Treating Patients with IV Iron Therapy: Special Considerations
ANNA CE Satellite Symposium, April 21, 2005

Welcome, Introduction and Program Overview

Steven Fishbane, MD
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This offering for 2.1 contact hours is being provided by the American Nephrology Nurses Association (ANNA), which is accredited as a provider and approver of continuing education in nursing by the American Nurses Credentialing Center-Commission on Accreditation (ANCC-COA). This educational activity is approved by most states and specialty organizations that recognize the ANCC-COA accreditation process. ANNA is an approved provider of continuing education in nursing by the California Board of Registered Nursing, BRN Provider No. 00910.
Date of Original Release: August 12, 2005
CE Credit Eligible Through: May 1, 2007
CE Credit Hours/Completion Time: 2.1
Target Audience: Nephrology nurses and technicians.
Method of Participation: Listen to the talk, read the PubMed abstracts of linked slides and references, take the post-test, and complete the evaluation form.
After participating in this program, the learner should be able to:
  1. Define serum ferritin and the current understanding of it in terms of safety and efficacy
  2. Review K/DOQI recommendations for treating patients based on serum ferritin levels
  3. Describe special concerns that exist in treating anemia in pediatric patients on dialysis
  4. Discuss dosing guidelines for administering IV iron in pediatric patients
  5. Evaluate the safety and efficacy of IV iron therapy
Dr. Fishbane has received grant/research support from Amgen, Hoffman-La Roche, Ortho Biotech, and Watson Pharma, Inc.; is a consultant for Hoffman-La Roche and Watson Pharma, Inc.; is a Speakers Bureau member for Amgen, Ortho Biotech, and Watson Pharma, Inc.; and is an Advisory Board member for Amgen, Hoffman-La Roche, Ortho Biotech, and Watson Pharma, Inc.

Unapproved/off-label usage: Use of iron to treat conditions other than anemia.

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.


Welcome and introduction
I would like to welcome you and thank you all very much for coming out this early in the morning. In today's program, we will be speaking about a number of issues that pertain specifically to iron treatment. My name is Steven Fishbane. I am the Associate Director of Nephrology at Winthrop-University Hospital in New York. I am a member of the KDOQI Anemia Workgroup that is currently writing the new KDOQI anemia guidelines that will be published sometime early in 2006.


Nephrology nurses face unique challenges
We will begin today's presentation by talking about some of the factors that frame today's 2 lectures. In the diagnosis of iron deficiency, one of the challenges that nurses and physicians face is that serum ferritin is a highly variable test, and there are going to be many patients that have relatively high levels of serum ferritin, and we always have the following question, don't we: What you do when the transferrin saturation is relatively low but the serum ferritin value is high? We will talk about that. When treating anemia in children, pediatric dialysis patients suffer complications related to anemia treatment that are particularly important, and they have an increased risk for lower hemoglobin and hematocrit levels, and in Dr. Warady's lecture today, he will speak more regarding this important patient population.


Robbin ML et al. Radiology. 2002 Oct;225(1):59-64.
Benefits of IV iron: optimizes HD therapy
What are the benefits of intravenous iron treatment? Without intravenous iron, absolute iron deficiency develops in most hemodialysis patients. If you do not treat with intravenous iron, patients will, for the most part, tend to become severely iron deficient. Functional iron deficiency, which we will speak about a bit more later, happens as well, but it is very clear that both erythropoietin and iron are important components of successful and adequate anemia treatment.


Chang CH et al. Clin Nephrol. 2002 Feb;57(2):136-41.
Senger JM et al. ANNA J. 1996 Jun;23(3):319-23; discussion 324-5.
Fishbane S et al. Am J Kidney Dis. 1995 Jul;26(1):41-6.
Besarab A et al. J Am Soc Nephrol. 2000 Mar;11(3):530-8.
Sunder-Plassmann G et al. ANNA J. Nephrol Dial Transplant. 1995 Nov;10(11):2070-6.
IV iron reduces EPO requirements
Here is some of the data that forms the basis of our thinking in this area. The initial study, which I will show more of later, by Chang et al., shows the yellow vertical bar representing EPO doses before an intensive intravenous iron course, and then you see a significant reduction in the need for erythropoietin after effective intravenous iron treatment. In fact, there are 14 published studies that show that intravenous iron is remarkably effective for improving anemia therapy, for getting better hemoglobin levels, and for reducing the overall EPO dose required.


Highest mortality risk seen with no iron use
This is an interesting study that was presented a couple of years ago at ASN by Sun et al. and what they did is look at the risk of death for patients in relationship to the amount of iron that they were treated with. In the first group of vertical bars, you will see that the absolute highest risk of death was in patients who were treated with no iron at all, and it would make sense that if you do not treat with one of the body's most important molecules and allow people to be severely iron deficient, that you are going to hurt function of key tissues and organs throughout the body.


Fudin R et al. Nephron 1998;79(3):299-305.
IV iron is more effective than oral iron
This is a study by Fudin et al. and it points out to a great extent just how ineffective oral iron is in the hemodialysis population. You will notice here, this is the oral iron group going from baseline to 12 months to 2 years, that the hemoglobin levels with oral iron by itself tended to decrease. If you gave no iron, hemoglobin levels tended to decrease, and please note that there is no difference in effectiveness between oral and no iron, so that in hemodialysis patients at least, oral iron has no demonstrable efficacy, and that is why intravenous iron forms such a cornerstone of treatment. In the intravenous iron group, Fudin et al, show a very brisk response. This is without any EPO treatment being given, so just with intravenous iron by itself, patients had a very significant improvement in hemoglobin levels.


Benefits of maintenance IV iron therapy
Maintenance iron: You can give intravenous iron in 2 ways. You could test every 3 months, and then if iron deficient, you can give a large dose like we typically do, 125 mg for 8 consecutive treatments, and that tends to be called a repletive strategy for iron treatments. The alternative is maintenance therapy. Simply giving weekly doses of intravenous iron in order to anticipate the fact that most dialysis patients become iron deficient, and maintenance iron therapy avoids the seesawing of starting and stopping iron treatment, which is probably not biologically the best way to give treatment, and it tends to keep hemoglobin, TSAT, and ferritin within the target ranges.


Appropriate IV iron maintenance dosing
K/DOQI guidelines suggest that most hemodialysis patients will require treatment with intravenous iron on a regular basis. That comes from the 2001 guidelines, and the objective of treatment is to achieve a serum ferritin of 100 to 800, and a transferrin saturation of 20% to 50% with weekly dosing of intravenous iron.


Nonhematologic effects of iron deficiency
Iron is important for raising hemoglobin levels and for being successful in achieving K/DOQI targets, but please recall that although iron in hemoglobin in red blood cells is a vitally important biological function, that the importance of iron in all of our bodies and in all of our patients goes far beyond just raising hemoglobin levels.


Bruner AB et al. Lancet. 1996 Oct 12;348(9033):992-6.
When we can look at some of the nonhematologic effects of iron, one of the interesting early studies, and this was from Johns Hopkins published in the Lancet, they looked at teenage girls for the most part who were iron deficient, and iron deficiency is very common in young women and particularly in the teenage years as people are growing fast and starting to menstruate, and they found that there was a decrease in cognition, in learning, memory, and that when they treated with iron before the hemoglobin level rose at all, as they treated the iron deficiency, that the girls' ability to think more clearly, to remember, and to learn were all improved. So iron plays an important role in cognition and in learning.


Sloand JA et al, Am J Kidney Dis. 2004 Apr;43(4):663-70.
Restless legs syndrome
Regarding restless legs syndrome, this is a problem that I am sure many of you have seen. Friday night of last week, I saw a patient in one of our dialysis units whose legs were just shaking like crazy throughout the treatment, a very disturbing symptom to the patient. While it has been known that patients with restless legs syndrome tend to have more iron deficiency than others, that does not prove though that treatment with iron would work. Here is a nice study from Sloand et al, published in 2004. What they did is they took patients with restless legs syndrome, half of them were treated with placebo, and you see that the symptoms of restless legs syndrome did not change, but when they treated with intravenous iron instead, there was a very sharp reduction in symptoms of restless legs syndrome. It did not completely eliminate the symptoms, but it did reduce them to a very important extent. So in patients who have restless legs syndrome on dialysis, one of the consideration should be, is the patient iron deficient.


Martinez-Torres C et al, Am J Physiol. 1984 Mar;246(3 Pt 2):R380-3.
I will not go through all the text on this slide, but I am sure you are aware that many patients on dialysis feel cold much of the time even when the weather is warm, and part of how the body regulates temperature and regulates the sensation of temperature, relates to iron status. Patients who are more iron deficient tend to feel cold more frequently, and it may be that intravenous iron treatment, although this is not well tested yet, could improve some of the dysregulation of temperature sensation.


Konofal E et al. Arch Pediatr Adolesc Med. 2004 Dec;158(12):1113-5.
Attention-deficit hyperactivity disorder
Interestingly, attention-deficit hyperactivity disorder (ADHD) seems also to have a link, to some extent, with iron status. Ferritin values are lower in children with attention-deficit disorder than they are in control children, suggesting at least the possibility that in children with ADHD that iron deficiency might be an important point that regulates - so that is an introduction.


Program goals
The goals of today's program: I will speak first and then Dr. Warady will speak after me. At the end, we will have a question and answer session. Again, as you have your questions, please do write them down on your Q and A cards, and they will be collected from you at the end of each of the lectures. Our program goals are to discuss some very special concerns - one of them regards serum ferritin and how we use it when the numbers tend to be on the high side. Managing patients with higher serum ferritin values, when do you treat with intravenous iron and when do you not treat these patients, and then we will look at this interesting and special population of the pediatric patients with kidney disease.

  1. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000 Am J Kidney Dis 2001 Aug;38(2):442.

  2. Nissenson AR, Lindsay RM, Swan S, Seligman P, Strobos J. Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American Clinical Trial. Am J Kidney Dis. 1999 Mar;33(3):471-82.

  3. Chang CH, Chang CC, Chiang SS. Reduction in erythropoietin doses by the use of chronic intravenous iron supplementation in iron-replete hemodialysis patients. Clin Nephrol. 2002 Feb;57(2):136-41.

  4. 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.

  5. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995 Jul;26(1):41-6.

  6. 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..

  7. Senger JM, Weiss RJ. Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment. ANNA J. 1996 Jun;23(3):319-23; discussion 324-5.

  8. Sunder-Plassmann G, Horl WH. Importance of iron supply for erythropoietin therapy. ANNA J. 1996 Jun;23(3):319-23; discussion 324-5.

  9. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls. Lancet. 1996 Oct 12;348(9033):992-6.

  10. Sloand JA, Shelly MA, Feigin A, Bernstein P, Monk RD. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis. 2004 Apr;43(4):663-70.

  11. Martinez-Torres C, Cubeddu L, Dillmann E, Brengelmann GL, Leets I, Layrisse M, Johnson DG, Finch C. Effect of exposure to low temperature on normal and iron-deficient subjects. Am J Physiol. 1984 Mar;246(3 Pt 2):R380-3.

  12. Konofal E, Lecendreux M, Arnulf I, Mouren MC. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2004 Dec;158(12):1113-5.

  13. NEXT TALK (Dr. Fishbane)