The role of hyperferritinaemia in pediatric severe malaria pathogenesis and kidney injury
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Ferritin, a highly conserved iron storage protein that sequesters iron from pathogens including Plasmodium falciparum, is part of the acute phase response in malaria pathogenesis. Ferritin levels are elevated in severe malaria, but the relationship between elevated ferritin and disease outcomes is not well understood. We hypothesize that hyperferritinaemia (HF) in severe malaria and subsequent kidney injury represents a response to free iron in the context of hemolysis rather than an acute inflammatory response. Plasma ferritin levels and other markers of interest were assessed using ELISA and Magpix Luminex assays in Ugandan children 6 months - 4 years of age. These children were previously enrolled in a prospective cohort study of severe malaria. The population included children with severe malaria (n=594) and community children without malaria (n=120) that were followed for one year. Children returned at one-month follow-up for an interim health assessment. Baseline prevalence of HF (ferritin ≥ 5000ng/ml) was 22.4% in children with severe malaria. Severe malaria with prostration, respiratory distress, severe anemia, jaundice, black water fever, and acute kidney injury (AKI) were the risk factors associated with HF. AKI was the strongest predictor of severe malaria [adjusted odd ratio (aOR) = 3.27; 95% confidence interval (CI): 1.95- 5.50, p<0.0001] consistent with its role as one of the primary organs for ferritin heavy chain production. Children with HF had higher AKI-mediated in- hospital mortality (11.3% vs. 6.1%) and higher AKI-independent post-discharge mortality [11.0% vs. 2.3%; p<0.001]. At one month follow up, ferritin levels were reduced relative to admission [baseline] levels but remained elevated compared to the community children. Consistent with our hypothesis, HF was strongly associated with markers of hemolysis and iron-mediated oxidative stress (LDH, hemin, cell free hemoglobin, heme oxygenase-1), depleted heme-hemoglobin scavengers (haptoglobin, hemopexin) and some cytokines [IL-10 and TNFα] but not with markers of the acute phase response [C-reactive protein (CRP) and a few cytokines [ IL-6, IL-1β]. HF appears to be an acute protective response to increases in free iron related to hemolysis and depleted heme-hemoglobin scavengers. Thus, plasma ferritin in severe malaria may represent a biomarker of hemolysis that can identify children at risk of AKI and repeated hemolytic episodes leading to increased post-discharge mortality. Interventions that can improve iron sequestration/chelation during acute hemolytic events or therapeutics targeting oxidative-stress mediated AKI may be effective to reduce severe malaria morbidity and mortality.