation End Products in Donor Lungs Is Associated with Primary Graft Dysfunction After Lung Transplantation

Abstract

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation.We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells

“…We reported that RAGE can be used as a biomarker of alveolar epithelial injury in an experimental study and in patients with ALI or acute respiratory distress syndrome (ARDS) (36). Subsequent studies also found that plasma RAGE had prognostic value for short-term outcomes in patients undergoing lung transplantation (5,7,26). Also, with use of an isolated perfused human lung model, there was an inverse correlation between RAGE levels in the samples from air space and alveolar fluid clearance in two studies (3,14), and our most recent clinical study reported the elevated RAGE levels in plasma had pathogenic and prognostic value in patients with ALI (6).…”

Primary graft dysfunction: pathophysiology to guide new preventive therapies

“…Several studies have implicated a role for RAGE in the mechanisms of PGD. First, elevated RAGE in BAL of lung donors was associated with increased PGD risk (odds ratio 1.77 per 0.25 mg/mL increase in RAGE) and the level of RAGE correlated with the severity of PGD[66]. Similarly, plasma RAGE in lung transplant recipients within 6 hours of reperfusion was associated with increased PGD (odds ratio 1.28 per 10mg/mL increase)[67].…”

Update on lung transplantation: programmes, patients and prospects

“…Elevated levels of one such DAMP, RAGE (receptor for advanced glycosylation end products), is an epithelial injury marker whose measurement in donor lung bronchoalveolar lavage and recipient blood has been linked to PGD risk [372,373]. Similarly, the level of long pentraxin 3 (a TLR agonist implicated in reperfusion injury) and endothelin-1 expression in both donors and recipients predicts PGD [374,375].…”