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- Title
Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study.
- Authors
Plewes, Katherine; Kingston, Hugh W. F.; Ghose, Aniruddha; Maude, Richard J.; Trent Herdman, M.; Leopold, Stije J.; Ishioka, Haruhiko; Uddin Hasan, Md. Mahtab; Shafiul Haider, Md.; Alam, Shamsul; Piera, Kim A.; Charunwatthana, Prakaykaew; Silamut, Kamolrat; Yeo, Tsin W.; Abul Faiz, Md.; Lee, Sue J.; Mukaka, Mavuto; Turne, Gareth D. H.; Anstey, Nicholas M.; Jackson Roberts II, L.
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
HEMOPROTEINS; HEMOGLOBIN polymorphisms; MALARIA; HABER-Weiss reaction; OXIDATION-reduction reaction; TREATMENT of acute kidney failure; ERYTHROCYTES; ACUTE kidney failure; ANTIGENS; ARACHIDONIC acid; CREATININE; HEMODIALYSIS; HEMOGLOBINS; LONGITUDINAL method; LIPID peroxidation (Biology); PROTEINS; RESEARCH funding; SEPSIS; OXIDATIVE stress; DISEASE complications
- Publication
BMC Infectious Diseases, 2017, Vol 17, p1
- ISSN
1471-2334
- Publication type
journal article
- DOI
10.1186/s12879-017-2373-1