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Circulating RIPK3 levels are associated with mortality and organ failure during critical illness
Kevin C Ma1,2, Edward J Schenck1,2, Ilias I Siempos1
1Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine.
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.
Insights
Elevated plasma levels of receptor-interacting protein kinase 3 (RIPK3) indicate a higher risk of in-hospital mortality and organ failure in critically ill patients. This finding highlights RIPK3 as a potential biomarker for severe illness outcomes.
Area of Science:
- Biochemistry
- Cell Biology
- Critical Care Medicine
Background:
- Necroptosis, a programmed cell death pathway, is increasingly recognized for its role in various diseases.
- Receptor-interacting protein kinase 3 (RIPK3) is crucial for necroptosis and implicated in critical illness models.
- Clinical evidence on extracellular RIPK3 in human critical illness remains limited.
Purpose of the Study:
- To investigate the clinical significance of extracellular RIPK3 levels in critically ill patients.
- To determine the association between plasma RIPK3 concentrations and patient outcomes, including mortality and organ failure.
Main Methods:
- Plasma RIPK3 levels were measured in 953 patients across 5 intensive care unit (ICU) cohorts in the USA and Korea.
- Patient data included phenotypic information and outcomes, prospectively collected.
- RIPK3 concentrations were analyzed in relation to survival and organ failure severity.
Main Results:
- Higher plasma RIPK3 levels were observed in non-survivors compared to survivors across all cohorts.
- Elevated RIPK3 levels were significantly associated with increased odds of in-hospital mortality, even after adjusting for illness severity.
- Increased RIPK3 concentrations correlated with more severe organ failure.
Conclusions:
- Elevated plasma RIPK3 levels in ICU patients are linked to in-hospital mortality.
- Higher RIPK3 concentrations are also associated with the development of organ failure.
- Extracellular RIPK3 may serve as a valuable prognostic biomarker in critical illness.
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