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 (CPB) 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 F 2 -isoprostanes and isofurans. In a case-control study, nested within an ongoing randomized trial of perioperative statin treatment and AKI, we compared levels of F 2 -isoprostanes and isofurans with plasma levels of free hemoglobin and myoglobin in 10 cardiac surgery AKI patients to 10 risk-matched controls. Peak plasma free hemoglobin concentrations were significantly higher in AKI subjects (289.0±37.8 versus 104.4±36.5 mg/dl, P=0.01), whereas plasma myoglobin concentrations were similar between groups. The change in plasma F 2 -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 isofurans levels correlated not only with peak free plasma hemoglobin concentrations (r 2 =0.39, P=0.001) but also with peak change in serum creatinine (r 2 =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 of hemeprotein-induced oxidative damage in the pathogenesis of postoperative AKI. KeywordsAcute kidney injury; oxidative stress; isoprostanes; isofurans; hemeprotein; cardiac surgery; cardiopulmonary bypass; NGAL Acute kidney injury (AKI) complicates the postoperative course in up to 30% of all cardiac surgery patients and independently predicts in-hospital mortality, morbidity, and mid-term and long-term survival. [1][2][3] Renal hypoperfusion, use of cardiopulmonary bypass (CPB), © 2010 Elsevier Inc. All rights reserved.Correspondence: Mias Pretorius, MBChB, MSCI, 561 PRB, Vanderbilt University Medical Center, Nashville, TN 37232, Fax: (615) 343-2551, Phone: (615) 343-0665, mias.pretorius@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Clinical Trial Registration Methods Study PopulationData were obtained from participants in the ongoing "The effect of atorvastatin on Acute Kidney Injury following cardiac surgery" (Statin AKI) study...

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

“…The ability of PM to sequester redox active metal ions may be of particular importance in the context of AKI since increased levels of free circulating iron have been shown to increase oxidative stress and promote AKI associated with rhabdomyolysis, sepsis, and cardiac surgery (4,5,7,27). It has also been shown that AKI increases intracellular levels of free catalytic iron, which increases oxidative stress and renal injury after IR-AKI (35).…”

“…Mild AKI is a precursor of chronic kidney disease (CKD), and there is an increased risk of end-stage renal disease (ESRD) in patients with severe AKI (8,11,12,15,62,67). Oxidative stress has been implicated as one of the principal drivers of renal injury and pathophysiology in all of the common causes of AKI (4,25,34,44,45,50). It occurs when the intrinsic antioxidant systems are unable to counteract the effects of excessive production of reactive oxygen species (ROS) and reactive carbonyl species (RCS), which can cause cellular damage via chemical modification to proteins, lipids, and nucleic acids (18,49,58).…”

“…The ability of PM to interfere with multiple aspects of oxidative stress is favorable for the treatment of AKI. In particular, there is extensive clinical and preclinical evidence that free iron contributes to the pathogenesis of AKI associated with crush injury (rhabdomyolysis) and ischemia-reperfusion-induced AKI (IR-AKI) (35), as well as AKI induced by sepsis and cardiac surgery (4,5,27). This suggests that free iron scavenging by PM may be advantageous for the treatment of AKI in a variety of different clinical scenarios.…”

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery

“…The mechanisms underlying postoperative AKI are not well defined but are associated with intraoperative hemolysis, hypotension, altered autoregulation of renal perfusion, inflammation, and oxidative stress [2,3,4]. Cardiopulmonary bypass (CPB) hemolyzes erythrocytes, increasing plasma concentrations of free hemoglobin [3].…”

“…Circulating hemeproteins damage the kidney by scavenging nitric oxide and increasing lipid peroxidation [5]. We previously demonstrated that postoperative AKI is associated with enhanced intraoperative hemeprotein release and enhanced lipid peroxidation in patients undergoing CPB [3]. Heme oxygenase-1 (HO-1), the inducible isoform of heme oxygenase, catalyzes the degradation of heme.…”