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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 Plewes, Katherine; Kingston, Hugh W; Ghose, Aniruddha; Maude, Richard J; Herdman, M. T; Leopold, Stije J; Ishioka, Haruhiko; Hasan, Md. M U; Haider, Md. S; Alam, Shamsul; Piera, Kim A; Charunwatthana, Prakaykaew; Silamut, Kamolrat; Yeo, Tsin W; Faiz, Md. A; Lee, Sue J; Mukaka, Mavuto; Turner, Gareth D; Anstey, Nicholas M; Jackson Roberts, L.; White, Nicholas J; Day, Nicholas P; Hossain, Md. A; Dondorp, Arjen M
Abstract
Background 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. Methods 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. Results 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. Conclusions 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.
Item Metadata
Title |
Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study
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Creator |
Plewes, Katherine; Kingston, Hugh W; Ghose, Aniruddha; Maude, Richard J; Herdman, M. T; Leopold, Stije J; Ishioka, Haruhiko; Hasan, Md. M U; Haider, Md. S; Alam, Shamsul; Piera, Kim A; Charunwatthana, Prakaykaew; Silamut, Kamolrat; Yeo, Tsin W; Faiz, Md. A; Lee, Sue J; Mukaka, Mavuto; Turner, Gareth D; Anstey, Nicholas M; Jackson Roberts, L.; White, Nicholas J; Day, Nicholas P; Hossain, Md. A; Dondorp, Arjen M
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Contributor | |
Publisher |
BioMed Central
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Date Issued |
2017-04-27
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Description |
Background
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.
Methods
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.
Results
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.
Conclusions
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.
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Subject | |
Genre | |
Type | |
Language |
eng
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Date Available |
2018-05-16
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution 4.0 International (CC BY 4.0)
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DOI |
10.14288/1.0366869
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URI | |
Affiliation | |
Citation |
BMC Infectious Diseases. 2017 Apr 27;17(1):313
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Publisher DOI |
10.1186/s12879-017-2373-1
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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Copyright Holder |
The Author(s).
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution 4.0 International (CC BY 4.0)