Anemia and Iron Management: Addressing Challenges and Generating Solutions
ANNA Lunch Symposium, September 25, 2005
Successfully Managing Patient Outliers: A Case Study Analysis
I am Dr. Folkert. I come from Bronx, New York. I am at the Montefiore Medical Center in the Albert Einstein College of MEdicine. I am the Medical Director at a unit and work in the hospital. I am working in the trenches with you. I am not going to come to these cases as some sort of ivory tower person who once in a while... But I come to you working in the trenches with you and taking care of patients in outliers. With that as a background let us go.
Here are the objectives: We are going to discuss the benefits of IV iron and EPO. You have already heard a lot about that. We are going to look at appropriate treatment practices for IV iron and EPO when we are looking at the challenging patients, the outliers. We are going to talk about some cases with high serum ferritin levels. We are again going to explore cases of functional iron deficiency versus RE blockade. And look at how we, again, think about and interpret patients that have hyporesponsiveness to EPO.
IV iron to optimize HD therapy
This you heard. This is just to help you review. To make sure that you are going to pass the test at the end of this. IV iron prevents absolute iron deficiency. That term, when it is used, means that because of blood loss, and/or not getting enough iron, you develop true iron deficiency. When you saw those cartoons of where iron stores are in the body, absolute iron deficiency means there just is not enough iron there. That is easy to fix because you just give iron to replete the stores.
Functional iron deficiency means that there is not enough iron bioavailable, meaning that the demand is there, the iron is in the stores, but you can not pull it out fast enough to make red cells.
As an aside, we often look at our dialysis patients and think they have anemia and that bone marrow must be kind of sluggish, but that is wrong. In fact, when you are making rounds in your dialysis patients their bone marrow is making red cells at a rate far faster, maybe up to four times faster than your marrow is. And that is because they have to make up for the blood loss. Plus, you are really driving the system with EPO, so it is a very dynamic system. Functional iron deficiency means that you do not deliver the iron fast enough to the marrow to be able to put it into the cells, so you make microcytic or not enough red cells.
Response of HgB to EPO plus IV iron
It is also true with IV iron that you get a higher hemoglobin in hemodialysis patients if you combine IV iron and EPO compared to either using just EPO or EPO and oral iron. Here is an example of that. This slide shows that you get a much more rapid response to getting the hemoglobin up and into target if you use EPO and iron. This is a little schizophrenic, so I have to point at one slide or the other. I am going to point at this one.
This one is just IV iron alone, and this is a negative slide. It tells you the percent that do not make the end point. So about 30 percent do not make the end point with just IV iron alone. But if you combine the two by 150 days almost everybody makes the endpoint and you know this already from your practice, right? You have to put those two together in order to have an effective response.
Do you worry about giving iron? I think everybody does, but I hope when we get to the end of the session today that you will feel a little more comfortable about treatment with iron and not harming patients.
Mortality risk with no iron use
This is data that was presented at the ASN in 2002. It is a retrospective look at people getting iron and what happens in terms of cardiovascular mortality or infectious mortality. Here is your reference range. It is 25 to 34 milligrams per dialysis session overall, so it is about 100 milligrams a week, 75 to 100 milligrams a week, which is typical maintenance dosing.
You can see in those usual ranges that the relative risk here for either of these problems is about one. This is your reference range. The patients that did not get any iron at all in this retrospective look in fact had the highest mortality risk for both of those problems. They did not get any iron at all. There is some increase here that we will come back to in a minute that it was up a little bit at really higher doses. But, again, you have to factor a lot of comorbid problems into this again in patients that are not responding because you may be trying to push with a lot of extra iron to these patients to get them up into target. They probably have a list of problems causing their anemia that Andrea went over: underlying cancer, underlying inflammations, and infections. And so they do not respond to the iron.
Effect of IV iron in HD
It is also true that iron not only works with EPO but in some instances iron itself causes a rise in hemoglobin. In fact, in this study these patients were all severely iron deficient. This group (Left-hand bars) got IV iron over this period of time up to 26 weeks, but no EPO. Their hemoglobins came into target even without EPO. Oral iron (middle bars) just does not work. It the same as no iron (Right-hand bars) and that I think the community has finally registered that fact, that oral iron in dialysis patients is not able to supply enough iron because of the high demand, and also you may not absorb enough of it, and so that does not work. IV iron plus EPO, it is a great combination.
Case Study 1
Let us do some cases. Here is the first case. It is a 64-year-old man. He has been on dialysis for 3 years. There is no clinical evidence of infection. He weighs 74.8 kilograms. We have not been able to get him into target hemoglobin. His hemoglobin is staying at around 10. His serum ferritin is 815 ng/mL, and his TSAT is 15%. Here is his current treatment. He is on a relatively high dose of EPO, 15,000 units with each dialysis treatment (three times a week). He has also on maintenance IV iron. He is getting 31.25 mg weekly in the face of that TSAT and that ferritin. Okay? There is the case.
Management-Case Study 1
How would you manage this patient? Life usually has many more than three choices, but we are only going to give you three today. You could administer oral iron and reassess in 1 month, increase EPO, and hold the iron because the ferritin is greater than 800 ng/mL, and you can increase the maintenance iron 62.5 mg. You have a few seconds to think about it. This is where if you get it wrong you fall through the floor.
How many want to do "A?" "A" is not the answer. How many want to do "B?" "B" would be to increase the EPO. He as already on 15,000 but like we said, his ferritin is already above the 800 ng/mL that DOQI would say. That is what we did not do either. "C," in this case we decided to increase the maintenance iron primarily because of that low TSAT. We decided we would ignore the ferritin that is above target and try to see if there would be a response to more iron.
Response to increased IV iron
Let us see what happened. Here is his hemoglobin of 10 g/dL in May. Iron is increased here in June, and you can see the hemoglobin increases nicely into target. The serum ferritin in this patient hangs still right around 800 ng/mL. It does not change a whole lot. Over this period of time with exposure to extra iron the TSAT comes up. So bottom line with this patient? Iron deficient or iron insufficiency. He is already on maintenance iron but not enough to make up for the demand. And he probably had low stores, and over this period of time you can see that you corrected and brought him into target. The concern there was you might not have given it because of that ferritin, because it is above the target and it would be above the recommendation, and we will come back to that in a second.
IV iron reduces EPO requirements
We know this, that if you give enough maintenance iron, and you know that from your centers and your patients, that you get a significant decrease in the amount of EPO that you need. This patient is already on a high dose. He was on 15,000, and when you gave him more iron he needed less EPO and was in target. That has been shown by a whole number of studies. This is pretty much common news now in our daily care of the patients. That was Case One. He was iron deficient. We will come back to that ferritin in a minute.
Case Study 2
A 72-year-old woman, and she has been on dialysis for 4 years. Her past response to EPO has been great. She weighs 61.9 kilograms. She has been able to stay in target, but now her hemoglobin level is starting to fall. And as it has been falling out of target range, the EPO has actually been increased from 9,000 to 15,000 with each treatment (dialysis three times a week), but still her hemoglobin has decreased fairly abruptly from 11 to 9.6 g/dL. The ferritin is remaining high while this drop happens, and the TSAT is low. We looked at the patient. We again do not see any obvious sign of infection anywhere. White count is not high. She is not having fevers, night sweats, and she is not on any IV iron because in part that high or high-ish ferritin.
Management of Case Study 2
What would you do with this patient? Here are your 3 choices again. You can give a repletion course of IV iron. In our terminology, a repletion course would be to give about a gram of iron over 8 to 10 treatments to fill the stores. Increase the EPO requirement up to 18,000 with each treatment or start maintenance IV iron. Those are your 3 choices.
How many want to just give a repletion course of iron? I will not embarrass you. That is the question. You do not have to raise your ... you do? Okay. It turns out we did not do that. It does not mean you were wrong. It just means we did not do that. I think when you talk about the outliers, and you realize how complicated it can be, that there is no gospel book to look up what was the right way to do this. That is important because if you get stuck with the outliers, to say there is "only" one right way you can do this, you will get in trouble. Because as you can see with these cases they are all a little bit different. They present to you often the same, but the treatment is not the same. You want to increase the EPO some more, even higher? It seems kind of like a lost cause. It was already tried; it was raised and after it was raised, in fact, the hemoglobin was still falling. It does not seem likely that that is going to help and so that was not done.
Response to maintenance IV iron
How about maintenance iron? This patient was not on any iron, so let us see maybe in fact, she will be happier if she gets some iron. Here you can see what happened. Here was this abrupt drop (January). IV iron is started here (February). In March you say, well, okay, it is working? Then you come back from vacation in April and it is not working. In May it is definitely not working. So the IV iron is not helping here, and the ferritin is, in fact, by May, starting to rise even higher. TSAT, very little change. The reality of those numbers is even in the face of the maintenance iron the TSAT is not going up. How in the world do you explain that?.
Why the patient did not respond?
Why did not the patient respond? Turns out that there was an occult infection. When we saw those numbers you get an indium scan and you find out there is an old piece of AV graft in one of the arms and it is surrounded by a little collection, a not so little collection of pus that is clinically not apparent. You have this very high inflammatory state in this case. The ferritin keeps rising, and you have RE blockade.
That is exactly what Andrea was saying. You just have to step back from a patient like this and you look at the trend. And the trend, when you start to look at it and think about it, tells you that something else is going on and in this case you have an infection. When the infection was treated, the hemoglobin increased. The EPO requirement started to fall back to where she used to be, and the ferritin starts to fall, of course, because the inflammation was taken care of. So, again, assess all possible causes for high serum ferritins.
Risk of death by serum ferritin level
I told you we would come back to these ferritins. The question is, "Are these high ferritins dangerous? When you go above 800 ng/mL, if your guideline tells you to go 800 ng/mL. Or you go to 850 ng/mL, and the doc comes and grabs you and says, "Oh, you are trying to kill my patients," or, "That is dangerous. How can you do that?" There has been a lot of concern about that, of course, as we take care of patients.
I want to show you two slides from a recent article by Dr. Kalantar-Zadeh just out in The Journal of the American Society of Nephrology. This is from the DaVita Database. You are looking at, I think, some 50,000 patients where they aggregated statistics, and followed these patients all during their times on dialysis. Instead of a one-snapshot look at the ferritin, it follows them through by quarters. And this gives you a much better idea about whether the patients that have high ferritins are sicker because you give them iron or because of other problems.
This is the DOQI zone. We were laughing about this, kind of, this is the "ESPN Zone" but this is the DOQI zone of safety, supposedly, 100 to 800 ng/mL. Let us look at just this purple line here. This is a case mix and it adjusts for the inflammation in these patients. This is malnutrition inflammatory complex (MICS) in these patients, which many patients have and that is why the ferritin is so high. If we go back to the previous case that had the infection around the graph, she would fall in here.
If you just look at it unadjusted, if you have a high ferritin the risk of death here for cardiovascular mortality goes high. What it is telling you is that the risk of death is there because of the underlying illness, either the malnutrition, the chronic infections and not per se because of the iron or the ferritin. Because, in fact, if you do the statistics and you take a case mix and an adjustment for inflammation you can see even way out here in this huge group of patients, that when the ferritin is up to 2,000 ng/mL, there is really no change in cardiovascular mortality if you factor out the other problems.
Risk of death by TSAT
This is a really important paper that I think the nephrology community will spend a lot of time on over the next few months or years to digest all the information. It tells you the same with the TSAT, that the low TSAT here, this is all-cause mortality with TSATs. When you are low, below 20% here, all-cause mortality goes up significantly. But in the range here (yellow bar), even up to the 50% range for the TSAT, when you factor in for inflammation and case mix, there is no increase in mortality. So that is important. That means that when we deal with outliers, if you have a ferritin that is 850 ng/mL and the patient is still anemic like we saw, giving them some iron to see if you will get their hemoglobin back up into target is not dangerous. I mean, the underlying inflammation that we did not find for a while in that patient is dangerous, but giving iron is not dangerous in that setting. I think this is very useful information to help assure us that we can look at outliers, and if we think they need a trial of iron to get better we should not worry about it. It also means you need to be more flexible sometimes in your guidelines about what you use for cutoffs, just like Andrea was saying.
Functional iron deficiency versus RE blockade
That is the first two. Let us talk again about functional iron deficiency versus RE blockade. Functional iron deficiency, as I mentioned, you need to get the iron to the marrow faster than you can deliver it. RE blockade is a defense mechanism that we have developed as we have evolved with our use of iron. It is a safety factor. If you have ongoing infection or inflammation, the body is not going to move iron around because it can be used by some bacteria for energy source in the face of infection. It is oxidative, so it can be damaging to cells and endothelial cells. In the face of acute inflammation or infection, RE blockade happens quickly. It stops movement of iron while you then heal the underlying problem.
Case Study 3
Case study 3. A 60-year-old woman. She is on hemodialysis. She has had some recent abdominal problems. She had a small bowel obstruction, and she was in the hospital with that for a while. She was sick, she was hypertensive, and she had a weight of 70.3 kg. She has an abrupt change in her labs. Her hemoglobin falls from 10.5 to 9.8 g/dL, and the ferritin takes a spike up to 750 ng/mL, and the TSAT falls. She is on 12,000 units of EPO with each treatment (three times per week), and she is on maintenance IV iron of 62.5 mg a week.
Management of case study 3
You are starting to see a theme here, 3 choices. What do you want to do? Reduce the iron and increase the EPO. Use an alternative iron marker to see if you can figure out what her iron stores are, like such as using a reticulocyte hemoglobin value to see what her iron stores are, or increase the maintenance IV iron.
How many want to do "A?" Either all bashful or you are all right. No, "A" is not the answer. That is good.
How about another marker to see if we can find out what the iron stores are like the reticulocyte hemoglobin content? How many people here use it in your unit? How many use it in the unit? A few. So how many want to use it in this case? A few. Well, you might be right, except that the literature, and those of us that have looked at it, it is not a very good marker, especially when there are acute changes. We were all excited when it first came out, that it would tell us exactly what the marrow was seeing for new red cell formation. It looked like it was going to be a good test. But it turns out it is not working so well, and people are still trying to define what the lower and upper limits of it should be to be helpful. We did not think it was going to be so helpful, so we decided to increase the maintenance IV iron and see if she would respond to that.
Response to IV iron in case 3
Let us see what happens. This is the background I just gave you. She has this 10.5 g/dL hemoglobin fall to 9.8 g/dL, and a rise in ferritin. The TSAT is falling. And even though we increased the IV iron, none of that had changed. So we increase the IV iron. There is no change here and the ferritin is staying high, and the TSAT, even in the face of the iron, is really not changing much at all either. The response to the IV iron here looks pretty suboptimal. It is very suboptimal.
Importance of assessing the whole patient
What happens here? We increased the iron and we said it is still down. It turns out then that she had had this history of small bowel obstruction. And she starts actually to get sicker, and she has more abdominal pain (January), and she has a small collection in the abdomen of walled off abscess. And so she has RE blockade, and she cannot use what is there until that is drained. And when the abdominal problem is gone, she can respond to the IV iron and EPO, so you get a nice rise in the hemoglobin (February). Ferritin starts to fall now. The inflammation is gone, and it is going to be a little better reflection of what her iron stores are. And you can see now that the TSAT starts to rise because there is no more RE blockade. So transferrin, in a sense, has been given iron, released by the RE system, and it can start to move it around. That is RE blockade.
Case Study 4
Then case study 4. This is a 65-year-old man with diabetes and hypertension on dialysis. He weighs 99.8 kg. He is a big guy. His hemoglobin is below target. Hemoglobin is 10 g/dL. The ferritin is 550 ng/mL. The TSAT is 22%. His current treatment is EPO 9,000 U three times a week. You can look at it and say "Really, not bad." These are kind of right close to range, and the hemoglobin is just a little bit low on EPO of 9,000 U.
Management of case study 4
Three choices. Give IV iron because he is within these guidelines, as I said. For the ferritin and TSAT you could just leave it and not do anything. Or, you could increase the EPO to 15,000 U. So there are your 3 choices.
How many want to do "A?" Some of you. It could be reasonable. It is not what we did. How about "B?" Watch and wait. That does not quite make sense, because we have already been watching and waiting and the numbers were sort of in target except for the hemoglobin, which is not in target, so I am guessing that if we watch and wait it will not get better. It is possible, but it probably will not.
Response to increased EPO dose in case 4
Let us increase the EPO to 15,000 U and see what happens. If we believe that the TSAT, which is on the low end of where the target of range is supposed to be, and the ferritin is in target, then maybe if the iron is there, give a little more EPO and see what happens. Hemoglobin is 10 g/dL. Increase the EPO in February and it starts to come up. Increased it a little bit more in March. Serum ferritin is falling in the face of that and by April the hemoglobin is down to 9.6 g/dL. TSAT stays fairly flat and then falls down to 20%. What is the problem?
Iron deficiency. That is right. So the people that wanted to do "A" and give the IV iron were the people that were right and those of us that took care of the case ... (yes, give yourself a hand. That's good. There will be a special reward for you on the way out). The people that wanted to do that, you were right. On the other hand, the people that wanted to increase EPO because you saw that the parameters were relatively in target, made a logical decision based on the numbers you had. It just happened to be wrong. That is what happens. That is why this is so challenging. I mean, if it was really easy to do, none of us would have to be here. We could be down at the art show or whatever. Because you would just plug it in, dah dah dah. This, this, this and then you would have it easy. Anemia management really would not take you any time at all and it would be really easy.
Repletion course of iron
But it is not like that, because here we had numbers that looked right and the patient was clearly wanting more iron. So give iron, up comes the hemoglobin. The serum ferritin now starts to rise, and the TSAT starts to rise. And by June, you could decrease the EPO dosing, a clear example of iron deficiency.
Managing the challenging patient
Those are the challenging patients, and they are challenging because they all at first blush look pretty much alike. That is true for RE blockade, and it is true for functional iron deficiency. The TSAT can be low. The serum iron can be low, is low. In RE blockade, as I said, you have an acute-phase response due to the inflammation or infection, and it is not going to allow release of iron from the stores. But in functional iron deficiency, the stores may be okay, you just cannot access it fast enough. Iron delivery from the RES is blocked here, and here it is too slow.
How do you sort of these out? You sort it out just like we have thought through it here. You look at the whole patients. You look at the trend, and then lots of times you end up giving iron to see if they respond. Some of them clearly will respond, especially the ones with functional iron deficiency or people that actually have more iron deficiency than you realize based on the numbers like the last case demonstrated. They are challenging patients. I think the new information, again, about the ferritins tells you not to be so scared of the ferritins for the outliers. Do not be too rigid with the cutoffs. They are listed as guidelines. They are not listed as law. I think that is a very important thing to remember. Many patients with high serum ferritin levels will respond to IV iron therapy. As our interventions improve, there hopefully will be fewer outliers, and the overall number of patients with positive outcomes will increase. Thanks for your attention.
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TO GO TO FIRST TALK (Dr. Easom)