In this retrospective study, we investigated that higher serum iron level was significantly associated with increased short- and long-term mortality in ICU patients with AKI. Moreover, transferrin exerted a beneficial effect on the short- and long-term mortality of ICU patients with AKI.
Catalytic iron is a transitional pool of non-transferrin bound iron (NTBI). It readily participates in redox cycling and causes damage to cell membranes, proteins, and DNA through redox reaction such as Fenton reaction [5-7]. The catalytic iron as a critical player in different types of AKI has been demonstrated in many animal models [8, 9]. A study in a rat model of ischemia/reperfusion injury (IRI) showed that no significant changes in total iron, non-heme or ferritin iron levels were observed, but catalytic iron level significantly increased after reperfusion . In IRI, there are possible self-protection mechanisms for regulating iron homeostasis . In a rat of the cisplatin-induced nephrotoxicity model, research supported the key role of iron in mediating tissue damage through hydroxyl radicals (or similar oxidants) . Another study demonstrated the protective effects of hydroxyl radical scavengers and iron chelators on penicillin-induced acute renal failure . Moreover, the protective effect of iron chelator deferoxamine on renal function was identified in rat models . And Ikeda Y et al. showed that restricting dietary iron could inhibit oxidative stress and inflammatory changes, thereby reducing renal tubular interstitial damage .
In recent years, researches on iron related measurements have gradually been carried out in humans. Several studies have shown that elevated levels of catalytic iron were associated with the increased incidence of AKI caused by different causes [5, 16-19]. Hepcidin is an essential regulator in iron homeostasis. It reduces extracellular iron levels through downregulating iron absorption in duodenal and ferroportin expression and cellular iron release in macrophages [18, 20]. And the protective role of hepcidin in AKI provides evidence on the key role of iron in mediating AKI . Meanwhile, a study involving 807 patients showed that plasm catalytic iron and hepcidin possibly be useful prognostic indicators in AKI patients . At present, most of the studies are about the relationships between iron-related measurements and morbidity of AKI rather than mortality. Few studies have reported the roles of iron-related measurements in mortality of AKI in humans. Our study investigated that higher serum iron level was significantly associated with short- and long-term mortality of patients with AKI. Clinically, serum iron levels on admission may be used as a prognostic marker for predicting prognosis of AKI, thereby taking interventions in advance to reduce mortality. In addition, our study found that the transferrin was a protective factor in short- and long-term mortality of patients with AKI. As the main protein that binds and transports iron into circulatory, transferrin increases its binding with overloaded iron. The potential mechanisms of transferrin protective role in AKI need further study.
In humans, the role of ferritin in AKI is conflicting. Several studies investigated that ferritin heavy chain had a protective effect on renal function [17, 22]. And some studies showed that lower level of ferritin was associated with increased morbidity of AKI after cardiopulmonary bypass [23, 24]. Dimitrijevic ZM et al. reported that elevated serum ferritin level was favorable for renal function recovery . However, this association has not been observed in a research of 120 patients . It was consistent with our study, in which ferritin had no significant correlation with the mortality in ICU patients with AKI.
Disturbances in cellular and systemic iron balance and AKI may affect each other. The kidney is an important player in preventing iron loss from the body by reabsorption . Different tubular segments paly different roles in handling iron. Proximal tubule has the majority of the reabsorption capacity [26, 27]. The kidney reabsorbs iron, even when systemic iron levels are high . Studies have shown that level of catalytic iron in urine increased, rather than decreased in AKI patients [28-30]. However, body iron stores are not low in AKI patients [19, 31]. The iron-mediated mechanisms in AKI are complex and may include multiple pathways. Excess iron is associated with OS, and production of oxygen free radicals causes damage to lipids, DNA, and proteins . While renal tubular epithelial cells are particularly vulnerable to OS due to the high number of mitochondria . In a rat model of acute ischemia, mitochondrial dysfunction caused by OS led to the production of proinflammatory cytokines . Free iron can amplify the inflammatory response through the intracellular uptake and catabolism of damaged, stored red blood cells by the monocyte-macrophage system . What’s worse, inflammatory response is important in the pathogenesis of AKI [3, 34]. Iron mediates OS, mitochondrial dysfunction, and inflammatory may be the potential mechanisms of AKI. Moreover, ferroptosis has been considered as a central player in AKI, characterized by the accumulation of lethal lipid ROS produced by iron-mediated lipid peroxidation [18, 35, 36]. As for the excess iron in AKI, degraded red blood cells, iron release from ferritin, and origination from mitochondria rich in heme and nonheme iron are the possible sources .
In terms of iron targeted therapy in AKI, the therapeutic effects of hepcidin, deferoxamine, apolipoprotein, and pharmacologic therapy with apotransferrin and hydroxyl radical scavengers have been reported in animal models [37, 38]. Combined with our study results, iron targeted therapy in patients with AKI needs further study.
Our study has several limitations. Firstly, this is a retrospective study with confounding bias due to missing values in the database and some indicators not recorded in the MIMIC-Ⅲ database. Secondly, MIMIC-Ⅲ is a signal center database between 2001 to 2012, so information may be relatively old while the sample size of our study is large. In addition, we selected the maximum values of iron-related parameters on ICU admission as research indicators and did not monitor the dynamic trend of serum iron levels changes. These may cause impacts on the results.