Prognostic value of admission H3.1 nucleosome levels in sepsis-associated acute kidney injury: a secondary analysis of the SISPCT randomised clinical trial

Background NETosis is a key innate immune defence mechanism where neutrophils release extracellular traps (NETs). However, excessive NET formation may damage organs during sepsis. We investigated the association between NETs and sepsis outcomes, including mortality and acute kidney injury (AKI). Methods We analysed levels of H3.1 nucleosomes in 971 patients with severe sepsis and septic shock from the SISPCT trial (Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock). We evaluated associations between H3.1 levels and mortality and the need for renal replacement therapy using multivariable Cox regression and receiver operating characteristic analyses. Results We analysed 971 critically ill patients with complete data including admission H3.1 levels. 443 patients (45.6%) presented with sepsis, 520 (53.6%) had septic shock, and eight patients had an unknown diagnosis as defined by Sepsis-3. Admission H3.1 levels were higher in patients with septic shock than with sepsis (median 921.84 vs 432.71 ng/mL; p<0.001). Admission H3.1 levels were higher in non-survivors, and in a univariate Cox analysis, each log-10 increase in H3.1 was associated with a hazard ratio of 1.86 (95% confidence interval 1.41–2.47, p<0.05). H3.1 was also higher in patients requiring renal replacement therapy with septic shock vs sepsis (1832 ng/mL vs 801.4 ng/mL, p=0.01) and demonstrated a dose-response relationship with the severity of AKI. Conclusion Elevated levels of H3.1 nucleosomes at admission are independently associated with mortality and severe kidney dysfunction requiring renal replacement therapy. Trial registration Clinicaltrials.gov Identifier, NCT00832039 .