Complement activation fragments are increased in critically ill pediatric patients with severe acute kidney injury

Background:Critically ill children with acute kidney injury (AKI) suffer from high morbidity and mortality rates, and lack treatment options. Emerging evidence implicates the role of complement activation in AKI pathogenesis, which could potentially be treated with complement inhibitors. The purpose of this study is to evaluate the association between complement activation fragments and severity of AKI in critically ill children. Methods:A biorepository of critically ill children from a prior multi-site study was leveraged to identify children with stage 3 AKI and matched to patients without AKI based on PELOD-2 (illness severity) scores. Specimens were analyzed for plasma and urine complement activation fragments of factor B, C3a, C4a, and sC5b-9. The primary outcomes were MAKE30 and severe AKI rates. Results:14 patients with stage 3 AKI (5 requiring renal replacement therapy [RRT]) were matched to 14 patients without AKI. Urine factor Ba and plasma C4a levels increased stepwise as severity of AKI increased, from no AKI to stage 3 AKI, to stage 3 AKI with RRT need. Plasma C4a levels were independently associated with increased risk of MAKE30 outcomes (OR 3.2; IQR 1.1-8.9), and urine Ba and plasma Bb, C4a, and C3a were independently associated with risk of severe stage 2-3 AKI on day 3 of admission. Conclusions:Multiple complement fragments increase as magnitude of AKI severity increases. Very high levels of urine Ba or plasma C4a may identify patients at risk for severe AKI, hemodialysis, and MAKE30 outcomes. The fragments may be useful as a functional biomarker of complement activation and may identify those patients to study complement inhibition to treat or prevent AKI in critically ill children. These findings suggest the need for further specific investigations of the role of complement activation in critically ill children at risk of AKI.