Iron deficiency in CKD: the role of hepcidin and ferroportin

Structure of hepcidin
Source: Tomas Ganz, Blood, 2003

In the latest issue of the New England Journal of Medicine, published today, there is a fantastic review on the role of hepcidin and ferroportin in regulating iron homeostasis. It’s written by Nancy Andrews, an expert in the field.

The main points made by Nancy Andrews excerpted from the article are:

"Ferroportin is a transmembrane iron exporter that transfers iron out of cells. This protein is important in the intestinal epithelium, where it allows dietary iron that is taken up by absorptive cells to enter the circulation, and in macrophages that recycle used iron from effete red cells.

Hepcidin, a small peptide produced by the liver, controls the activity of ferroportin by attaching to it and targeting the protein for destruction in the lysosome. Hepcidin levels fluctuate in response to the body's iron needs. In simple terms, more hepcidin causes less iron absorption, and less hepcidin causes more iron absorption."

Normal Iron Balance

Nancy Andrews also refers to a very nice paper by Gloria Preza published in the JCI in November 2011. It is also available open access. Preza and co-workers have developed minihepcidins or hepcidin agonists that are small peptides that could in the future be used in the treatment of iron overload.  A hepcidin agonist is not going to be very useful, in of itself, in the iron deficiency syndrome that is common in CKD patients  (≈40% of patients with advanced CKD have iron deficiency); however, the important point is that the development of hepcidin antagonists are probably just round the corner.

I would also highly recommend a mini-review by Dan Coyne, published in Kidney International that is available open access.

The main points from Dan Coyne’s article are:

Source: HDCN (ANNA Symposium, 2005)

1. Chronic kidney disease (CKD) is associated with increased hepcidin levels, and this likely contributes to the incidence and severity of anemia, and resistance to erythropoiesis-stimulating agents (ESAs).

2. Elevated hepcidin contributes to the dysregulation of iron homeostasis in CKD.

3. In patients with CKD, although parenteral iron in CKD can bypass some of the iron-blocking effects of hepcidin, free iron and iron stores increase, anemia is only partially corrected, and ESA dose requirements remain significantly higher than physiological replacement.

Key facts about hepcidin from Dan Coyne’s article are:

1. Hepcidin controls intestinal absorption of iron and its distribution throughout the body.

2. The liver produces hepcidin.

Iron deficiency in CKD

3. High-circulating hepcidin reduces iron absorption in response to oral or intravenous iron (limited iron leads to low hepcidin levels, which allows enhanced intestinal iron absorption and release of storage iron).

4. The kidney is the major route of hepcidin clearance.

5. Hepcidin, prohepcidin, and hepcidin metabolites increase in chronic kidney disease (CKD) and are very high in dialysis patients.

6. Elevated hepcidin appears to have a major role in the development and severity of anemia in CKD.

The bottom-line: we are in for an interesting few years in the management of CKD anemia. Not only do we have exciting new ESAs emerging onto the clinical stage, but also the world of new iron therapies is not far behind.