(82) Elevated Renin Is Associated with AKI and Mortality in Pediatric Severe Malaria

Background: Renin has been identified as a biomarker of acute kidney injury (AKI) and mortality in critical illness. In the present study, we assessed plasma renin levels in Ugandan children hospitalized with severe malaria (SM) and community children (CC).

Objectives: The primary objective of this analysis is to establish whether elevated renin is associated with AKI and predicts mortality in hospitalized children with severe malaria.

Design/Methods: Plasma renin levels were assessed in 594 children with SM and 120 CC enrolled across two referral hospitals in Uganda. Children were eligible if they were between 6 months to 4 years of age and had evidence of malaria infection by rapid diagnostic test (RDT) or direct visualization by microscopy. Renin and host biomarker levels were assessed on plasma or serum samples using Luminex or ELISA. We established a population reference range where children with values greater than the 99th percentile from the CCs were defined as having elevated renin. AKI was defined and staged using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria based on a fold increase in creatinine over estimated baseline.

Results: The mean age of children was 2.1 years and 44.3% were female. Severe (stage 2 or 3) AKI was present in 117 children (19.7%). Children with SM had higher renin levels than community children and 26.9% of children with SM had elevated renin. Among children who died, 62.8% had elevated renin (p < 0.0001), corresponding to 3.53-fold increased odds (95% confidence interval, 2.8 to 10.4, p< 0.0001) of mortality compared to children without elevated renin. Among the 10.9% of children who had both elevated renin and severe AKI, there was a 10-fold increase in mortality (29.2%) compared to when neither condition was present (2.9%). Using multivariable logistic regression to identify clinical signs associated with elevated renin, severe AKI and acidosis were independently associated with elevated renin. We evaluated biomarkers associated with multiple pathways of host response to infection, and elevated renin was associated with markers of hemolysis, endothelial activation, nitric oxide bioavailability, and kidney injury.

Conclusions: Renin is elevated in children with SM and strongly associated with mortality, particularly when it occurs concurrently with AKI. Additional studies are needed to elucidate the role of renin in malaria pathogenesis to understand whether interventions targeting renin could be beneficial in severe malaria.