The Role of Iron Deficiency in Anemia Management: Key Controversies
ASN Renal Week Official Symposium, November, 2005
Questions received during this symposium have been paraphrased
and the answers submitted by the panelists are presented.
As soon as the iron leaves the sucrose, is it bound to transferrin? Also, is it possible that some iron is not bound to neither sucrose nor transferrin?
What is the optimal dosing schedule for IV iron?
Are there situations where you want to hold your maintenance IV iron therapy?
Should we extend the administration time of IV iron to 4 hours or longer?
Should we give iron to patients with ferritin levels between 500 and 2000?
You demonstrated that ferritin is actually a poor measure of overall iron stores. Are there novel markers of iron stores on the horizon?
What about performing functional iron tests when in doubt as to the need for iron?
Panelist Responses(Back to question index) As soon as the iron leaves the sucrose, is it bound to transferrin? Also, is it possible that some iron is not bound to neither sucrose nor transferrin?
Audience: This is a question out of ignorance. As soon as the iron leaves the sucrose, is it bound to transferrin? Or, is there a time period where you have iron not protected by sucrose or transferrin? And, could that be a problem?
Dr. Agarwal: The earliest time point I tested was 15 minutes, so I do not know whether this can happen in seconds. And if it happened in seconds, I do not know how would we would measure it.
Audience: What you called free iron, you measured as transferrin. But what if there was some iron that was not attached to sucrose anymore, but was not attached to transferrin yet? Is that possible? Just remember, when all these compounds came out, people were worried, that if you give too much too quickly, patients would get reactions. Then people asked, "Could it be free iron? Can free iron exist?" So, you called it free iron, but you measured transferrin. I am just not sure.
Dr. Agarwal: Well, we are measuring that part of iron that can be bound to transferrin. So, in other words, if you took that drug solution which has both transferrin and iron, you will probably find a lot of iron which is still bound to the drug. Some of this iron will never get bound to transferrin, even if you incubated it for days. It is possible that there is some non-transferrin-bound iron, which is bioactive. We do not know how to detect that accurately.
Dr. Zager: One experiment that we did is we took the iron preparations and incubated them with cells and measured MDA, but we did it in high concentrations of desferrioxamine (DFO). So that basically, you are binding up any free iron that is released, and even in the presence of DFO, the iron compounds will still induce oxidative stress, so the iron does not have to be released from the carbohydrate in order to induce oxidative stress.
(Back to question index) Are there situations where you want to hold your maintenance IV iron therapy?
Audience: First of all, I wanted to congratulate you, the speakers, on your presentations. That was an outstanding review. My question to each of you is this. I would like you to speculate, given the adverse events that you are talking about that we should be concerned about clinically, can you recommend what you think would be the optimal recipe that we should use to provide the IV iron? Should we be giving 1 g a day? Should we be giving a 1 g over a month? Should we be giving a little bit now and then? Regularly every week? Or split up the dose? What would your suggestion be?
Dr. Wish: Again, I think, when we look at the whole issue of iron therapy, we are looking at safety versus efficacy. And also maybe cost at some point, in terms of the whole picture and its effect on EPO dosing. But just addressing the iron issues, I feel that it is probably safest to give it in small doses. That is just an intuitive feeling that I have. And I think we have a number of data slides here that suggest that some of these intermediate outcome parameters are dose-related that may be potentially toxic, at least in vitro if not in vivo . And I think avoiding iron deficiency in terms of maintaining optimal erythropoiesis is clearly a goal. So if we are going to go with the maintenance kind of paradigm, that means giving small doses frequently, as opposed to waiting until a patient becomes iron deficient and giving a large dose. So, I think you can make a twofold argument for small dosing frequently, both in terms of the potential safety, and in terms of the efficacy in avoiding iron deficiency. At least that would be my spin.
Dr. Agarwal: I think it is like food. You need to eat, and you probably do not want to eat just one meal a day, or once a week.
(Back to question index) Are there situations where you want to hold your maintenance IV iron therapy?
Audience: I want to expand a little bit on your answer to the last question. Would you speculate that there might be clinical situations in which you would want to hold your maintenance IV iron? For instance, in an acute illness or injury? In a CKD patient? Perhaps someone whose renal function appears to be declining? Also, I wonder if this could apply to other organs? Presumably, you can get iron-mediated oxidative damage to the heart? Or, another organ in which some type of acute process is going on?
Dr. Agarwal: We do not have any definitive answers to that, but I think given Dr. Zager’s data on increased mortality in animals if they are septic, I think it would be prudent not to give intravenous iron if your patient is septic, in the ICU, or hypotensive. That certainly is a situation to avoid. Regarding your second question, "What about a patient with declining kidney function?" We really do not have an answer one way or the other. And it is question of balance. Maybe if you improve hemoglobin, and if you are truly iron deficient, maybe you will have a good outcome. On the other hand, if you have increased oxidative stress and further injury, maybe you will accelerate the damage. Maybe in those patients you might want to use oral iron. I do not know. I think we need data, long-term trials to come with the answers that you are asking.
Dr. Kalantar-Zadeh: Just expanding on the current question and the previous questions. From our data that I showed you, unfortunately, two of the slides were missing. The association between IV iron and mortality in our study showed that patients who receive IV iron up to 400 mg per month, which means 100 mg per week, had better survival compared to those who did not receive any iron. However, for those who received 400 mg or above, the survival was not any better than for those who did not receive any iron. So in other words, perhaps a safe approach to IV iron would be something in the magnitude of 50 to 100 mg of IV iron - any of the 3 IV iron preparations that are available in the United States - per week, for a hemodialysis patient. This can be considered as maintenance dose. In our practice, we do hold IV iron when a patient has an acute infection. We do not do it based on our own data. We just do it because that is how we are trained. I think for 2 or 3 decades they kept telling us iron is associated with infection, so therefore we continue doing that until something shows the opposite. So I guess that is what is being practiced in many places, in many dialysis facilities, as well as in CKD clinics. When there is acute infection, we hold the iron. At the same time, when a patient receives erythropoietin, there is no reason to wait until that patient becomes iron deficient in order to start IV iron.
(Back to question index) Should we extend the administration time of IV iron to 4 hours or longer?
Audience: The FDA has given approval for relatively rapid administration of the iron preparations, for example, during dialysis. In terms of the ability to induce oxidative stress, would it be reasonable to extend the duration of the administration to 4 hours, or a longer period of time, to minimize the potential toxic risks?
Dr. Agarwal: That is a great idea. I do not know of any data to support it.
(Back to question index) Should we give iron to patients with ferritin levels between 500 and 2000?
Audience: I have a question about the patients who have a ferritin level of between 500 and 2000. According to the concept of the new KDOQI guidelines, we should not give those patients IV iron. But we have just heard that there is so much evidence that this is an acute phase reaction mostly. So what should we do? Or should we follow the new KDOQI guidelines when they come?
Dr. Kalantar-Zadeh: That is a very good question again. And the answer is that we probably should follow KDOQI guidelines because if you practice here, you should follow KDOQI guidelines. If you practice in Europe, you should follow KDIGO and Best European guidelines. However, we do have problems with the guidelines because some of us believe that the current draft, which again is not the final guidelines -- it may be the same, as you see. It may be modified. I hope it is modified, and it becomes more reasonable -- but if we are not supposed to give IV iron to any patient whose ferritin is more than 500, in the United States, then according to the USRDS data, over half of dialysis patients should not receive any IV iron, while they continue receiving erythropoietin. So this probably will lead to the fact that erythropoietin will not be effective, because I personally believe that these two go hand in hand. It does not make sense to give iron without erythropoietin, and it does not make sense to give erythropoietin without iron. Patients are supposed to receive both of them. So you are right. There are confusing data, and our data versus the current KDOQI guidelines are not consistent with each other. I am hoping that we can find some solution in the upcoming weeks.
Dr. Wish: One of the things that are in the current DOQI draft that perhaps is not emphasized as much as I think it should be, is this. There is a statement towards the end of the iron section that emphasizes, or perhaps does not emphasize as much as it should, that the IV iron ceiling for the ferritin of 500 is based on a target ferritin and not necessarily on an observed ferritin. I am not sure of the exact word that they use; "resulting" ferritin, or "achieved" ferritin. I think “achieved” is the word that they use. So basically what are they saying is that you treat with IV iron as you see fit to optimize erythropoiesis. And if it so happens that the ferritin goes above 500, that you achieve a ferritin over 500, that is okay, because you are still providing the optimal balance between iron therapy and erythropoietin. But to aim for a ferritin of greater than 500 because you think that additional IV iron is necessary to achieve that higher target is what they are trying to discourage. Now, I am not sure that that is a clear cut approach. And I think it is causing more confusion than it is solving. They cite as their evidence for the ferritin ceiling of 500, data, or the lack of data, failing to demonstrate a response to IV iron among patients who have ferritins of over 500, and they say cite two studies. Both of those studies had very, very few patients that actually had ferritins of over 500. So the problem is we do not have a lot of data. And I think that once we have a really good prospective study of the effectiveness of IV iron used by either decreasing EPO requirements, or improving hemoglobin among patients with ferritins of greater than 500, we will have better evidence to support the recommendations. But right now, I think we all share that confusion.
(Back to question index) You demonstrated that ferritin is actually a poor measure of overall iron stores. Are there novel markers of iron stores on the horizon?
Dr. Wish: Not that I am aware of. I inventoried everything that was out there!
(Back to question index) What about performing functional iron tests when in doubt as to the need for iron?
Audience: Continuing with that same question. What would the panel think of doing functional iron tests in all patients in which you doubt whether you should give iron? If they have a constant level of hemoglobin for a certain amount of erythropoietin, what would be against trying with one-time intravenous iron and see what happens?
Dr. Agarwal: I think that is a great idea. Give it a shot and see if it the patient responds. If it does not respond, then do not use it.
Dr. Wish: That certainly would be the most empirical approach. And I think most of us who are, I think, somewhat disturbed about that ferritin ceiling, would probably agree. The ferritin ceiling is not based on lot of data. It is more opinion-based than evidence-based. In fact, it is an opinion that, with ferritins of greater than 500, the potential risks, none of which have ever been documented in any kind of literature of administering IV iron in that setting, outweigh the benefits. So I think that if you are used to using IV iron, and if you are comfortably using IV iron, and if you have seen the literature, coupled with the fact that there is not an epidemic of IV iron toxicity among the hundreds of thousands of dialysis patients worldwide who have been receiving IV iron on a regular basis, many of whom have ferritins well into the 4 digits, and if you are secure that perhaps a little more IV iron in the EPO-resistant patient will probably do more good than harm, then I think that empirical approach is extremely reasonable.
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