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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.

Background: Acute respiratory distress syndrome (ARDS) is potentially underrecognized by clinicians. Early recognition and subsequent optimal treatment of patients with ARDS may be facilitated by usage of biomarkers. Surfactant protein D (SP-D), a marker of alveolar epithelial injury, has been proposed as a potentially useful biomarker for diagnosis of ARDS in a few studies. We tried to validate the performance of plasma SP-D levels for diagnosis of ARDS., Methods: We conducted a retrospective analysis using data from three (two in USA and one in Korea) prospective biobank cohorts involving 407 critically ill patients admitted to medical intensive care unit (ICU). A propensity score matched analysis (patients with versus without ARDS, matched 1:1) was carried out using significant variables from multiple logistic regression. The diagnostic accuracy of plasma SP-D as a diagnostic marker of ARDS was assessed by receiver operating characteristic curve analysis., Results: Out of the 407 subjects included in this study, 39 (10%) patients fulfilled ARDS criteria. Patients with ARDS had higher SP-D levels in plasma (p < 0.01) and higher hospital-mortality (p < 0.001) than those without ARDS. Thirty eight subjects with ARDS (cases) were successfully matched for propensity for ARDS with 38 subjects without ARDS (controls). Plasma levels of SP-D were higher in cases with ARDS compared to their matched controls without ARDS [median 20.8 ng/mL (interquartile range, 12.7-38.4) versus 7.9 (4.1-17.0); p = 0.001]. The area under the receiver operating characteristic curve for SP-D for the diagnosis of ARDS was 0.71 (95% confidence intervals, 0.60-0.83). A cut-off point of 12.7 ng/mL for SP-D yielded sensitivity of 74% and specificity of 63%., Conclusions: High levels of SP-D within 48 h after ICU admission might serve as a diagnostic marker for ARDS in patients hospitalized in medical ICU. Further prospective trials are required to validate the diagnostic role of SP-D in ARDS, and if its usefulness is greater in direct than in indirect ARDS, as well as across different strata of severity of ARDS.