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Beneficial effects of iron therapy in renal failure patients on hemodialysis

1999; Elsevier BV; Volume: 55; Linguagem: Inglês

10.1046/j.1523-1755.1999.055suppl.69067.x

1523-1755

Steven Fishbane, Sanjeev Mittal, John K. Maesaka,

Hemoglobinopathies and Related Disorders

Beneficial effects of iron therapy in renal failure patients on hemodialysis. Iron deficiency is a common problem in patients treated with hemodialysis. If not detected and treated appropriately, the effectiveness of recombinant human erythropoietin therapy is compromised. Much has been learned in recent years with respect to iron therapy for hemodialysis patients. A series of studies have clearly defined the efficacy of intravenous iron compounds, and recently released clinical practice guidelines have set the appropriate clinical context for the use of these agents. The purpose of this article is to examine the beneficial effects of iron replacement therapy for hemodialysis patients. Beneficial effects of iron therapy in renal failure patients on hemodialysis. Iron deficiency is a common problem in patients treated with hemodialysis. If not detected and treated appropriately, the effectiveness of recombinant human erythropoietin therapy is compromised. Much has been learned in recent years with respect to iron therapy for hemodialysis patients. A series of studies have clearly defined the efficacy of intravenous iron compounds, and recently released clinical practice guidelines have set the appropriate clinical context for the use of these agents. The purpose of this article is to examine the beneficial effects of iron replacement therapy for hemodialysis patients. Recombinant human erythropoietin (rHuEPO) has been available for the treatment of the anemia of end-stage renal failure in the United States since 1989. The effect has been a marked improvement in hematocrit values1.Powe N.R. Griffiths R.I. Greer J.W. Watson A.J. Anderson G.F. De Lissovoy G. Herbert R.J. Eggers P.W. Milam R.A. Whelton P.K. Early dosing practices and effectiveness of recombinant human erythropoietin.Kidney Int. 1993; 43: 1125-1133Abstract Full Text PDF PubMed Scopus (25) Google Scholar, and probably of the quality of life, lifespan, and functional status of hundreds of thousands of dialysis patients. It has been clear, however, that the maximal potential of the medication has not been reached. In the first full year of clinical use in the United States, only 44% of patients experienced a hematocrit of greater than 30%1.Powe N.R. Griffiths R.I. Greer J.W. Watson A.J. Anderson G.F. De Lissovoy G. Herbert R.J. Eggers P.W. Milam R.A. Whelton P.K. Early dosing practices and effectiveness of recombinant human erythropoietin.Kidney Int. 1993; 43: 1125-1133Abstract Full Text PDF PubMed Scopus (25) Google Scholar. In 1993 it was estimated that 43% of patients still had a hematocrit below that value2.Young E.W. Bloembergen W.E. Woods J.D. Emmert G. Port F.K. Wolfe R.A. Jones C.A. Held P.J. Iron use among erythropoietin treated US hemodialysis patients.J Am Soc Nephrol. 1996; 7 (abstract): 1469Google Scholar. With the realization that anemia therapy in the United States has not achieved optimal outcomes, there has been a rapidly growing appreciation of the importance of iron management to improve the effectiveness of rHuEPO therapy. The purpose of this article is to review the subject of iron therapy for hemodialysis patients treated with rHuEPO. Iron deficiency almost always occurs on the basis of chronic blood loss. In primary care, iron deficiency is seen mostly in young women with heavy menstrual blood loss, and in older patients with gastrointestinal malignancies which lead to chronic mucosal bleeding. Hemodialysis patients, similarly, become iron deficient primarily due to chronic blood loss. The hemodialysis procedure itself leads to the lost of 1 to 2 grams of iron per year (normal blood loss should be <400 mg per year) due to blood retention by the dialysis lines and filter3.Van Wyck D.B. Stivelman J.C. Ruiz J. Kirlin L.F. Katz M.A. Ogden D.A. Iron status in patients receiving erythropoietin for dialysis-associated anemia.Kidney Int. 1989; 35: 712-716Abstract Full Text PDF PubMed Scopus (203) Google Scholar. Additional sources of blood loss are related to blood sampling for laboratory testing, accidental bleeding from the dialysis access, surgery, and occult gastrointestinal bleeding. The net effect is a marked reduction in the overall supply of iron. In addition to the reduction of the body's iron stores, there is also an increase in the demand for iron in patients treated with rHuEPO, which may lead to iron deficiency even if iron stores are not fully depleted4.Cavill I. Macdougall I.C. Erythropoiesis and iron supply in patients treated with erythropoietin.Erythropoiesis. 1992; 3: 50-55Google Scholar,5.Eschbach J.W. Egrie J.C. Downing M.R. Browne J.K. Adamson J.W. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin.N Engl J Med. 1987; 316: 73-78Crossref PubMed Scopus (1729) Google Scholar. This occurs because during the intense stimulus to produce new red blood cells induced by intravenous rHuEPO, the body is unable to optimally access even fairly normal iron stores6.Brugnara C. Collela G.M. Cremins J. Langley Jr, R.C. Schneider T.J. Rutherford C.J. Goldberg M.A. Effects of subcutaneous recombinant human erythropoietin in normal subjects: Development of decreased reticulocyte hemoglobin content and iron-deficient erythropoiesis.J Lab Clin Med. 1994; 123: 660-667PubMed Google Scholar. Only approximately 3 mg of the body's total iron supply of 3,000 to 5,000 mg circulates in blood7.Fairbanks V.F. Beutler E. Iron metabolism,.Williams Hematology. 5th ed. McGraw-Hill Inc, New York1995: 369-380Google Scholar. In the five to seven hours of intense red cell production following intravenous rHuEPO therapy8.Macdougall I.C. Roberts D.E. Neubert P. Dharmasena A.D. Coles G.A. Williams J.D. Pharmacokinetics of intravenous, intraperitoneal, and subcutaneous recombinant human erythropoietin in patients on CAPD.Contr Nephrol. 1989; 76: 112-121Crossref PubMed Google Scholar, this small quantity of circulating iron is insufficient to match demand for iron by the erythron. Thus, among hemodialysis patients, the body's supply of iron is reduced, and the demand for iron is increased, leading to the frequent development of iron deficiency. Therapy with iron is, therefore, vitally important for patients treated with hemodialysis. Oral iron formulations are the simplest, most convenient, and least expensive method for supplementing iron. The most commonly used form in the United States is ferrous sulfate, which is usually dispensed as 325 mg tablets of which 20% is elemental iron. Table 1 is a compilation of common forms of oral iron currently available. Several principles guide the therapeutic use of oral iron for hemodialysis patients. First, 200 mg of elemental iron should be administered per day. Second, the pills should be consumed between meals, since several chemicals present in food can markedly impair iron absorption9.Hallberg L. Bioavailability of dietary iron in man.Annu Rev Nutr. 1981; 1: 123-147Crossref PubMed Scopus (416) Google Scholar. Finally, since iron is absorbed relatively proximally in the gastrointestinal tract, enteric coated formulations should in general be avoided.Table 1Table 1. Oral iron supplements Open table in a new tab There has been increasing recognition in recent years that oral iron supplements may not be effective for the majority of patients treated with hemodialysis. Recent studies have suggested that hemodialysis patients do not absorb oral iron normally10.Kooistra M.P. van Es A. Struyvenberg A. Marx J.J.M. Low iron absorption in erythropoietin-treated hemodialysis patients.J Am Soc Nephrol. 1995; 6 (abstract): 543Google Scholar,11.Donnelly S.M. Posen G.A. Ali M.A. Oral iron absorption in hemodialysis patients treated with erythropoietin.Clin Invest Med. 1991; 14: 271-276PubMed Google Scholar. Kooistra et al found that iron absorption in iron deficient hemodialysis patients was 44% less efficient compared to iron deficient normals10.Kooistra M.P. van Es A. Struyvenberg A. Marx J.J.M. Low iron absorption in erythropoietin-treated hemodialysis patients.J Am Soc Nephrol. 1995; 6 (abstract): 543Google Scholar. A classic study by Eschbach, Cook and Finch found that hemodialysis patients absorb almost no iron from the diet until the serum ferritin concentration drops to below 50 ng/ml, a value consistent with severe iron deficiency in hemodialysis patients12.Eschbach J.W. Cook J.D. Finch C.A. Iron absorption in chronic renal disease.Clin Sci. 1970; 38: 191-196Crossref PubMed Scopus (56) Google Scholar. These data suggest that hemodialysis patients probably do not absorb any significant amount of iron provided by oral iron supplements. It is, therefore, unlikely that oral iron could deliver enough iron to keep up with the relentless ongoing blood loss hemodialysis patients experience. In addition to problems with the absorption of oral iron, poor patient compliance is probably a superimposed secondary barrier to effectiveness. Gastrointestinal side effects are common with oral iron, which may be caused by the production of reactive oxygen species in the gut13.Schneider W. The fate of iron compounds in the gastrointestinal tract.Arzneimittelforschung. 1987; 37: 92-95PubMed Google Scholar. Typical symptoms include constipation, dyspepsia, diarrhea, and bloating14.Hallberg L. Ryttinger L. Solvell L. Side effects of oral iron therapy. A double-blind study of different iron compounds in tablet form.Acta Med Scand Suppl. 1966; 459: 3-10PubMed Google Scholar. Other factors contributing to poor compliance with oral iron supplements include inconvenience and nonreimbursed cost. In a study reported in 1995 by Wingard et al, 46 hemodialysis patients were randomized to one of four oral iron treatment groups15.Wingard R.L. Parker R.A. Ismail N. Hakim R.M. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin.Am J Kidney Dis. 1995; 25: 433-439Abstract Full Text PDF PubMed Scopus (133) Google Scholar. Patients were followed for a prospective six-month period, with intensive monitoring of patients' compliance with oral iron. At the completion of follow-up, mean hematocrit values remained below 30% in three of four treatment groups. Similarly, the transferrin saturation remained below 20% in three of four treatment groups, and there was a trend to reduced serum ferritin concentrations15.Wingard R.L. Parker R.A. Ismail N. Hakim R.M. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin.Am J Kidney Dis. 1995; 25: 433-439Abstract Full Text PDF PubMed Scopus (133) Google Scholar. This study suggests that even in the best case scenario of intensive support of drug compliance, oral iron is not likely to maintain long-term iron balance. Much of our understanding of the lack of effectiveness of oral iron therapy comes from studies comparing oral iron to intravenous iron supplements. These studies will be discussed in the following section. In the United States only one form of intravenous iron has been available for clinical use, iron dextran. This molecule compartmentalizes iron in a dense central core of ferricoxyhydroxide (the same iron core found in ferritin). Dextran chains, which are polymers of glucose, extend out radially from this core solubilizing the molecule. Other forms of intravenous iron have been used for years among hemodialysis patients treated in other parts of the world. Specifically in Europe, there has been a wealth of experience utilizing ferric gluconate and iron saccharate, as well as iron dextran. After intravenous injection of iron dextran, the molecule is removed from plasma by macrophages of the reticuloendothelial system with a half-life in plasma of between 5.9 hours and three days16.Kamakakom K. Cavill I. Jacobs A. The metabolism of intravenously administered iron dextran.Br J Haematol. 1973; 25: 637-643Crossref PubMed Scopus (26) Google Scholar,17.Wood J.K. Milner P.F.A. Pathak U.N. The metabolism of iron-dextran given as a total dose infusion to iron deficient Jamaican subjects.Br J Haematol. 1968; 14: 119-129Crossref PubMed Scopus (50) Google Scholar. There is rapid intracellular splitting of iron dextran, leading to a peak in serum ferritin levels within two weeks of a therapeutic course18.Vercammen M. Goedhuys W. Boeyckens A. De Roy R. Sennesael J. Sevens S. Gorus F. Iron and total iron binding capacity in serum of patients receiving iron-dextran: Kodak Ektachem methodologies, spectrophotometry, and atom absorption spectrometry compared.Clin Chem. 1990; 36: 1812-1815PubMed Google Scholar. The drug is most commonly administered as a course of 1,000 mg divided over ten consecutive hemodialysis treatments. We evaluated this regimen in 28 hemodialysis patients with presumed iron deficiency based on a serum ferritin < 100 ng/ml. There was a significant increase in mean hematocrit into the targeted range, from 29.1% to 32.9%, with an accompanying reduction in rHuEPO dose requirements by 11%. An interesting observation was that the majority of patients remained somewhat iron deficient after the course of intravenous iron. After 10 weeks of observation, 71% of patients had serum ferritin levels that again dropped below 100 ng/ml. A serum ferritin concentration of <28 ng/ml at baseline predicted all patients who would be underdosed with iron using this popular dosing regimen19.Fishbane S. Lynn R.I. The efficacy of iron dextran for the treatment of iron deficiency in hemodialysis patients.Clin Nephrol. 1995; 44: 238-240PubMed Google Scholar. These data suggest that the degree of iron deficit in these patients was likely greater than 1,000 mg, or that ongoing losses of iron in the 10-week follow-up were greater than expected. In a similar study, Sunder-Plassman and Hörl administered iron saccharate 1,000 mg intravenously over ten consecutive hemodialysis treatments to patients with suspected iron deficiency. Patients received repeated courses of treatment as needed to correct the iron deficiency. The mean hemoglobin increased from 9.4 g/dl to 11.1 g/dl with a reduction of rHuEPO dose requirements from 217 μ/kg/week to 63 μ/kg/week20.Sunder-Plassman G. Hörl W.H. Importance of iron supply for erythropoietin therapy.Nephrol Dial Transplant. 1995; 10: 2070-2076PubMed Google Scholar. Taken together, these studies support the efficacy of intravenous iron therapy for iron deficient hemodialysis patients. It is clearly not sufficient, however, to treat with 1,000 mg of either iron therapy without rechecking the effect on iron status, given the likelihood that many patients require more than 1,000 mg to correct their iron deficiency. We recommend retesting the serum ferritin two weeks after completion of a therapeutic course, and retreating if it is still below 100 ng/ml. Recently the term "maintenance intravenous iron therapy" has been used increasingly. In essence it refers to using small doses of intravenous iron on a regular ongoing basis to maintain iron balance. Macdougall et al randomized 31 patients to either no iron treatment, oral iron therapy (ferrous sulfate 200 mg tid), or intravenous iron dextran therapy (125 mg per week) at the initiation of rHuEPO therapy. After four months of follow-up intravenous iron was the most effective therapy for improving mean hemoglobin, from 7.3 g/dl to 11.9 g/dl. Interestingly, there was no difference in efficacy between the oral iron and no iron groups21.Macdougall I.C. Tucker B. Thompson J. Baker L.R.I. Raine A.E.G. A randomised controlled study of iron supplementation in patients treated with erythropoietin.J Am Soc Nephrol. 1993; 4 (abstract): 428Google Scholar. Our group randomized 75 patients to treatment with either oral iron or intravenous iron dextran 200 mg/week. After four months of follow-up, patients treated with intravenous iron had 5.8% higher hematocrits, and a 46% mean reduction in the rHuEPO dose requirement. The dose used was probably excessive, however, as the mean serum ferritin concentration increased to 754 ng/ml22.Fishbane S. Frei G.L. Maesaka J. Reduction of recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.Am J Kidney Dis. 1995; 26: 41-46Abstract Full Text PDF PubMed Scopus (332) Google Scholar. Senger and Weiss found a 6% increase in hematocrit and a 75% reduction in rHuEPO requirements after six months of iron dextran at 25 to 50 mg per week23.Senger J.M. Weiss R.J. Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment.ANNA J. 1996; 23: 319-323PubMed Google Scholar. Schaefer and Schaefer achieved a 43% reduction of rHuEPO dose by administering 40 mg of intravenous ferric gluconate per week24.Schaefer R.M. Schaefer L. Management of iron substitution during rHuEPO therapy in chronic renal failure patients.Erythropoiesis. 1992; 3: 71-75Google Scholar. Sunder-Plassman and Hörl studied iron saccharate at a dose of 30 to 120 mg per week and achieved a 40% long-term reduction in the mean rHuEPO dose20.Sunder-Plassman G. Hörl W.H. Importance of iron supply for erythropoietin therapy.Nephrol Dial Transplant. 1995; 10: 2070-2076PubMed Google Scholar. Taylor et al treated 46 hemodialysis patients with 62.5 mg biw of ferric gluconate, which resulted in a 33% reduction in rHuEPO requirements after six months25.Taylor J.E. Peat N. Porter C. Morgan A.G. Regular low dose intravenous iron therapy improves response to erythropoietin in hemodialysis patients.Nephrol Dial Transplant. 1996; 11: 1079-1083Crossref PubMed Scopus (114) Google Scholar. Sepandj treated hemodialysis patients with 50 mg weekly of iron saccharate for six months, resulting in a 14% increase in mean hematocrit and 34% reduction of mean rHuEPO dose26.Sepandj F. Jindal K. West M. Hirsch D. Economic appraisal of maintenance parenteral iron administration in treatment of the anemia in chronic haemodialysis patients.Nephrol Dial Transplant. 1996; 11: 319-322Crossref PubMed Scopus (83) Google Scholar. Taken together, the results of these studies provide firm evidence demonstrating the marked efficacy of chronic dosing with intravenous iron compounds (Table 2).Table 2Table 2. Studies of maintenance iron therapy for hemodialysis patients Open table in a new tab Intravenous iron dextran therapy is associated with a small but important risk for allergic reactions (discussed elsewhere in this issue). The incidence of such reactions is on the order of 6 to 7 in 1,000 patients treated27.Hamstra R.D. Block M.H. Schocket A.L. Intravenous iron dextran in clinical medicine.JAMA. 1980; 243: 1726-1731Crossref PubMed Scopus (242) Google Scholar,28.Fishbane S. Ungureanu V.D. Maesaka J.K. Adam G. Kaupke C.J. Lim V. Wish J. A multicenter study of the safety of intravenous iron dextran in hemodialysis patients.Am J Kidney Dis. 1996; 28: 528-534Google Scholar. Because of these reactions, there has been interest in evaluating other intravenous iron compounds for use in the United States. Two recent studies utilizing ferric gluconate indicate that this may be the next agent available in this country. In one study 46 iron deficient hemodialysis patients were treated with 1,000 mg of intravenous ferric gluconate over eight hemodialysis treatments. At day 47 of follow-up there was a 13.7% increase in hematocrit, and a 61.6% increase in serum ferritin29.Nissenson A.R. Lindsay R.M. Swan S. Lambrecht L.L. Seligman P. Ferric gluconate is safe and effective in hemodialysis patients: North American Trial.J Am Soc Nephrol. 1996; 7 (abstract): 1459Google Scholar. In a second study, nine patients who had previously experienced an allergic reaction after treatment with intravenous iron dextran were challenged with ferric gluconate. None of the patients experienced an adverse reaction, suggesting that this agent is safe in patients previously found to be allergic to iron dextran30.Nissenson A.R. Swan S. Lambrecht L.L. Anderson P. Schweitzer S. Ferrix gluconate is safe in hemodialysis patients who react to iron dextran.J Am Soc Nephrol. 1996; 7: 1460Google Scholar. Concern has been raised with regard to early release of iron by ferric gluconate. Physical chemical studies have suggested that ferric gluconate does not bind iron as avidly as iron dextran31.Geisser P. Baer M. Schaub E. Structure/histiotoxicity relationships of parenteral iron preparations.Arzneimittelforschung. 1992; 42: 1439-1452PubMed Google Scholar. Zanen et al found that rapid infusions of ferric gluconate resulted in greater than 100% saturation of transferrin32.Zanen A.L. Adriaansen H.J. van Bommel E.F.H. Posthuma R. de Jong GMTh Oversaturation of transferrin after intravenous ferric gluconate in haemodialysis patients.Nephrol Dial Transplant. 1996; 11: 820-824Crossref PubMed Scopus (114) Google Scholar. The clinical significance of this observation is unclear, as ferric gluconate has been used in Europe for many years with an anecdotal reputation for good safety. It is likely that this aspect of ferric gluconate is more of academic interest than clinical importance. A novel method for intravenous iron treatment is administration by total dose infusion (administering the entire therapeutic dose at one time). Recently, Auerbach et al randomized 43 hemodialysis patients to receive iron dextran as total dose infusion, 500 mg sequential infusions until the total dose was reached, or 100 mg sequential infusions to total dose33.Auerbach M. Winchester J. Wahab A. Richards K. McGinley M. Hall F. Anderson J. Briefel G. A randomized trial of three iron dextran infusion methods for anemia of erythropoietin treated dialysis patients.Am J Kidney Dis. 1998; 31: 81-86Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar. The total dose was administered in 500 ml of 0.9% saline over two hours. At the conclusion of study, the total dose infusion was found to be as effective as divided dose infusions, and less expensive to administer33.Auerbach M. Winchester J. Wahab A. Richards K. McGinley M. Hall F. Anderson J. Briefel G. A randomized trial of three iron dextran infusion methods for anemia of erythropoietin treated dialysis patients.Am J Kidney Dis. 1998; 31: 81-86Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar. Given all that has been learned regarding various forms of iron therapy for hemodialysis patients in the past several years, how do we synthesize a rational approach to therapy? The recently completed NKF-DOQI Guidelines for anemia management provided several recommendations that provide standards of care specific for iron therapy34.NKF-DOQI Clinical practice guidelines for the treatment of anemia of chronic renal failure.Am J Kidney Dis. 1997; 30: 192-240PubMed Google Scholar. The first states that the transferrin saturation should be maintained at greater than 20%, and the serum ferritin greater than 100 ng/ml. In patients in whom iron indices are not abnormal by these criteria, yet who still have hematocrit values of <33 to 36%, a course of intravenous iron should be used, and the response evaluated. Importantly, the tests of iron status should not be performed within a two-week window period after a dose of intravenous iron. The group estimated that the weekly required intravenous iron dose for patients on maintenance therapy would be 25 to 100 mg per week. With regard to the issue of potentially overusing intravenous iron, the guidelines recommend that patients' transferrin saturation should not be allowed to increase to greater than 50%, and the serum ferritin not greater than 800 ng/ml to minimize the risk of iron overload. Finally, when oral iron is used, the recommendation is to provide 200 mg per day of elemental iron in two to three divided doses, preferably between meals. In conclusion, there has been a great surge of interest in iron therapy for hemodialysis patients in recent years. It has become clear that the initial suboptimal results with respect to anemia outcomes in the United States were at least partially due to a lack of attention to the importance of iron therapy to successful rHuEPO therapy. This is supported by 1993 USRDS data showing that 50% of hemodialysis patients had a transferrin saturation < 20%, 25% had a transferrin saturation < 10%, and 56% had a serum ferritin of <200 ng/ml. Clearly, iron deficiency was epidemic among American hemodialysis patients. Initial data suggest that there has been some improvement recently, perhaps mirroring the increased recognition of the importance of iron therapy. Future studies should lead to refinements and improvement in methods of iron replacement.