Oral and IV iron differ in terms of their uptake kinetics, which has an impact on the clinical effectiveness of these therapies. In this expert video interview, recorded for COMPACT RENAL, Professor Tomas Ganz highlights:
- Differences in the uptake kinetics of oral and IV iron,
- Clinical scenarios for treating with oral or IV iron, and
- Iron therapy in patients with inflammation
How do oral and IV iron differ in terms of their uptake kinetics?
So the question is how iron differs when it’s administered orally versus when it’s administered intravenously or parenterally. The uptake of iron in the two conditions is quite different. In the case of the oral iron, the uptake takes place through enterocytes, and that uptake, the absorption of iron, is controlled by the interaction of hepcidin and ferroportin. And the higher the hepcidin, the less absorption takes place at the intestinal mucosa.
When the enterocyte is highly iron loaded, it upregulates ferroportin and potentially delivers more iron. However, it is impossible to deliver the kinds of doses of ferrous iron that it takes to upregulate ferroportin because ferrous iron is quite irritating to the mucosa.
So in general, we are limited by the tolerability of ferrous iron in how much iron we can deliver by that route, and we generally cannot overcome the inhibitory effect of hepcidin in that condition.
In contrast, if you’re looking at the absorption of intravenous iron, it takes place at the macrophage level. So all of the iron preparations have to be processed by macrophages and then the iron is loaded onto transferrin, and that’s the functional iron that’s used for the production of hemoglobin.
We are able to deliver much higher doses of intravenous iron that induce the export of iron in macrophages. As iron accumulates in macrophages, it upregulates ferroportin and induces its own export. And because we can give much higher doses of intravenous iron, we can overcome the hepcidin block. And the more iron we give, the more ferroportin is upregulated, and the more iron is exported and loaded onto transferrin.
This is further compounded by the problem that enterocytes only live two days, so they don’t have a lot of time to get loaded with iron. And macrophages live for weeks, months, so there is a lot more time for them to actually get loaded with the iron that’s delivered. The net result is that enterocytes generally cannot deliver enough iron to plasma to overcome the effect of inflammation, but the macrophages can, especially when relatively high doses of IV iron are used.
So the underlying physiology is similar, but the tolerance for oral iron dosing is much lower. So the amount of iron that we can deliver through the intestine is much lower than the amount of iron that we can deliver through the macrophage.
Based on your knowledge of iron metabolism, when would you treat a patient with CKD with oral iron and when would you use IV iron?
So the question that is posed is under what circumstances should we treat patients with CKD with oral iron versus IV iron. The answer to that is that patients with chronic kidney disease have various inflammatory problems that underlie the disease or contribute to the causation of the disease. And in addition, they also have reduced clearance of hepcidin by the kidney. Because of that, their hepcidin levels generally are quite high, and so they absorb iron poorly.
There may be an occasional patient with chronic kidney disease who is similar to the patients with classical iron deficiency by having low hepcidin and low ferritin, which is a correlate of hepcidin.
So that occasional patient who has low ferritin and low hepcidin, therefore, would be a reasonable candidate for oral iron therapy. But this requires a ferritin of less than 20, which is quite rare in this patient population. Once you get into a region where you have both iron deficiency and an inflammatory component, oral iron will be poorly absorbed and IV iron has to be administered to overcome the hepcidin block and to deliver sufficient iron, to macrophages and to transferrin, to provide for the needs of erythropoiesis.
So to recapitulate, the rare patient who has low ferritin, ferritin under 20, will still absorb oral iron. But most of the patients with CKD and underlying inflammatory conditions or inflammatory conditions that complicate CKD will require IV iron in order to effectively deliver iron to erythropoiesis.
Does an inflamed patient require more iron to overcome the hepcidin block?
So the question is, does an inflamed patient require more iron to overcome hepcidin block. And the clear answer is yes. And the reason for that is that when IV iron is administered, it has to be reprocessed by macrophages into a form that can be loaded onto transferrin and delivered to the marrow to make hemoglobin and red cells.
That effect of iron is competed for by inflammation, which induces high levels of hepcidin via interleukin-6, induces very high levels of hepcidin. And that hepcidin then degrades ferroportin, the molecule through which iron is to be exported. So on one hand, iron is loaded into macrophages to induce ferroportin. On the other hand, inflammation generates hepcidin that degrades the ferroportin.
So under the conditions of inflammation, it takes more stored iron in macrophages to induce ferroportin sufficiently to export the iron and to load it onto transferrin. Interestingly, this is not something that hematologists discovered or iron scientists discovered. This is an outcome of empirical observations by nephrologists who, when confronted with patients who were unresponsive to erythropoietin, empirically discovered that if they administer relatively high doses of intravenous iron, they could overcome this resistance to erythropoietin and they could induce erythropoiesis.
We don’t exactly know where the limits of this kind of treatment are. And at some point it is very likely that if we keep escalating the amount of IV iron that we administer, that we will get a toxicity signal. We don’t know when it will happen, we don’t how much iron this takes. But it is quite likely that if we continue increasing the dose, that we will run into problems.
So a balanced approach of giving erythropoietin and IV iron, is probably the safest approach under the current circumstances, until we learn more about the limits of this approach, how much IV iron we can administer and get away with.