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Iron Treatment Strategies in Dialysis-Dependent CKD
Iron Treatment Strategies in Dialysis-Dependent CKD Richa Pandey, Reem Daloul, and Daniel W. Coyne, MD
Summary: Iron deficiency is common in patients on chronic dialysis, and most require iron-replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional irondeficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care. Semin Nephrol 36:105-111 C 2016 Elsevier Inc. All rights reserved. Keywords: ,
I
ron deficiency is a frequent problem in hemodialysis patients because of ongoing blood losses related to the dialysis treatment. Each milliliter of packed red blood cells contains approximately 1 mg of iron. Early estimates of iron losses in hemodialysis patients before the use of erythropoietin-stimulating agents (ESAs) when the mean hematocrit was 25% to 28% placed minimum iron losses at 3 mg/d or approximately 1 g/y,1 while others placed blood losses higher at 2 to 3 g/y.2 Although improvements in dialysis technology reduced procedural blood loss and destruction by the dialysis circuit, treatment with ESAs increased hematocrit to 30% to 36%, leading to larger iron losses. Currently, estimated iron losses in stable hemodialysis patients are placed at 2.0 to 2.5 g/y, with hospitalizations and procedures increasing the losses further. Peritoneal dialysis patients also have iron deficits, estimated at approximately 1 g/y, caused by gastrointestinal blood loss, diagnostic phlebotomy, and procedures. Studies by Eschbach et al1 showed that intestinal iron absorption in hemodialysis patients parallels absorption in healthy adults. Iron absorption is appreciable when the serum ferritin concentration is less than 70 to 100 ng/mL. Iron absorption decreased to Washington University, St. Louis, MO. Financial disclosure and conflict of interest statements: none. Address reprint requests to Daniel W. Coyne, MD, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8129, St. Louis, MO 63110. E-mail: [email protected] 0270-9295/ - see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2016.02.004
Seminars in Nephrology, Vol 36, No 2, March 2016, pp 105–111
0.6% to 4.6% of the ingested iron when greater than this ferritin range. Because many hemodialysis patients have increased ferritin (and hepcidin) concentrations from inflammation, intravenous (IV) iron administration, and occasionally transfusions, one would expect oral iron to be ineffective in replacing ongoing iron losses in hemodialysis patients. Consistent with this, trials of oral iron supplementation in hemodialysis have failed to show appreciable efficacy.
ORAL IRON Oral iron is inexpensive and the most physiologic treatment of iron deficiency. Multiple preparations are readily available for clinical use and consist mostly of ferrous salts. Bivalent iron (ferrous) is believed to be three times better absorbed than the trivalent ferric iron.3 Efficacy of ferrous iron is limited by gastrointestinal side effects, frequent administration, and diminished enteral absorption as a result of interaction with food, phosphate binders, and reduced gastric acidity. In three small randomized clinical trials in dialysis patients, providing 50 to 300 mg of daily elemental iron, failed to significantly improve iron stores, and ferritin concentration decreased comparably in both groups.4-6 Efficacy was not significantly different among various oral iron preparations tested. A trial randomizing hemodialysis patients to receive 200 mg elemental iron via four different preparations found iron and anemia indices did not improve greatly with any agent, and by 6 months ferritin levels had decreased significantly in all groups.7 105
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Heme iron is absorbed in the intestine via a different transporter than ferrous iron. An early open-label study of heme iron polypeptide in dialysis patients suggested efficacy,8 consistent with a study showing higher bioavailability of heme iron than iron salts.9 A more recent rigorous randomized trial prescribing 240 mg of heme iron polypeptide or 210 mg of ferrous sulfate showed neither agent significantly improved hemoglobin, transferrin percentage saturation (TSAT), or lowered epoetin dose.10 Multiple small, randomized, controlled trials examined the efficacy of oral iron preparations in comparison with intravenous iron. The results of these studies are well summarized in two meta-analyses that showed comparable results.11,12 Despite significant heterogeneity among studies, intravenous iron was uniformly more efficacious in dialysis patients. Major clinical outcomes such as all-cause mortality and cardiovascular morbidity and mortality were not well reported, but there were no significant differences in these outcomes between IV and oral iron. However, none of the studies were powered for these safety end points.
INTRAVENOUS IRON ADMINISTRATION Since 2011, the use of IV iron has increased in the US dialysis population because of safety concerns about ESAs, and IV iron use usually is more cost effective than ESA. Parenteral iron formulations currently approved for use in the United States and Europe are listed in Table 1. Each of these preparations has an iron core surrounded by a carbohydrate shell. The presence of this carbohydrate shell prevents the immediate release of free iron, and severe toxic reactions.13 The formulations differ in the size of the iron core and the type of carbohydrate shell, which affect maximum tolerated dose, rate of infusion, and rate of reactions.14 Parenteral iron is taken up by macrophages in the reticuloendothelial system (Fig. 1). The rate of uptake is influenced by the molecular weight of the compound. After uptake, the carbohydrate shell is metabolized and iron is either stored intracellularly in tissue ferritin or transferred through ferroportin to circulating transferrin.14 This process increases transferrin saturation, enhancing erythropoiesis, but will increase hepcidin levels, which further impairs intestinal iron absorption, and can lead to excessive storage iron. Iron dextrans require a test dose before infusions. Low-molecular-weight iron dextran was approved for use in 1991. A retrospective chart analysis of 573 hemodialysis patients given low-molecular-weight iron dextran showed adverse reactions in 4.7%, including four serious anaphylactoid reactions.15 Dexferrum is a high-molecular-weight iron dextran. In a Food and Drug Administration database review, drug-related adverse events were significantly higher with Dexferrum compared
R. Pandey, R. Daloul, and D.W. Coyne
with low-molecular-weight iron, with an odds ratio of 5.5 (range, 4.9-6.0).16 Because of this, many experts strongly advise against the use of this drug. A more recent analysis of Medicare data suggested that anaphylactic risk after first iron exposure was approximately 3.6 times higher with iron dextrans than iron sucrose, with intermediate rates for ferric gluconate and ferumoxytol.17 Sodium ferric gluconate complex (Ferrlecit and Nulecit) and iron sucrose (Venofer) have been used extensively in Europe for decades before approval in the United States in 1999 and 2001, respectively. No test dose is required, and both have been administered safely to patients with prior iron dextran allergies.18,19 The currently approved dose of sodium ferric gluconate complex is 125 mg, although administration of 250 mg as a slow infusion also may be safe.18,20 Iron sucrose (Venofer) is approved for injection of 100 mg or infusions of up to 300 mg over 2 hours.19 Three newer products have been approved for use in chronic kidney disease patients (Table 1). Ferric carboxymaltose (FCM), ferumoxytol, and iron isomaltoside can be administered as larger doses infused over 15 minutes. Ferric carboxymaltose (Injectafer and Ferinject) usually is given as two 750-mg infusions over 15 minutes 1 week apart.21,22 Ferric carboxymaltose can be administered in smaller doses to hemodialysis patients.23 Ferumoxytol (Feraheme) initially was approved as a 510-mg injection administered over 17 to 60 seconds.24 Ferumoxytol also has been compared with oral iron and iron sucrose in various populations.25 Because of 79 spontaneous reports of serious hypersensitivity reactions including 18 deaths despite immediate medical intervention and emergency resuscitation, the Food and Drug Administration has altered the prescribing information significantly. Ferumoxytol should not be used in patients with other iron allergies, and should be administered only as a diluted infusion over 15 minutes. The risks of its use should be weighed when treating the elderly or patients with multiple drug allergies.26
INTRAVENOUS IRON ADMINISTRATION REGIMENS IN THE DIALYSIS POPULATION Intravenous iron in hemodialysis patients is administered as either intermittent large doses whenever TSAT or ferritin is decreased below a threshold, or as small maintenance doses intended to replace ongoing losses. The large, infrequent dosing is sometimes called bolus dosing or load and hold, and usually administers 1 g of iron over 2 to 3 weeks, whereas maintenance dosing administers 25 to 100 mg of iron every 1 to 2 weeks.
Carbohydrate Shell
Maximum Approved Single Dose, Administration Time
Common Off-Label Maximum Dose and Administration Time
Generic Name of Iron Product (Brand Name)
Molecular Weight (Kd) Year of US FDA Approval
Low-molecular-weight iron dextran (INFeD)
1991
165
Dextran
100 mg over 430 s
Z1,000 mg IV over 4 hours
Iron dextran, high molecular weight (Dexferrum)
1996
265
Dextran
100 mg over 430 s
Z1,000 mg IV over 4 hours
Sodium ferric gluconate complex (Ferrlecit, Nulecit) Iron sucrose (Venofer) Newer iron products Ferumoxytol (Feraheme): FDA issued a black box warning on 3/30/15 for anaphylactic shock Ferric carboxymaltose (Injectafer in the United States; Ferinject in the European Union) Iron isomaltoside (Monofer in the European Union, not approved in the United States)
1999
289-444
Gluconate
250 mg IV over 15 minutes
2000
34-60
Sucrose
125 mg IV push over 10 min 200 mg IV over 2-5 min
Yes, 25 mg, monitor 15-30 min Yes, 25 mg, monitor 15-30 min No
300 mg IV over 1 hour
No
2009
750
Polyglucose sorbitol
510 mg IV, o1 min
Same dose as 15-min infusion
No
2013
150
Carboxymaltose
750 mg slow push or infusion over 15 min
None
No
2009 for Europe only, not submitted for US approval
150
20 mg/kg over 30 to Isomaltoside 60 min (linear oligosaccharide)
None
No
Test Dose Requirement
Iron treatment and dialysis in CKD
Table 1. Currently Available Iron Products
Abbreviation: FDA, Food and Drug Administration.
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Figure 1. Iron balance in chronic hemodialysis patients. Hemodialysis patients have high ongoing iron requirements as a result of losses from the gastrointestinal tract, impaired iron absorption as a result of high hepcidin levels, and ongoing dialysis-related blood losses. Intravenous iron products are taken into the reticuloendothelial system where the carbohydrate shell is removed, and iron is stored intracellularly in ferritin, or exported to maintain higher transferrin saturation. The higher storage iron leads to higher hepcidin levels, further impairing intestinal iron absorption. GI, gastrointestinal; RBC, red blood cell.
The maintenance dose usually is adjusted to maintain TSAT or serum ferritin above a specific threshold. No large randomized controlled trials have compared the two regimens, but some data from observational and small prospective trials are shown in Table 2. There are concerns that higher doses of IV iron over a short period could lead to temporary oversaturation of transferrin and more nontransferrin bound iron, with subsequent enhanced oxidative damage and infectious risk.27,28 A small trial showed that despite administering comparable amounts of IV iron, maintenance dosing was more efficacious than bolus dosing.29 Large observational data support that maintenance dosing regimens are more efficacious, and are associated with lower infection risk compared with bolus dosing, particularly in patients with central venous catheters. Compared with no iron therapy, maintenance iron dosing was not associated with additional risk.30 Recent observational DOPPS data associated monthly IV iron doses greater than 300 mg to a higher risk of mortality.31 Overall, trial and observational data suggest maintenance dosing is more efficacious and has a lower risk than higher-dose intermittent IV iron.
FERRITIN AND TSAT TARGETS IN CLINICAL PRACTICE There is great controversy regarding the serum ferritin level at which iron supplementation should be stopped. The 2006 National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines recommended using a serum ferritin cut-off value of 500 ng/mL to separate routine use of IV iron in dialysis patients from
R. Pandey, R. Daloul, and D.W. Coyne
using iron based only on other factors such as low hemoglobin level, high ESA dose, or other clinical factors. Most studies have not found a significant relationship between higher pretreatment ferritin concentration and response to IV iron.32-35 The lack of a robust relationship between pretreatment ferritin concentration and response to IV iron reflect the shortcomings of using a ferritin cut-off value to determine the need for intravenous iron. Two studies in nondialysis CKD patients found that absolute iron deficiency confirmed by bone marrow biopsy was common despite serum ferritin values greater than 200 ng/mL, and even patients with apparently adequate iron stores responded to IV iron therapy.36,37 These findings support that iron deficiency is underdiagnosed, and can be present despite having a ferritin level in the normal range.
SERUM FERRITIN AND TSAT AS INFLAMMATORY MARKERS Several non–iron-dependent factors can regulate ferritin levels such as inflammation, liver dysfunction, and malnutrition.38 Proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β increase ferritin synthesis.39,40 Inflammation and nutritional status are associated significantly with serum ferritin levels (between 200 and 2,000 ng/mL) in dialysis patients.41 Similar to ferritin, TSAT has its shortcomings as a marker of iron status. Apart from having diurnal variation, transferrin and TSAT levels also are influenced by nutritional status and inflammation. Transferrin levels are low in malnutrition, making TSAT appear higher. In states of inflammation TSAT might be artificially low given that transferrin is an acute phase reactant and is increased with inflammation.
IV IRON IN SPECIAL POPULATIONS There is no consensus definition of ESA hyporesponsiveness in dialysis patients, although all involve either failure to achieve a desired hemoglobin target and/or use of a high ESA dose. ESA hyporesponders usually have inflammation, increased ferritin levels, and relatively low transferrin saturation. Absolute and functional iron deficiency may be a contributing or sole cause of ESA hyporesponsiveness. The DRIVE trial tested whether IV iron was efficacious in ESA hyporesponders on hemodialysis, defined as a hemoglobin level less than 11 g/dL, an epoetin dose of 22,500 U/wk or higher or 225 U/kg/wk or higher, ferritin level of 500 ng/mL or higher, and a transferrin saturation of 25% or less.42 At the time, the mean hemoglobin concentration in US dialysis patients was 12 g/dL. All patients received a 25% increase in
Iron treatment and dialysis in CKD
109
Table 2. Comparison Between Bolus and Maintenance Regimen Study
Type of Study
Besarab, 1999
1 g IV dextran over 10 dialysis IV dextran pulse to achieve TSAT4 30%, then, 25 - 100 mg every 1 sessions, when TSAT 2 weeks to maintain TSAT of 30% o20% or ferritin level o200 50% ng/mL Prospective 62.5 mg every 1-4 wk 6.25-21.3 mg in every hemodialysis session Retrospective o1,000 mg iron use over 41,000 mg IV iron use over 6 mo review 6 mo Retrospective o1,000 mg iron use over 41,000 mg IV iron use over 6 mo review 6 mo Prospective 1,000 mg iron sucrose over 10 100 mg iron sucrose weekly for 10 wk HD sessions Retrospective 4400 mg/mo o400 mg/mo review
Bolaños, 2002 Feldman 2002 Feldman 2004 Aronoff 2004 KalantarZadeh 2005
Intervention Arm 1
Prospective
Schiesser 2006 Brookhart 2013
Prospective
Brookhart 2013 Freburger 2014
Retrospective review Retrospective review
Retrospective review
Kshirsagar Retrospective 2013 review
Intervention Arm 2
Results ESA dose reduced in arm 2 by 50%
Significant increment in serum Hb level in arm 2 Arm 1 with 18% increased rate of death Compared with no iron, arm 1 had a higher mortality rate No difference in safety in either regimen Compared with no iron, doses 4400 mg/mo tended to be associated with higher death rates None 50 mg IV iron sucrose weekly for 6 mo 38.5% reduction in dose of darbepoetin α Consecutive doses Z100 mg All other iron doses during the month More infections in intervention arm 1 with potential of exceeding 600 mg during 1 mo 4200 mg/mo iron o200 mg/mo iron More infections in intervention arm 1 Consecutive doses Z100 mg All other iron doses during the month Higher rate of hospitalization for infection in arm 1 with potential of exceeding 600 mg during 1 mo Consecutive doses Z100 mg All other iron doses during the month Higher average hemoglobin and lower average epoetin with potential of exceeding dose in arm 1 600 mg during 1 mo
ESA dose. Those patients randomized to 1 g of IV iron had a greater increase in mean hemoglobin level (1.6 versus 1.1 g/dL; P ¼ .028) and a significant decrease in epoetin dose requirements compared with patients randomized to receive no iron.42,43 Despite the concerns for use of iron in inflamed patients, those randomized to IV iron had significantly less serious adverse events than the control group.43 The use of IV iron in these ESA hyporesponders was more cost effective.44 Based on the results of the DRIVE studies, 1 g of iron can be administered to ESA hyporesponders or simply those patients on higher ESA doses as a therapeutic trial, and such management has been shown to reduce ongoing ESA requirements and to increase hemoglobin level.45
IRON OPTIONS IN THE PERITONEAL DIALYSIS POPULATION Although there is a consensus that intravenous iron supplements are superior to standard doses of oral iron for iron-deficiency anemia in hemodialysis patients, there is no consensus for treatment of peritoneal dialysis
patients. The Kidney Disease Outcome Quality Initiative guidelines do not recommend a preferred route of iron administration for peritoneal dialysis patients. Multiple small nonrandomized studies have evaluated enteral iron absorption in peritoneal dialysis patients compared with normal subjects with conflicting results.46-49 The efficacy of oral iron compared with intravenous iron was evaluated in two small openlabel randomized trials,6,50 two prospective observational studies,51,52 and a prospective cross-over trial.53 All reached similar results. Intravenous iron was more efficacious than oral iron in treating iron-deficiency anemia based on changes in hemoglobin and iron status markers. Nevertheless, the lack of large, welldesigned, randomized, clinical trials comparing IV with oral iron, the smaller iron losses in peritoneal dialysis patients (compared with hemodialysis patients), and the lower cost of oral iron therapy may make it preferable in some patients. Poor tolerance of oral preparations, resistant anemia, and need of large dosages of ESA are situations in which patients likely will benefit more from monthly or every-other-month IV iron administration.
110
SUMMARY Use of IV iron products in hemodialysis patients remains the standard treatment for the inevitable iron deficiency that occurs as a result of ongoing blood loss and stimulation of erythropoiesis with ESA therapy. Maintenance of adequate iron stores by continuing repletion doses appears more efficacious and possibly safer than large intermittent repletion doses. The average stable patient on hemodialysis will require 2.0 to 2.5 g/y of iron. Available IV iron products differ in maximal single dose and carbohydrate shell, but should be equally efficacious on a milligram for milligram of iron basis. Although use of oral iron in patients on peritoneal dialysis is an option, IV iron is more efficacious in most patients and provides significant sparing of ESA doses.
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R. Pandey, R. Daloul, and D.W. Coyne 14. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol. 2004;15 (Suppl 2): S93-S98. 15. Fishbane S, Ungureanu VD, Maesaka JK, et al. The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis. 1996;28:529-34. 16. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant. 2004;19:1571-5. 17. Wang C, Graham DJ, Kane RC, Xie D, Wernecke M, Levenson M, et al. Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA. 2015;314:2062-8. 18. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61: 1830-9. 19. Aronoff GR, et al. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int. 2004; 66:1193-8. 20. Folkert VW, Michael B, Agarwal R, et al. Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety of higher-dose (4 or ¼250 mg) administration. Am J Kidney Dis. 2003;41:651-7. 21. Onken JE, Bregman DB, Harrington RA, et al. Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial. Nephrol Dial Transplant. 2014;29:833-42. 22. Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion. 2014;54:306-15. 23. Covic A, Mircescu G. The safety and efficacy of intravenous ferric carboxymaltose in anaemic patients undergoing haemodialysis: a multi-centre, open-label, clinical study. Nephrol Dial Transplant. 2010;25:2722-30. 24. Provenzano R, Schiller B, Rao M, et al. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol. 2009;4:386-93. 25. Macdougall IC, Strauss WE, McLaughlin J, et al. A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKD. Clin J Am Soc Nephrol. 2014;9:705-12. 26. FDA Drug Safety Communication: FDA strengthens warnings and changes prescribing instructions to decrease the risk of serious allergic reactions with anemia drug Feraheme (ferumoxytol). Available from: http://www.fda.gov/Drugs/DrugSaf ety/ucm440138.htm. 27. Kamanna VS, Ganji SH, Shelkovnikov S, Norris K, Vaziri ND. Iron sucrose promotes endothelial injury and dysfunction and monocyte adhesion/infiltration. Am J Nephrol. 2012;35: 114-9. 28. Scheiber-Mojdehkar B, Lutzky B, Schaufler R, Sturm B, Goldenberg H. Non-transferrin-bound iron in the serum of hemodialysis patients who receive ferric saccharate: no correlation to peroxide generation. J Am Soc Nephrol. 2004;15: 1648-55. 29. Besarab A, Kaiser JW, Frinak S. A study of parenteral iron regimens in hemodialysis patients. Am J Kidney Dis. 1999;34: 21-8. 30. Brookhart MA, Freburger JK, Ellis AR, et al. Infection risk with bolus versus maintenance iron supplementation in hemodialysis patients. J Am Soc Nephrol. 2013;24:1151-8. 31. Bailie GR, Larkina M, Goodkin DA, Li Y, Pisoni RL, Bieber B, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015;87:162-8.
Iron treatment and dialysis in CKD 32. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol. 1996;7:2654-7. 33. Lin JL, Chang MY, Tan DT, Leu ML. Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients. Am J Nephrol. 2001;21:91-7. 34. Mittman N, Sreedhara R, Mushnick R, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis. 1997;30:912-22. 35. Mitsuiki K, Harada A, Miyata Y. Assessment of iron deficiency in chronic hemodialysis patients: investigation of cutoff values for reticulocyte hemoglobin content. Clin Exp Nephrol. 2003;7:52-7. 36. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol. 2006;19: 161-7. 37. Stancu S, Bârsan L, Stanciu A, Mircescu G. Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease? Clin J Am Soc Nephrol. 2010;5: 409-16. 38. Worwood M. Ferritin. Blood Rev. 1990;4:259-69. 39. Rogers JT, Bridges KR, Durmowicz GP, et al. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem. 1990;265:14572-8. 40. Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem. 1995;270:15285-93. 41. 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;19:141-9. 42. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the
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Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) study. J Am Soc Nephrol. 2007;18:975-84. Kapoian T, O'Mara NB, Singh AK, et al. Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol. 2008;19:372-9. Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. 2008;74: 1588-95. Coyne DW, Sims A, Bingel B. Results of an anemia management program to reduce high epoetin doses by targeted use of i.v. ferric gluconate. Nephrol Nurs J. 2008;35:583-7. Milman N. Iron absorption measured by whole body counting and the relation to marrow iron stores in chronic uremia. Clin Nephrol. 1982;17:77-81. Dittrich E, et al. Is absorption of high-dose oral iron sufficient in peritoneal dialysis patients? Perit Dial Int. 2000;20:667-73. Domoto DT, Martin KJ. Failure of CAPD patients to respond to an oral iron absorption test. Adv Perit Dial. 1992;8:102-4. Tinawi M, Martin KJ, Bastani B. Oral iron absorption test in patients on CAPD: comparison of ferrous sulfate and a polysaccharide ferric complex. Nephron. 1996;74:291-4. Li H, Wang S-X. Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Perit Dial Int. 1008;28:149-154. Ficheux M, Cuny P, Lecouf A, et al. Treatment of iron deficiency by a bolus intravenous iron dextran in peritoneal dialysis. Nephrol Ther. 2011;7:558-61. Ahsan N. Intravenous infusion of total dose iron is superior to oral iron in treatment of anemia in peritoneal dialysis patients: a single center comparative study. J Am Soc Nephrol. 1998;9: 664-8. Johnson DW, Herzig KA, Gissane R, et al. A prospective crossover trial comparing intermittent intravenous and continuous oral iron supplements in peritoneal dialysis patients. Nephrol Dial Transplant. 2001;16:1879-84.
Summary: Iron deficiency is common in patients on chronic dialysis, and most require iron-replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional irondeficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care. Semin Nephrol 36:105-111 C 2016 Elsevier Inc. All rights reserved. Keywords: ,
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ron deficiency is a frequent problem in hemodialysis patients because of ongoing blood losses related to the dialysis treatment. Each milliliter of packed red blood cells contains approximately 1 mg of iron. Early estimates of iron losses in hemodialysis patients before the use of erythropoietin-stimulating agents (ESAs) when the mean hematocrit was 25% to 28% placed minimum iron losses at 3 mg/d or approximately 1 g/y,1 while others placed blood losses higher at 2 to 3 g/y.2 Although improvements in dialysis technology reduced procedural blood loss and destruction by the dialysis circuit, treatment with ESAs increased hematocrit to 30% to 36%, leading to larger iron losses. Currently, estimated iron losses in stable hemodialysis patients are placed at 2.0 to 2.5 g/y, with hospitalizations and procedures increasing the losses further. Peritoneal dialysis patients also have iron deficits, estimated at approximately 1 g/y, caused by gastrointestinal blood loss, diagnostic phlebotomy, and procedures. Studies by Eschbach et al1 showed that intestinal iron absorption in hemodialysis patients parallels absorption in healthy adults. Iron absorption is appreciable when the serum ferritin concentration is less than 70 to 100 ng/mL. Iron absorption decreased to Washington University, St. Louis, MO. Financial disclosure and conflict of interest statements: none. Address reprint requests to Daniel W. Coyne, MD, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8129, St. Louis, MO 63110. E-mail: [email protected] 0270-9295/ - see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2016.02.004
Seminars in Nephrology, Vol 36, No 2, March 2016, pp 105–111
0.6% to 4.6% of the ingested iron when greater than this ferritin range. Because many hemodialysis patients have increased ferritin (and hepcidin) concentrations from inflammation, intravenous (IV) iron administration, and occasionally transfusions, one would expect oral iron to be ineffective in replacing ongoing iron losses in hemodialysis patients. Consistent with this, trials of oral iron supplementation in hemodialysis have failed to show appreciable efficacy.
ORAL IRON Oral iron is inexpensive and the most physiologic treatment of iron deficiency. Multiple preparations are readily available for clinical use and consist mostly of ferrous salts. Bivalent iron (ferrous) is believed to be three times better absorbed than the trivalent ferric iron.3 Efficacy of ferrous iron is limited by gastrointestinal side effects, frequent administration, and diminished enteral absorption as a result of interaction with food, phosphate binders, and reduced gastric acidity. In three small randomized clinical trials in dialysis patients, providing 50 to 300 mg of daily elemental iron, failed to significantly improve iron stores, and ferritin concentration decreased comparably in both groups.4-6 Efficacy was not significantly different among various oral iron preparations tested. A trial randomizing hemodialysis patients to receive 200 mg elemental iron via four different preparations found iron and anemia indices did not improve greatly with any agent, and by 6 months ferritin levels had decreased significantly in all groups.7 105
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Heme iron is absorbed in the intestine via a different transporter than ferrous iron. An early open-label study of heme iron polypeptide in dialysis patients suggested efficacy,8 consistent with a study showing higher bioavailability of heme iron than iron salts.9 A more recent rigorous randomized trial prescribing 240 mg of heme iron polypeptide or 210 mg of ferrous sulfate showed neither agent significantly improved hemoglobin, transferrin percentage saturation (TSAT), or lowered epoetin dose.10 Multiple small, randomized, controlled trials examined the efficacy of oral iron preparations in comparison with intravenous iron. The results of these studies are well summarized in two meta-analyses that showed comparable results.11,12 Despite significant heterogeneity among studies, intravenous iron was uniformly more efficacious in dialysis patients. Major clinical outcomes such as all-cause mortality and cardiovascular morbidity and mortality were not well reported, but there were no significant differences in these outcomes between IV and oral iron. However, none of the studies were powered for these safety end points.
INTRAVENOUS IRON ADMINISTRATION Since 2011, the use of IV iron has increased in the US dialysis population because of safety concerns about ESAs, and IV iron use usually is more cost effective than ESA. Parenteral iron formulations currently approved for use in the United States and Europe are listed in Table 1. Each of these preparations has an iron core surrounded by a carbohydrate shell. The presence of this carbohydrate shell prevents the immediate release of free iron, and severe toxic reactions.13 The formulations differ in the size of the iron core and the type of carbohydrate shell, which affect maximum tolerated dose, rate of infusion, and rate of reactions.14 Parenteral iron is taken up by macrophages in the reticuloendothelial system (Fig. 1). The rate of uptake is influenced by the molecular weight of the compound. After uptake, the carbohydrate shell is metabolized and iron is either stored intracellularly in tissue ferritin or transferred through ferroportin to circulating transferrin.14 This process increases transferrin saturation, enhancing erythropoiesis, but will increase hepcidin levels, which further impairs intestinal iron absorption, and can lead to excessive storage iron. Iron dextrans require a test dose before infusions. Low-molecular-weight iron dextran was approved for use in 1991. A retrospective chart analysis of 573 hemodialysis patients given low-molecular-weight iron dextran showed adverse reactions in 4.7%, including four serious anaphylactoid reactions.15 Dexferrum is a high-molecular-weight iron dextran. In a Food and Drug Administration database review, drug-related adverse events were significantly higher with Dexferrum compared
R. Pandey, R. Daloul, and D.W. Coyne
with low-molecular-weight iron, with an odds ratio of 5.5 (range, 4.9-6.0).16 Because of this, many experts strongly advise against the use of this drug. A more recent analysis of Medicare data suggested that anaphylactic risk after first iron exposure was approximately 3.6 times higher with iron dextrans than iron sucrose, with intermediate rates for ferric gluconate and ferumoxytol.17 Sodium ferric gluconate complex (Ferrlecit and Nulecit) and iron sucrose (Venofer) have been used extensively in Europe for decades before approval in the United States in 1999 and 2001, respectively. No test dose is required, and both have been administered safely to patients with prior iron dextran allergies.18,19 The currently approved dose of sodium ferric gluconate complex is 125 mg, although administration of 250 mg as a slow infusion also may be safe.18,20 Iron sucrose (Venofer) is approved for injection of 100 mg or infusions of up to 300 mg over 2 hours.19 Three newer products have been approved for use in chronic kidney disease patients (Table 1). Ferric carboxymaltose (FCM), ferumoxytol, and iron isomaltoside can be administered as larger doses infused over 15 minutes. Ferric carboxymaltose (Injectafer and Ferinject) usually is given as two 750-mg infusions over 15 minutes 1 week apart.21,22 Ferric carboxymaltose can be administered in smaller doses to hemodialysis patients.23 Ferumoxytol (Feraheme) initially was approved as a 510-mg injection administered over 17 to 60 seconds.24 Ferumoxytol also has been compared with oral iron and iron sucrose in various populations.25 Because of 79 spontaneous reports of serious hypersensitivity reactions including 18 deaths despite immediate medical intervention and emergency resuscitation, the Food and Drug Administration has altered the prescribing information significantly. Ferumoxytol should not be used in patients with other iron allergies, and should be administered only as a diluted infusion over 15 minutes. The risks of its use should be weighed when treating the elderly or patients with multiple drug allergies.26
INTRAVENOUS IRON ADMINISTRATION REGIMENS IN THE DIALYSIS POPULATION Intravenous iron in hemodialysis patients is administered as either intermittent large doses whenever TSAT or ferritin is decreased below a threshold, or as small maintenance doses intended to replace ongoing losses. The large, infrequent dosing is sometimes called bolus dosing or load and hold, and usually administers 1 g of iron over 2 to 3 weeks, whereas maintenance dosing administers 25 to 100 mg of iron every 1 to 2 weeks.
Carbohydrate Shell
Maximum Approved Single Dose, Administration Time
Common Off-Label Maximum Dose and Administration Time
Generic Name of Iron Product (Brand Name)
Molecular Weight (Kd) Year of US FDA Approval
Low-molecular-weight iron dextran (INFeD)
1991
165
Dextran
100 mg over 430 s
Z1,000 mg IV over 4 hours
Iron dextran, high molecular weight (Dexferrum)
1996
265
Dextran
100 mg over 430 s
Z1,000 mg IV over 4 hours
Sodium ferric gluconate complex (Ferrlecit, Nulecit) Iron sucrose (Venofer) Newer iron products Ferumoxytol (Feraheme): FDA issued a black box warning on 3/30/15 for anaphylactic shock Ferric carboxymaltose (Injectafer in the United States; Ferinject in the European Union) Iron isomaltoside (Monofer in the European Union, not approved in the United States)
1999
289-444
Gluconate
250 mg IV over 15 minutes
2000
34-60
Sucrose
125 mg IV push over 10 min 200 mg IV over 2-5 min
Yes, 25 mg, monitor 15-30 min Yes, 25 mg, monitor 15-30 min No
300 mg IV over 1 hour
No
2009
750
Polyglucose sorbitol
510 mg IV, o1 min
Same dose as 15-min infusion
No
2013
150
Carboxymaltose
750 mg slow push or infusion over 15 min
None
No
2009 for Europe only, not submitted for US approval
150
20 mg/kg over 30 to Isomaltoside 60 min (linear oligosaccharide)
None
No
Test Dose Requirement
Iron treatment and dialysis in CKD
Table 1. Currently Available Iron Products
Abbreviation: FDA, Food and Drug Administration.
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Figure 1. Iron balance in chronic hemodialysis patients. Hemodialysis patients have high ongoing iron requirements as a result of losses from the gastrointestinal tract, impaired iron absorption as a result of high hepcidin levels, and ongoing dialysis-related blood losses. Intravenous iron products are taken into the reticuloendothelial system where the carbohydrate shell is removed, and iron is stored intracellularly in ferritin, or exported to maintain higher transferrin saturation. The higher storage iron leads to higher hepcidin levels, further impairing intestinal iron absorption. GI, gastrointestinal; RBC, red blood cell.
The maintenance dose usually is adjusted to maintain TSAT or serum ferritin above a specific threshold. No large randomized controlled trials have compared the two regimens, but some data from observational and small prospective trials are shown in Table 2. There are concerns that higher doses of IV iron over a short period could lead to temporary oversaturation of transferrin and more nontransferrin bound iron, with subsequent enhanced oxidative damage and infectious risk.27,28 A small trial showed that despite administering comparable amounts of IV iron, maintenance dosing was more efficacious than bolus dosing.29 Large observational data support that maintenance dosing regimens are more efficacious, and are associated with lower infection risk compared with bolus dosing, particularly in patients with central venous catheters. Compared with no iron therapy, maintenance iron dosing was not associated with additional risk.30 Recent observational DOPPS data associated monthly IV iron doses greater than 300 mg to a higher risk of mortality.31 Overall, trial and observational data suggest maintenance dosing is more efficacious and has a lower risk than higher-dose intermittent IV iron.
FERRITIN AND TSAT TARGETS IN CLINICAL PRACTICE There is great controversy regarding the serum ferritin level at which iron supplementation should be stopped. The 2006 National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines recommended using a serum ferritin cut-off value of 500 ng/mL to separate routine use of IV iron in dialysis patients from
R. Pandey, R. Daloul, and D.W. Coyne
using iron based only on other factors such as low hemoglobin level, high ESA dose, or other clinical factors. Most studies have not found a significant relationship between higher pretreatment ferritin concentration and response to IV iron.32-35 The lack of a robust relationship between pretreatment ferritin concentration and response to IV iron reflect the shortcomings of using a ferritin cut-off value to determine the need for intravenous iron. Two studies in nondialysis CKD patients found that absolute iron deficiency confirmed by bone marrow biopsy was common despite serum ferritin values greater than 200 ng/mL, and even patients with apparently adequate iron stores responded to IV iron therapy.36,37 These findings support that iron deficiency is underdiagnosed, and can be present despite having a ferritin level in the normal range.
SERUM FERRITIN AND TSAT AS INFLAMMATORY MARKERS Several non–iron-dependent factors can regulate ferritin levels such as inflammation, liver dysfunction, and malnutrition.38 Proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β increase ferritin synthesis.39,40 Inflammation and nutritional status are associated significantly with serum ferritin levels (between 200 and 2,000 ng/mL) in dialysis patients.41 Similar to ferritin, TSAT has its shortcomings as a marker of iron status. Apart from having diurnal variation, transferrin and TSAT levels also are influenced by nutritional status and inflammation. Transferrin levels are low in malnutrition, making TSAT appear higher. In states of inflammation TSAT might be artificially low given that transferrin is an acute phase reactant and is increased with inflammation.
IV IRON IN SPECIAL POPULATIONS There is no consensus definition of ESA hyporesponsiveness in dialysis patients, although all involve either failure to achieve a desired hemoglobin target and/or use of a high ESA dose. ESA hyporesponders usually have inflammation, increased ferritin levels, and relatively low transferrin saturation. Absolute and functional iron deficiency may be a contributing or sole cause of ESA hyporesponsiveness. The DRIVE trial tested whether IV iron was efficacious in ESA hyporesponders on hemodialysis, defined as a hemoglobin level less than 11 g/dL, an epoetin dose of 22,500 U/wk or higher or 225 U/kg/wk or higher, ferritin level of 500 ng/mL or higher, and a transferrin saturation of 25% or less.42 At the time, the mean hemoglobin concentration in US dialysis patients was 12 g/dL. All patients received a 25% increase in
Iron treatment and dialysis in CKD
109
Table 2. Comparison Between Bolus and Maintenance Regimen Study
Type of Study
Besarab, 1999
1 g IV dextran over 10 dialysis IV dextran pulse to achieve TSAT4 30%, then, 25 - 100 mg every 1 sessions, when TSAT 2 weeks to maintain TSAT of 30% o20% or ferritin level o200 50% ng/mL Prospective 62.5 mg every 1-4 wk 6.25-21.3 mg in every hemodialysis session Retrospective o1,000 mg iron use over 41,000 mg IV iron use over 6 mo review 6 mo Retrospective o1,000 mg iron use over 41,000 mg IV iron use over 6 mo review 6 mo Prospective 1,000 mg iron sucrose over 10 100 mg iron sucrose weekly for 10 wk HD sessions Retrospective 4400 mg/mo o400 mg/mo review
Bolaños, 2002 Feldman 2002 Feldman 2004 Aronoff 2004 KalantarZadeh 2005
Intervention Arm 1
Prospective
Schiesser 2006 Brookhart 2013
Prospective
Brookhart 2013 Freburger 2014
Retrospective review Retrospective review
Retrospective review
Kshirsagar Retrospective 2013 review
Intervention Arm 2
Results ESA dose reduced in arm 2 by 50%
Significant increment in serum Hb level in arm 2 Arm 1 with 18% increased rate of death Compared with no iron, arm 1 had a higher mortality rate No difference in safety in either regimen Compared with no iron, doses 4400 mg/mo tended to be associated with higher death rates None 50 mg IV iron sucrose weekly for 6 mo 38.5% reduction in dose of darbepoetin α Consecutive doses Z100 mg All other iron doses during the month More infections in intervention arm 1 with potential of exceeding 600 mg during 1 mo 4200 mg/mo iron o200 mg/mo iron More infections in intervention arm 1 Consecutive doses Z100 mg All other iron doses during the month Higher rate of hospitalization for infection in arm 1 with potential of exceeding 600 mg during 1 mo Consecutive doses Z100 mg All other iron doses during the month Higher average hemoglobin and lower average epoetin with potential of exceeding dose in arm 1 600 mg during 1 mo
ESA dose. Those patients randomized to 1 g of IV iron had a greater increase in mean hemoglobin level (1.6 versus 1.1 g/dL; P ¼ .028) and a significant decrease in epoetin dose requirements compared with patients randomized to receive no iron.42,43 Despite the concerns for use of iron in inflamed patients, those randomized to IV iron had significantly less serious adverse events than the control group.43 The use of IV iron in these ESA hyporesponders was more cost effective.44 Based on the results of the DRIVE studies, 1 g of iron can be administered to ESA hyporesponders or simply those patients on higher ESA doses as a therapeutic trial, and such management has been shown to reduce ongoing ESA requirements and to increase hemoglobin level.45
IRON OPTIONS IN THE PERITONEAL DIALYSIS POPULATION Although there is a consensus that intravenous iron supplements are superior to standard doses of oral iron for iron-deficiency anemia in hemodialysis patients, there is no consensus for treatment of peritoneal dialysis
patients. The Kidney Disease Outcome Quality Initiative guidelines do not recommend a preferred route of iron administration for peritoneal dialysis patients. Multiple small nonrandomized studies have evaluated enteral iron absorption in peritoneal dialysis patients compared with normal subjects with conflicting results.46-49 The efficacy of oral iron compared with intravenous iron was evaluated in two small openlabel randomized trials,6,50 two prospective observational studies,51,52 and a prospective cross-over trial.53 All reached similar results. Intravenous iron was more efficacious than oral iron in treating iron-deficiency anemia based on changes in hemoglobin and iron status markers. Nevertheless, the lack of large, welldesigned, randomized, clinical trials comparing IV with oral iron, the smaller iron losses in peritoneal dialysis patients (compared with hemodialysis patients), and the lower cost of oral iron therapy may make it preferable in some patients. Poor tolerance of oral preparations, resistant anemia, and need of large dosages of ESA are situations in which patients likely will benefit more from monthly or every-other-month IV iron administration.
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SUMMARY Use of IV iron products in hemodialysis patients remains the standard treatment for the inevitable iron deficiency that occurs as a result of ongoing blood loss and stimulation of erythropoiesis with ESA therapy. Maintenance of adequate iron stores by continuing repletion doses appears more efficacious and possibly safer than large intermittent repletion doses. The average stable patient on hemodialysis will require 2.0 to 2.5 g/y of iron. Available IV iron products differ in maximal single dose and carbohydrate shell, but should be equally efficacious on a milligram for milligram of iron basis. Although use of oral iron in patients on peritoneal dialysis is an option, IV iron is more efficacious in most patients and provides significant sparing of ESA doses.
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Iron treatment and dialysis in CKD 32. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol. 1996;7:2654-7. 33. Lin JL, Chang MY, Tan DT, Leu ML. Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients. Am J Nephrol. 2001;21:91-7. 34. Mittman N, Sreedhara R, Mushnick R, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis. 1997;30:912-22. 35. Mitsuiki K, Harada A, Miyata Y. Assessment of iron deficiency in chronic hemodialysis patients: investigation of cutoff values for reticulocyte hemoglobin content. Clin Exp Nephrol. 2003;7:52-7. 36. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol. 2006;19: 161-7. 37. Stancu S, Bârsan L, Stanciu A, Mircescu G. Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease? Clin J Am Soc Nephrol. 2010;5: 409-16. 38. Worwood M. Ferritin. Blood Rev. 1990;4:259-69. 39. Rogers JT, Bridges KR, Durmowicz GP, et al. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem. 1990;265:14572-8. 40. Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem. 1995;270:15285-93. 41. 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;19:141-9. 42. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the
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Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) study. J Am Soc Nephrol. 2007;18:975-84. Kapoian T, O'Mara NB, Singh AK, et al. Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol. 2008;19:372-9. Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. 2008;74: 1588-95. Coyne DW, Sims A, Bingel B. Results of an anemia management program to reduce high epoetin doses by targeted use of i.v. ferric gluconate. Nephrol Nurs J. 2008;35:583-7. Milman N. Iron absorption measured by whole body counting and the relation to marrow iron stores in chronic uremia. Clin Nephrol. 1982;17:77-81. Dittrich E, et al. Is absorption of high-dose oral iron sufficient in peritoneal dialysis patients? Perit Dial Int. 2000;20:667-73. Domoto DT, Martin KJ. Failure of CAPD patients to respond to an oral iron absorption test. Adv Perit Dial. 1992;8:102-4. Tinawi M, Martin KJ, Bastani B. Oral iron absorption test in patients on CAPD: comparison of ferrous sulfate and a polysaccharide ferric complex. Nephron. 1996;74:291-4. Li H, Wang S-X. Intravenous iron sucrose in peritoneal dialysis patients with renal anemia. Perit Dial Int. 1008;28:149-154. Ficheux M, Cuny P, Lecouf A, et al. Treatment of iron deficiency by a bolus intravenous iron dextran in peritoneal dialysis. Nephrol Ther. 2011;7:558-61. Ahsan N. Intravenous infusion of total dose iron is superior to oral iron in treatment of anemia in peritoneal dialysis patients: a single center comparative study. J Am Soc Nephrol. 1998;9: 664-8. Johnson DW, Herzig KA, Gissane R, et al. A prospective crossover trial comparing intermittent intravenous and continuous oral iron supplements in peritoneal dialysis patients. Nephrol Dial Transplant. 2001;16:1879-84.