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

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.

Keywords: Apoptosis survival pathways; Inflammation; Innate immunity.

Figure 1. Number of recruited subjects and date ranges among individual cohorts and overall.

WCM, Weill Cornell Medicine; BWH, Brigham and Women’s Hospital; SMC, Samsung Medical Center; ASAN, Asan Medical Center; PSHMC, Penn State Hershey Medical Center.

Figure 2. Distribution of SOFA score among individual cohorts and overall.

SOFA, sequential organ failure assessment; WCM, Weill Cornell Medicine; BWH, Brigham and Women’s Hospital; SMC, Samsung Medical Center; ASAN, Asan Medical Center; PSHMC, Penn State Hershey Medical Center.

Figure 3. Association between RIPK3 level and in-hospital mortality.

Odds ratios and 95% confidence intervals represent increase in risk of in-hospital mortality associated with a 10-fold rise in RIPK3 level. RIPK3 level is presented as median value (black line), interquartile range (box), and maximum and minimum values (whiskers) overall and among individual cohorts. WCM, Weill Cornell Medicine; BWH, Brigham and Women’s Hospital; SMC, Samsung Medical Center; ASAN, Asan Medical Center; PSHMC, Penn State Hershey Medical Center.

Figure 4. Association between RIPK3 level and organ failure measured by SOFA score.

Regression curve for quadratic modeling of RIPK3 association with SOFA score shown in black line, with shaded area representing 95% point-wise confidence interval.

Figure 5. Association between RIPK3 level and individual SOFA components.

The components evaluated were (A) respiratory, (B) cardiovascular, (C) neurologic, (D) hematologic, (E) renal, and (F) hepatic organ systems. Regression curve for quadratic modeling of RIPK3 association with each SOFA component is shown by the black line, with shaded area representing 95% point-wise confidence interval.

Figure 6. RIPK3 levels of patients with organ failure and shock compared to those with organ failure but without shock or those without organ failure.

RIPK3 level is presented as median value (black line), interquartile range (box), and maximum and minimum values (whiskers). P values are Kruskal-Wallis nonparametric comparisons with Bonferroni’s adjustment for multiple comparisons.