The online version of this article (doi:10.1186/s12879-017-2373-1) contains supplementary material, which is available to authorized users.
Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown.
As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined.
AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 μM; 95% CI, 6.2–12.3 μM), F2-isoprostane (56.7 pg/ml; 95% CI, 45.3–71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1–140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 μM; 95% CI, 4.0–6.6 μM; P = 0.018; F2-IsoPs: 27.8 pg/ml; 95% CI, 23.7–32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2–57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2-IsoPs. Plasma F2-IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2-IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2-IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2-IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis.
Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.
Additional file 1: Figure S1. Supplement to Plewes K, Kingston HWF, Ghose A, et al. Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study. Cell-free hemoglobin, and oxidative stress measures at enrolment stratified by malaria severity. Plasma cell-free hemoglobin (n = 185), F2-isoprostanes (n = 82) and isofurans (n = 82) were significantly more elevated on enrolment in those with severe malaria compared to uncomplicated malaria. Geometric mean and 95% CIs shown. Abbreviations : AKI, acute kidney injury; CFH, cell-free hemoglobin; pF2-IsoP, plasma F2-isoprostanes; pIsoF, plasma isofurans. (DOCX 1707 kb)12879_2017_2373_MOESM1_ESM.docx
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- Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study
Hugh W.F. Kingston
Richard J. Maude
M. Trent Herdman
Stije J. Leopold
Md. Mahtab Uddin Hasan
Md. Shafiul Haider
Kim A. Piera
Tsin W. Yeo
Md. Abul Faiz
Sue J Lee
Gareth D.H. Turner
Nicholas M. Anstey
L. Jackson Roberts II
Nicholas J. White
Nicholas P.J. Day
Md. Amir Hossain
Arjen M. Dondorp
- BioMed Central
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