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

Kevin C. Ma, Edward J. Schenck, Ilias I. Siempos, Suzanne M. Cloonan, Eli J. Finkelzstein, Maria A. Pabon, Clara Oromendia, Karla V. Ballman, Rebecca M. Baron, Laura E. Fredenburgh, Angelica Higuera, Jin Young Lee, Chi Ryang Chung, Kyeongman Jeon, Jeong Hoon Yang, Judie Ann Howrylak, Jin Won Huh, Gee Young Suh, Augustine Mk Choi

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4 Citations (Scopus)

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FUNDING: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number13
DOIs
StatePublished - Jul 12 2018

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Receptor-Interacting Protein Serine-Threonine Kinases
Critical Illness
Protein Kinases
Mortality
Hospital Mortality
Organized Financing
Odds Ratio
Intensive Care Units
Korea
Blood Proteins
Cell Death
Theoretical Models

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Ma, K. C., Schenck, E. J., Siempos, I. I., Cloonan, S. M., Finkelzstein, E. J., Pabon, M. A., ... Choi, A. M. (2018). Circulating RIPK3 levels are associated with mortality and organ failure during critical illness. JCI insight, 3(13). https://doi.org/10.1172/jci.insight.99692
Ma, Kevin C. ; Schenck, Edward J. ; Siempos, Ilias I. ; Cloonan, Suzanne M. ; Finkelzstein, Eli J. ; Pabon, Maria A. ; Oromendia, Clara ; Ballman, Karla V. ; Baron, Rebecca M. ; Fredenburgh, Laura E. ; Higuera, Angelica ; Lee, Jin Young ; Chung, Chi Ryang ; Jeon, Kyeongman ; Yang, Jeong Hoon ; Howrylak, Judie Ann ; Huh, Jin Won ; Suh, Gee Young ; Choi, Augustine Mk. / Circulating RIPK3 levels are associated with mortality and organ failure during critical illness. In: JCI insight. 2018 ; Vol. 3, No. 13.
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abstract = "BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FUNDING: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.",
author = "Ma, {Kevin C.} and Schenck, {Edward J.} and Siempos, {Ilias I.} and Cloonan, {Suzanne M.} and Finkelzstein, {Eli J.} and Pabon, {Maria A.} and Clara Oromendia and Ballman, {Karla V.} and Baron, {Rebecca M.} and Fredenburgh, {Laura E.} and Angelica Higuera and Lee, {Jin Young} and Chung, {Chi Ryang} and Kyeongman Jeon and Yang, {Jeong Hoon} and Howrylak, {Judie Ann} and Huh, {Jin Won} and Suh, {Gee Young} and Choi, {Augustine Mk}",
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Ma, KC, Schenck, EJ, Siempos, II, Cloonan, SM, Finkelzstein, EJ, Pabon, MA, Oromendia, C, Ballman, KV, Baron, RM, Fredenburgh, LE, Higuera, A, Lee, JY, Chung, CR, Jeon, K, Yang, JH, Howrylak, JA, Huh, JW, Suh, GY & Choi, AM 2018, 'Circulating RIPK3 levels are associated with mortality and organ failure during critical illness', JCI insight, vol. 3, no. 13. https://doi.org/10.1172/jci.insight.99692

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness. / Ma, Kevin C.; Schenck, Edward J.; Siempos, Ilias I.; Cloonan, Suzanne M.; Finkelzstein, Eli J.; Pabon, Maria A.; Oromendia, Clara; Ballman, Karla V.; Baron, Rebecca M.; Fredenburgh, Laura E.; Higuera, Angelica; Lee, Jin Young; Chung, Chi Ryang; Jeon, Kyeongman; Yang, Jeong Hoon; Howrylak, Judie Ann; Huh, Jin Won; Suh, Gee Young; Choi, Augustine Mk.

In: JCI insight, Vol. 3, No. 13, 12.07.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Circulating RIPK3 levels are associated with mortality and organ failure during critical illness

AU - Ma, Kevin C.

AU - Schenck, Edward J.

AU - Siempos, Ilias I.

AU - Cloonan, Suzanne M.

AU - Finkelzstein, Eli J.

AU - Pabon, Maria A.

AU - Oromendia, Clara

AU - Ballman, Karla V.

AU - Baron, Rebecca M.

AU - Fredenburgh, Laura E.

AU - Higuera, Angelica

AU - Lee, Jin Young

AU - Chung, Chi Ryang

AU - Jeon, Kyeongman

AU - Yang, Jeong Hoon

AU - Howrylak, Judie Ann

AU - Huh, Jin Won

AU - Suh, Gee Young

AU - Choi, Augustine Mk

PY - 2018/7/12

Y1 - 2018/7/12

N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FUNDING: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FUNDING: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

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U2 - 10.1172/jci.insight.99692

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Ma KC, Schenck EJ, Siempos II, Cloonan SM, Finkelzstein EJ, Pabon MA et al. Circulating RIPK3 levels are associated with mortality and organ failure during critical illness. JCI insight. 2018 Jul 12;3(13). https://doi.org/10.1172/jci.insight.99692