New Anemia Therapies

Translating Novel Strategies From Bench to Bedside

Iain C. Macdougall, BSc, MD, FRCP

Disclosures

Am J Kidney Dis. 2012;59(3):444-451. 

In This Article

Hepcidin Modulation

Hepcidin is a small defensin-like peptide produced largely by the liver, but also by other cells, such as the macrophage and adipocyte.[35] In addition to its antimicrobial properties, it is the master regulator of iron metabolism, controlling the amount of dietary iron absorbed from the duodenum and also the release of iron from cells in the reticuloendothelial system (Kupffer cells, splenic macrophages, etc; Fig 4).[36] Hepcidin is upregulated by a variety of stimuli, such as inflammation and iron overload, and downregulated by anemia, hypoxia, and iron deficiency. It now is recognized that uremia, as a chronic inflammatory state, also upregulates hepcidin, and in particular, dialysis patients have much higher serum hepcidin levels than healthy individuals.[37] It currently is believed that this has a part in the pathogenesis of anemia in CKD by limiting iron availability to the bone marrow. At a molecular level, hepcidin binds to the main iron exporter protein ferroportin, which controls iron efflux from duodenal enterocytes, hepatocytes, and macrophages.[38] The regulation of hepcidin is complex, but one of the major stimuli to its production is interleukin 6 (IL-6), produced as part of the inflammatory response. Other molecules, such as hemojuvelin and BMP-6 (bone morphogenetic protein 6), also have a role.[39]

Figure 4.

Regulation of iron availability by hepcidin. Abbreviation: Fe-Tf, plasma iron bound to transferrin.

As with other inflammatory anemias, it has been hypothesized that antagonizing hepcidin may ameliorate the anemic state, and there is laboratory evidence to support this assumption. A group of scientists recently generated a monoclonal antibody against hepcidin and have shown that this improves anemia in an inflammatory mouse model.[40] An RNA-based an gonist of hepcidin also has been created. It consists of a 44-nucleotide L-RNA oligonucleotide produced using so-called Spiegelmers technology (RNA molecules in which the ribose component is levorotatory, or the mirror image of the natural right-handed sugar moiety). The Spiegelmer is linked to a 40-kDa pegylation chain (NOX-H94), which has been shown to ameliorate the anemia of inflammation in cynomolgus monkeys.[41]

Rather than antagonizing the hepcidin molecule per se, another strategy could be to inhibit the production of hepcidin. This could be achieved by using antisense oligonucleotides or silencing messenger RNA transcribed from the hepcidin gene (HAMP).

None of the strategies to suppress hepcidin production or antagonize this peptide have been subjected to clinical trials. A theoretical concern could be that inhibition of hepcidin might exacerbate the risk of infections, given its endogenous antimicrobial properties. However, there are counterarguments to this suggestion, and it may be possible to suppress hepcidin to "safe" levels without obliterating hepcidin activity completely.

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