VIDEO: Recent developments in anemia care

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Well, there's two recent developments in terms of our understanding of the pathophysiology of anemia, especially with regard to patients with chronic renal disease which is a nephrologist is my specialty. The first is the discovery of hepcidin, which occurred around 2000. It's already 23 years ago but it's still having its ramifications in terms of our understanding of the very important contribution that inflammation has to the genesis of anemia not only in patients with chronic kidney disease, but in a variety of other disorders such as heart failure for example. Rheumatoid arthritis would be another example, those patients are anemic because they're in a highly inflamed state. And hepcidin, which is a protein that's produced by the liver, immobilizes iron and decreases iron absorption from the GI tract. So you don't have the adequate delivery of iron to the bone marrow to support red blood cell production.

And there's been increased understanding about the role of hepcidin specifically, in patients with chronic kidney disease as contributing to not only the anemia, but also the failure of other therapies such as iron supplementation, as well as erythropoietin producing agents to raise the hemoglobin level by the expected amount. So very often in these highly inflamed patients, oral iron supplementation is not adequate because they don't absorb the iron because of the effective hepcidin to downregulate iron absorption from the GI tract. And even if and when the iron is absorbed, it becomes locked in storage sites within the body because of the hepcidin and therefore is not delivered to the bone marrow where it obviously needs to be in order to support red blood cell production. So that is a target of a variety of products that are in the pipeline to down-regulate the production of hepcidin or decrease its effect in terms of its sequestering iron in the body. None of these products that are targeting hepcidin have reached the market yet, but that's a very fertile area of further investigation and possible therapeutic benefit down the road.

The second important development in our understanding of anemia, and specifically in patients with a chronic kidney disease, is the discovery of the hypoxia inducible factor pathway. So hypoxia inducible factor is a two subunit protein that is made by cells in the kidney in response to decreased tissue oxygen content. And we all know that the kidney is the major source of erythropoietin. This has been understood for many, many years, and we assumed that the reason that patients with chronic kidney disease become anemic is because you have fewer of these erythropoietin producing cells that stimulate the genes to make erythropoietin. And while that is true, that is now known not to be the whole story, that because patients with chronic kidney disease have lower levels of metabolism of oxygen because they're injured and they're not consuming oxygen for the active transport processes that are necessary for the reabsorption of osmolarity filtrate. Even if you have anemia and you have decreased oxygen delivery to the tissue in the kidney, the decrease in oxygen consumption may make the oxygen concentration around these cells that detect the oxygen concentration in the area seem normal. So even a low red count is counterbalanced by lower oxygen consumption, and as a result this decreases the activation of the erythropoietin gene and decreases the synthesis of erythropoietic and in turn decreases the red cell production by the bone marrow.

So there are a number of pharmaceutical agents now that have been developed to leverage this new understanding of the role of hypoxia inducible factor and basically increase its synthesis by decreasing its degradation. They target the enzyme that breaks down one of the subunits of hypoxia inducible factor allowing for more hypoxia inducible factor to reach the nucleus of these cells, and that allows for more transcription of the erythropoietin gene and ultimately more red cell production. A nice side benefit of the HIF approach, hypoxia inducible factor approach to anemia treatment is not only are you producing more endogenous erythropoietin and thereby decreasing the need for exogenous erythropoietin administration with ESAs, but because the hypoxia inducible factor stimulation of red cell production also involves increasing the transcription of a variety of genes that are related to iron metabolism, iron absorption, and iron transport, you may be able to overcome that other issue that I mentioned. And that's the impairment of iron transport in the setting of these high hepcidin levels in many of our chronic kidney disease patients who are inflamed. So again, you kind of get a twofer with this new approach to anemia treatment. The HIF, prolo hydroxylase inhibitor therapy because you're stimulating epo production and at the same time you're stimulating better mobilization of iron to the bone marrow.