In current practices, correction of anemia became feasible in CKD patients because of introducing erythropoiesis-stimulating agents (ESAs). Although erythropoietin deficiency is the major cause of renal anemia, a certain proportion of CKD patients are hyporesponsive to ESA treatment. This is called ESA resistance, and CKD patients with ESA resistance have a poorer prognosis than those without ESA-resistant renal anemia.2

Different causes of ESA resistance were proposed, among which iron deficiency is the first one to be considered. However, other causes may be difficult to be eliminated because chronic or systemic inflammation mainly underlies the mechanism of ESA resistance. Anemia of chronic disease including renal anemia is currently known as anemia of inflammation. Furthermore, congestive heart failure as well as CKD may be the condition of systemic inflammation and immune activation, in which overproduction of cytokines such as interleukin-1β, tumor necrosis factor-α (TNF-α), and interleukin-6 by macrophages and interferon-γ by lymphocytes may blunt erythropoietin production, impair the erythropoiesis response, and increase hepcidin levels.3

Hepcidin, a 25-amino-acid peptide hormone, is predominantly synthesized in the liver. It binds to the cellular iron exporter ferroportin, which mediates all the major flows of iron into plasma and extracellular fluid.4 Thus, plasma iron falls when the hepcidin level is increased because of iron trapping within duodenal enterocytes, splenic and hepatic macrophages, and hepatocytes. This typically occurs in systemic inflammation and leads to anemia due to iron underutilization. Hepcidin production is transcriptionally regulated by plasma iron concentration, iron stores in the liver, erythropoietic activity, and inflammation. In CKD, inflammation and impaired renal clearance increase plasma hepcidin, inhibiting duodenal iron absorption and sequestering iron in macrophages. Hepcidin inhibition should be the reasonable option to treat renal anemia because abnormal upregulation of hepcidin is an important cause of ESA resistance in CKD.

In this issue of Journal, Min et al,5 reported that the serum hepcidin level was independently associated with cardiac geometry in CKD patients. In particular, the increased relative wall thickness (RWT) measured in echocardiography could represent hepcidin upregulation. This result may offer an explanation why we more frequently encounter ESA resistance in CKD patients with heart failure than in those without. RWT may be an important prognostic factor in patients with diastolic heart failure.

Left ventricular mass (LVM) is the other important parameter of left ventricular geometry. Four types of left ventricular geometry are grouped based on RWT and LVM: normal geometry, concentric remodeling, eccentric left ventricular hypertrophy, and concentric left ventricular hypertrophy. The present study showed that both RWT and LVM were associated with the serum hepcidin level.5 According to multivariate analysis results, however, RWT only was independently associated with hepcidin upregulation. Interestingly, this association was independent of inflammatory markers such as C-reactive protein concentration and white blood cell count.

The authors interpreted their results from the liver-heart link. They postulated that the congested liver induced by diastolic heart failure might enhance hepatic production of hepcidin. However, they showed no association between hepcidin and E/e′, a reliable echocardiographic parameter of diastolic dysfunction.

Circulating (systemic) hepcidin is mainly derived from liver, and its serum level is correlated with hepcidin expression in liver. Besides, local hepcidin was known to be synthesized in organs including heart. The role of local hepcidin may be independent of iron metabolism because cardiac hepcidin expression but not ferritin staining was increased in rats with coronary artery ligation. Interestingly, similar results were obtained from rats with subtotal nephrectomy.6 The latter finding suggests a role of cardiac hepcidin in renocardiac failure. Whether cardiac expression of hepcidin is connected to the serum level needs to be verified in clinical studies. Hepcidin inhibitors can be promising therapeutic agents to correct anemia in cardiorenal syndrome.