Chitinase-3-like 1 is a biomarker of acute kidney injury and mortality in paediatric severe malaria

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 2010Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2225-5) contains supplementary material, which is available to authorized users.

Chitinase-3 like-protein-1 function and its role in diseases

“…228 Especially, CHI3L1 is thought as a novel biomarker of malaria-associated AKI and an independent risk factor for mortality that is associated with wellestablished pathways of severe malaria pathogenesis including inflammation, endothelial activation, and hemolysis. 229 A singlecenter prospective cohort study indicates that serum CHI3L1 combined with urine CHI3L1 is a good predictor of AKI associated with elective cardiac surgery at stage ≥2 within 12 h after the time of post-operative ICU admission. 230 In chronic kidney disease, urinary CHI3L1 is associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin.…”

“…Renal disease Kidney injury CHI3L1↑in pediatric severe malaria, 229 ischemic injury, 17 cardiac surgery-associated, 230 adult critically ill, 228 Osteoarthritis CHI3L1↑ 47,[297][298][299][300] Rheumatoid arthritis CHI3L1↑, [241][242][243][244][245][246]301 autoantigen, [248][249][250] autoantibody, 252 targeted therapy 247,251,259,260 CHI3L1 IN CARDIOVASCULAR DISEASES Atherosclerosis, coronary artery disease, peripheral artery disease, and giant cell arteritis Plasma CHI3L1 levels correlate with the severity of coronary 189,190 and carotid 191 atherosclerosis. Moreover, atherosclerosis is exacerbated by CHI3L1 in amyloid precursor protein transgenic mice.…”

Novel kidney injury biomarkers in tropical infections: a review of the literature

“…Another study found increased KIM-1 and matrix metalloproteinase-3 (MMP-3) expression in tissues from autopsied patients with malaria-associated AKI 47 . Chitinase-3-like 1 (CHI3L1), a glycoprotein that has been recently proposed as a urinary biomarker for AKI, was also associated to AKI in children with severe malaria, and evidenced its association with mortality 48 . Approximately 31% of patients with malaria-associated AKI had normal levels of creatinine at presentation, illustrating the importance of new AKI biomarkers 39 .…”

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

“…Following up on these studies, Conroy et al [99] investigated in a clinical trial if inhaled NO was an effective adjunct therapy for severe malaria in children in Uganda and investigated changes in CH31L as a potential biomarker for kidney damage. The rationale and hypothesis that children with malaria might benefit from exposure to nitric oxide (NO) as an adjunct therapy was first proposed in 2011.…”