Hepcidin—The Culprit Explaining Disturbed Iron Homeostasis in Chronic Renal Disease?

In chronic renal disease, iron metabolism is often deranged and functional iron deficiency with low transferrin saturation but high serum ferritin concentration is frequent. This poses diagnostic dilemmas as illustrated by the observation that liver iron content measured by superconducting quantum interference device (SQUID) is very poorly correlated to the serum ferritin concentration (1). Abnormal regulation of iron metabolism is also thought to contribute to anemia and reduced responsiveness to erythropoietin. In the past, a vexing issue had been which pathomechanisms account for the disturbed iron metabolism in patients with anemia of chronic disease. Anemia of chronic disease is generally normocytic and normochromic, but may become hypochromic or microcytic; it tends to be associated with low serum iron and and high serum ferritin, low transferrin saturation, shortened red cell survival, and hyporesponsiveness to erythropoietin, features that are also common in chronic renal disease. Anemia of chronic disease is characterized by increased storage of tissue iron, but at the same time by diminished iron release from the reticuloendothelial system (RES) and by diminished iron absorption from the intestine, resulting in diminished availability of iron for erythropoiesis. The recent work of Nemeth et al. (2) goes a long way toward explaining the pathomechanisms underlying the disturbed iron metabolism in the anemia of chronic disease by documenting that IL-6 stimulates synthesis and secretion of hepcidin, a negative regulator of iron metabolism. Why is this observation important and potentially relevant for the understanding of the disturbed handling of iron in renal disease? Hepcidin inhibits the release of iron from macrophages and from cells of the RES (3), its absorption from the intestine and its transplacental passage (4,5). This leads to decreased serum iron concentrations and reduced availability of iron for erythropoiesis. The finding of Nemeth et al. that inflammation causes increased hepcidin synthesis, secretion and excretion in the urine is presumably also relevant for chronic renal failure, a known state of microinflammation and deranged iron metabolism. This is of obvious interest to the nephrologist (6), not in the least because the known constellation of intestinal iron malabsorption (7) and tissue sequestration of iron (1), so commonly found in renal patients, closely resemble the abnormalities of iron handling seen in inflammatory states. What Is Hepcidin? Hepcidin’s discovery is a beautiful example of how unpredictable the ultimate results of scientific investigation can be. In 2000 Krause et al. screened human blood ultrafiltrate for antimicrobial peptides. They isolated and characterized a 25–amino-acid peptide with eight disulfide-bonded cystein residues, a member of the defensin family, which he called LEAP (liver-expressed antimicrobial peptide) (8). The cDNA sequence predicted an 84–amino-acid prepropeptide with two consensus cleavage sites. The same peptide was also isolated from human urine and called “hepcidin,” i.e., a bactericidal substance of hepatic origin (9). It turns out that hepcidin is not a bactericidal substance alone (although presumably not bactericidal in the blood because the bactericidal properties are abrogated by 140 mmol/L NaCl). Hepcidin also restricts the availability of iron for erythropoiesis and other iron-dependent processes by inhibiting intestinal iron absorption and by promoting its sequestration in the RES—a host defense mechanism which makes a lot of sense biologically (10), because bacteria need iron among other things for the production of superoxide dismutase required for the defense against oxygen radicals produced by the host. This may explain why hepcidin has been strongly preserved in evolution down to fish and insects (11–13). Hepcidin is the long-sought central regulator of iron metabolism (14) that plays a crucial role in iron homeostasis. This is suggested by the observation of severe iron overload in mice lacking hepcidin (15) and conversely by fatally severe iron deficiency of transgenic mice overexpressing hepcidin (5). Similarly in humans, loss of function mutations of hepcidin cause one form of severe juvenile hemochromatosis (16). Conversely, a study in patients with autonomous hepcidin overxpression in hepatic adenomas documented that increased hepcidin production causes severe iron-resistant hypochromic anemia, which is reversible after resection of the hepcidin-producing adenoma (17). How Is This Important Substance Regulated? The work of Nicolas (18) addressed the effects of blood loss (phlebotomy), hypoxia (hypobaric chamber), and inflammation (injection of turpentine) on hepcidin expression. Anemia and hypoxia caused decreased hepcidin expression in the liver, a biologically useful response, because rapid mobilization of iron from the RES (and later iron absorption from the intestine) provide iron for erythropoiesis, thus correcting the stimuli of anemia and hypoxia, respectively. The response to the inflammatory stimulus was remarkable. A single injection of turpentine caused a decrease of serum iron in wild-type mice (but not in hepcidin knock-out mice) as well as a dramatic increase of hepcidin mRNA in the liver, analogous to the effect of LPS in mice (19). In agreement with this experimental finding, an increased excretion of hepcidin in the urine was also seen in patients with anemia of chronic disease secondary to inflammatory disorders and infections (20) The study of Nemeth (2) now carries this issue one step further by showing, in human liver cell cultures, in mice, and in human volunteers, that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin production and decreased serum iron concentration provoked by inflammation. In the model of inflammation by turpentine injection, a decrease in serum iron concentration and increased hepcidin expression in the liver were observed in wild-type mice, but not in IL-6 knock-out mice, underlining the crucial role of IL-6 for the hepcidin response to inflammation. The salient observation was made in human volunteers. IL-6 infusion caused a rapid, major increase of hepcidin excretion in the urine. This was paralleled by a decrease in serum iron and in transferrin saturation. In contrast, dietary iron caused a rapid increase of hepcidin excretion in study subjects, but in an ancillary experimental study such increase was also seen in IL-6 knock-out mice, indicating that the hepcidin response to the stimulus of iron load is IL-6–independent. This field is rapidly moving and many questions are currently unresolved. Injection of erythropoietin into mice caused a dramatic decrease of hepcidin expression in the liver (21), but it remains unclear whether this is due to a direct effect of erythropoietin or an indirect effect of consumption of iron for erythropoiesis. It also remains to be seen whether erythropoietin is directly involved in the downregulation of hepcidin in response to hypoxia and anemia. An obvious question is whether hepcidin concentrations are altered in renal patients. In two studies (22,23) increased prohepcidin concentrations were found in renal patients, but the methodology is still not completely satisfactory and, above all, prohepcidin is presumably not the active agent. Hepcidin currently can not be measured in blood and measurement of urinary hepcidin remains the methodological gold standard (2). Are there perspectives for diagnosis and therapy? It is a suggestive possibility that when blood-hepcidin measurements become available, this would provide a more satisfactory index of “functional iron deficiency” necessitating iron supplements. It is also theoretically conceivable that some day inhibitors of hepcidin will facilitate restoration of hemoglobin concentrations in the anemia of chronic disease by augmenting intestinal iron absorption and particularly by releasing sequestered iron from the RES for erythropoiesis.