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Complement Activation Fragments Are Increased in Critically Ill Pediatric Patients with Severe AKI
Erin K Stenson1,2, Zhiying You3, Ron Reeder4
1Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
Insights
Complement activation fragments are linked to acute kidney injury (AKI) severity in critically ill children. Elevated levels may predict severe AKI and adverse outcomes, suggesting potential therapeutic targets.
Area of Science:
- Pediatric Nephrology
- Critical Care Medicine
- Immunology
Background:
- Critically ill children with acute kidney injury (AKI) face high mortality and limited treatments.
- Emerging evidence suggests complement activation contributes to AKI pathogenesis.
- Complement inhibitors are potential therapeutic agents for AKI.
Purpose of the Study:
- To investigate the association between complement activation fragments and AKI severity in critically ill children.
- To identify potential biomarkers for AKI progression and outcomes.
Main Methods:
- Utilized samples from critically ill children with stage 3 AKI and matched controls without AKI.
- Analyzed plasma and urine for complement activation fragments: factor B, C3a, C4a, and sC5b-9.
- Assessed outcomes including Major Adverse Kidney Events by 30 days (MAKE30) and severe AKI rates.
Main Results:
- Urine factor Ba and plasma C4a levels increased with AKI severity.
- Plasma C4a was independently associated with increased risk of MAKE30 outcomes.
- Several complement fragments (urine Ba, plasma Bb, C4a, C3a) were linked to severe AKI risk.
Conclusions:
- Complement fragment levels correlate with AKI severity in critically ill children.
- Elevated urine Ba or plasma C4a may identify patients at high risk for severe AKI and adverse outcomes.
- These fragments could serve as biomarkers for complement activation and inform targeted complement inhibition therapies.
Background:
Children who are critically ill with 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 children who are critically ill.
Methods:
A biorepository of samples from children who are critically ill from a prior multisite study was leveraged to identify children with stage 3 AKI and matched to patients without AKI on the basis of 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:
In total, 14 patients with stage 3 AKI (five requiring 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 (OR, 1.9; IQR, 1.1-3.1), plasma Bb (OR, 2.7; IQR, 1.1-6.8), C4a (OR, 13.0; IQR, 1.6-106.6), and C3a (OR, 3.3; IQR, 1.3-8.4) 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 children who are critically ill. These findings suggest the need for further specific investigations of the role of complement activation in children who are critically ill and at risk of AKI.
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