Managing Patients With IV Iron and EPO:
Practical Techniques
(Part II)

Andrea Easom, MA, MNSC, APRN, BC, CNN
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This satellite symposium is sponsored by an unrestricted educational grant from Watson Pharma, Inc. This activity has been planned and produced in accordance with CE guidelines and policies. From a CE symposium held on April 5, 2005 at the American Nephrology Nurses' Association (ANNA) Annual Meeting in Nashville, TN. This symposium was approved by ANNA. It was not part of the official ANNA Annual Meeting.
This activity provides 1.8 contact hours. The American Nephrology Nurses’ Association (ANNA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. ANNA is a Provider approved by the California Board of Registered Nursing, provider number CEP 00910.
Posting Date: September 15, 2006
CE Credit Eligible Through: September 15, 2008
CE Credit Hours/Completion Time: 1.8
Target Audiences: Nurses, nurse practitioners, and other healthcare professionals who treat and manage patients with CKD.
Method of participation: Listen to the talk, read the PubMed abstracts linked to data slides and talk references, take the post-test, read the linked abstracts in the post-test answer feedback material.
The educational objectives for this talk are presented on the conference page. To view the objectives, click here.
Andrea Easom, MA, MNSc, APN, BC, CNN, is a member of the Speakers Bureau for Watson Pharma, Inc., Abbott, Amgen, and Pfizer.
No disclosed off-label use.

This ANNA Satellite symposium was developed in conjunction with Fallon Medica and ANNA, and sponsored by a restricted educational grant from Watson Pharma, Inc.

The CE policy and disclosure statements of ANNA are given in detail on the Symposium Home Page. The CE policy statements of HDCN are listed on this page.


Why the controversy
Why is there controversy? Why is there so much controversy that we cannot get a consensus on what is the upper level of these indices? It is because the research is just not there and because our patients are unique. There are so many things going on with them and there are so many things that play into the results that we see.


Serum ferritin levels in normal subjects
This slide is an older slide. You can see it is 1979, but what they took were normal males and normal females, and I do not want to say anything negative about anybody that I ever speak to, but I have never found anybody that has been in this study. I do not know what that says about us. Look at the males in particular. Look at those ranges. Normal males and females. These were males and females that had no known chronic illness, no known reason to have any inflammation or infection and yet their range was almost up to 500. If they are normal people, it is almost 500 and now then we are saying at 500 if we got more than 500 ferritin in our patients, we need to be looking and seeing is there something else going on?


Kalantar-Zadeh K et al. Am J Kidney Dis. 1995 Aug;26(2):292-9.
Serum ferritin - highly specific test for iron deficiency
I truly believe that high ferritins mean something. I just think that we are not smart enough to always know what they mean. Because ferritin is 100% specific. If it is low, it is going to tell you that your iron stores are low.


Kalantar-Zadeh K et al. Am J Kidney Dis. 1995 Aug;26(2):292-9.
Serum ferritin - not a sensitive test for iron deficiency
But, it is not that sensitive. Only 41% sensitivity, and it is because when it is high, we do not know if it is because you are iron replete or if there are non-iron reasons, and I hope that you have understood that we have lots of patients who have a lot of reasons to have problems with serum ferritins and low transferrins.


Fudin R et al. Nephron. 1998;79(3):299-305.
Serum ferritin levels during iron deficiency
This is a study by Fudin which was an Israeli study. We could have never done that study here in the United States. I am not going to explain the study, but what I do want you to look at is those baseline serum ferritins. You can see these were all incident patients before the study started and look at the ranges. The averages are in the 200 to 250 to 260 range average but when you look at ranges, some of those ranges went up to 500. Look at that bottom line. In 36 of the 39 patients, they had no stainable iron in their bone marrow. Here we have ferritins of 200, which we said a while ago that they may be iron replete and they go all the way up to over 500 and in this small study, but it is provocative, there was no iron in the bone marrow. In this particular group of patients, 500 was not enough for some of them but 200 did not mean that they had adequate stores either. So, you have to go back and look.


Bistrian BR et al. Am J Kidney Dis. 1999 Oct;34(4 Suppl 2):S35-9.
Infectious and inflammatory states
If you stop and think about the patients who are in your patient population, look at these things. I can tell you that I have some patients who have a number of these problems. I find access site infections, abscessed teeth, gout. Some of you all have big numbers of hepatitis B, hepatitis C patients in your patient population and then peripheral vascular disease. I mean I am always having sore toes, wounds on their legs, etc., going on. When those things are going on and your hemoglobin is going down, it is inflammation and/or infection. We have to look and see what is happening there.


Kalantar-Zadeh K et al. Nephrol Dial Transplant. 2004 Jan;19(1):141-9.
Serum CRP versus serum ferritin
Do many of you all get CRPs? We used to get CRPs when they first came out back in the 1990s, and then we decided we were not smart enough to know what to do with them and we do not get them anymore. But those of you that are privileged enough to get them and that is part of your package, C-reactive protein is a nonspecific marker for inflammation. You should get a baseline when the patients are at their healthiest whenever that may be and then if you are having a problem, you can repeat the CRP and if it is elevated from that baseline, you know that something is going on, be it infection or inflammation, in that particular patient, and you can look deeper into it. You can see when you divide the patients in the 200-800 and the 800-2000 group that obviously the ones who are in the higher group have higher C-reactive proteins. The only people who I get these in right now are my multiple myeloma patients and it really does work. That is one of the first things when they start running fevers that we get and then we judge whether to treat them or not treat them.


Clinical interpretation of serum ferritin
When you are looking at patients who have elevated serum ferritins the big thing is to rule out do they have an active infection? I always think back of those days when we were using DFO, and you know we were chelating iron in our sickle cell anemia patients and our patients who were getting gobs of transfusions. That particular set of patients would get these just gosh awful fungal infections, because some bacteria and fungus love iron-rich blood and that is the reason, if you are giving iron and someone has an active infection, what the transferrin is supposed to do is take it and put it in storage as a protective mechanism, and that is called inflammatory iron block. You always want to rule out active infection. You look and see when you gave your last dose of IV iron. If you gave it on Monday and you checked your iron on Wednesday, maybe it was your dose of iron that created a problem. Look and see. Does the patient live there? Those of you all that heard me speak in Kansas City know that I have patients, I looked at my patients, had about 20% of them that fell out in that 800+ ferritin but 50% of that 20% kind of lived there. They ran between 800 and 1000, sometimes a little over and sometimes a little under but that was just their normal. They had some underlying something that caused that ferritin to be up. If we can dig in and find out what that is that is great because maybe we can help them but holding iron is not going to be one of those things that probably does. Then, you look at the last time you drew your serum ferritin. Again that keys in with your dosing. You have to weigh what is the risk and what is the benefit of giving that iron dose. We want to do no harm but we want the patient to receive the benefit of iron if they need to have it.


Hudson JQ et al. Clin Ther. 2001 Oct;23(10):1637-71.
Bistrian BR et al. Am J Kidney Dis. 1999 Oct;34(4 Suppl 2):S35-9.
Functional iron deficiency/inflammatory block
How do you judge this? Remember functional deficiency is when, for whatever reasons, a patient is just not mobilizing iron. It is not bioavailable to meet the needs of that particular patient. Then inflammatory iron block is what I just described. There is an infection and the transferrin is taking the iron into storage.


Response of iron
So, what can you do? Try it. They might like it. You give a dose of iron. If you have no response to the iron, then you have inflammatory iron block. Now remember I said inflammatory. It could be infectious, it may not be infectious but at that point you need to look.


Treatment of functional iron deficiency
How long should that trial be? If you start a trial of iron today, it is going to take at least a month, maybe 6 weeks, before you start seeing the Hb inch up but it is going to be at least a month. So what I do in those cases after I have ruled out any active infection is, I start them on low-dose iron; because that way the iron is bioavailable, we can use it and see if it is going to make a difference. If the hemoglobin goes up and/or you can decrease your EPO dose, then you have a functional iron deficiency, and I think we are missing a lot of functional iron deficiency in our malnourished, poorly dialyzed, bone diseased patients, and we are also missing that balance, because even though we trend the EPO, many of us are not trending the iron. I always say that my experience and even though I told you I have been at the University 30 years, does not mean that I am at a university-owned unit. I used to be and then it was RCG and then it was Gambro and now it is DaVita, and it has been in different sections. In 2 of those companies, they have kind of batted us around because there are not that many corporate dialyses in Arkansas until just recently. I have had the privilege of dealing with a lot of different anemia managers a lot of different ways even in my own unit and the privilege of talking to many of you all and what I found is that your novice anemia manager, the job is so overwhelming, that they concentrate on that EPO dose because that is really what you all get worked up about and then they forget that there is an iron dose over here and both of them need to be trended. If that patient does not respond, I cannot reinforce this enough, that is when you stop. That is when you go looking for that occult access infection in that old graft or something else going on with the patient because you are looking to do no harm and you want to see what is going on.


Besarab A et al. J Am Soc Nephrol. 2000 Mar;11(3):530-8.
Besarab study
This is a study that I have heard some people like and some people do not. I like it because I had the experience with it. I had a doctor that went and heard Besarab give this talk, probably at ASN 2000-2001, and what Besarab thought he would do is he would get all of the transferrin saturations up above 30 and if he could do that he thought that he could have a stable hemoglobin with much less EPO and actually it worked. He got everybody's transferrin saturation up to above 30, 30 to 35 but look what happened to his ferritins. They kind of went up, up, up. Now, this is cumulative data. My doctor came back and said, okay I am a taxpayer. I would like to use 40% less EPO and so he tried it, and I will tell you that I found the same thing out that Besarab did. I cannot keep my TSATs above 30 in all of my patients without having ferritin problems. What I learned to do, that is when I got my big experience in trending iron, I said, okay 30 is not working for me, let me shoot for the mid 20s. That is where I shoot for, the mid 20s, and when I start seeing my TSATs going up and they are trending up above mid 20, that is when I start tweaking my dose back down. Again, a balance. It works well for me. That is not to say that I do not have patients with TSATs higher than that because I certainly do and Besarab with him getting his patients' TSATS up in the above 30 range, probably treated a lot of functional iron deficiency and that is one of the reasons that he got to use 40% less EPO. So trend your EPO and trend your iron, not just one or the other.


Managing iron parameters
I hope you have understood that is difficult to determine if the IV iron is going to be beneficial in your patients with higher serum ferritins. You just have to try it. In my experience, 8 to 9 times out of 10, it works. Patients are individuals just like we nurses are individuals and they all have patient-specific disease states that have to be considered. That means that we have to use those assessment skills that we have all known and learned and possess. We just have to hone them. We have to build that village around us to let us know what is going on with those patients.


Serum ferritin
I looked at our serum ferritins because I wanted to see how many of my patients in my unit had ferritins above 500, and I encourage all of you to do this, too. If your ferritins are above 800, which is what we have been looking at, you can see in my unit that anywhere from around 12% to almost 24% in this 3-month period were above 800, and I have a very novice anemia manager who is missing tweaking iron, but even when I look at it sporadically, it is somewhere in that neighborhood, usually more in the 20% range, so December was an unusual month; but that is what you want to look at in your protocols. If you have somewhere in the 10% to 20% that fall out of your protocol, those are the patients who you say, okay I need to take a closer look. When you add in all of those patients who are above 500, that takes me up to about 50 patients a month that I am supposed to look at, and I think that that is a little unreasonable on a monthly basis, but I think we ought to do it at least once. I think we need to look at those patients, see what their ferritins are, see if they live there, talk to them: Is there something that you can do?

I tell a story about one of my patients on rounds; her ferritin was up, her transferrin saturation was down, her albumin was down. I said, "you know your lab is screaming at me that something is wrong with you?" What is going on? She was quiet for a minute, denied everything, and I just looked at her and I said, you know how you have this little voice, and I said, "Are you doing drugs again?" and she hung her head, and she was. After dialysis, she came to my office, wanted to get into rehab, we got her in rehab. She got off drugs and her numbers came down. I say the moral to that story is that if your patient is a drug user and they have a sudden relapse, their ferritins may well go up; but if they are on a stable dose that may just be those people who "live there" (in that ferritin range) and you are just going to have to look. I point this out to say that ferritins mean something. We are not saying that they do not mean something but it is just that we cannot always figure out exactly what they mean.


Face behind the numbers
There is a patient, a face behind that number, and they may not be nearly as cute as my Megan but you should expect about 20% of your patients to fall out of a protocol, so as you are looking and seeing what you are doing, I think this is a wonderful opportunity to look and see, have I missed something? One of my collaborating physicians, I have 5, said that there was an article, which I have not found yet, and he has not produced. He has told me he would. I will get it sooner or later, but he had read a review article that said that we had this huge number of bowel cancers that we were missing in our incident hemodialysis patients, and I can tell you when I looked at my data in the fall, the people who were above 2000, I had 2 patients who had above 2000 ferritin, one was just diagnosed with bowel cancer, and the other one with multiple myeloma. Again, high ferritins mean something, we just do not always know what they mean, but those outliers, and whatever the protocol is that you use or whatever algorithm you use, they need further assessment. You need to look at their history. Do they live there, and you just need to get a dispensation from the Pope or whoever your prescriber may be to have a higher ferritin in them but discuss it with whoever is your prescriber because ultimately it is their responsibility. But you know what, they need our guidance because that same physiology that I just went over with you all, I do that with my physicians, with my nephrology fellows every other year, so that I hit all of them, and I can tell you that it is a new way of looking at things for them. They certainly have much deeper background in physiology than I do but to point out the nuances is important.


Process for validating inflammatory state
Go and do a further exam. Take those shoes off, look and see if there are some sores, what is happening with them. Look at further testing. Do you need to get a CRP? I do not use reticulocyte hemoglobins. We have one unit that does and the doctor has not been favorably impressed with what his results have been; reticulocyte hemoglobin levels tell you if you are iron depleted, but they do not tell you if you are overloaded; but you can look, if you have that test available and you like using it, that may give you a clue. Look at what that albumin is. See what is going on there. Work them up anyway and see where your history and physical exam lead you.

If you do not know what is going on, consult your APN or your MD; I use my MDs just like I use my husband, you know. Well, not exactly! If I do not know what is going on and we have such a rich knowledge, especially those of you all that have been nursing for a long time. You know how when you know something is not right, but you just cannot figure out what it is, well that is when I go to my doctors and you know, I am kind of like Dean Witter at the University. If I say it, they kind of listen. I say something is wrong, I cannot figure out what it is, and then if they cannot figure it out either, it makes me feel better. If I find out later truly what was wrong and I missed it, I say well, he missed it too. But get as many people to look in as possible, because the more people who are looking, even your care techs and all, it is amazing the knowledge they have because they are with the patient for the whole treatment. The patient tells them stuff. So get everybody you can involved when you are worried.

I do not believe in worrying alone. I like to celebrate with people and I like to worry with them too. When I am worried, I want you all to worry, and that is essentially what I tell patients. If I am rounding on them, and there is something funky in their lab, I say this really bothers me. I give some questions and I say I am going to watch this. I want you to help me watch it and if you come up with anything, I will give them a list for whatever, I want you to let me know. That way if they are doing something they are not supposed to do, they are caught. If we caught all of our kids, and we all got caught the first time we were doing things we were not supposed to do, we would probably all be better people, but I truly believe that the anemia manger in your unit should be and could be the first person who knows your patient is in trouble, and if we give them the time, the resources, and the knowledge to do the job the way it is meant to be done; they can be such an asset, not just to outcomes that are linked to money but to the quality of care and the quality of life that our patients can have. We are so important and integral in that, and I do believe that correcting anemia in my 30 years has been the major thing that has added benefit to my patients' lives.


In summary, when you look at those labs, do not just look at labs. Think about the person that is behind that lab. Identify that patient history, get to know it, look at what the possible barriers to EPO efficiency are, use a systematic logical thought process in what you are doing. I hope that I have added some pearls to what you are looking at. Look at iron availability. Did you hold the iron for some reason, and you have not started it? I give little small doses, 31.25 mg of iron and that is kind of my low dose, 31.25 once a week. I have tried other things, and we can talk about it in the question and answer period, but that tends to work out best for us. Some people do not like to do that because you are using 2 doses out of 1 vial and so for those people 62.5 mg every other week may be preferable; and then I go up from there. Occasionally, I have to go down in dose - our patients are individuals. We should expect that we cannot have everybody on the same dose. Also, look at your EPO dosing and go in there and actually look at the patients who are using big, big doses of EPO, and see if you are treating those people with iron appropriately. Then look at those patient-specific targets that we looked at before.


I want to just thank you. This, again, is not Deborah Bowe. This is my Megan who is a little bit older, but I thank you all so much for the work that you do with our patients because together we have made a difference and we do make a difference on a daily basis in the lives of so many people. I am looking forward to hearing Deborah talk about her experiences with CQI and how she has been handling iron in their unit. I will turn it over to her now. Thank you.

  1. Kalantar-Zadeh K, Kleiner M, Dunne E, Ahern K, Nelson M, Koslowe R, Luft FC. Total iron-binding capacity-estimated transferrin correlates with the nutritional subjective global assessment in hemodialysis patients. Am J Kidney Dis. 1998 Feb;31(2):263-72.

  2. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998 Jan;35(1):35-54.

  3. Cavill I. Iron status as measured by serum ferritin: the marker and its limitations. Am J Kidney Dis. 1999 Oct;34(4 Suppl 2):S12-7.

  4. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis. 2001 Jan;37(1 Suppl 1):S182-238.

  5. Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med. 1993 Jan 21;328(3):171-5.

  6. Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients. Nephrol Dial Transplant. 2004 Jan;19(1):141-9.

  7. Movilli E, Cancarini GC, Zani R, Camerini C, Sandrini M, Maiorca R. Adequacy of dialysis reduces the doses of recombinant erythropoietin independently from the use of biocompatible membranes in haemodialysis patients. Nephrol Dial Transplant. 2001 Jan;16(1):111-4.

  8. Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H, Kleiner M, Luft FC. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis. 1995 Aug;26(2):292-9.

  9. Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79(3):299-305.

  10. Bistrian BR, Khaodhiar L. The systemic inflammatory response and its impact on iron nutriture in end-stage renal disease. Am J Kidney Dis. 1999 Oct;34(4 Suppl 2):S35-9.

  11. Hudson JQ, Comstock TJ. Considerations for optimal iron use for anemia due to chronic kidney disease. Clin Ther. 2001 Oct;23(10):1637-71.

  12. Besarab A, Amin N, Ahsan M, Vogel SE, Zazuwa G, Frinak S, Zazra JJ, Anandan JV, Gupta A. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol. 2000 Mar;11(3):530-8.

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