H3.1 Nucleosomes to Predict Renal Replacement Therapy and Mortality in Sepsis—A Secondary Analysis of the SISPCT Randomized Control Trial

OBJECTIVES: The release of neutrophil extracellular traps is a key immune host defense mechanism that can contribute to organ damage during sepsis if excessive. We evaluated presentation H3.1 nucleosome levels in patients with sepsis, septic shock, and sepsis-associated acute kidney injury (AKI). We sought to determine if plasma H3.1 nucleosome levels could serve as predictive biomarkers for both renal replacement therapy (RRT) requirements and 28-day mortality. DESIGN: A secondary analysis of prospectively collected samples from the large multicenter Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients with Severe Sepsis or Septic Shock (SISPCT) trial. SETTING: Patients from 33 ICUs in Germany recruited between November 6, 2009, and June 6, 2013, including a 90-day follow-up period. PATIENTS: A total of 971 patients with complete data on plasma H3.1 admission levels with sepsis and septic shock, and 927 patients with complete data on RRT requirements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated associations between H3.1 levels and mortality and the time to commencement of RRT using multivariable Cox regression. A total of 443 patients (45.6%) presented with sepsis, and 520 patients (53.6%) had septic shock. Admission H3.1 levels were higher in patients with septic shock than sepsis (median, 921.84 vs. 432.71 ng/mL; p < 0.001). In a multivariable analysis for 28-day mortality, a one unit increase in log10 H3.1 levels was associated with a 48% increase in 28-day mortality (adjusted hazard ratio [HR], 1.48, 95% CI, 1.07-2.04; p = 0.02). Plasma H3.1 was also higher in patients with stage 3 AKI requiring RRT with septic shock vs. sepsis (1832 vs. 801.4 ng/mL; p = 0.01). In a multivariable Cox regression controlling for maximum lactate, procalcitonin, and C-reactive protein levels, plasma H3.1 levels were significantly higher in patients who developed AKI requiring RRT when compared with patients who did not develop AKI, with one log10 increase of H3.1 increasing the risk of 28-day RRT by 80% (adjusted HR, 1.8; 95% CI, 1.34-2.40; p < 0.001). CONCLUSIONS: Elevated levels of H3.1 nucleosomes at admission are associated with mortality and AKI requiring RRT. TRIAL REGISTRATION: The trial was registered in clinicaltrials.gov, identifier: NCT00832039.