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Published ahead of print on May 30, 2007
Clin J Am Soc Nephrol 2: 688-693, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.00420107
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Dialysis

Role of Oral Iron in the Management of Long-Term Hemodialysis Patients

Ilan Lenga*, Charmaine Lok{dagger}, Rosa Marticorena{ddagger}, Joyce Hunter{ddagger}, Niki Dacouris{ddagger}, and Marc Goldstein{ddagger}

* Lakeridge Health Corporation, Oshawa, and {dagger} University Health Network and {ddagger} Division of Nephrology, St. Michael's Hospital, Toronto, Ontario, Canada

Address correspondence to: Dr. Marc B. Goldstein, St. Michael's Hospital, 30 Bond Street, Toronto Ontario, Canada M5B 1W8. Phone: 416-864-5290; Fax: 416-864-3042; E-mail: marc.goldstein{at}utoronto.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 
Background: The literature contends that oral iron supplementation is relatively ineffective in patients who are on long-term hemodialysis (HD), and intravenous iron is the superior form of supplementation.

Design, setting, participants, and measurements: Data were prospectively abstracted from a cross-sectional cohort of all patients in the long-term in-center HD program at St. Michael's Hospital (SMH) from April 1, 2003, to April 1, 2004. Laboratory data were measured monthly. SMH data were compared with those in eight other centers in the Toronto Region Dialysis Registry.

Results: A total of 93% of the 151 patients tolerated oral iron. Eighty-eight (58%) patients received oral iron exclusively, and 60 (40%) patients received intravenous iron with or without oral iron. Of the patients who received oral iron exclusively, 73% maintained a hemoglobin of ≥110 g/L and 93% maintained a hemoglobin of ≥100 g/L. A total of 74% had an iron saturation ≥20%, and 36% had a ferritin level >100 g/L. Among the patients who were on oral iron alone and had hemoglobin of ≥110 g/L, the same amount of erythropoietin was used regardless of ferritin levels (P = 0.17), but less erythropoietin was used when they reached the target for either iron saturation or both iron indices (P = 0.02 and 0.03, respectively). Among the centers in the Toronto Region Dialysis Registry, hemoglobin levels and erythropoietin dosages did not differ among the three centers that predominantly used oral iron versus the six centers that predominantly use intravenous iron (P = 0.46 and 0.95, respectively).

Conclusions: Oral iron is a well-tolerated and effective form of iron supplementation in long-term HD patients.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 
With the introduction of erythropoietin therapy, it became evident that iron deficiency was an important component of the anemia that generally is present in patients who receive long-term hemodialysis (HD) (1,2). Iron supplementation is almost always necessary to maintain iron stores that are sufficient to enable optimal hematopoiesis with erythropoietin. Because of the risk for serious allergic reactions with the early forms of intravenous iron, it had been the policy of our HD program to use oral iron supplementation whenever possible. This policy has been relatively successful in achieving our anemia management targets despite several randomized studies indicating that intravenous iron is the superior form of iron supplementation (3,4). Some authors even suggested that patients who are treated with oral iron fare no better than those who receive no iron supplementation at all (4,5). These observations have led the authors of the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) guidelines to state, "A trial of oral iron is acceptable in the hemodialysis patient (opinion) but is unlikely to maintain the TSAT >20%, serum ferritin >100 ng/ml, and Hct/hemoglobin (Hb) at 33 to 36%/11 to 12 g/dl (evidence) ... most hemodialysis patients will require intravenous iron on a regular basis (evidence)" (6,7). Consequently, most centers in North America supplement iron primarily via the intravenously route in the chronic hemodialysis population.

The purpose of this study was to describe, in a formal manner, the apparent discrepancy between the prevailing position with respect to iron supplementation in the long-term HD population and our center's anecdotal results. This study does not purport to compare the relative efficacy of oral iron and intravenous iron supplementation. Rather, by describing the St. Michael's Hospital experience, we can define the outcomes that are achieved with the routine initiation of iron supplementation via the oral route. In addition, recently, a regional group of HD programs in the greater Toronto area in Ontario, Canada, known as Toronto Regional Dialysis Registry (TRDR), compared specific HD benchmarks for continuous quality improvement. This provided us with the opportunity to compare the outcomes of our anemia management strategy with those of other regional centers. Because some of these centers primarily use oral iron and the majority use intravenous iron, we were able to examine the feasibility and the appropriateness of using oral iron as the form of supplementation in achieving anemia management targets and optimal erythropoietin use in the long-term HD population.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 Disclosures
 References
 
Two analyses were performed: (1) On the St. Michael's Hospital (SMH) population to enable a definition of the detailed characteristics of the population and their anemia management and (2) on the TRDR data to enable comparisons of the outcomes and erythropoietin dosages across the centers with different iron supplementation policies.

SMH Data Set
The SMH HD center is a University of Toronto–affiliated dialysis unit that cares for approximately 220 long-term in-center HD patients and actively participates in the TRDR. For the SMH population, we abstracted prospectively collected data from a cohort of long-term, in-center HD patients who were dialyzed during the interval from April 1, 2003, to April 1, 2004. Anemia parameters, iron indices, and anemia management data were collected monthly. The erythropoietin preparation generally used was Eprex (Ortho-Biotech, Toronto, ON, Canada). It was expected that only a small number of patients would be receiving darbepoetin (Aranesp, Amgen Ltd., Thousand Oaks, CA.), and they were excluded from the analysis of erythropoietin dosage to eliminate errors through dosage conversion. Patients were excluded when they died, left the SMH dialysis program, changed modalities, or received a transplant before the end of the study period.

The SMH study population was divided into four groups according to the forms of iron supplementation used: (1) Oral iron alone, (2) oral and intravenous iron, (3) intravenous iron alone, and (4) no iron supplementation. All patients at SMH are initiated using oral iron and are switched to intravenous iron only when they are deemed intolerant to oral iron. The criterion for intolerance is gastrointestinal symptoms (nausea, bloating, abdominal discomfort, and constipation) that cannot be controlled with stool softeners or laxatives. As well, patients who continue to have Hb <100 g/L and iron deficiency (ferritin <100 g/L or transferrin saturation [TSAT] <20%) despite compliance with maximum tolerated oral iron of up to 600 mg three times daily of ferrous fumarate (Palafer; GlaxoSmithKline, Mississauga, ON, Canada) receive 1 g of intravenous iron sucrose (Venofer; Genpharm, Darmstadt, Germany) divided into 10 doses, administered after each treatment. These patients continue their oral iron, and the need for additional intravenous iron is determined by their iron indices and Hb. For the purposes of this study, patients who received only intravenous iron were grouped with those who received combined oral and intravenous iron. The collection and reporting of the data were approved by the research ethics board of St. Michael's Hospital. Because all patients began with oral iron and only those who failed oral therapy received intravenous iron, this data set allowed us to describe but not compare the characteristics of patients who were treated successfully with oral iron and those who required intravenous iron.

TRDR Data Set
The TRDR is a registry of 15 long-term HD units and their satellites within the Metropolitan Toronto catchment area (approximately 4 million population). All of the HD units participate in a monthly census, and nine of these sites, including SMH, voluntarily participate in a more detailed follow-up survey for registered patients. The data collected represent a "snapshot" of all of the in-center HD patients’ characteristics in each center on October 31, 2004. For this analysis, we used the same snapshot of data provided by SMH to the TRDR on October 31, 2004 which is less detailed than the full SMH data set that was used in our first analysis. The TRDR data were used to allow a comparison of erythropoietin dosages and anemia outcomes in patients who were treated with oral iron with those in patients who received intravenous iron supplementation.

Statistical Analyses
In the complete SMH patient database, the data were not normally distributed (Kolmogorov-Smirnov test); therefore, continuous variables were reported as medians along with the 25th and 75th percentiles and were compared using the Mann-Whitney U test. In contrast, the TRDR data set was found to be normally distributed according to normal probability plots, kurtosis, and Wilk Shapiro tests for normality. Continuous variables within the TRDR data set were reported as means (SD); comparisons between SMH oral iron users and intravenous iron users were analyzed using t tests. Nominal variables were reported by proportion with comparisons made by {chi}2 test or Fisher exact test as appropriate. All tests of significance were two-sided with a P < 0.05. The statistical software used was SAS (version 8.2; SAS Institute, Cary, NC). For maintaining the confidentiality of the participating sites in the TRDR data set, the numbers of patients who underwent dialysis in each center were available only to the person doing the statistical analysis and are not provided.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 Disclosures
 References
 
SMH Data Set
A total of 151 patients were eligible for the study. The characteristics of the patients and their distribution among the four methods of iron supplementation are presented in Table 1. Three (2%) patients received no iron supplementation, and they were not included in the study. Therefore, the study population consists of 148 patients. A minority (5%) of patients received intravenous iron therapy exclusively, and this is the population deemed to be truly intolerant of oral iron.


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  		Table 1. Demographic characteristics of the SMH HD populationa

 
The demographic and laboratory information for the two groups is listed in Table 2. There was no apparent demographic difference between patients who were treated adequately on oral iron alone and those who failed oral therapy and required intravenous iron. Patients who receive intravenous iron have lower Hb and iron saturation than those who receive oral iron alone. Relative to the current NKF-DOQI guidelines, 73% of patients who were on oral iron alone were capable of maintaining a Hb ≥110 g/L, and 93% maintained a hemoglobin of ≥100 g/L. For all patients, receiving any form of iron supplementation, this represents 43 (64 of 148) and 55% (82 of 148), respectively.


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  		Table 2. SMH population characterized as to route of iron supplementation

 
The median daily dosages of oral iron were 900 mg (600 to 900 mg) in the oral iron group and 725 mg (338 to 900 mg) in the oral + intravenous group (P = 0.06). The median annual intravenous iron dosage was 1000 mg (1000 to 1950 mg).

The impact of achieving target iron indices on erythropoietin dosage in the oral iron group is depicted in Table 3. Patients who were below the NKF-DOQI target for Hb received no more erythropoietin regardless of whether they achieved the ferritin and/or iron saturation targets (data not shown). In patients who achieved the target for Hb, the same amount of erythropoietin was used regardless of ferritin levels (P = 0.17). However, patients who reached the target for either iron saturation or both iron indices received significantly less erythropoietin than those who did not reach these targets (P = 0.03).


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  		Table 3. Weekly erythropoietin dosages for patients on oral iron with Hb >110 g/L, depending on iron indicesa

 
Comparison with TRDR Data Set
The analysis was performed on the 1398 of 1827 patients who were in the TRDR database and for whom iron supplementation data were known. All nine participating in-center HD units achieved Hb levels within national guideline recommendations with averages within centers ranging from 110 to 122 g/L (Table 4). Three centers (hospitals 2, 4, and 7) predominantly used oral iron supplementation (>70%), and six centers predominantly favored intravenous iron supplementation.


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  		Table 4. Data from the nine TRDR participating hospitalsa

 
When all of the hospitals that were predominantly using oral iron in the TRDR were compared with their intravenous-using counterparts, the Hb levels did not differ (P = 0.46), the ferritin was lower (P < 0.0001), and the iron saturation was higher (26.0 versus 24.2%; P = 0.02) in the oral iron users. There was no difference in the erythropoietin dosage between the two groups (Table 5).


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  		Table 5. Comparison of all hospitals that predominantly use oral iron with those that predominantly use intravenous iron

 
Table 6 reports the dialysis centers’ ability to achieve NKF-DOQI guidelines for anemia management, on the basis of their iron supplementation policy. It is evident that more patients who received intravenous iron exceeded the target for ferritin; however, that is not the case for the target for Hb or TSAT.


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  		Table 6. Achievement of NKF-DOQI guidelines for anemia management in patients in the TRDR database according to their iron supplementation policya

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 Disclosures
 References
 
The practice of many dialysis units to adopt intravenous iron as the primary form of supplementation in the effort to achieve NKF-DOQI guidelines for iron indices is largely based on the beliefs that (1) oral iron is ineffective in long-term HD patients, (2) the use of intravenous iron will reduce erythropoietin use, and (3) there is widespread intolerance to oral iron. The results of this report challenge these contentions and establish the effectiveness and tolerability of oral iron in the long-term HD population. This study is not comparing and cannot compare the effectiveness of oral versus intravenous iron.

With our iron supplementation strategy, 73% of patients who were on oral iron alone, which represents 43% of the total population, were able to maintain an adequate Hb level, as defined by NKF-DOQI guidelines. Only 20% both were anemic (Hb <110 g/L) and had one or more inadequate iron indices. In the group of patients who were on oral iron and achieved the target Hb ≥110 g/L, the erythropoietin dosage was significantly higher in those with a TSAT <20% but was not influenced by the ferritin level (Table 3). These results are in keeping with the ferritin levels reflecting an underlying inflammatory state rather than the iron stores (8), and these patients would probably benefit from intravenous iron (3). The recently published Dialysis patients Response to IV iron with Elevated ferritin (DRIVE) study (9) evaluated the dynamics of patients with high ferritin levels, anemia, and TSAT in a lower range. In that study, patients with high ferritin (500 to 1200 ng/ml), Hb <11 g/dl, TSAT <25%, and erythropoietin dose ≥225 IU/kg per wk or >22,500 IU/wk responded with a significantly higher Hb when their erythropoietin dosage was increased by 25%, along with 1 g of ferric gluconate intravenously, than those who received the same increase in erythropoietin but no additional intravenous iron. The response to intravenous iron was similar, whether the ferritin level was < or >800 ng/ml. The authors concluded that the ferritin levels are poor indicators of iron deficiency and that intravenous iron is effective in overcoming inflammation-mediated reticuloendothelial blockade ("functional iron deficiency"). These results also indicate that several of the guidelines of anemia management require reconsideration.

The use of intravenous iron may well reduce erythropoietin usage, even in conditions of significant inflammation. In addition to the cost, there may be other benefits to reduction of the erythropoietin dosage in minimizing adverse effects. Some of the toxic effects that are attributed to erythropoietin are hypertension (10,11), access thrombosis (12,13), and cerebrovascular events (14); however, these are indirectly associated and could be causally associated with the increased hematocrit, rather than a direct effect of the drug. Erythropoietin has been directly associated with the development of pure red cell aplasia (15); however, this phenomenon does not seem to be dosage related (16).

There may be a sound financial argument in favor of striving to reduce erythropoietin use, but the safety of using intravenous iron to reduce erythropoietin use is an open question. Although the new formulations of intravenous iron have drastically reduced the risk for immediate adverse effects, a variety of long-term consequences of intravenous iron have been contemplated in the literature. Intravenous iron bypasses the physiologic controls of iron absorption and storage, thereby exposing the patient to higher levels of circulating free iron and higher tissue levels of iron. A number of authors recently reviewed the link between free or stored iron and a variety of disease states, including cardiovascular disease (17,18), carcinogenesis (19,20), and infection (21). Patients with chronic kidney disease and those who are on dialysis are at increased risk for cardiovascular disease. A number of studies have demonstrated that intravenous iron generates oxidative stress (22–24) and endothelial dysfunction (25), both thought to play an important role in the pathogenesis of atherosclerosis (26,27). The so-called "iron hypothesis" linking coronary artery disease and total body iron load remains a compelling and provocative debate (28–30).

Our data indicate that oral iron is indeed effective in patients who are on long-term HD, despite evidence to the contrary (3–5). It is likely that the success of oral iron use in our program stemmed from our past success, resulting in a committed multidisciplinary effort and ongoing vigilance in routinely seeking reasons for poor responses to oral supplements and promoting methods to enhance compliance. Constipation, bloating, and abdominal discomfort were usually resolved with diet and/or prescription modification and stool softeners. In patients who had persistently low iron indices, other reasons for iron deficiency were pursued and treated. Finally, in patients who tolerated oral iron well, dosages were titrated up to 600 mg three times daily when iron indices remained low. Although adverse effects from oral iron are common, true intolerance is rare. In our study population, only 5% of patients were truly intolerant of oral iron, usually as a result of severe constipation. We did not carry out a quality-of-life evaluation, and although our patients were willing to continue oral iron supplementation, it is possible that the adverse effects had a negative impact on their quality of life. If a randomized study of oral versus intravenous iron is carried out, then it would be important to include a quality-of-life assessment. Similarly, it would be important to document the comorbidities of infection, cardiovascular disease, and carcinoma, which might be influenced by the form of iron supplementation.

A major limitation of this study is that one cannot evaluate the efficacy of oral iron compared with intravenous iron with respect to the dosage requirement for erythropoietin, because patients received intravenous iron only after they had failed oral iron therapy. As expected from our protocol, SMH patients who received intravenous iron had lower Hb levels and higher erythropoietin doses. Recognizing this, we instead evaluated the effectiveness of our strategy of iron replacement with respect to achieving NKF-DOQI guidelines, compared with eight other dialysis programs in our region (in the Greater Toronto Area). Although the TRDR database is limited by the lack of data on demographics, comorbidities, and the reason for patients’ being assigned to a particular group, the data set clearly indicates that the centers that favor the use of oral iron were as successful as their intravenous iron–favoring counterparts in meeting the NKF-DOQI guidelines for anemia management, without requiring increased erythropoietin use. Given the equivalence of these findings, there may be a direct cost savings to using a management strategy that emphasizes oral iron use, but a formal economic evaluation including both direct and indirect costs was not done.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
Disclosures
 References
 
Although intravenous iron is an essential tool in anemia management of long-term HD patients, the enthusiasm for its widespread adoption as the primary agent for supplementation must be tempered by the potential safety concerns, the increased cost, and the evidence that so many patients can indeed be successfully treated with oral iron alone.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
References
 
None.


   Acknowledgments
 
This research was supported in part by the St. Michael's Hospital Baxter Chronic Renal Failure Research Fund and the Ortho-Biotech St. Michael's Hospital Clinical Research Fund, both unrestricted, nondirected grants. The study was conceived, designed, and analyzed by the investigators.

We recognize and appreciate the commitment of the hemodialysis nurses, pharmacists, and dietitians at SMH to excellent patient care. The critical review of the manuscript by Dr. Phil McFarlane is gratefully acknowledged. We also appreciate the suggestions made by Drs. Rob Foley and Vanita Jassal and Mr. Shaul Tarek.

We gratefully acknowledge the participation of the following dialysis programs in the TRDR, who shared their anemia management data: Humber River Regional Hospital, Dr. David Mendelssohn; Lakeridge Health Corp., Dr. George Buldo; Oakville Trafalger Hospital, Dr. Daniel Sapir; Orillia Soldier's Memorial Hospital, Dr. Leo Lam; Peterborough Regional Health Center, Dr. Clair Williams, St. Joseph's Health Centre, Dr. Stavros Karanicolas; Sunnybrook Health Sciences Center, Dr. David Naimark; and University Health Network, Dr. Robert Richardson.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received January 24, 2007. Accepted April 25, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 

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