In this retrospective study, we evaluated the prognostic role of different serum iron levels in short-term and long-term mortality of AKI patients. We investigated that high serum iron was significantly associated with the short-time and long-time mortality risk of severe AKI patients. Moreover, transferrin exerted a beneficial effect on the short-time and long-time mortality risk of patients with AKI.
Catalytic iron, labile iron, was a transitional pool of non-transferrin bound iron (NTBI). It readily participated in redox cycle and caused 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 was demonstrated in many animal models [8, 9]. Study in a rat model of ischemia/reperfusion injury (IRI) shown that no significant changes in total iron, non-heme and ferritin iron levels were observed, but rather catalytic iron significantly increased after reperfusion . In IRI, there were possible self-protection mechanism for regulating iron homeostasis . In a rat of cisplatin-induced nephrotoxicity model, research supported that 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 . Consistent with this study, the protective effect of iron chelator deferoxamine on renal function was identified in rat models of intramuscular glycerol injection and intravenous hemoglobin injection induced acute renal failure . And animal experiment had shown that restricting dietary iron can inhibit oxidative stress and inflammatory changes, thereby reducing renal tubular interstitial damage .
In recent years, researches on iron-related measurements had gradually been carried out in humans. Several studies have shown that elevated levels of catalytic iron were associated with increased incidence of AKI caused by different causes [5, 16–19]. Hepcidin was an essential regulator in iron homeostasis through downregulating iron absorption in duodenal and ferroportin expression and cellular iron release in macrophage to reduce extracellular iron levels [18, 20]. And the protective role of hepcidin in AKI provided evidence on the key role of iron in mediating AKI . Meanwhile, a study involving 807 patients showed plasm catalytic iron and hepcidin possibly be useful indicators for prognosing the mortality of AKI . At present, most studies are about the relationship between iron related measurements and morbidity of AKI, rather than mortality. Few studies had predicted the role of iron-related indicators in AKI mortality in humans. Our study investigated that high concentrations of excess serum iron levels and 90-day mortality of AKI were significantly correlated. Clinically, the prognosis of AKI can be assessed by measuring serum iron for taking interventions in advance to reduce mortality. In addition, this study found that the transferrin was a protective factor in 28-day, 90-day and one-year mortality of AKI. The mechanism may be that transferrin, as the main protein that bound and transported iron in blood, increased bonding with iron when it overloaded.
In humans, the role of ferritin in AKI were conflicting. Study investigated that ferritin heavy chain had protective effect on renal function [17, 22]. And some study showed that low level of ferritin was associated with increased morbidity of AKI after cardiopulmonary bypass [23, 24]. Elevated serum ferritin levels were favourable for renal function recovery . However, this association was not seen in a 120 patients research. It was consistent with our study, ferritin was no significant correlation with the mortality of AKI.
Disturbances in cellular and systemic iron balance and AKI may affect each other. The kidney was an important player in preventing iron loss from the body by reabsorption . Different tubular segments paly different roles in handling iron. Proximal tubule had majority of the reabsorption capacity [26, 27]. The kidney reabsorbed iron even when systemic iron levels were high . Level of catalytic iron in urine increased, rather than decreased in AKI patients [28–30]. However, body iron stores were not low in AKI patients [19, 31]. The iron-mediated mechanisms in AKI were complex and may include multiple pathway. Excess iron was associated with OS, and production of oxygen free radicals caused damage to lipids, DNA and proteins . While, renal tubular epithelial cells were 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 . And free iron could 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 was important in the pathogenesis of AKI [3, 34]. Iron mediated OS, mitochondrial dysfunction and inflammatory may be the potential mechanism of AKI. Moreover, ferroptosis was recently considered as a central player in AKI, which characterized by the accumulation of lethal lipid ROS produced through 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 were the possible sources .
In terms of iron targeted therapy in AKI, the therapeutic effects of hepcidin, deferoxamine, apolipoprotein, pharmacologic therapy with apotransferrin and hydroxyl radical scavengers were reported in animal models [37, 38]. Combined with our study results, it showed further study on taking interventions of serum iron concentration for improving the prognosis in AKI needed completed.
We also acknowledged several limitations of this study. Firstly, this was a retrospective study with confounding bias due to missing values in the database and some indicators not recorded in MIMIC-Ⅲ database. Secondly, this was a signal center database between 2001 to 2012, so information may relatively old while the sample size of our study was large. In addition, we selected the largest measurements of serum iron and other iron-related indicators after admission as research indicators. Meanwhile we did not monitor the dynamic trend of serum iron levels changes. These may cause impacts on the results.