Urinary Hepcidin-25 and Risk of Acute Kidney Injury Following Cardiopulmonary Bypass

Ho, Julie; Reslerova, Martina; Gali, Brent; Gao, Ang; Bestland, Jennifer; Rush, David; Nickerson, Peter; Rigatto, Claudio

doi:10.2215/cjn.01000211

Cited by 62 publications

(65 citation statements)

References 33 publications

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“…Furthermore, iron chelation with deferoxamine has been reported to provide protection and significantly improve the severity and outcomes of AKI (2,3,5,(15)(16)(17)(18)(19)(20)(21)33). Additionally, other endogenous proteins involved in iron regulation and chelation, such as hepcidin and NGAL, have been shown to protect against AKI (21,(34)(35)(36)(37). Our current findings corroborate the injurious role of iron in AKI and delineate the renal proximal tubule as the major site of iron-induced injury.…”

Section: Discussionsupporting

confidence: 79%

Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Zarjou¹,

Bolisetty²,

Joseph³

et al. 2013

J. Clin. Invest.

174

166

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Ferritin plays a central role in iron metabolism and is made of 24 subunits of 2 types: heavy chain and light chain. The ferritin heavy chain (FtH) has ferroxidase activity that is required for iron incorporation and limiting toxicity. The purpose of this study was to investigate the role of FtH in acute kidney injury (AKI) and renal iron handling by using proximal tubule-specific FtH-knockout mice (FtH PT-/-mice). FtH PT-/-mice had significant mortality, worse structural and functional renal injury, and increased levels of apoptosis in rhabdomyolysis and cisplatin-induced AKI, despite significantly higher expression of heme oxygenase-1, an antioxidant and cytoprotective enzyme. While expression of divalent metal transporter-1 was unaffected, expression of ferroportin (FPN) was significantly lower under both basal and rhabdomyolysis-induced AKI in FtH PT-/-mice. Apical localization of FPN was disrupted after AKI to a diffuse cytosolic and basolateral pattern. FtH, regardless of iron content and ferroxidase activity, induced FPN. Interestingly, urinary levels of the iron acceptor proteins neutrophil gelatinase-associated lipocalin, hemopexin, and transferrin were increased in FtH PT-/-mice after AKI. These results underscore the protective role of FtH and reveal the critical role of proximal tubule FtH in iron trafficking in AKI.

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Section: Discussionsupporting

confidence: 79%

Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Zarjou¹,

Bolisetty²,

Joseph³

et al. 2013

J. Clin. Invest.

174

166

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“…31 Although human studies have indicated a positive correlation between increased urinary hepcidin levels and protection against AKI, its direct role has not been examined in any models of AKI. 32 Here, we present evidence that renal IRI induces dynamic changes in renal and extrarenal iron homeostasis. Hepcidin-deficient mice sustain more severe renal injury after IRI and synthetic hepcidin mitigates renal IRI.…”

mentioning

confidence: 75%

Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis

Scindia¹,

Dey²,

Thirunagari³

et al. 2015

Journal of the American Society of Nephrology

120

119

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Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidininduced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusioninduced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin-deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemiareperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.

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“…16 Nevertheless, urinary hepcidin measurements may have utility in specific conditions, such as noninvasive measurement in children, screening in low-resource settings, or prediction of acute kidney injury. 17 …”

Section: Hepcidin Structure and Kineticsmentioning

confidence: 99%

Hepcidin in the diagnosis of iron disorders

Girelli

Nemeth

Swinkels

2016

Blood

342

291

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The discovery of the iron-regulatory hormone hepcidin in 2001 has revolutionized our understanding of iron disorders, and its measurement should advance diagnosis/treatment of these conditions. Although several assays have been developed, a gold standard is still lacking, and efforts toward harmonization are ongoing. Nevertheless, promising applications can already be glimpsed, ranging from the use of hepcidin levels for diagnosing iron-refractory iron deficiency anemia to global health applications such as guiding safe iron supplementation in developing countries with high infection burden.

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Urinary Hepcidin-25 and Risk of Acute Kidney Injury Following Cardiopulmonary Bypass

Cited by 62 publications

References 33 publications

Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis

Hepcidin in the diagnosis of iron disorders

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