Hepcidin--a well-known iron biomarker with prognostic implications in chronic kidney disease

Abstract

Studying hepcidin in humans is en vogue as demonstrated by an increasing number of publications addressing this key hormone of iron homeostasis over the last decade. As a key regulator of iron transport, hepcidin has been clearly implicated in the pathogenesis of anaemia in chronic kidney disease (CKD), but a more complex pathophysiology is beginning to emerge in which altered iron biology contributes more widely to the complications of uraemia. In CKD, anaemia is caused by a variety of mechanisms, including erythropoietin (EPO) deficiency and resistance and impaired iron metabolism [1]. A (chronic) inflammatory state has been shown to be involved, in part, as a cause or as a consequence of these processes [2]. In particular, disordered iron transport caused by inflammation may accelerate arterial disease, for example by increasing arterial stiffness, thus further enhancing the risk for cardiovascular (CV) events in CKD patients [2–5]. In this issue of Nephrology, Dialysis Transplantation, Neelke van der Weerd and colleagues present intriguing epidemiological data linking hepcidin levels with CV endpoints in haemodialysis (HD) patients [6]. The first reports about hepcidin described its antibacterial and antifungal activities in serum and urine [7, 8], but subsequently focus shifted as its important role in iron metabolism was discovered. Hepcidin 25, an active metabolite, is the key regulator of iron transport, governing intestinal absorption as well as release from the reticuloendothelial system, by its action on the iron export channel, ferroportin: hepcidin leads to internalization of ferroportin, which results in reduced plasma iron and therefore diminished iron availability. Hepcidin synthesis and release themselves are regulated by changes in iron storage, hypoxia and erythropoiesis [9–11]. Although hepcidin can be considered as an acute-phase protein [12] in particular in infectious diseases, levels of the hormone are also elevated in chronic (low grade) inflammation [9, 13]. Hepcidin levels have been described in association with markers of inflammation (e.g. C-reactive protein and interleukin-6), anaemia (e.g. haemoglobin and endogenous EPO) and most strongly with iron status (e.g. ferritin). Both anaemia and chronic inflammation are frequently detected in CKD, which explains the interest about hepcidin in nephrology and especially in the setting of renal anaemia . While insufficient endogenous EPO synthesis in advanced CKD surely represents a major mechanism in the development of renal anaemia [14], a number of reports have shown that EPO levels frequently are within the ‘normal’ range despite being low for the degree of anaemia . The phenomenon of ‘relative EPO deficiency’ is perhaps better described as a ‘blunted EPO response’ and might be insufficient to cause anaemia without the contribution of other mechanisms [15–17]. Further insight comes from the anaemia of chronic disease, with which renal anaemia shares several pathomechanisms, including inflammation and ‘relative’ iron deficiency, that is, insufficient iron availability despite adequate iron stores. In a landmark review article by Weiss [11], these mechanisms were clearly depicted and considered as crucial for the development of anaemia of chronic diseases, which is also frequently described as anaemia of chronic inflammation. A number of publications over the last years have focused on these mechanisms, and a robust body of evidence is developing about the pathophysiologic role of hepcidin in disorders of iron metabolism including renal anaemia. More recently emerging are a small number of studies suggesting a role for hepcidin in the development of CV disease, and as a biomarker and prognostic factor for clinical outcomes, in particular in CKD. IN F O C U S