Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response

Abstract

Acute kidney injury (AKI) frequently afflicts patients undergoing cardiopulmonary bypass and independently predicts death. Both hemoglobinemia and myoglobinemia are independent predictors of postoperative AKI. Release of free hemeproteins into the circulation is known to cause oxidative injury to the kidneys. This study tested the hypothesis that postoperative AKI is associated with both enhanced intraoperative hemeprotein release and increased lipid peroxidation assessed by measuring F₂-isoprostanes and isofurans. In a case-control study nested within an ongoing randomized trial of perioperative statin treatment and AKI, we compared levels of F₂-isoprostanes and isofurans with plasma levels of free hemoglobin and myoglobin in 10 cardiac surgery AKI patients to those of 10 risk-matched controls. Peak plasma free hemoglobin concentrations were significantly higher in AKI subjects (289.0 ± 37.8 versus 104.4 ± 36.5mg/dl, P = 0.01), whereas plasma myoglobin concentrations were similar between groups. The change in plasma F₂-isoprostane and isofuran levels (repeated-measures ANOVA, P = 0.02 and P = 0.001, respectively) as well as the change in urine isofuran levels (P = 0.04) was significantly greater in AKI subjects. In addition, change in peak plasma isofuran levels correlated not only with peak free plasma hemoglobin concentrations (r² = 0.39, P = 0.001) but also with peak change in serum creatinine (r² = 0.20, P = 0.01). Postoperative AKI is associated with both enhanced intraoperative hemeprotein release and enhanced lipid peroxidation. The correlations among hemoglobinemia, lipid peroxidation, and AKI indicate a potential role for hemeprotein-induced oxidative damage in the pathogenesis of postoperative AKI.

Trial registration: ClinicalTrials.gov NCT00791648.

Figure 1

Case and Control Subject Selection

Figure 2

Oxidative stress response in A) all subjects as measured by plasma F₂-isoprostane (F2-isoP) and isofuran (IsoF) concentrations and B) as a percentage change from baseline. Base, baseline; 30min, 30min of cardiopulmonary bypass (CPB); post, post CPB; ICU, intensive care unit; 6hrs, 6 hours after arrival in ICU; POD, postoperative day. Plasma concentrations of both F₂-isoprostanes and isofurans increased significantly during surgery (ANOVA P=0.01 isoprostanes; P=0.003 isofurans). The percentage change from baseline was significantly greater for isofurans compared to F₂-isoprostanes (ANOVA P=0.02 for effect of biomarker). *P<0.05, †P<0.01 versus baseline. §P<0.01 versus F₂-isoprostanes.

Figure 3

Oxidative stress response in A) all subjects as measured by urine F₂-isoprostane (F2-isoP) and isofuran (IsoF) concentrations and B) as a percentage change from baseline. Base, baseline; 30min, 30min of cardiopulmonary bypass (CPB); post, post CPB; ICU, intensive care unit; 6hrs, 6 hours after arrival in ICU; POD, postoperative day. Urine concentrations of both F₂-isoprostanes and isofurans increased significantly after surgery (ANOVA P=0.001 isoprostanes; P=0.008 isofurans). The percentage change from baseline was significantly greater for isofurans compared to F₂-isoprostanes (ANOVA P=0.01 for effect of biomarker). *P<0.05, †P<0.01 versus baseline. ‡P<0.05 versus isofurans, §P<0.01 versus F₂-isoprostanes.

Figure 4

Plasma oxidative stress response as measured by percentage change from baseline for A) plasma F₂-isoprostanes (F2isoP) and B) plasma isofurans (isoF) in subjects who developed postoperative acute kidney injury (AKI) compared to controls. Base, baseline; 30min, 30min of cardiopulmonary bypass (CPB); post, post CPB; ICU, intensive care unit; 6hrs, 6 hours after arrival in ICU; POD, postoperative day. Plasma F₂-isoprostane and isofuran concentrations increased significantly more during and following surgery in subjects who developed AKI (ANOVA P=0.02 and P=0.001, respectively). *P<0.05 versus controls.

Figure 5

Urine oxidative stress response as measured by percentage change from baseline for A) urine F₂-isoprostanes (F2isoP) and B) urine isofurans (isoF) in subjects who developed postoperative acute kidney injury (AKI) compared to controls. Base, baseline; 30min, 30min of cardiopulmonary bypass (CPB); post, post CPB; ICU, intensive care unit; 6hrs, 6 hours after arrival in ICU; POD, postoperative day. Urine isofuran concentrations continued to rise and remain elevated in AKI subjects as compared to non-AKI control subjects (ANOVA P=0.04). *P<0.05 versus controls.

Figure 6

Correlations between A) percentage change from baseline in peak plasma isofurans vs. peak plasma free hemoglobin and B) percentage change from baseline in peak plasma isofurans vs. percentage change from baseline in peak creatinine. ● acute kidney injury (AKI), ○ control.