Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study

Abstract

BackgroundIntravascular 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.MethodsAs 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.ResultsAKI 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.ConclusionsCell-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-017-2373-1) contains supplementary material, which is available to authorized users.

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“…Systemic inflammation is the net result of an interplay between pro- and anti-inflammatory responses, and a shift towards a pro-inflammatory status can cause malfunctioning of the host's mitochondria in malaria, leading to organ damage [ 34 ]. The resulting oxidative stress as observed in uncomplicated malaria is known to play a role in pathogenesis [ 35 ]. For instance, lipid peroxidation and antioxidant enzyme activity associate with cholestatic jaundice in P. vivax patients [ 36 ], and oxidative stress causes hepatocyte apoptosis in murine malaria models [ 37 , 38 ].…”

Kinetic and Cross-Sectional Studies on the Genesis of Hypoargininemia in Severe Pediatric Plasmodium falciparum Malaria

“…Glutamine has a recognized role in maintaining the intestinal barrier function (21)(22)(23) and has a potential prognostic utility in critical illnesses (24,25). As the precursor to antioxidant cofactors, such as glutathione and NAD, low plasma glutamine levels might reduce the ability to resist the oxidative stress of malaria (26)(27)(28)(29) and other disease states. While one observational study found glutamine levels to be in the normal range among Gabonese children with severe malaria (30), low blood glutamine levels have been described in Ghanaian children with severe malaria (31) and Malawian children with cerebral malaria (32).…”

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