Anemia and Iron Management: Addressing Challenges and Generating Solutions
ANNA Lunch Symposium, September 25, 2005
Minimizing the Implications of Iron-Deficiency Anemia With Appropriate Treatment
Anemia and iron management.
Moderator: I am very honored and pleased to introduce the first speaker, who is Ms. Andrea Easom, who is one of you all. She is a clinical instructor in the Division of Nephrology at the College of Medicine, University of Arkansas for Medical Sciences in Little Rock. She is also a family nurse practitioner and holds several degrees in nursing and psychology, as well as being certified in nephrology nursing. During the course of her academic and professional development, she has received several honors, including the Nurse in Washington Internship, which is provided by a grant from the American Nephrology Nurses Association. She is currently a member of several professional organizations, including being a board member of the National Kidney Foundation of Arkansas, an editorial advisory board member of Nephrology News and Issues , and a professional section member of the American Diabetes Association. I look forward to hearing her talk. She has lectured extensively and conducted numerous workshops, and authored or coauthored over 15 publications that address the latest developments in hemodialysis and peritoneal dialysis treatment, challenges facing Nephrology Nurses, and current issues involving the management of patients with end-stage renal disease.
She has participated in many research activities, including a study on the efficacy and safety of intravenous iron in anemic patients that are receiving peritoneal dialysis. I am happy to introduce Andrea. She is going to be speaking to us on minimizing the implications of iron-deficiency anemia with appropriate treatment.
Ms. Easom: Being from the South I always like to be included in "y'all." So, I am glad to be one of "y'all."
Minimizing the implications of iron-deficiency anemia
Nurses, especially nephrology nurses, I think are wonderful people. We have a hard job and we have a lot of expectations. The expectations, especially on nephrology nurses, are growing and growing. I want to talk about some of those as we go through the talk today.
The objectives are listed here. As you think about what we are talking about today, I really want you to think about the patients that you have in your dialysis units, and think about the protocols that you are following. Because we have developed, especially in Nephrology Nursing, with all of the data that we have available, and especially in the area of iron and anemia management in general, we follow a very specific protocol. So, we are very protocol-driven. And sometimes we have to think out of the box. What I am hoping today is to help you think out of the box, and empower you to take care of your patients who are what we would call "outliers." In doing that, we are going to talk about some of the comorbidities that are associated with iron-deficiency anemia. We are going to summarize the current guidelines, especially K/DOQI, and we are going to look at the importance of both EPO and iron, the timing of it, and actually focusing more on the maintenance dosing of iron. Are we doing it right? Think about what you are doing in your units.
Anemia risk factors in hemodialysis patients
This is strictly from K/DOQI, and it looks at some of the factors that are associated with anemia in our patient population. Those top 3 are things that we think of quite often. We think of iron-deficiency anemia due to blood losses, and we think about what iron deficiency anemia is doing to the balance of EPO and iron. We also think of infection and inflammation, specifically the reticuloendothelial blockade, which Dr. Folkert is going to focus on a little bit later. What I am going to start out talking about is something that we do not talk about nearly as much. It is looking at the data for the coexisting medical conditions, especially the top 3. Because in preparing to talk to you all the day, I have stopped and looked at what we are doing in our unit, just like I am asking you to do in your unit. What I found was that 20% of our patients had ferritins that were above 800 ng/mL. Of the ones that were above 800 ng/mL, 50% of those were in the 800 to 1000 ng/mL range; about 25 percent of them were in the 1000 to 1500 ng/mL range. Then I had actually 2 patients that were between 1500 and 2000 ng/mL and 2 patients that were over 2000 ng/mL. I looked at these comorbid conditions in them. Many of them fell into parathyroid problems and cancer problems. But when you stop and think, malnutrition, dialysis adequacy, and bone disease are rampant through our patient population. Those factors fall into the functional iron deficiency that we are going to talk about a little later. As you are looking at your outliers, because as things progress and we get paid for performance, you are going to have to be accountable for those patients. We want to see what can we do to bring them into target.
First of all, let us look at malnutrition. When we think of malnutrition, we generally think of albumins, and we do have a lot of patients with low albumins. We try to have them between 3.7 g/dL or even over 4 g/dL, but lots of them fall underneath. That is one factor that we look at, and albumin is not really the greatest factor because it has got a long half-life. So, malnutrition can exist for a long time before it is reflected in a lower albumin. All of the plasma proteins are probably affected when your albumins are also low.
Total iron-binding capacity in hemodialysis patients
Let us look at total iron-binding capacity because that is one of our iron functions. This is a study done by Kalantar. What he did is he correlated TIBC (Total Iron Binding Capacity) with subjective global assessment. The subjective global assessment, if we have any dietitians in the group, were done both by a dietitian and by a physician. As you can see, as patients got more and more malnourished, their total iron-binding capacity went down. In this stage here (green bar), you are severely malnourished. It was around 150 to 170 mg/dL. This is very important because what we are going to see in a few minutes is TIBC is the denominator for configuring your transferrin saturation, those TSATs (Transferrin Saturation levels) that we use to decide how we are going to treat people with iron. In your malnourished patients, if your TIBC is less than 200 mg/dL, you probably have a falsely elevated TSAT.
He also, in a different study, looked at serum ferritins and correlated the same way (global assessment of nutrition). As you can see, we have serum ferritins here (y-axis) and your subjective global assessment along the bottom (x-axis). If you go and look in your most severe group, those ferritins were quite elevated. The mean is right here, over 1000 to 1100 ng/mL. And if you look at the range, the low end of the range is around 800 ng/mL. We may well be holding iron in our most malnourished patients. When you are looking at those ferritins that are out of line and you are looking at holding them, some of those patients you may need to consider differently.
Adequacy and quality of dialysis
Looking at adequacy is always a problem. I will be honest. I looked at adequacy this week in our patient population, and I had to redraw about 50% of the studies because patients had short treatment, low blood flows, a few did not get them. That is an ongoing issue, and one of those outcomes we look at. What they found is that if you increase your dialysis dose, you get a higher hemoglobin or a decreased EPO usage. In one of the studies, the middle study by Ifudu, what he did was he increased the URRs (urea reduction ratio)from 65% to 72%, and his mean hematocrits went up from 28% to 32%, fairly significant. He did two things. He changed the membrane, and he increased the dose of dialysis, so, a longer time. It is pretty unclear what the effect was. There is not a cause and effect. There was only a relationship. We are going to look at another study in just a minute that kind of shows the same thing. Also, in a 1-year study looking at dialysis with ultrapure dialysate compared to regular dialysate, the ultrapure patients ended up with less need for EPO. They had less EPO utilization.
Relationship between dialysis adequacy and EPO responsiveness
In this study by Movilli, where he just looked at patients. Note that those patients are on target. They meet your guidelines. Their hematocrits were 35%. He divided the patients into Group A and Group B. Group A had Kt/V less than 1.2 and Group B had them above 1.4. Look at the doses of EPO. Perhaps some of those patients who are poorly dialyzed do not meet your targets here. In my group, I have already told, you many of those patients do not stay on very long. They also are not quite compliant in other things. They may well have high ferritins and have iron needs that we are not recognizing. But big differences in those EPO doses.
Pathway of Renal Bone Disease
Parathyroid hormone; we could spend all day on that. We have certainly seen, at least I have seen patients who have had parathyroidectomies and amazingly huge doses of EPO. These EPO doses can be reduced, and you can maintain the patients fairly easily after their parathyroidectomy because of less inflammation.
Effect of PTH and bone fibrosis on EPO efficacy
This study I found particularly interesting. Rao took 90 of his patients and only 18 met these pretty specific criteria. They were on dialysis and EPO greater than a year. They met target: 35% hematocrits within 8 to 12 weeks of starting the EPO. And they were able to stay on fairly constant doses of EPO and maintain that hematocrit. They had no symptoms of parathyroid disease or aluminum bone disease. Their serum aluminums were okay and there was no known cause to resistance of EPO.
Response to EPO
He divided those patients into 2 groups. One group, he called the poor response group. They needed more EPO, more than 100 units per kilo 3 times a week, and then the good response group that needed less than 100 units/kg.
What he found was that the EPO dose in the poor group was higher, the PTH was quite elevated around 800, and that they had marrow fibrosis. We look at PTH, and very few of us get bone marrow biopsies, but we know what is going on with our PTH as we are titrating it. We need to stop and think "What is happening to the bone?" I did not think about it either, that that bone, as it fibroses, you get calcium and phosphorus mobilized out of it. Then that marrow is not going to be good marrow. It is going to require more EPO. And, actually, it may not have enough iron. In the good group, much less EPO. Their PTH levels were not in target, but they were close. And some may well have been on target. But their mean PTH was high, and only 1% were fibrosis.
Additional causes of inadequate response to EPO therapy
Those are a few examples of patients that may well not have the iron stores that they need. But to make sure that we are all on the same page, I thought we might just step back and do a little bit of physiology. Because that way we are all on the same page in looking at what is going on.
You can see across the bottom. This is one of my favorite slides. It takes your stem cell from the bone marrow into the red blood cell, the mature red blood cell, taking around 25 days. This is why they tell you not tweak those EPO doses more than once a month because you have not seen the reflection of what your change was. Then, when you stop and think, red blood cells have a normal life span is around 120 days. Our patient population may not to live as long. It is going to be more like 90 days, give a plus or minus depending on what is happening with your patient. What is happening with the timing? Timing is all important. Right here, around day #15, #16, that is when EPO receptors come around your cells in that burst-forming unit and they actually surround the cell and protect it as it goes into the colony-forming unit. That is when EPO needs to be present and EPO gets into the cells. Next, when it goes into the next phase, which is right around day #20, then transferrin receptors are all around that cell, and they are taking iron into the cell. If you do not have iron present on day #19, #20, whenever it will be in this particular patient. If you do not get your iron in then, you are not ever going to get your iron in. If it does not go in during formation, then you are going to have a microcytic cell and it will never have the iron-carrying capacity that it should have. Then, as the cell goes out into circulation, you get the reticulocyte, which is important when you are assessing later on, and then your mature red blood cell.
Normal iron cycle
Let us look at the normal cycle. In normal folks, your iron absorption and iron loss match. You get 1 to 2 mg of iron that gets absorbed in the gut, and you lose 1 to 2 mg a day. Then you have transferrin, and the important thing to look at is transferrin has very little iron in it, about 3 to 4 mg. Total body iron is usually around 3 g or that neighborhood. What the transferrin does is it is kind of like the iron taxi. It picks up iron from the gut and it takes it wherever it needs to go. One transferrin can make about 10 trips a day. It is pretty efficient. It will take the iron either into iron storage, into the reticuloendothelial systems, such as the liver, the spleen, and the bone marrow. It is also used for red blood cell formation. Then we have about 300 mg that are used for myoglobin and other enzymes, but you have about a third or a fourth of your iron in storage and the rest of it is more in the active phase.
Iron cycle in hemodialysis
What happens in our patient population? First off you look and you see that there is less iron absorption. Why? Our patients are malnourished and they take binders. Binder binds with some of the iron that is in the food they eat, or iron pills that they may take at the same time that they are taking their binders, which they should not have. Next, you can look and see that transferrin is down, because in the presence of inflammation and malnutrition, transferrin is an acute-phase reactant too, but it is a negative one. It goes down, as does albumin. You have less of those transporters running around. When you look at iron storage, the serum ferritin may well not reflect the tissue ferritin, which is where the iron is actually stored, and we are going to talk about that a little bit more. When we look at iron utilization and the red blood cell formation, what are we doing? We are up there flogging that bone marrow to make more red blood cells with superphysiological doses of EPO. At the same time, patients are losing 3 to 9 mg of iron a day during their dialysis, left in the dialyzer, in the wash-back, etc., and then we still have a small amount that is used for muscle.
Monitoring iron status
Let us look at some of the factors that we look at when we are looking at iron. We look at the serum ferritin, which is a reflection of the iron stores. And we look at TSATs, which are the circulating iron. Look at those ranges. They are huge. And the reason they are huge is because there is great variability. Even in normal, healthy people, serum ferritin may be as high as 400 ng/mL. Then we have hemoglobin, which has a very narrow target to hit.
Let us look at some of this variability and see why. We have tissue ferritin, which is in the reticuloendothelial system and we have iron. Iron comes into that system and serum ferritin goes out. In a perfect world, serum ferritin should be reflective of iron stores. This is not necessarily the case in our patients, because due to infection, inflammation, and other things, serum ferritin will be released into circulation. If you took someone, one of our patients with a serum ferritin (let us just pick 500), and compared it to a normal, healthy person that is around that same range, our patients would have less iron stores at any given level of ferritin than the normal population.
Definition of TSAT
Then TSAT, again it is not a direct measure. The TIBC is the denominator here. This is a cartoon that shows you that if your TSAT was 30% and your TIBC is less than 200 mg/dL, you actually have much less circulating iron than if your TSAT is above 200 mg/dL. It is just the factor of any denominator. This is actually a reflection of your transferrin, not a direct measure, but it correlates pretty well.
K/DOQI guidelines to manage iron supply
When we look at those guidelines, those targets were supposed to hit. For serum ferritin, I would tell you that if you have a ferritin that is under 100 ng/mL, you can be pretty comfortable that your patient is iron deficient. I am not so sure above 800 ng/mL. You can see that this is opinion-based, because when the experts got together, it was really hard for them to decide because they used just evidence-based data on what that cutoff should be. I hope after we finish today, that we will give you enough food for thought that you can say "Hmm" also, and be able to challenge that when you think it needs to be challenged. Then the transferrin saturation, again it is the measure of circulating iron and we kind of go with those. I know in my patient population, I will shoot for somewhere in the mid 20s to 30s, though you are going to find them all over the place.
Adult in-center hemodialysis patients
When we looked, we looked at all of those things and we looked at a little bit of the research that supported that. Let us look at some of our clinical performance measures. This is the percent of patients that meet your hemoglobin targets of 11 g/dL. Where are the problems? Females? A little bit lower. That kind of makes sense. Catheter patients? 71% met the target of 11 g/dL. When you think about your catheter patients, sometimes they are either new patients or they are also some of the sickest of the sick. They may well have measures of inflammation or some of those coexisting things, and we may be having them be iron deficient. Patients that have lower Kt/Vs, patients with lower albumins. All the things we talked about, those are your outlying patients frequently. Then your incident patients, your new patients who have been on less than 6 months, and the only way to get those corrected probably is to get good anemia management programs in your CKD programs. I hope we have a lot of APNs that are doing that.
Treating with proper IV iron dosages
I hope it gives you cause to think, "Hmm, how am I treating those patients?" When we look at iron, this is the percent of patients (y-axis) and this is the mean iron dose (x-axis). You can see that 20% of the patients got less than 100 mg a month. And if you go with the figure of somewhere around 200 to 270 mg of iron a month lost, this patient is going to be iron deficient. I would imagine that the question would be, and this is not obviously causal, but are there those patients that get to a serum ferritin of 800 ng/mL and we just hold them? Because that is what happens in a protocol-driven world. You get to a serum ferritin of 800 ng/mL, it says stop. Is that your only alternative? You should have prescribers. You should have APNs or physicians that are prescribers. If you go and assess that patient and look what is going on with them, look for the cause, then go to whoever your prescriber is. And many of those patients may well need to be continued on iron, at least a maintenance dose. I also find as I have worked with different anemia managers in our own clinic, again that novice to expert. When you get that brand new anemia manager, it is pretty overwhelming for them. And they are focusing on EPO and focusing on trying to meet those targets. It is not until they get a little experience that they start tweaking the iron also. I would tell you that all of it is a tweak. When my anemia manager comes and I am looking at something and occasionally there are those patients that get up to 800 ng/mL and you are looking and seeing what you have done and you have missed an opportunity to tweak that iron, that maintenance iron dose down. As you are tweaking your EPO doses, you should also be looking at your iron doses and seeing what is going on and making adjustments accordingly.
IV iron dosing by K/DOQI guidelines
We do have the guidelines, and they are kind of our bible. We want to replete patients who are obviously iron depleted with ferritins below 100 ng/mL and TSATs below 20%, and we do that in many different ways. This says give a course of 1 gm of iron over 8 to 10 consecutive dialysis sessions. What I get my anemia manager to do is this. I do not order "X" level of ferritin, I order iron. However, we are ordering it on patients that I am titrating. We get ferritins every month, and so then we stop. It should be this balance. You can do it a lot of different ways. If they do not replete, you obviously treat again. Hopefully you will be looking at why they are not getting repleted. And then you get maintenance doses, either 250 to 1000 mg within 12 weeks. Again, I do weekly, biweekly dosing for my maintenance iron. You all need to look at your protocols and see what you want to do. The problem area here is the iron overload, as they call it, serum ferritins of above 800 ng/mL and TSATs above 50%. Look what it says, "Withhold IV iron supplementation for up to 3 months." How many protocols do you just stop the iron, and you do not even check anything for 3 months? This does not say look again in 3 months. It says up to 3 months. I would suggest to you on your patients that are your outliers who have those high ferritins, those patients should be checked on a monthly basis. Their ferritins should be checked monthly, you should tweak whatever you need to tweak. You will learn more about that as we go on today, but they may well be needing iron, and if you give them iron you may bring your outliers up to target ranges.
Anemia lab trending methodology
You should have a way to do that that is systematic and you are trending them. When you are assessing your anemia, you need to be looking at hemoglobin, TSAT, and serum ferritins at the very least. You ought to look at them over time, all the way for 3 months to a year, especially if you are only getting ferritins every 3 months. Then look at what your dosing is. I actually take our page when she comes to me. I only look at probably whatever our outliers are, so I have already told you that is going to be 10% to 20% generally. I will even mark when we change the dose, so I get a better idea of what is happening with that patient, and see, is it something that we are doing? Did we manage correctly? How should we tweak it this time?
Interpreting lab trends
If you are not sure what are going on, you should also be thinking about that patient. If it is inconclusive from just your trending and you did not do it, it did not make sense to you, you need to go back to what is going on with your patient, because that is truly the most specific thing. I will give you an example. I was rounding on a patient within the last three months, and she was fairly stable, but on this particular round her ferritin was up, her albumin was down, and just things were not right. I looked at her and I said, "What's going on? Because your body is screaming to me that something is wrong." I sat there, and she used to do a lot of drugs and she had been fairly drug-free. I said, "Are you doing drugs again?" She looked at me and she said, "Yes." She was doing crack and marijuana. From just telling her, "Your body is screaming" and she is realizing what she is doing, she got in rehab, she is off drugs, and her numbers have come down. That did not even make our list of "other conditions." I guess if their drug use is stable, you are not going to see a fluctuation, but hers actually did.
Interpreting Lab Trends: Hgb
It goes into patient-specific things. They do not know what is going on until something happens and you bring it to their attention.
Interpreting lab trends: Ferritin
If your ferritin is high, first of all, you need to look and see why. Was it a slow increase? Is it accumulation over time? If that is the case, we blew it. We have all done it. We had an opportunity to tweak that maintenance dose down, and we did not do it. You learn and you get better at it. That is how we go from novice to expert. Maybe it is a slow progression of disease. One of the people that I looked at that was on my over 1500, I just found out this week, has bowel cancer that was just diagnosed. If the ferritin is up, we need to be asking "Why?" What is happening? Your patient is screaming. I have a lot of patients who live in that 800 to 1500 range, and you are going to titrate a maintenance iron dose based on what is happening with them.
If you have abrupt increase, something is happening. Are they infected? Is there some inflammatory process that is going on? Did they get some blood? Did you or the lab make an error? Because timing matters. If you normally get lab on Monday and all of a sudden you got lab on Tuesday, it could well just be a dilutional factor that you are looking at. You have patients that gain a whole lot more fluid, they are a lot wetter on Monday than they are. You have to look and consider everything that is happening, and stop and think.
Estimated annual iron losses in hemodialysis patients
This is an old slide, 1975, mainly because there is not new data on this. We probably do not have an annual iron loss of 2.7 g. It could be closer to 2 g of iron. This is plus and minus for our patients. If patients are losing a couple of grams a year in iron, does it not make sense that they have some type of maintenance iron on board. Do not just replete them and wait until they get depleted to replete them again. You really need to learn to tweak and manage your iron administration. It has to be there on day 19 or 20.
In summary, when you are looking at your lab, think about the patient behind that lab, especially on your outliers. Know what their patient history is or if it is just come on your radar. Go back and look and see what is going on with that patient. What are some of those possible barriers that we have talked about? Use a logical system to analyze what is going on and identify the cause. Just do not presume that it was the iron or presume it was the EPO. Look a little bit deeper. Look at iron availability. Are they on a maintenance dose? Perhaps they should be. Look at your EPO dosing. Are we doing it? Do we have them in a yo-yo? Did you have to stop them when you did not want to? What is going on there? Focus on those patient-specific targets that we are looking at. Are they inflamed? Are they infected? Is it your malnutrition patient? Do they have a catheter in? Have they lost blood? Are they adequately dialyzed? Are they taking drugs again? What is happening? Because we all spend much more time with our patients than the physician is able to, and we are invaluable to them. If you will then take your patients that are outliers and you think some of these conditions are happening, if you have got functional iron deficiency you really cannot tell that from RE blockade. You have to give them a dose of iron or put them on some type of iron and see does it work. If it works, then it is functional iron deficiency. If it did not work, it is blockade. We have an expert here who is fixing to tell us all about that. I am through. If you have questions, want to talk about anything, put them out on your card, we will pick them up, and at the end, we will talk more.
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