Novel Biomarkers, Oxidative Stress, and the Role of Labile Iron Toxicity in Cardiopulmonary Bypass-Associated Acute Kidney Injury

Abstract

Cardiac surgery-associated acute kidney injury (AKI) is common and carries a poor prognosis. Hemodynamic and inflammatory factors and the release of labile iron, contributing to oxidation from reactive oxygen species are among the major determinants of cardiac surgery-associated AKI. The diagnosis of AKI is typically delayed because of the limitations of currently used clinical biomarkers indicating loss of renal function. However, several novel renal biomarkers, which predict AKI or protection from AKI after cardiopulmonary bypass (CPB), have been identified as early markers of kidney injury. In this state-of-the-art review, the authors analyze the pathophysiological implications of recent findings regarding novel renal biomarkers in relation to CPB-associated AKI. Neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and alpha-1 microglobulin predict the development of CPB-associated AKI, while hepcidin isoforms appear to predict protection from it, and these biomarkers are involved in iron metabolism. Neutrophil gelatinase-associated lipocalin participates in local iron transport. Liver-type fatty acid-binding protein and alpha-1 microglobulin function as high-affinity heme-binding proteins in different species, while hepcidin is central to iron sequestration and when increased in the urine appears to protect from CPB-associated AKI. Free iron-related, reactive oxygen species-mediated kidney injury appears to be the unifying pathophysiological connection for these biomarkers. Such novel findings on renal tubular biomarkers were further combined with other lines of evidence related to hemolysis during CPB, the associated excess of free heme and iron, knowledge of the effect of free iron on renal tubular cells, and recent trial evidence targeting free iron-mediated mechanisms of AKI. Novel biomarkers point toward free iron-mediated toxicity to be an important mechanism of AKI in patients receiving cardiac surgery with CPB.

Urine Catalytic Iron and Neutrophil Gelatinase Associated Lipocalin as Companion Early Markers of Acute Kidney Injury After Cardiac Surgery: A Prospective Pilot Study

“…As expected, urine catalytic iron in those that developed AKI remained elevated compared to baseline for at least 48 h postoperatively. The fact that there was no significant difference in urine NGAL and catalytic iron level between the AKI and non-AKI group is consistent with our very small sample size and the large known variation in NGAL levels [20] .…”

Review article: Acute kidney injury in critical illness

“…Such activity may be more toxic in acidic surroundings, implying that increasing tubular pH by urinary alkalization with sodium bicarbonate may provide protection from oxidant injury. 68 Indeed, this has been found in a small phase II randomized trial of high-risk cardiac surgery patients receiving sodium bicarbonate for urine alkalization. 69 …”

The Metamorphosis of Acute Renal Failure to Acute Kidney Injury

“…The pathophysiology of AKI in relation to potential biomarkers has been reviewed and discussed specifically in relation to AKI following cardiopulmonary bypass (Haase et al (2010)), AKI with varying aetiology ), and AKI involving biomarker mediators of inflammation (Akcay et al (2009)). Reviews of biomarker performance specific to nephrotoxic injury Ferguson et al (2008)), septic AKI (Bagshaw et al (2007)), ischemic injury following cardiopulmonary bypass (Haase et al (2010)), acute allograft rejection and ischemic injury (Alachkar et al (2010)) as well as broader reviews across aetiologies (Coca et al (2008); Edelstein & Faubel (2010); Endre & Westhuyzen (2008);Malyszko (2010)) have been published within the last 4 years. We have published a more specialist review considering biomarkers in the early phase of injury (Pickering & Endre (2009c)) and there has been one meta-analysis of the performance of NGAL (Haase et al (2009)).…”