Catalytic iron and acute kidney injury

Abstract

Acute kidney injury (AKI) is a common and often devastating condition among hospitalized patients and is associated with markedly increased hospital length of stay, mortality, and cost. The pathogenesis of AKI is complex, but animal models support an important role for catalytic iron in causing AKI. Catalytic iron, also known as labile iron, is a transitional pool of non-transferrin-bound iron that is readily available to participate in redox cycling. Initial findings related to catalytic iron and animal models of kidney injury have only recently been extended to human AKI. In this review, we discuss the role of catalytic iron in human AKI, focusing on recent translational studies in humans, assay considerations, and potential therapeutic targets for future interventional studies.

Keywords: AKI; HO-1; ferritin; labile iron; non-transferrin-bound iron.

Fig. 1.

Distribution of cellular and extracellular iron. Extracellular (plasma) iron represents a small portion (∼3 mg) of total body iron (∼3,000–5,000 mg), the vast majority of which is intracellular (e.g., stored in ferritin, hemoglobin, and other cellular iron-containing proteins). Under normal physiological conditions, plasma iron is transferrin bound. In some disorders, a small portion of plasma iron is non-transferrin-bound iron (NTBI). The latter is either bound to albumin or to low-molecular-weight chelates, such as citrate. A portion of circulating NTBI is readily available to participate in redox cycling and is referred to as plasma catalytic iron or labile plasma iron (LPI).

Fig. 2.

Plasma catalytic iron levels and adverse outcomes following cardiac surgery. A: plasma catalytic iron levels are significantly higher at the end of cardiopulmonary bypass (CPB) compared with preoperative (Preop) levels. †P < 0.001 and †††P < 0.05 for within-group comparison to preoperative levels. Furthermore, catalytic iron levels at the end of CPB and on postoperative day 1 (POD#1) are higher in patients who develop in-hospital death or need for renal replacement therapy (death/RRT). *P < 0.01 for between-group comparisons. Bars represent median (25th–75th interquartile range). B: patients with catalytic iron levels in the highest compared with lowest quartile on POD#1 have a greater risk of death/RRT, AKI, and in-hospital mortality after adjusting for age and preoperative estimated glomerular filtration rate. *P < 0.05. [Adapted from Leaf et al. (32) with permission.]

Fig. 3.

Proposed pathophysiological mechanisms of catalytic iron-induced AKI. 1: Hemolysis, which can occur through endogenous or exogenous processes, results in the release of free hemoglobin (Hgb) into the plasma. 2: Free Hgb is bound by haptoglobin, and the complex is taken up by monocytes and macrophages via the scavenger receptor, CD163. CD163 can also facilitate receptor-mediated endocytosis of free Hgb, even in the absence of haptoglobin (48). 3: Once internalized, Hgb is broken down into heme, which is degraded further by heme oxygenase-1 (HO-1) into carbon monoxide (CO), biliverdin, and Fe²⁺. The latter is oxidized into Fe³⁺ and sequestered by ferritin, which is upregulated by HO-1 (41). 4: Free Hgb not sequestered by haptoglobin may be oxidized into free heme in the circulation. 5: Free heme is sequestered by hemopexin and taken up by hepatocytes, vascular smooth muscle cell (VSMCs), and other cell types via the scavenger receptor, CD91, also known as low density lipoprotein receptor-related protein 1 (LRP1). 6: When the ability of haptoglobin and hemopexin to scavenge free Hgb and free heme is overwhelmed, respectively, nonenzymatic degradation (i.e., in the absence of HO-1) may release catalytic iron from heme. 7: This catalytic iron catalyzes the formation of free radicals, which can damage macromolecular components of cells, resulting in AKI (5). 8: Even in the absence of catalytic iron generation, free Hgb and free heme may contribute to AKI by a variety of mechanisms, including nitric oxide (NO) sequestration, which results in vasoconstriction (14), oxidant-mediated cellular damage (46), vascular injury (30), and induction of apoptosis in the presence of other cytotoxic agonists, such as tumor necrosis factor (TNF) (49). Key targets for potential therapeutic intervention are colored in red. CPB, cardiopulmonary bypass; DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.