Urine Complement Factor Ba Is Associated with AKI in Critically Ill Children

KEY POINTS: Complement activation, specifically factor B, is implicated in AKI pathogenesis in animal models. Urine Ba (an activation fragment of factor B) was significantly higher in critically ill children with stage 3 AKI and sepsis-AKI. If larger studies show similar association between urine Ba and AKI severity, clinical trials of factor B inhibition are warranted. BACKGROUND: Critically ill children with AKI have high morbidity and mortality rates and lack treatment options. Complement activation is implicated in AKI pathogenesis, which could be treated with complement-targeted therapeutics. We assessed for an association between urine Ba, an activation fragment of the alternative complement pathway, and AKI in a large cohort of critically ill children. METHODS: A biorepository of children requiring mechanical ventilation was leveraged. AKI was based on pediatric version of the RIFLE criteria—stage 1: 25% decreased eGFR or urine output (UOP) <0.5ml/kg per hour for 8 hours; stage 2: 50% decreased eGFR or UOP <0.5 ml/kg per hour for 16 hours; stage 3: 75% decreased eGFR or UOP <0.3ml/kg per hour for 24 hours or anuric for 12 hours. ELISAs were performed to quantitate urine Ba values. Log Ba was used in ANOVA with pairwise comparison by the Tukey method. Logistic regression was performed to test the association between urine Ba and AKI diagnosis. RESULTS: Seventy-three patients were included, of which 56 had AKI: 26 (46%) stage 1, 16 (29%) stage 2, and 14 (25%) stage 3. Ba was significantly higher in patients with stage 3 AKI compared with all other stages. Ba was higher in sepsis-associated AKI compared with non–sepsis-associated AKI. Multivariate analysis included urine Ba, urine IL-18, urine NGAL, sepsis, and Pediatric Risk of Mortality Scores-II (an estimate of illness severity) and showed a significant association between urine Ba and AKI (odds ratio 1.57, 95% confidence interval, 1.13 to 2.20; P 0.007). CONCLUSION: Urine Ba is significantly increased in patients with AKI compared with patients without AKI. In patients with similar illness severity, a doubling of urine Ba level was associated with a 57% increase in AKI diagnosis of any stage. Further studies are needed to study complement inhibition in treatment or prevention of AKI in critically ill children.