Oral Iron for Patients Receiving Dialysis: What is the Evidence? Elisabeth M. Hodson,*† and Jonathan C. Craig*† *Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia, and †Sydney School of Public Health, University of Sydney, Sydney, Australia

ABSTRACT This review aims to summarize the available evidence of the effectiveness of oral iron in patients receiving dialysis. Four small randomized controlled trials (105 evaluated patients) compared oral iron supplements with placebo or no treatment; hemoglobin and ferritin levels did not differ significantly between groups at the end of the studies, while transferrin saturation levels fell in the placebo group in two studies. One trial (46 evaluated patients), comparing different ferrous iron preparations, found that hemoglobin levels and iron indices were maintained, but not increased. Another trial (54 evaluated patients) compared heme iron polypeptide with ferrous sulfate; hemoglobin

and transferrin saturation levels remained stable with both agents, but ferritin levels fell with heme iron polypeptide, but not ferrous sulfate. Two observational studies found that iron supplements can maintain hemoglobin and iron indices. Oral iron supplements were poorly tolerated. These sparse data suggest that oral iron is of little or no benefit in raising hemoglobin and iron indices in patients receiving dialysis. Further data are required to determine if oral iron can maintain adequate iron indices following iron replenishment using intravenous iron supplements.

Background

Heme iron polypeptide, produced by hydrolysis of bovine hemoglobin, is absorbed via a different gut receptor so its bioavailability may be greater than that of ferrous salts in dialysis patients (3). Iron status is routinely assessed using percentage transferrin saturation (TSAT) and serum ferritin levels though hypochromic red cells and reticulocyte hemoglobin content are more accurate measures of iron deficiency (4,5); these other indices have not been widely utilized or included in clinical practice guidelines (6,7). To date, hepcidin levels have not proved to be useful predictors of response to iron therapy (8). In patients receiving dialysis, target levels for iron indices were set at >20% for TSAT and >100 lg/l for ferritin in earlier clinical practice guidelines (6,9) with the more recent guidelines suggesting a trial of iron therapy in adult dialysis patients when TSAT is ≤30% and ferritin is ≤500 lg/l (7). The superiority of intravenous over oral iron in dialysis patients has been established in randomized controlled trials (10,11). The aim of this review is to summarize the available evidence on the effectiveness of oral iron in patients receiving dialysis.

Patients receiving dialysis treatment are at risk of iron deficiency because of insufficient intake of iron from food, reduced gastrointestinal iron absorption and from blood loss from the gut and hemodialysis procedures. Treatment of anemia with erythrocytestimulating agents (ESA) increases the iron required to achieve and maintain satisfactory hemoglobin levels. Untreated iron deficiency or reduced iron availability are the most common causes of failure to respond to ESA. The peptide hormone, hepcidin, plays an important role in iron metabolism. It is upregulated by inflammation and increased iron stores and downregulated by iron depletion. Circulating levels of hepcidin are increased in dialysis patients leading to reduced iron absorption from the gut and inhibition of iron release from reticuloendothelial stores (1,2). Commonly prescribed iron supplements contain ionic (nonheme) iron as ferrous salts. The absorption of ferrous iron supplements occurs via a gut receptor controlled by hepcidin. Address correspondence to: Dr Elisabeth Hodson, Centre for Kidney Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Australia, Tel.: 61 2 9845 1469, Fax: 61 2 9845 1491, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 1 (January–February) 2014 pp. 8–10 DOI: 10.1111/sdi.12149 © 2014 Wiley Periodicals, Inc.

Efficacy of ferrous iron supplements Randomized controlled trials Five RCTs evaluating oral iron supplements in dialysis patients were identified (12–16). In four studies, which recruited 130 patients, oral iron (50– 8

ORAL IRON FOR PATIENTS RECEIVING DIALYSIS

300 mg elemental iron daily) was compared with placebo or no treatment for 3 months (12,15), 4 months (14), and 12 months (13). Patients were receiving ESAs in two studies (12,15), were commenced on ESA at the start of one study (14) and were not on ESA in the fourth study (13). Of the 105 patients evaluated, all 57 patients in two studies (14,15) and 20 of 29 patients in a third study (12) were considered iron-replete (ferritin >100 lg/l and transferrin >20%) while the remaining 28 patients were iron-deficient (12,13). Overall, the studies found that oral iron did not raise hemoglobin or ferritin levels significantly compared with placebo or no treatment and that TSAT fell in untreated patients in two studies (13,14). In two (12,14) of three studies (12–14), where baseline values were reported, ferritin levels fell in both treated and untreated patients during follow-up. In iron-deficient patients, one study (12) found no significant difference in hematocrit or iron indices between groups, although only 9 of 24 iron deficient patients completed the study. In the second study (13) of 19 iron-deficient patients, hemoglobin and ferritin levels did not differ between groups, while TSAT levels fell in untreated patients; there was no significant difference in the amount of blood transfused between treated and untreated patients. In one study, ESA dose was increased more frequently in untreated patients compared with oral iron-treated patients (14); ESA dose did not differ between groups in two studies (12,15). Adverse effects were reported in two studies (12,15). Both studies found that bloating and dyspepsia were more common in iron-treated groups. In one study, gastrointestinal symptoms occurred in 50% of patients receiving oral iron compared with 20% receiving placebo, although no patient ceased iron therapy because of adverse effects (15). Thus, compared with placebo or no treatment, oral iron supplements did not increase hemoglobin or iron indices. Compared with baseline values, hemoglobin or hematocrit did not deteriorate; however, iron indices tended to fall. There were insufficient data to determine whether the response to oral iron differed between those patients considered iron-replete and those considered iron-deficient. One RCT compared different iron preparations in hemodialysis patients (16). Forty-six patients were randomized to receive 200 mg/day of elemental iron from one of four oral iron preparations (ferrous fumarate [two preparations], ferrous sulfate, iron polysaccharide) for 6 months. There was no control group. All treatment groups increased hematocrit to, and maintained it at, the lower limit of target (29– 32%) with significant increases in hematocrit with all preparations except iron polysaccharide. TSAT levels remained stable. Ferritin levels tended to fall, although the decreases were not significant in any group. However, the authors concluded that the downward trend in ferritin levels suggested that oral iron alone was insufficient to maintain adequate iron stores for ESA responsiveness in the longer term.

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Observational studies An observational study found that oral iron can be effective and well tolerated in hemodialysis patients in contrast to the limited trial data (17). The hemoglobin levels, iron indices, and ESA dosage in 151 stable hemodialysis patients were evaluated; 85 received only oral iron and 60 received oral and intravenous iron. Intravenous iron was only administered to those patients who had hemoglobin 100 lg/l) in both groups at study beginning and at 6 months. Both forms of oral iron were poorly tolerated with dose reduction or cessation of treatment due to adverse events or nonadherence to therapy occurring in 44% in the heme iron polypeptide group and in 23% in the ferrous sulfate group. The cost of treatment with heme iron polypeptide was about seven times the cost of ferrous sulfate. Both heme iron polypeptide and ferrous sulfate maintained hemoglobin or hematocrit and iron indices without an increase in ESA dose. However, only peritoneal dialysis patients, a population with lower iron requirements than those on hemodialysis, were stud-

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Hodson and Craig

ied. Heme iron polypeptide did not offer any advantages over ferrous sulfate because there was no difference in relative efficacy and both medications were poorly tolerated. Observational studies Heme iron polypeptide was evaluated in a nonrandomized prospective comparator study (18). Twenty-eight hemodialysis patients, who had been receiving maintenance intravenous iron therapy were treated with heme iron polypeptide for 6 months and were compared with those in 31 patients, who continued on intravenous iron therapy. Within the heme iron polypeptide group, hematocrit, TSAT levels and monthly ESA dose during follow-up did not differ from baseline levels. However, mean ferritin levels fell significantly during heme iron polypeptide treatment from 611 to 462 lg/l. Compared with the intravenous group, hematocrit and TSAT levels and ESA dose did not differ between groups, but ferritin levels were significantly lower in heme iron polypeptide-treated patients. Three patients (9.7%) left the study because of gastrointestinal side effects. Thus, heme iron polypeptide maintained hematocrit and TSAT without increases in ESA dose, although ferritin levels tended to fall. Conclusion The relatively sparse trial data evaluating the effects of oral iron, compared with placebo or with no iron therapy, show that there is no benefit of administering oral iron to patients on dialysis to increase hemoglobin and iron indices. However, less robust evidence from observational studies and trials comparing different oral iron preparations suggests that oral iron supplements may maintain hemoglobin and iron indices at least for some months, although frequently at the price of poor tolerance. RCTs are required to determine if, after intravenous iron loading, oral iron can maintain target hemoglobin and iron indices without increases in ESA dose and thus determine whether oral iron has any role in patients receiving dialysis. Conflict of Interest The authors report no conflict of interest.

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Oral iron for patients receiving dialysis: what is the evidence?

This review aims to summarize the available evidence of the effectiveness of oral iron in patients receiving dialysis. Four small randomized controlle...
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