Iron Repletion in ESRD

1. Iron Repletion in ESRD Saleem Bharmal 2/9/10

2. Case • ESRD on maintenance hemodialysis who is noted to have a Hgb 10.6/TSAT 19%/Ferritin 617/iron 46/TIBC 238/on EPO 4000U/week • What would you do in this situation in terms of ESA and iron? • Patient EPO decreased to 3000U and started on Ferrilicit 125mgx8 doses(1000mg total) • 1 month later Hgb 11.1 (iron not checked)

3. Case • 2 months later: Hgb 10.8/iron 36/TIBC 225/TSAT 16%/Ferritin 1075/on EPO 3000U/week • What would you do in now? • Kept patient on current dose of EPO no IV iron given • One month later Hgb 10.7

4. Case • 2 months later: Hgb 9.9/iron 54/TIBC 230/TSAT 17%/Ferritin 706/on EPO 3000U/week • What would you do now? • Ferrilicit 125mgx8(total 1gram) given and kept on EPO 3000U • 1 month later: Hgb 10.4 • 2 month later: Hgb 10.2/TSAT 31%/Ferritin 1120/EPO 3000U/week

5. Anemia in ESRD • According to the National Health and Nutrition Examination Survey (NHANES) and the Prevalence of Anemia in Early Renal Insufficiency (PAERI) study the suggested incidence of anemia in stage 5 CKD is more than 70% • The most well-known causes are inadequate erythropoietin (EPO) production and iron deficiency.

7. Iron Deficiency in Hemodialysis Patients • Dialysis patients commonly suffer iron loss from gastrointestinal bleeding, blood drawing, and/or, most important with hemodialysis, the dialysis treatment itself. • Hemodialysis patients lose an average of 1 to 2 g of iron per year.

8. Type of Iron Dysfunction in HD patients • Absolute iron deficiency • Functional iron deficiency • Inflammatory Block

9. Absolute Iron Deficiency • TSAT falls below 20% (plasma iron divided by total iron binding capacity x 100) • Serum ferritin concentration is less than 200 ng/mL among hemodialysis patients. Fishbane S., J. Am. Soc. Nephrol. 1996 2654-2657

10. Functional Iron Deficiency • Characterized by the presence of adequate iron stores as defined by conventional criteria, but an inability to sufficiently mobilize this iron from the liver and other storage sites to adequately support erythropoiesis with the administration of erythrocyte stimulating agents (ESA). • Serum ferritin level is either normal or elevated, but the TSAT typically is about 20% or less. • The hallmark of functional iron deficiency is that it responds to iron supplements with an increase in hemoglobin and/or decrease in ESA requirements.

11. Inflammatory Block or Reticuloendothelial Blockade • Inflammatory iron block occurs among patients with refractory anemia due largely to an underlying inflammatory state. • Also characterized with TSAT < 20% and elevated Ferritin 100-800+ ng/ml • Hepcidin, an acute phase reactant may play a role by preventing the release of iron from macrophages to circulating transferrin. • Usually does not respond to iron therapy

12. Functional Iron Deficiency vs. Inflammatory Block • With functional iron deficiency iron administration will usually increase in hemoglobin and/or decrease in ESA requirements. • With increasing dose of ESA ferritin levels may decreased with functional but not inflammatory block • Inflammatory block is most likely present if the weekly administration of intravenous iron fails to result in increased erythropoiesis; instead results in progressive increase in ferritin concentrations.

13. DRIVE StudyJASN (18) 2007 • Study to help answer the question of what is the efficacy of IV iron administration in HD patient with low TSAT and high ferritin levels. • 134 patients with anemia (hgb < 11 g/dL), elevated ferritin (500 to 1200 ng/mL), low TSAT levels (≤25 %), and high ESA requirements (≥225 U/kg per week or ≥22,500U/week) • Randomly assigned to ferric gluconate (125 mg with 8 consecutive dialysis sessions) or placebo. • Patients with known infections or recent significant blood loss were excluded. • At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited

14. At 6 wk, hemoglobin increased significantly more (P 0.028) in the intravenous iron group (1.6 1.3 g/dl) than in the control group (1.1 1.4 g/dl). • More patients responded (Hgb increase > 2) after intravenous iron than in the control group (P 0.041).

15. Ferritin <800 or >800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. • Superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. • Ferritin decreased in control and increased after intravenous. • Intravenous iron resulted in a greater increase in TSAT than in control subjects

16. CHOIR, CREATE and TREAT

17. Alternative measures of iron status • The percentage of hypochromic cells (%HYPO) • Hepcidin Levels: Can help distinguish functional iron deficiency form Inflammatory block and may help determine when iron stores adequately replete. • The reticulocyte hemoglobin content (CHr) • The proper role for these alternative measures of iron status, which are not widely available in the United States, in the dialysis patient is uncertain.

18. Reticulocyte Hemoglobin Content (CHr) • The reticulocyte Hb content (CHr) is a measure of the amount of Hb in the reticulocytes. • The CHr is a reasonably good reflection of how much iron was available to the bone marrow for incorporation into new red blood cells a few days before. Reticulocytes are released into the circulation about two days prior to maturation into red blood cells. • It has been shown that CHr compares favorably with serum ferritin and TSAT in predicting a response to intravenous iron. • Fishbane S. et al (KI 2001) showed a cutoff of >32 pg had a much greater utility compared to >29pg, and a majority of the patients who received intravenous iron therapy on the basis of a CHr >32 pg had an average of 23% reduction in their erythropoietin requirements. Also showed in randomized trial that CHr was equivalent to TSAT/Ferritin in maintaining Hgb and ESA dosing but used less IV iron

19. IV Iron Preparations for HD patients • Adequate iron stores are essential for achieving maximum benefit from erythropoietic agents • Decreased iron stores or decreased availability of iron are the most common reasons for resistance to the effect of ESAs. • Patients with percent transferrin saturation ≤20 percent and ferritin between 200 and 500 ng/mL, administer iron therapy prior to the use of ESAs if an underlying infection has been excluded. • The most common cause of resistance to ESA is iron deficiency, which can be present at the time of initiation of ESA treatment or can develop as the result of exhaustion of iron stores due to the increase in erythropoiesis caused by ESA treatment. • To ensure an adequate response with erythropoietic agents, most dialysis patients will require supplemental iron on a continuing basis. • For hemodialysis patients use of parenteral iron rather than oral iron therapy should be used.

20. IV Iron Preparations for HD patients • Iron dextran (INFeD) • Iron sucrose (Venofer) • Sodium ferric gluconate (Ferrlecit) • Ferumoxytol (Feraheme)

21. Iron Dextran • Composed of a mixture of synthetic polymers of glucose, is highly effective when given for loading or maintenance therapy. • Anaphylaxis to intravenous iron dextran therapy may occur in both nonuremic and uremic patients, occasionally resulting in death. It is thought to be due to the high-molecular weight dextran moiety, which may share carbohydrate antigens with gastrointestinal organisms. • Study (Fishbane et al AJKD 1996) that reviewed 573 hemodialysis patients treated with intravenous iron dextran: 4.7% had adverse reactions most common being itching, dyspnea or wheezing. 1.7% had reaction classified as anaphylactoid. Among the 10 anaphylactoid reactions, 6 occurred with doses other than test dose. • Administration: Test dose: 25mg mixed with 50ml NS given over 5 minutes. If tolerated than can give up to 500 to 1gram as slow IV infusions.

22. Sodium Ferric Gluconate • Has fewer life-threatening and fatal adverse reactions than iron dextran. In addition, its relative efficacy and adverse reaction profile are as good or better than iron dextran. • Administration: 125 mg of sodium ferric gluconate complex in sucrose can be given at each consecutive hemodialysis treatment for a total of eight doses (1000 mg in total).

23. IV Iron Sucrose • This formulation is effective and well-tolerated for either loading or maintenance therapy. Studies found that iron sucrose and sodium ferric gluconate complex were equally effective and safe. • Administration: 125 mg of sodium ferric gluconate complex in sucrose can be given at each consecutive hemodialysis treatment for a total of eight doses (1000 mg in total).

24. Ferumoxytol • Approved by the FDA in June 2009, is an iron dextran nanoparticle. • Ferumoxytol appears to be safe and effective when given as a rapid infusion of up to 510 mg in patients with CKD and patients on dialysis. • Administration: 510 mg of ferumoxytol can be administered intravenously at a rapid rate (up to 30 mg/sec) and be given as 3-8 days apart.

25. Maintenance Therapy: Intermittent vs Continuous • With intermittent regimens, provides a total dose of 1000 mg whenever iron indices fall below the target levels of a transferrin saturation of ≥20 percent and a serum ferritin concentration of ≥200 ng/mL. • A continuous dosing regimen consists of the regular administration of low doses of parenteral iron, which is designed to prevent the development of iron deficiency once adequate iron stores have been established. • With intermittent therapy, iron is only given when iron indices are clearly inadequate; such regimens are likely to result in less than ideal delivery of iron to the marrow, which then results in an inadequate amount of iron available for continued effective erythropoiesis.

26. Evidence for use of Continuous Therapy • Study #1 • 24 patients were randomly assigned to either a regimen in which an initial iron dextran dose of 300 to 500 mg was followed by 25 to 100 mg every one to two weeks (to maintain a transferrin saturation between 30 and 50 percent) or an intermittent dosing regimen (to maintain a transferrin saturation >20 percent or a ferritin level >200 ng/mL). • A hemoglobin level of 10 to 11 g/dL was achieved in both groups. • However, the amount of EPO required in the maintenance group was significantly less than that utilized in the intermittent group (1569 versus 3527 units).

27. Evidence for use of Continuous Therapy • Study #2 • 26 hemodialysis patients with adequate iron indices (serum ferritin level >100 ng/mL and transferrin saturation >20 percent) were randomly assigned to receive intravenous sodium ferric gluconate either in a continuous (6.25 to 21.3 mg in every hemodialysis session) or an intermittent regimen (62.5 mg every 1 to 4 weeks). • At 16 weeks, the continuous group had a significant increase in serum hemoglobin level versus baseline values (11.8 versus 11.0 g/dL, respectively), whereas no differences were obtained in intermittent group (baseline and 16 weeks were 11.2 and 11.1 g/dL, respectively)

28. TSAT goal 20-30% or 30-50% • Study by Besarab et al. (JASN 2000): “Optimization of Epoetin Therapy with Intravenous Iron Therapy in Hemodialysis Patients” • Examines the effects of a maintenance intravenous iron dextran (ivID) protocol that increased TSAT in ESRD hemodialysis patients from conventional levels of 20 to 30% (control group) to those of 30 to 50% (study group) for a period of 6 months • 42 HD patients 16- to 20-wk run-in period, during which maintenance ivID and rhEPO were administered in amounts to achieve average TSAT of 20 to 30% and baseline levels of hemoglobin of 9.5 to 12.0 g/dl

29. After the run-in period, 19 patients randomized to the control group received ivID doses of 25 to 150 mg/wk for 6 months • 23 patients randomized to the study group received four to six loading doses of ivID, 100 mg each, over a 2-wk period to achieve a TSAT .30% followed by 25 to 150 mg weekly to maintain TSAT between 30 and 50% for 6 months • Erythropoietin (EPO) dosage was adjusted every 4 wk to maintain hemoglobin at the same value

30. Progressive increase in serum ferritin to 658 ng/ml in the study group

32. Epoetin dose requirements for the study group decreased by the third month and remained 40% lower than for the control group

33. Closing • Given the negative evidence with high dose ESA: • Should we aim for TSAT of 30-50%? • Should we give IV iron even if ferritin > 800ng/ml if no signs of active infection? • What are the long term effects of iron loading, oxidative stress, WBC dysfunction, vascular damage? • Are TSAT and Ferritin good enough markers? Should we be using CHr? • Should we keep our ESRD on continuous maintenance IV iron instead of intermittent? Check iron levels every few weeks instead of every few months.