Oral Iron for Patients Receiving Dialysis: What is theEvidence?

Elisabeth M. Hodson,*† and Jonathan C. Craig*†*Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia, and †Sydney Schoolof Public Health, University of Sydney, Sydney, Australia

ABSTRACT

This review aims to summarize the available evidence ofthe effectiveness of oral iron in patients receiving dialysis.Four small randomized controlled trials (105 evaluatedpatients) compared oral iron supplements with placebo orno treatment; hemoglobin and ferritin levels did not differsignificantly between groups at the end of the studies,while transferrin saturation levels fell in the placebo groupin two studies. One trial (46 evaluated patients), compar-ing different ferrous iron preparations, found that hemo-globin levels and iron indices were maintained, but notincreased. Another trial (54 evaluated patients) comparedheme iron polypeptide with ferrous sulfate; hemoglobin

and transferrin saturation levels remained stable withboth agents, but ferritin levels fell with heme iron poly-peptide, but not ferrous sulfate. Two observational studiesfound that iron supplements can maintain hemoglobinand iron indices. Oral iron supplements were poorly toler-ated. These sparse data suggest that oral iron is of littleor no benefit in raising hemoglobin and iron indices inpatients receiving dialysis. Further data are required todetermine if oral iron can maintain adequate iron indicesfollowing iron replenishment using intravenous ironsupplements.

Background

Patients receiving dialysis treatment are at risk ofiron deficiency because of insufficient intake of ironfrom food, reduced gastrointestinal iron absorptionand from blood loss from the gut and hemodialysisprocedures. Treatment of anemia with erythrocyte-stimulating agents (ESA) increases the iron requiredto achieve and maintain satisfactory hemoglobinlevels. Untreated iron deficiency or reduced ironavailability are the most common causes of failureto respond to ESA. The peptide hormone, hepcidin,plays an important role in iron metabolism. It isupregulated by inflammation and increased ironstores and downregulated by iron depletion. Circu-lating levels of hepcidin are increased in dialysispatients leading to reduced iron absorption fromthe gut and inhibition of iron release from reticulo-endothelial stores (1,2). Commonly prescribed ironsupplements contain ionic (nonheme) iron as ferroussalts. The absorption of ferrous iron supplementsoccurs via a gut receptor controlled by hepcidin.

Heme iron polypeptide, produced by hydrolysis ofbovine hemoglobin, is absorbed via a different gutreceptor so its bioavailability may be greater thanthat of ferrous salts in dialysis patients (3).Iron status is routinely assessed using percentage

transferrin saturation (TSAT) and serum ferritinlevels though hypochromic red cells and reticulocytehemoglobin content are more accurate measures ofiron deficiency (4,5); these other indices have notbeen widely utilized or included in clinical practiceguidelines (6,7). To date, hepcidin levels have notproved to be useful predictors of response to irontherapy (8). In patients receiving dialysis, target levelsfor iron indices were set at >20% for TSAT and>100 lg/l for ferritin in earlier clinical practice guide-lines (6,9) with the more recent guidelines suggestinga trial of iron therapy in adult dialysis patients whenTSAT is ≤30% and ferritin is ≤500 lg/l (7). The supe-riority of intravenous over oral iron in dialysispatients has been established in randomized con-trolled trials (10,11). The aim of this review is to sum-marize the available evidence on the effectiveness oforal iron in patients receiving dialysis.

Efficacy of ferrous iron supplements

Randomized controlled trials

Five RCTs evaluating oral iron supplements indialysis patients were identified (12–16). In fourstudies, which recruited 130 patients, oral iron (50–

Address correspondence to: Dr Elisabeth Hodson, Centrefor Kidney Research, The Children’s Hospital at Westmead,Locked Bag 4001, Westmead NSW 2145, Australia, Tel.: 612 9845 1469, Fax: 61 2 9845 1491, or e-mail: elisabeth.hod-son@health.nsw.gov.au.

Seminars in Dialysis—Vol 27, No 1 (January–February) 2014pp. 8–10DOI: 10.1111/sdi.12149© 2014 Wiley Periodicals, Inc.

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300 mg elemental iron daily) was compared withplacebo or no treatment for 3 months (12,15),4 months (14), and 12 months (13). Patients werereceiving ESAs in two studies (12,15), were com-menced on ESA at the start of one study (14) andwere not on ESA in the fourth study (13). Of the105 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 andtransferrin >20%) while the remaining 28 patientswere iron-deficient (12,13).

Overall, the studies found that oral iron did notraise hemoglobin or ferritin levels significantly com-pared with placebo or no treatment and that TSATfell in untreated patients in two studies (13,14). Intwo (12,14) of three studies (12–14), where baselinevalues were reported, ferritin levels fell in both trea-ted and untreated patients during follow-up. Iniron-deficient patients, one study (12) found no sig-nificant difference in hematocrit or iron indicesbetween groups, although only 9 of 24 iron deficientpatients completed the study. In the second study(13) of 19 iron-deficient patients, hemoglobin andferritin levels did not differ between groups, whileTSAT levels fell in untreated patients; there was nosignificant difference in the amount of blood trans-fused between treated and untreated patients. Inone study, ESA dose was increased more frequentlyin untreated patients compared with oral iron-trea-ted patients (14); ESA dose did not differ betweengroups in two studies (12,15).

Adverse effects were reported in two studies(12,15). Both studies found that bloating and dys-pepsia were more common in iron-treated groups.In one study, gastrointestinal symptoms occurred in50% of patients receiving oral iron compared with20% receiving placebo, although no patient ceasediron therapy because of adverse effects (15).

Thus, compared with placebo or no treatment,oral iron supplements did not increase hemoglobinor iron indices. Compared with baseline values,hemoglobin or hematocrit did not deteriorate; how-ever, iron indices tended to fall. There were insuffi-cient data to determine whether the response to oraliron differed between those patients considerediron-replete and those considered iron-deficient.

One RCT compared different iron preparations inhemodialysis patients (16). Forty-six patients wererandomized to receive 200 mg/day of elemental ironfrom one of four oral iron preparations (ferrousfumarate [two preparations], ferrous sulfate, ironpolysaccharide) for 6 months. There was no controlgroup. All treatment groups increased hematocrit to,and maintained it at, the lower limit of target (29–32%) with significant increases in hematocrit with allpreparations except iron polysaccharide. TSAT levelsremained stable. Ferritin levels tended to fall,although the decreases were not significant in anygroup. However, the authors concluded that thedownward trend in ferritin levels suggested that oraliron alone was insufficient to maintain adequate ironstores for ESA responsiveness in the longer term.

Observational studies

An observational study found that oral iron canbe effective and well tolerated in hemodialysispatients in contrast to the limited trial data (17).The hemoglobin levels, iron indices, and ESA dos-age in 151 stable hemodialysis patients were evalu-ated; 85 received only oral iron and 60 received oraland intravenous iron. Intravenous iron was onlyadministered to those patients who had hemoglobin<100 g/l and iron deficiency (ferritin <100 lg/l orTSAT <20%), despite compliance with oral supple-ments. Among patients treated only with oral iron,73%, 36%, and 74% maintained satisfactory hemo-globin levels (≥110 g/l), ferritin levels (≥100 lg/l),and TSAT levels (≥20%), respectively, based on thethen current KDOQI guidelines (6).In the same study, the authors also compared

their patients with those from eight other centersproviding detailed data to the Toronto RegionDialysis Registry and found that their results didnot differ overall. When data from three centers, inwhich patients received predominantly oral iron(exclusively in >70%), were compared with datafrom six centers where most patients received intra-venous iron, there were no differences in hemoglo-bin or ESA dosage, while TSAT levels were slightlybut significantly higher in orally treated patients(26% versus 24%). Ferritin levels were significantlylower with oral therapy (211 lg/l) compared withintravenous therapy (397 lg/l), although above theKDOQI target levels.

Efficacy of heme iron polypeptide

Randomized controlled trials

The Hematocrit trial compared 6 months treat-ment with heme iron polypeptide (240 mg elementaliron daily) with ferrous sulfate (210 mg elementaliron daily) in 62 peritoneal dialysis patients (3).There was no untreated control group. Both groups(intention-to-treat population of 54 patients) main-tained median hemoglobin (111 versus 113 g/l atbaseline), ferritin (124 versus 292 lg/l, decline notsignificant), and TSAT (22 versus 20%) levels with-out a change in median ESA dose. About half ofthe patients were considered iron-replete (TSAT>20% and ferritin >100 lg/l) in both groups atstudy beginning and at 6 months.Both forms of oral iron were poorly tolerated

with dose reduction or cessation of treatment dueto adverse events or nonadherence to therapy occur-ring in 44% in the heme iron polypeptide groupand in 23% in the ferrous sulfate group. The costof treatment with heme iron polypeptide was aboutseven times the cost of ferrous sulfate. Both hemeiron polypeptide and ferrous sulfate maintainedhemoglobin or hematocrit and iron indices withoutan increase in ESA dose. However, only peritonealdialysis patients, a population with lower ironrequirements than those on hemodialysis, were stud-

ORAL IRON FOR PATIENTS RECEIVING DIALYSIS 9

ied. Heme iron polypeptide did not offer any advan-tages over ferrous sulfate because there was no dif-ference in relative efficacy and both medicationswere poorly tolerated.

Observational studies

Heme iron polypeptide was evaluated in a non-randomized prospective comparator study (18).Twenty-eight hemodialysis patients, who had beenreceiving maintenance intravenous iron therapywere treated with heme iron polypeptide for6 months and were compared with those in 31patients, who continued on intravenous iron ther-apy. Within the heme iron polypeptide group,hematocrit, TSAT levels and monthly ESA doseduring follow-up did not differ from baseline levels.However, mean ferritin levels fell significantly dur-ing heme iron polypeptide treatment from 611 to462 lg/l. Compared with the intravenous group,hematocrit and TSAT levels and ESA dose did notdiffer between groups, but ferritin levels were signif-icantly lower in heme iron polypeptide-treatedpatients. Three patients (9.7%) left the studybecause of gastrointestinal side effects. Thus, hemeiron polypeptide maintained hematocrit and TSATwithout increases in ESA dose, although ferritinlevels tended to fall.

Conclusion

The relatively sparse trial data evaluating theeffects of oral iron, compared with placebo or withno iron therapy, show that there is no benefit ofadministering oral iron to patients on dialysis toincrease hemoglobin and iron indices. However, lessrobust evidence from observational studies andtrials comparing different oral iron preparationssuggests that oral iron supplements may maintainhemoglobin and iron indices at least for somemonths, although frequently at the price of poortolerance. RCTs are required to determine if, afterintravenous iron loading, oral iron can maintaintarget hemoglobin and iron indices withoutincreases in ESA dose and thus determine whetheroral iron has any role in patients receiving dialysis.

Conflict of Interest

The authors report no conflict of interest.

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