Abstract
BackgroundChitinase-3-like 1 (CHI3L1) is a glycoprotein elevated in paediatric severe malaria, and an emerging urinary biomarker of acute kidney injury (AKI). Based on the hypothesis that elevated CHI3L1 levels in malaria are associated with disease severity, the relationship between plasma CHI3L1 levels, AKI and mortality was investigated in Ugandan children enrolled in a clinical trial evaluating inhaled nitric oxide (iNO) as an adjunctive therapy for severe malaria.MethodsPlasma CHI3L1 levels were measured daily for 4 days in children admitted to hospital with severe malaria and at day 14 follow up. AKI was defined using the Kidney Disease: Improving Global Outcomes consensus criteria. This is a secondary analysis of a randomized double-blind placebo-controlled trial of iNO versus placebo as an adjunctive therapy for severe malaria. Inclusion criteria were: age 1–10 years, and selected criteria for severe malaria. Exclusion criteria included suspected bacterial meningitis, known chronic illness including renal disease, haemoglobinopathy, or severe malnutrition. iNO was administered by non-rebreather mask for up to 72 h at 80 ppm.ResultsCHI3L1 was elevated in patients with AKI and remained higher over hospitalization (p < 0.0001). Admission CHI3L1 levels were elevated in children who died. By multivariable analysis logCHI3L1 levels were associated with increased risk of in-hospital death (relative risk, 95% CI 4.10, 1.32–12.75, p = 0.015) and all-cause 6 month mortality (3.21, 1.47–6.98, p = 0.003) following correction for iNO and AKI. Treatment with iNO was associated with delayed CHI3L1 recovery with a daily decline of 34% in the placebo group versus 29% in the iNO group (p = 0.012). CHI3L1 levels correlated with markers of inflammation (CRP, sTREM-1, CXCL10), endothelial activation (Ang-2, sICAM-1) and intravascular haemolysis (LDH, haem, haemopexin).ConclusionsCHI3L1 is a novel biomarker of malaria-associated AKI and an independent risk factor for mortality that is associated with well-established pathways of severe malaria pathogenesis including inflammation, endothelial activation, and haemolysis.Trial registration Clinicaltrials.gov, NCT01255215. Registered December 7th 2010
Highlights
Chitinase-3-like 1 (CHI3L1) is a glycoprotein elevated in paediatric severe malaria, and an emerging urinary biomarker of acute kidney injury (AKI)
CHI3L1 levels at presentation are associated with disease severity and AKI Levels of CHI3L1 were available for 159 children at admission (Fig. 1)
Children with CHI3L1 levels in the highest quartile were more likely to have AKI (p = 0.034), and there was a strong relationship between CHI3L1 and severity of AKI with 5.9% of children with CHI3L1 levels in the lowest three quartiles having stage 3 AKI compared to 28.2% of children with CHI3L1 levels in the highest quartile having stage 3 AKI (p < 0.0001)
Summary
Chitinase-3-like 1 (CHI3L1) is a glycoprotein elevated in paediatric severe malaria, and an emerging urinary biomarker of acute kidney injury (AKI). Despite early reports that inhaled NO (iNO) was associated with increased splanchnic and renal blood flow [16], a meta-analysis of adults with acute respiratory distress syndrome found that iNO treatment was associated with a 50% increased risk of developing AKI (relative risk, 95% CI 1.50, 1.11–2.02) [17]. This has been confirmed in another meta-analysis including non-ARDS patients [18], but the effect was strongest in patients with ARDS with prolonged exposure and a high cumulative dose. There was no association between iNO and AKI when restricting the analysis to children who developed AKI after treatment was initiated
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