title: Alterations in Systemic Extracellular Heme and Hemopexin Are Associated With Adverse Clinical Outcomes in Ugandan Children With Severe Malaria.
abstract: Malaria remains a major cause of global mortality. Extracellular heme, released during malaria-induced hemolysis, mediates a number of pathogenic processes associated with vascular and organ injury. Hemopexin (hpx) facilitates the degradation of extracellular heme. In this study, we explore the hypothesis that dysregulation of the heme-hpx axis is associated with disease severity, acute kidney injury (AKI), and outcome.
  
  
  
  Plasma levels of hemin and hpx (at admission, day 3, and day 14) were assessed in children with severe malaria in Jinja, Uganda.
  
  
  
  The ratio of heme to hpx was higher at admission and decreased with recovery (median, 0.043 [interquartile range {IQR}, 0.007-0.239] on day 1, 0.024 [IQR, 0.005-0.126] on day 3, and 0.008 [IQR, 0.002-0.022] on day 14; P < .001). Ratios of heme to hpx at admission were higher in children with as compared to those without severe anemia (median, 0.124 [IQR, 0.024-0.431] vs 0.016 [IQR, 0.003-0.073]; P < .0001), children with as compared to those without respiratory distress (median, 0.063 [IQR, 0.017-0.413] vs 0.020 [IQR, 0.004-0.124]; P < .01), and children with as opposed to those without stage 3 AKI (median, 0.354 [IQR, 0.123-2.481] vs 0.037 [IQR, 0.005-0.172], P < .01). The heme to hpx ratio at admission was associated with 6-month mortality (median, 0.148 [IQR, 0.042-0.500] vs 0.039 [IQR, 0.007-0.172]; P = .012).
  
  
  
  The ratio of heme to hpx is associated with disease severity and adverse clinical outcomes in Ugandan children, and dysregulation of the heme axis may contribute to malaria pathogenesis.
authors: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Department of Laboratory Medicine and Pathobiology.
authors: Robyn E
authors: RE
authors: Elphinstone
authors: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Department of Pediatrics, Indiana University, Indianapolis.
authors: Andrea L
authors: AL
authors: Conroy
authors: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada.
authors: Michael
authors: M
authors: Hawkes
authors: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital.
authors: Laura
authors: L
authors: Hermann
authors: Department of Pediatrics, Jinja Regional Referral Hospital, Uganda.
authors: Sophie
authors: S
authors: Namasopo
authors: Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston.
authors: H Shaw
authors: HS
authors: Warren
authors: Department of Pediatrics, Indiana University, Indianapolis.
authors: Chandy C
authors: CC
authors: John
authors: Department of Medicine, University of Washington, Seattle.
authors: W Conrad
authors: WC
authors: Liles
authors: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Department of Laboratory Medicine and Pathobiology Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto.
authors: Kevin C
authors: KC
authors: Kain
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D006418:Heme / Q000378:metabolism*; D006466:Hemopexin / Q000378:metabolism*; D006801:Humans; D008288:Malaria / Q000097:blood* / Q000378:metabolism*; D008297:Male; D010949:Plasma / Q000378:metabolism*; D012720:Severity of Illness Index; D014454:Uganda
chemical_list: D006418:Heme; D006466:Hemopexin
keywords: acute kidney injury; anemia; heme; hemopexin; metabolic acidosis; pediatric; respiratory distress; severe malaria