Circulating cell death biomarkers may predict survival in human lung transplantation

Kohei Hashimoto, Rickvinder Besla, Ricardo Zamel, Stephen Juvet, Hyunhee Kim, Sassan Azad, Thomas K. Waddell, Marcelo Cypel, Mingyao Liu, Shaf Keshavjee, Robert Jeen-chen Chen

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Rationale: Immediate graft performance after lung transplantation is associated with short-and long-Term clinical outcomes. However, the biologic mechanism that determines outcomes is not fully understood. Objectives: To investigate the impact of cell death signals at 24 and 48 hours after lung transplantation on short-and long-Term clinical outcomes. Methods: Plasma samples were collected pretransplantation and at 24 and 48 hours after transplant from 60 bilateral lung transplant recipients. Ten patients had primary graft dysfunction (PGD) grade 3 (PaO2/FIO2 ratio ,200 or on extracorporeal membrane oxygenation support) at 72 hours after transplant (PGD group). The remaining 50 patients were defined as the control group. Levels of plasma M30 (signifying epithelial apoptosis), M65 (signifying epithelial apoptosis plus necrosis), and high-mobility group box 1 protein (HMGB-1; signifying necrosis of all cell types) were measured by ELISA and correlated with clinical outcomes. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. Prediction accuracy of markers was assessed by calculated area under the curve of receiver operating characteristic graph. Measurements and Main Results: The PGD group had significantly higher M30 and M65 levels at 24 and 48 hours after transplant compared with the control group. There was no significant difference in HMGB-1. Area under the curve for 1-year survival was 0.86, 0.93, and 0.51 for M30, M65, and HMGB-1 at 48 hours, respectively. Survival analysis showed that higher M30 and M65 levels at 24 and 48 hours were significantly associated with worse survival. M65 at 48 hours remained significant even after adjustment for PGD. HMGB-1 was not significantly associated with survival. Conclusions: Recipient plasma concentration of epithelial cell death markers (M30, M65) after lung transplantation is negatively correlated with early graft performance and long-Term survival.

Original languageEnglish
Pages (from-to)97-105
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume194
Issue number1
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

Primary Graft Dysfunction
HMGB Proteins
Lung Transplantation
Cell Death
Biomarkers
Transplants
Survival
Survival Analysis
Area Under Curve
Necrosis
Apoptosis
HMGB1 Protein
Control Groups
Extracorporeal Membrane Oxygenation
ROC Curve
Epithelial Cells
Enzyme-Linked Immunosorbent Assay
Lung

Keywords

  • Apoptosis
  • Cytokeratin
  • Ischemia Reperfusion Injury
  • Necrosis
  • Primary Graft Dysfunction

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Circulating cell death biomarkers may predict survival in human lung transplantation. / Hashimoto, Kohei; Besla, Rickvinder; Zamel, Ricardo; Juvet, Stephen; Kim, Hyunhee; Azad, Sassan; Waddell, Thomas K.; Cypel, Marcelo; Liu, Mingyao; Keshavjee, Shaf; Chen, Robert Jeen-chen.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 194, No. 1, 01.07.2016, p. 97-105.

Research output: Contribution to journalArticle

Hashimoto, K, Besla, R, Zamel, R, Juvet, S, Kim, H, Azad, S, Waddell, TK, Cypel, M, Liu, M, Keshavjee, S & Chen, RJ 2016, 'Circulating cell death biomarkers may predict survival in human lung transplantation', American Journal of Respiratory and Critical Care Medicine, vol. 194, no. 1, pp. 97-105. https://doi.org/10.1164/rccm.201510-2115OC
Hashimoto, Kohei ; Besla, Rickvinder ; Zamel, Ricardo ; Juvet, Stephen ; Kim, Hyunhee ; Azad, Sassan ; Waddell, Thomas K. ; Cypel, Marcelo ; Liu, Mingyao ; Keshavjee, Shaf ; Chen, Robert Jeen-chen. / Circulating cell death biomarkers may predict survival in human lung transplantation. In: American Journal of Respiratory and Critical Care Medicine. 2016 ; Vol. 194, No. 1. pp. 97-105.
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abstract = "Rationale: Immediate graft performance after lung transplantation is associated with short-and long-Term clinical outcomes. However, the biologic mechanism that determines outcomes is not fully understood. Objectives: To investigate the impact of cell death signals at 24 and 48 hours after lung transplantation on short-and long-Term clinical outcomes. Methods: Plasma samples were collected pretransplantation and at 24 and 48 hours after transplant from 60 bilateral lung transplant recipients. Ten patients had primary graft dysfunction (PGD) grade 3 (PaO2/FIO2 ratio ,200 or on extracorporeal membrane oxygenation support) at 72 hours after transplant (PGD group). The remaining 50 patients were defined as the control group. Levels of plasma M30 (signifying epithelial apoptosis), M65 (signifying epithelial apoptosis plus necrosis), and high-mobility group box 1 protein (HMGB-1; signifying necrosis of all cell types) were measured by ELISA and correlated with clinical outcomes. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. Prediction accuracy of markers was assessed by calculated area under the curve of receiver operating characteristic graph. Measurements and Main Results: The PGD group had significantly higher M30 and M65 levels at 24 and 48 hours after transplant compared with the control group. There was no significant difference in HMGB-1. Area under the curve for 1-year survival was 0.86, 0.93, and 0.51 for M30, M65, and HMGB-1 at 48 hours, respectively. Survival analysis showed that higher M30 and M65 levels at 24 and 48 hours were significantly associated with worse survival. M65 at 48 hours remained significant even after adjustment for PGD. HMGB-1 was not significantly associated with survival. Conclusions: Recipient plasma concentration of epithelial cell death markers (M30, M65) after lung transplantation is negatively correlated with early graft performance and long-Term survival.",
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author = "Kohei Hashimoto and Rickvinder Besla and Ricardo Zamel and Stephen Juvet and Hyunhee Kim and Sassan Azad and Waddell, {Thomas K.} and Marcelo Cypel and Mingyao Liu and Shaf Keshavjee and Chen, {Robert Jeen-chen}",
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AU - Hashimoto, Kohei

AU - Besla, Rickvinder

AU - Zamel, Ricardo

AU - Juvet, Stephen

AU - Kim, Hyunhee

AU - Azad, Sassan

AU - Waddell, Thomas K.

AU - Cypel, Marcelo

AU - Liu, Mingyao

AU - Keshavjee, Shaf

AU - Chen, Robert Jeen-chen

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N2 - Rationale: Immediate graft performance after lung transplantation is associated with short-and long-Term clinical outcomes. However, the biologic mechanism that determines outcomes is not fully understood. Objectives: To investigate the impact of cell death signals at 24 and 48 hours after lung transplantation on short-and long-Term clinical outcomes. Methods: Plasma samples were collected pretransplantation and at 24 and 48 hours after transplant from 60 bilateral lung transplant recipients. Ten patients had primary graft dysfunction (PGD) grade 3 (PaO2/FIO2 ratio ,200 or on extracorporeal membrane oxygenation support) at 72 hours after transplant (PGD group). The remaining 50 patients were defined as the control group. Levels of plasma M30 (signifying epithelial apoptosis), M65 (signifying epithelial apoptosis plus necrosis), and high-mobility group box 1 protein (HMGB-1; signifying necrosis of all cell types) were measured by ELISA and correlated with clinical outcomes. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. Prediction accuracy of markers was assessed by calculated area under the curve of receiver operating characteristic graph. Measurements and Main Results: The PGD group had significantly higher M30 and M65 levels at 24 and 48 hours after transplant compared with the control group. There was no significant difference in HMGB-1. Area under the curve for 1-year survival was 0.86, 0.93, and 0.51 for M30, M65, and HMGB-1 at 48 hours, respectively. Survival analysis showed that higher M30 and M65 levels at 24 and 48 hours were significantly associated with worse survival. M65 at 48 hours remained significant even after adjustment for PGD. HMGB-1 was not significantly associated with survival. Conclusions: Recipient plasma concentration of epithelial cell death markers (M30, M65) after lung transplantation is negatively correlated with early graft performance and long-Term survival.

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KW - Apoptosis

KW - Cytokeratin

KW - Ischemia Reperfusion Injury

KW - Necrosis

KW - Primary Graft Dysfunction

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