Treating Patients with IV Iron Therapy: Special Considerations
ANNA CE Satellite Symposium, April 21, 2005
Assessing the Validity of Higher Serum Ferritin Values in Determining Iron Status
Treating patients with IV iron therapy: Special considerations
I will speak about, "What high ferritin values mean." I am going to speak a little bit about iron physiology to introduce the subject.
...I will get much more directly into the clinical issues that relate to higher ferritins. We will look at some specific cases that I am sure you will find will be very familiar to you.
Assessing serum ferritin
K/DOQI guidelines are currently reassessing this subject. The purpose of my presentation today is not to say what the new K/DOQI target is going to be. That is secret. It is not supposed to be discussed at all yet in public; although, it will be later. Rather, we want to look at some of the factors that help you understand where target ferritin values should be and why it is particularly important for you to individualize based on the patient's characteristics.
I am not going to speak about transferrin saturation. TSAT is a good test for diagnosing iron deficiency, but for looking at the upper levels of iron, transferrin saturation is not helpful. For one thing, there have been very few published studies. For another, while ferritin is a marker of storage iron, it tells you how much iron is in the body. Transferrin saturation tells you something very different, which is about circulating iron, and that probably is not the most important thing to be looking at when you are trying to look for the possibility of iron overload. Transferrin saturation also suffers from remarkable variability. If you measure it in the same patient from day to day, the numbers will bounce up and down to a remarkable extent.
Balancing risks versus benefits
Whenever we talk about potential target levels for iron tests, we have to be very clear that this is balancing. It is a balancing of the effectiveness of iron treatment against potential safety concerns. The efficacy part, many of you have a very good feel for, but for people who were not in practice 10 years ago, you might not know about how different things were at that time. In 1993, based on United States Renal Data Systems data, half of dialysis patients in the United States were iron deficient. More remarkably, 25% of patients, 1 out of every 4 patients, had severe absolute iron deficiency, transferrin saturations below 10%. At that time, we were leaving 1 in 4 patients severely deficient, and we were not meeting a very basic health need for these patients. That is what led to a lot of the interest in the community for correcting what was a very clear problem. Iron, of course, has many benefits, including the erythropoietic benefits of allowing your patients to get to hemoglobin target levels, and the economic benefits of reducing the amount of erythropoietin that is required. Iron therapy often leads to 40% to 50% reductions in EPO doses. Also, we just discussed these non-erythropoietic effects of iron that may improve other functions of the body, whether it is cognition, thermoregulation, or restless legs syndrome.
Iron in the human body
Iron is needed by every cell in the body. It is perhaps the most important element for the human body, but we trade off those benefits against potential risks. We do not know much about potential risks. We saw that if you do not treat with iron that patients tend to have higher mortality suggesting that these risks may be more theoretic, but this decision is ultimately balancing. In terms of physiology, iron in the body, we tend to have 3000 to 4000 mg of iron in our bodies. Women generally, because of menstruation, have less iron in the body than men do. Most of iron in the body is present in red cells and their precursors, the erythron. Within the erythron, there is about 2000 mg of iron. If you want to test for this important pool, you need direct measures of iron status. Tests, such as CHR or reticulocyte hemoglobin content, tell you about the most important iron pool. The second most important pool of iron is approximately 1000 mg located in storage tissues throughout the body. That is the liver, spleen, and bone marrow for the most part, but that is where iron in our bodies is stored away for potential need at a later point. Storage tissue iron is measured best by looking at serum ferritin concentrations. Within the circulation, there is only a tiny amount of iron; notice, 3000 to 4000 mg of iron in the body, and you know we always pay attention to serum iron concentrations, but in fact there is only about 2 mg of iron in the bloodstream - and that is measured by transferrin saturation. It may be the least important way of looking at the body's total iron status.
EPO and iron equilibrium
As the bone marrow makes red blood cells, it goes from stem cells to cells that increasingly take on the characteristics of the mature red blood cell. Erythropoietin works in colony-forming unit cells that are pretty close to becoming red blood cells. Iron is added in the very next step as the proerythroblast is produced. From this stage, it is approximately 7 days until mature red cells enter the circulation. EPO is important and iron is important. If neither is present, erythropoiesis producing red blood cells simply will not move forward normally.
Pathobiology of iron balance
Pathobiology: What goes wrong in chronic kidney disease? Almost all iron deficiency in the United States is never because of not taking in enough iron. We eat much more iron in our diets than the amount that we need. Almost all iron deficiency is a result of excessive bleeding, and your hemodialysis patient bleeds continuously. They lose blood in the lines and filters with every treatment, but they have other sources of blood loss. The other sources include occult gastrointestinal bleeding, excessive phlebotomies, withdrawing blood all the time from patients, and loss of blood and iron from the body in women who still menstruate. Blood loss is the major reason, but reduced iron availability is also important. This relates to problems such as inflammation. Inflammation, we know when it is there because people have ulcers in their legs or they have skin infections, but one of the important lessons in treating dialysis patients over the past 5 years is that many patients have inflammation present without us really being clinically aware of that fact.
Changes in iron balance
Let us talk about what happens during EPO treatment. As you use EPO to raise the hemoglobin concentration, to produce new red blood cells, a very important change happens in iron. Iron deficiency often develops. What happens could either be relative iron deficiency where iron stores of the body are fairly normal, but patients still do not respond well to EPO or what has been termed functional iron deficiency. The way that we treat with EPO does not match the way all of your bodies right now are using erythropoietin. Erythropoietin is always present. If your hemoglobin level decreases by a bit, you will produce a large amount of EPO in order to correct the reduction in hemoglobin. For patients on dialysis or with chronic kidney disease, we treat with much larger doses of EPO. We get extremely high levels of erythropoietin into the body. We make red blood cells faster than nature really intended to have red blood cells produced. As you make red blood cells faster than they are supposed to be produced, it is very rare that there is enough iron immediately available to produce normal red blood cell precursors. Remember, 4000 mg of iron in the body, but only 2 mg in the bloodstream. As you make red cells very rapidly, there is just not enough iron immediately available to produce normal red blood cells.
Impact of rising Hgb level
Functional iron deficiency, the math of this. As you take a patient and increase their hemoglobin level from 10.5 up to 13.5, you end up needing about 500 mg of iron to accomplish this. That is iron that can almost never be obtained from patients who are iron deficient. What ends up happening as a result is, as the hemoglobin level is increasing during EPO treatment, it tends to increase to the point where you get iron deficiency and then tends to flatten out. If you look at your patients who have relatively low hemoglobin levels and you have increased EPO dose, you will see that iron deficiency develops very frequently in those patients.
Let us move on to the section on diagnosis. How do we diagnose iron deficiency in patients with kidney disease? Of course, there are 2 primary tests that are used, serum ferritin and transferrin saturation. Diagnosing iron deficiency is key because iron management drives successful anemia treatment to get those good hemoglobin levels and to avoid huge doses of EPO; 15,000 units of EPO and 18,000 units of EPO should never be required. Accurate iron diagnosis is important because it gets iron to the patients needed and allows you to avoid iron treatment in patients who are not really iron deficient.
Current schema in CKD
The current schema, which you know well, is serum ferritin when less than 100 indicates iron deficiency and when greater than 800 is the point where we are told to stop iron treatment. Transferrin saturation, when less than 20%, indicates iron deficiency and when greater than 50%, the current K/DOQI recommendation is to stop iron treatment.
Diagnostic test attributes
These diagnostic tests, though, have problems. Their accuracy is poor in general. It is not like a lot of diagnostic tests that we use in medicine that have fairly good accuracy. You must be aware that ferritin and transferrin saturation are simply loose approximations of what the patient's iron status really is. The variability of tests is high. They bounce around a lot. Why do we use them? They are easy to use. They are not particularly expensive. They are very widely available. Because of that, they remain the cornerstone in the diagnosis of iron deficiency.
Serum ferritin, let us get more specifically into our subject matter for today. Ferritin, of course, reflects storage iron in the body, but ferritin does not just reflect iron status. Ferritin is a potent acute-phase reactant, which essentially means, that if you are infected or if you have inflammation in your body, ferritin values shoot upward to a dramatic degree. That is a problem because if we have a test that we want to inform us as to the patient's iron status, but the test is being driven by another potent factor which is commonly present, then it is clear that ferritin will often not tell us much about what the patient's iron status is. That makes iron diagnosis and management a bit more complicated. In the normal population, if any of you had a ferritin value of less than 15 ng/mL or so, then you would probably be iron deficient, but in hemodialysis patients where the numbers are pushed upwards by these other factors, such as inflammation, forget about a 15 number, we often have iron deficient patients whose ferritins are 100 or 300 or 500. Ferritin behaves very differently in this patient population.
This is data from Kamyar Kalantar-Zadeh from UCLA. What it shows here - I am going to go to the right-sided panel - if you look at this data, we are looking at ferritin values above and below 800. Think of your patients who have ferritin values in that range and then patients who have very high ferritin values. The marker that they use is CRP, which of course is a marker for inflammation. They find here that patients with high ferritin values generally have high CRP values that are substantially higher than patients with lower ferritin values. This suggests the fact that in a lot of patients who have high ferritins that it might be that inflammation is what drives the high ferritin. If you think about your own experience, I am sure you will agree that this is true. It is rare that your patient has a 1000 ng/mL ferritin because you have treated them with too much IV iron. It is much more common for it to be driven by other factors, such as the presence of inflammation.
How accurate are these tests? I am going to look at 3 studies from about 6 to 8 that are good studies on the subject, but these are a very good representation. What they do here is they look at typical cutoff values for ferritin, and they define sensitivity and specificity. Sensitivity means, if you take all iron deficient patients, what percentage will the test actually detect. The flip side of that, how many will be missed. When you look at serum ferritin, please note that the sensitivity in all of these studies is less than 50% and is even lower in the Nicola Tessitore study, 35%, which means when you use these current cutoff values you are missing most patients who are iron deficient. Stated in another way, most patients who are iron deficient have ferritin values of greater than 100 ng/mL. The 100 cutoff is not magic. It does not mean that the patient with an 80 ferritin is iron deficient whereas the one with 150 value is not. These are just not very accurate diagnostic tests.
Here is a more graphical representation. If you look at the ferritin value on the graph of approximately 100 ng/mL for ferritin, you see that the sensitivity, the ability to detect iron deficiency is remarkably low, but on the flip side of this, as you get up to 500 or so, you have successfully diagnosed in these studies almost all the iron deficiency that was present.
At first glance, that would suggest to you the question: Why would I ever treat with intravenous iron when the ferritin value is greater than 500 because patients simply should not respond? But these 5 studies represent bone marrow studies, and an approach to diagnosis called functional iron studies. It seems to me that both studies have a lot of potential to underestimate the amount of effect of intravenous iron.
We now have newer data, and I would like you to see some of the more recent studies. The first is the study from Taiwan. Erythropoietin availability is not great, the cost is great, there are limitations. They focus very effectively on intravenous iron. If you want to project yourself out 3 or 4 years from now, when bundling of services becomes more important issue, this may turn out to be a particularly relevant slide for us because when we are at risk as a dialysis provider for both iron and EPO, EPO is far more expensive, so doing effective iron treatment becomes quite important. These are patients, 149 patients, treated with intravenous iron. The starting ferritin value was 930. They are treating a large number of patients who by K/DOQI criteria should not even be treated with intravenous iron. In the course of the study, they raised the ferritin value from 930 up to 1383 ng/mL. Although they show little change in hematocrit, they show a sharp reduction of 28%, I believe, in the need for erythropoietin. So, even at these very high values of ferritin, it appears that iron maintains its effectiveness. Please do not take the message from this that your patients with 900 ferritins should be treated with intravenous iron. I am simply trying to make the point here that many patients with high ferritin values still could derive benefit from treatment. This is a nonrandomized trial. As part of the K/DOQI process, we do not consider this type of study to have a lot of evidence value, but there are better designed studies.
Targeting higher serum ferritin
This is a study by De Vita et al, and I am one of the authors on this study. This was a relatively small study. It is 36 hemodialysis patients. This is a randomized control trial. We targeted half the patients to achieve a ferritin of 200 and half the patients to achieve a target of 400. We are starting to look now at higher values for ferritin and how that drives the efficacy of treatment. The actual ferritins achieved - as you see in the third bullet point - 261 in the low group and 387 in the high group. If the 100 target of KDOQI makes sense, then you would not expect the 387 group to necessarily do any better than the 261 group, but in fact there was a substantial improvement at 28% reduction in EPO dose requirements with a higher ferritin target. Indeed, there does seem to be continued effectiveness as you go up to higher values.
Optimization of EPO therapy
Anatole Besarab from Henry Ford Hospital did a study published a couple of years ago where he took 32 hemodialysis patients. It is a relatively small study, but this is a randomized control trial, so it is very relevant and of good evidentiary value. He randomized patients to either TSAT, transferrin saturation of 20 to 30 or TSAT of 30 to 50. By doing that, patients in the low group achieved a ferritin of 297. In the high group, the ferritin achieved was 730. Do you think that the higher value for ferritin would improve responsiveness? Here you look at TSAT values and you saw how they separated, not particularly great. You see the separation in ferritin, which really was impressive and got us up to that 730 ferritin value.
When you look at hemoglobin achieved, not a very dramatic difference between the 2 groups. When you look at the amount of iron that was used, of course it takes a lot more iron to get patients up to that 730 ferritin value. But, the headline and the primary defined endpoint for the study is, what happened to EPO use. By getting ferritin values up to 730, there was a substantial reduction in overall need for EPO, and that was a 40% reduction. It is a dramatic decrease in the overall need for EPO. The Chang study, the Besarab study, and the De Vita study give us evidence that iron treatment maintains much of its effectiveness at some of these higher values that we look at. There is a current study that is in progress right now, which is led by Daniel Coyne from Washington University looking at treatment of patients with higher levels of ferritin to look for evidence of continued effectiveness.
Summary of efficacy
When we summarize the data, what have we learned? The Chang study shows us that raising ferritin with IV iron from 930 to 1300 ng/mL leads to greater EPO responsiveness. De Vita and Besarab: The De Vita study shows going up to 387 ng/mL improves responsiveness, Besarab shows that going up to 730 does, also. We see that the earlier studies with less direct methodology did not quite show the full spectrum of effectiveness of intravenous iron treatment.
I said at the beginning that in coming up with targets, you would be very interested in balancing how effective the treatment is going to be against the possibility for safety concerns. When looking at iron treatment, the first safety concern that comes to my mind, and I think by far the most important, is the risk for anaphylaxis and anaphylactoid-type reactions, where with iron dextran, maybe 1 in 200 or so patients treated would have a relatively severe reaction. The good news here is that the newer intravenous irons that do not have dextran as part of them have a much lower risk for reactions. When a reaction does occur, and I am sure you have all seen this, they are just not very severe. It is not the same catastrophic-type reaction that you see with iron dextran. There is another potential risk with iron. There remains some concern at least for infection with excessive intravenous iron use. The literature has not to any great extent borne this out as an important problem, but we need to be reasonable and conservative in the way that we treat patients. If you have somebody who is acutely infected, you would not want to treat that patient during bacteremia or other severe infections with intravenous iron treatment. Oxidative tissue injury is a question that comes up and is being researched, and potential links to cardiovascular disease have at least some potential importance.
Case study 1
Let us look at a couple of case studies, and these should look real familiar to you as I get to the end of my presentation. We will start with a 64-year-old man on dialysis for 3 years. In the past, he responded well to EPO, but over the past 3 months, the hemoglobin level has been decreasing. It takes more and more EPO to get the patient there. This happens all the time in your units. As it happens, the serum albumin is decreasing, and the iron status shows a TSAT of 13% and a ferritin of 782. Do you treat the patient?
Treatment with intravenous iron
Here is what happened. The patient was treated with intravenous iron. Initially, the low hemoglobin of 9.6 rose a bit, but only up to 10.4, and really did not respond over the course of 4 months of treatment with intravenous iron. Eventually we learned what the reason is, that the high ferritin in this patient was being caused by an infection, not in the patient's current graft, but in an old graft in the other arm, which had not been used for years, but now had a smoldering infection. There was no redness. There was no warmth. There was no drainage. It was only by performing an indium scan that it turned out that this was the case. The graft was removed, and the patient got better quickly. Within 2 months, the hemoglobin level came back up, the EPO dose requirements went down, but the message in this case is intravenous iron was not effective because of the presence of infection.
Case study 2
This is a 71-year-old man with a hemoglobin of 10, the TSAT is 9%, and the ferritin is 802. There is no evidence in this patient that infection is present.
This patient responds briskly to intravenous iron. The initial hemoglobin levels are less than 10 or just around 10. With intravenous iron treatment, the hemoglobin level rises through 11, through 12, and as high as 13. No increase in EPO dose. This is purely the effect of iron driving up very successfully the patient's hemoglobin level.
The message of these 2 slides in concert with what we have spoken about from the studies is that not everybody with a high ferritin and low transferrin saturation will respond to intravenous iron, but some will. That is why it is really important to individualize treatments. You look at whether infection is present. If infection is present, then intravenous iron is not the treatment to be using. One way to look for that, if you can find obvious infection, is check the CRP level as a marker for inflammation. Consider a more direct test of iron, such as reticulocyte hemoglobin content or CHr. Consider the hemoglobin and EPO dose. Is it a crucial factor in this patient? Does the patient already have 14 g/dL hemoglobin, where the iron numbers would have been quite as important, or is the patient struggling to get hemoglobin levels up to 11. Consider intravenous iron treatment because some of these patients will respond very effectively.
In conclusion, the upper target for serum ferritin has to reflect a balance or a compromise between our knowledge on the effectiveness of treatment and potential safety, but ultimately whatever the guidelines are, it comes down to treatment at the individual patient level. It is up to the nurses, doctors, and others caring for the patients to consider these factors in making decisions regarding intravenous iron treatment.
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