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JCI Insight. 2018 Jul 12;3(13). pii: 99692. doi: 10.1172/jci.insight.99692. [Epub ahead of print]

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness.

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Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine.
NewYork-Presbyterian Hospital.
Division of General Internal Medicine, Joan and Sanford I. Weill Department of Medicine, and.
Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, New York, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School. Boston, Massachusetts, USA.
Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Division of Pulmonary, Allergy, and Critical Care Medicine, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.



Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness.


Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data.


In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure.


Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure.


Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.


Apoptosis survival pathways; Inflammation; Innate immunity

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