Managing Patients With IV Iron and EPO :
Practical Techniques (Part I)
Balanced approach to anemia therapy
Let us get started with where we are going. We are talking about a balanced approach. You know that old song, "Love and marriage, you can't have one without the other."
Managing patients with IV iron and EPO
We could have a whole day's session on that today, but it is still true for iron and EPO, to have both of them work the way they are supposed to, you have to have a balance, and that is going to be more and more important as the new guidelines come out.
Let us talk about what we are going to talk about today. The first thing is understanding the importance of each one and looking at a little physiology because I think the first thing we need every morning is a nice dose of physiology. So those of you who have heard me before will get a refresher course in physiology and the ones who have not I hope it will make it plain to you, give you some insight on what is going on - because I think if we understand the physiology, then we are going to be able to make better decisions when we are looking at our protocols and looking at our patients.
We are going to review the K/DOQI guidelines, which is going to be a little tricky because the new ones are in press, so I cannot tell you exactly what they are going to look like, but I can tell you what we know and the information that I have will be coming from one presentation that I heard from Trish McCarley who represented all nursing in that endeavor, because she was the only nurse whow was on that committee, and I really appreciate her stepping up and taking that role, because we need nursing representation everywhere, and from transcripts, from Dr. Fishbane and Dr. Foley. The guidelines are in press so they could still change, but I will give you what I know of them and then we will have to wait and see.
We are going to discuss some of the limitations of iron and what we are looking at so that you understand when you are looking at your protocols what that number means because that is one of the biggest things that we need to understand along with what are some of the influences that our patients have that change those protocols. Are those true measures or not true measures, and then some of the things that you can do as you are dealing with that.
Starting out with erythropoiesis - and we cannot use pointers because I am not very good like this or I would be working at the airport - If you look across the top, you see EPO and iron and that is where those things fit in. We are going to talk about it as we go, but those are the 2 big barriers, having the balance that we are going to talk about today in EPO and in iron. Imagine yourself, you are a stem cell. You are in the bone marrow and you want to grow up and be a red blood cell. It is going to take you 25 days to get down in circulation when you look down at the horizontal bar at the bottom. You come out as a reticulocyte. We are going to talk about that in a second. But look down there at the timing. I do not even care if you remember what these stand for, but that is a blast-forming unit. About that time, that is when the EPO receptors actually come around the cell, and they protect the cell, and they are like Bob Barker's show, "Come on down." They want the EPO to come on down and be incorporated into the cell so the cell can mature. Then around 19 to 20 days, it changes, and there are more transferrin receptors around the cells, and it is doing the same thing to the iron and it is saying, "Come on down," so that it can incorporate iron into the cell. The interesting thing is that if you do not have iron there then, you cannot put in later, so it is important that it is there at that time, and we have to think that everyday is a day 19 to 20 to a cell or a number of cells in the body and that is why it is so important to have maintenance iron. It is interesting because as I understand it, the new K/DOQI guidelines are going to be silent on repletion but maintenance is just iron therapy and it does not give you all the repletion things that we had in the last guidelines. Day 21, the cell comes out and says, "Boy, I am a reticulocyte!" but it takes another 4 days for it to be a red blood cell.
Let us stop and think about what we are doing in our units. I do not know how often you all get hemoglobins but we get them at least twice a month, and if someone is out of range, we get them weekly. I tell the anemia managers in our unit to just keep a ruler on their desk and if they have changed their EPO dose within the last month, and they want to change it again, just to hit themselves over the knuckles with that ruler and stop. You may have to pad the ruler for if the physician comes back and wants to change the EPO dose. I cannot tell you that I never change the dose because I am not consistent to never or always do almost anything. If I have a good reason, I might, but we get so busy that it is important that you look back and see when the dose was last changed, because you can see from this that if you have made a change within the last 2 weeks for instance, you have not seen the result of your change. If you change it again now, you are kind of just like that dog chasing its tail. You are not going to know what is going on. You need to trend the Hb levels, and if something really bad happens, to adjust to it; but most of the times one just is trending data and to make sure things are going on, except when you have the EPO dose on hold. As soon as you start seeing patients' Hb levels start trending down, if you wait until the Hb gets close to 11, and it was 13, you may be too late (to prevent a drop below 11). As I start seeing patients trend down, I restart the EPO and then kind of watch. That is a little bit about trending Hb levels fits in, and how important this is.
Normal iron cycle
Let us take a look at the normal iron cycle. Iron is pretty well balanced in the body. You lose 1-2 mg a day. You absorb 1-2 mg in the gut; you lose 1-2 mg in the gut. Then you have transferrin. I look at transferrin as like the iron taxi. It actually is a protein and what it does is it picks up 2 iron molecules and takes it wherever it wants to go, and it can make about 10 trips a day. It is taking the iron to storage to wherever the need is and then we have about a third of the iron or a fourth of the iron in storage in the liver and some other tissues. We have about two-thirds or three-fourths of it that is actively in red blood cells or in the RE system and then we have a very small amount in the muscle from myoglobin and other enzymes. Go back and look at transferrin because I did not make a point that I wanted to. Look how much iron is in transferrin, precious little, 3-4 mg.
Iron cycle in hemodialysis
Let us look at iron in our hemodialysis patients. They absorb less iron. Why? Malnutrition for one thing. Also, if we are trying to get their secondary hyperparathyroidism treated, we give them a lot of phosphate binders and so iron binds to some of the drugs that we give them, so they get less iron in, and yet have the same amount of iron out. Look at the transferrin in this cartoon, you can see there is about half of it. Why is that? First of all, we always know that ferritin is an acute phase reactant. The transferrin is also an acute phase reactant. Ferritin goes up, but transferrin and albumin both go down, and so usually most of our patients have less transferrin than the normal person. We have decreased iron stores in our patients. If you tested a patient who is on dialysis and a patient who is not on dialysis, and you looked at what their serum ferritin is, for any given serum ferritin level, the dialysis patient will probably actually have less iron that is in storage, and I am going to show you a little research on that in just a little bit. Then what are we doing to that bone marrow? We are just flogging the heck out of it with a lot of EPO because we need to get those outcomes better. We have these big, big doses of EPO that we are giving patients who are supraphysiological. At the same time, we are losing iron. I am going to show, it is an older slide, but you can lose 1.5 g to 2.5 g or in that neighborhood iron a year just in our hemodialysis processes by bleeding at the end of dialysis, the blood that is left in the dialyzer, etc.
Markers of iron
The markers of iron. We look at them. We have serum ferritin, which I hope you understand now is an indirect measure because the ferritin that is actually in the blood stream does not reflect the amount of iron that we actually have in storage. We have transferrin, but we actually do not measure transferrin, do we? We measure transferrin saturation. We are going to talk a little bit more about that. Then we have hemoglobin, which is the only one that we actually truly measure. The iron indices that we look at are indirect measures, lots of things affect them, and that is one of the reasons there is so much controversy on what is the right dose, what are the right indices to look at?
Definition of TSAT
I did not know this until I started talking for what seems like eons ago, but it was just a little over a year, that TIBC - total iron-binding capacity - is actually a surrogate marker for transferrin. When we look at transferrin saturation, you can see that the equation here that your TIBC is the denominator and what we found is that if that TIBC is low, which is under 200, then your transferrin saturation may be falsely high. When I am trending iron and looking at the sheets that the anemia manager brings me, then one of the things I always look at is what is that TIBC and if it is below 200, then I think, well my TSAT may not be reliable. If it is above 200, I take the TSAT at face value. You can see from the cartoon down there that the serum that has a low TIBC has less iron in it than the serum that has a TIBC above 200.
Transferrin - iron transport
To simplify things, and there are a lot of issues, but they are not simple - Obviously, if the doctors are fussing and going on and arguing about it, there is always more to the story - but we can look at this simplistically as transferrin being the circulating iron transport protein - remember, a protein, and we are going to talk about malnutrition - and it has the 2 iron binding sites; so that iron is immediately available. When you give especially the new iron agents that have very good bioavailability, even in small doses, if your ferritins are high, then that iron is immediately available for the body to use. Serum transferrin is generally elevated because you need more taxis if you have iron deficiency, but in the presence especially of malnutrition, inflammation, and chronic disease, transferrin is low. Most of our patients have malnutrition, inflammation, and chronic disease. So, we really need to be looking at it patient by patient and that is my take-home message for all day. In case you miss it, I will tell you again.
Ferritin. In the perfect world, which our patients do not live in, when iron goes into storage, a serum ferritin comes out, so the iron goes in and tissue ferritin is very, very rich in iron and into circulation comes the serum ferritin. Also, for a lot of reasons, anytime there is infection or inflammation, more serum ferritin comes in. If patients have poor clearances of serum ferritin or if they have liver disease, you are going to have even higher serum ferritins, so when you are looking at ferritins and adjusting for what is going on, you really have to look and see what is the history. Is there something hidden or missing? Have I missed tweaking a dose of iron or is there more to the story? And frequently, there is more to the story.
Mean prescribed weekly EPO dose
This is data from the 2004 Clinical Performance Measures project, and you can see on the vertical axis - that is your EPO dose in units per kilogram per week - and the horizontal axis is your hemoglobin. And you kind of think, "Oh, the lower hemoglobins, it makes sense that they are on a lot more EPO," but look you have some higher hemoglobins that are also using a lot of EPO. And I would suggest to you that when you are using really big doses of EPO, it may be that what you are dealing with is functional iron deficiency. I know when I have a patient who is really iron deficient and anemic, I may start them on both (iron and EPO), even though those old guidelines said replete their iron and then start the EPO, I do not think many of us do that, but if they are iron deficient, I generally start them on the iron and on a lower dose of EPO because we need that balance, and I bet you that the people who are on the +14 g/dL Hb side got a nice-sized dose of EPO along with their iron and they kind of overshot. Again, it is a balance. Those of you who are sitting in the audience, I did not ask before but if I ask for a raise of hands on how many are anemia managers, how many would raise your hands? Go ahead and do it and keep them up. How many of you all work with anemia managers, keep your hands up. How many of you all manage people who are anemia managers? How many of you all work in CKD clinics that should have an anemia manager? If all the hands are up or just about all of them, the people who did not raise your hand need to be nice to all of these people who raised their hands because they have a tough job.
I am from Arkansas; Hillary Clinton is from there. You know how she said it takes a village to raise a child. I think it takes a major city to take care of a dialysis patient. Together, we need to look and if your anemia manager is not familiar with your caseload of patients, those patients are your responsibility. You need to be telling her or him what they need to know from the things that we are going to be talking about today because it is going to be very important to have teams and go back to the real CQI process that we talked about back in the 1990s; and Debbie is going to give you some good examples of that and what they have done in their unit in a little bit.
Estimated iron losses in HD patients
This is an older slide, but I put it here to remind myself. I told you that patients are losing a great amount of iron. I have some people who are all the way up who are still probably losing 2.5 g or that neighborhood iron a year. If you look at that and say - our patients are losing that much iron - how are you giving that back to them?
Distribution of mean iron doses
This is the data again from 2004 and look at those patients: We had a third of the patients who were getting less than 100 mg of iron a month. If you are looking at 2.5 g per year iron loss, or in that neighborhood, you are looking at losses of 250 to 270 mg a month. You have well over 50% of your patients who are getting less than 200 mg of iron a month. If that is the case, you need to think, hmm why? This patient, by my protocol, or whatever you are going by, is not on that much iron. Should they be? Are we missing the boat to balance the iron and the EPO? Then, those higher doses are probably patients who replete, and I will tell you that even though I do not replete, I do that because I am getting old, I am just not smart enough to remember to start something after 8 or 10 doses. If you are looking at iron on a monthly basis, then what I would like to do is I just generally start out at 125 mg twice a week. In a month, I have given the dose that usually is a repletion dose and it is time to look and see where they are at. For some people most of the time you have to tweak it down at that point, but some people need a little bit more. You have to come into a different mindset on what you are doing and how you are doing it.
Monitoring iron status
K/DOQI guidelines. Here is the skinny as I understand it. Serum ferritin, the old guidelines are 100 to 800. The newer guidelines are going to bump that 100 up to 200, and they are not really going to give you a definite target for when to stop. They are going to say to look at patients at 500. Now we look at patients all the time. We really need to assess the patient and see where they are and what we need to be doing. The same thing with your TSAT, which is your circulating iron - it is going to start at 20 and not give you an upper limit. We are going to talk more about that and then instead of having a hemoglobin target, the new verbiage is you are going to have a hemoglobin range that is going to be between 11 and 13.
IV iron dosing
I do not really have time to talk about all the reimbursement stuff that is coming along with that but that actually are some of the reimbursement changes that are happening this month.
The guidelines look like they are in press, but they may be postponed just a little bit.
I thought they were coming up quickly, but it may take another couple of months.
Percentage of patients with mean HgB less than or equal to 11
I love this slide. This data is freely available to us, and we have gotten a little better in some of our areas but let us talk about this from an overall patient standpoint. Where are our problem areas? You need to know these in your units, and you can think about this right now. Where are my problem areas and who are these patients who I am dealing with? If you look across the first bar that is really a dip, here are catheter patients. I could tell you those catheter patients are my new patients, my sicker patients, my malnourished patients, but those patients usually fall below target. What can I do to bring them up? Are they that way because their ferritins are high and we are frequently holding? Should I go to whoever your prescriber is if you are fortunate enough to have an APN because of all the nephrology nurses, I think we APNs really can be such an asset to your unit because most of us are just freely available to you. Look at the Kt/V. The patients who have low Kt/V are the next ones who do not meet targets as well, 70%. Are those your catheter patients? Are those your patients who chronically cut their treatment short? What is going on there? What can you do to increase adequacy because we know that if you increase adequacy, your outcomes will be better. Look at serum albumin, 62% when the serum albumins are low. Remember that those are proteins that we are looking at that our transferrin saturation is based on. If they are malnourished, those indices you are looking at are not true and perhaps they may need a deeper assessment than what we are giving... and obviously, those patients who have been on therapy for a short amount of time. If you actually collect that data and show your doctor those outcomes, maybe you can entice them to start an anemia management clinic in their offices.
Anemia risk factors in HD patients
What are the things that put our patients at risk for anemia? Obviously, blood loss. The balance of that EPO and iron that we are going to talk more about. Infection and inflammation, and that is one of the big things like - Why do we not just give everybody gobs of iron? The big things that you hear, especially in the chronic kidney disease, in your earlier stages of CKD, is oxidation injury, and I will tell you that I come from the University of Arkansas and many of my collaborative physicians and the Chief of Nephrology, we do a lot of bench research on oxidation injury. What we would tell you and what some of my folks would say is - How much iron do you need? You need the least amount of iron to get the job done, but I hope that you will realize by the time we get through, that we are not getting the job done with the amount of iron we are frequently giving. We have the assessment skills to do this. We can argue we do not have the time but if we get everybody involved from the reuse tech and the patient care tech feeding us information, it will make the job of the anemia manager and the job of the prescribers in the unit so much easier. I am going to focus a little bit and show you some of the research because this is in evidence in today's meeting, on malnutrition, adequacy, and bone disease.
Effect of serum PTH on EPO dose
The first issue we are going to talk about is bone disease. This is a study that was done by Rao in 1993, but I like the way that he did it. He took patients of his that had been on dialysis for over a year, and they had been on EPO over a year, and looked like that they had gotten in their target range in a reasonable amount of time, they had been maintained with a reasonably stable dose of EPO. No symptoms of hyperparathyroid disease or aluminum-related bone disease. Serum aluminums were fine, and there was no known cause for any EPO resistance. Then he separated them. He put the poor response group for those who had big doses of EPO, above 100 units per kilogram per week at 3 times a week and then the good response group was less than that.
Let us look at his results. There was a huge difference in how much EPO it took. These were stable hematocrits but just by controlling their bone disease, they were able to use lower doses of EPO, and we see that all the time because if you get a patient who has had a parathyroidectomy, the one thing that always amazed me is that after that parathyroidectomy, they have been on these huge doses of EPO, and they come back to reasonable doses of EPO, and you can get them into target.
TIBC and Nutritional SGA
This is the nutritional data here. This is by Kalantar-Zadeh, and these are TIBCs again. This is protein. You can see they did subjective global assessments, and the TIBC is on the vertical axis and you can see that I said TIBCs below 200 may not be reliable and when you get over to the severely malnourished, the doctor just did not do these. The doctor did one, but he was validated by a dietitian. I am sure he thought he was validating the dietitian, I am not sure which way that worked, but they were validated SGAs. You can see from this that truly the more malnourished your patient is, the lower the TIBC, which would be the lower amount of transferrin.
Serum ferritin and malnutrition in HD patients
On the reverse side, this data has been updated, and it is 2004 data with serum ferritins. Look at the serum ferritins in the malnourished patients. If you go over to the severely malnourished patients, the ferritin range there was from 800 all the way up into the low 1000s. That is a significantly high ferritin that you would go, "Hmm, maybe I should not be giving iron to this patient," when in fact this patient is severely malnourished, and if they do not have an active infection, probably you do need to give them low-dose iron and see if it works. If it does not work, you should stop.
Dialysis adequacy versus EPO response
This is the slide that should have followed the bone slides. You can see that that held true. Group A, which was the group that had the big doses of EPO, requiring 185 units/kg/week. They were the patients who had the low Kt/V. It took 185 units/kg/week of EPO to get the same response as a much lower EPO dose in patients who had good dialysis adequacy. This was the study by Movilli where they looked at what your adequacy was, what your Kt/V was. The ones who were poorly dialyzed or did not meet adequacy targets used more than twice the amount of EPO per treatment than the group B, which was well dialyzed. If you are looking at what is going on with your patients and how much EPO you are using, this would be another way to look at, "If I treated these patients with iron, do they need it or do they not?" Also, if can I improve their dialysis adequacy? So looking at access and other things can improve your outcomes.
I apologize for the slide being out of order. This is the poor versus the good. You can see that the poor used 174 units per kg 3 times a week compared to the good group that used 56. That is a huge difference. Look at those PTHs. A big difference in whether they were out of target or in target range. When they actually did bone marrow biopsies, the ones who were in the poor group required lots of EPO had problems with their bone marrow. That is just another reason to listen to all of the secondary hyperparathyroidism talks and try to start treatments early and get these patients where their bone marrow does not suffer this damage.
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