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Iron Overload in the Erythropoietin Era.

"Too much of a good thing" is still too much. Some nephrology professionals are concerned that end stage renal disease (ESRD) patients might receive excess iron when maintenance parenteral iron therapy is used for patients receiving erythropoietin (EPO) therapy to manage anemia. A possible sequelae, iron overload, can be serious. This article attempts to define the scope of this issue -- the extent of iron overload in ESRD patients, the consequences, and the proper management of ESRD patients with this presentation.

From Iron Overload to Functional Iron Deficiency

Although there is a resurgence of attention about iron overload, the condition was actually more common before EPO therapy was introduced into clinical practice. Using a serum ferritin level of [is greater than] 2000 ng/mL as an indicator of iron overload, Hakim and his colleagues at renal centers in Boston and New York found that 62 of 150 hemodialysis (HD) patients (41%) were iron overloaded (Hakim et al., 1987). A recent study by Coco and Dressler (1999) found that stainable iron (a marker of overload) was present in 65% of bone marrow samples taken from chronic hemodialysis patients in the pre-EPO era, while only 28% of recent cases (post-EPO era) had stainable iron. The authors concluded that adequate hematocrits could be achieved with parenteral iron and EPO without risking iron overload (Coco & Dressler, 1999). According to Eschbach and Adamson (1999), few HD patients are iron overloaded today unless they require frequent red blood cell (RBC) transfusions or cannot be treated with EPO.

Patients undergoing HD therapy for ESRD are at risk for iron deficiency. The chronic blood losses with each HD treatment from residual blood in the extracorporeal circuit and small losses from vascular access and intermittent blood work create more episodes of blood loss than in peritoneal dialysis (PD) patients, so PD patients generally lose less blood (Nissenson & Strobos, 1999). Barring chronic sources of blood loss, PD patients are not usually candidates for parenteral iron maintenance therapy. Both groups of patients are at risk for functional iron deficiency, in which iron levels are insufficient to meet the demands of EPO-stimulated erythropoiesis. Much of the focus of this article addresses HD patients, since they are more likely to require parenteral iron therapy and/or maintenance iron therapy to ensure adequate response to EPO therapy.

Iron deficiency is currently a greater concern than iron overload in HD patients. Using a serum ferritin level less than 100 ng/mL as an indicator for absolute iron deficiency, a group of British investigators found that 12/46 (26%) of EPO-treated patients were iron deficient (Taylor, Peat, Porter, & Morgan, 1996). Functional iron deficiency is even more common, although there is controversy over its assessment. Although the National Kidney Foundation-Dialysis Outcomes Quality Initiative guidelines (NKF-DOQI) recognizes transferrin saturation (TSAT) less than 20% as a marker of functional iron deficiency (NKF-DOQI[TM] Clinical Practice Guidelines, 1997), other investigators suggest that patients with TSATS as high as 30% might still have functional iron deficiency (Fishbane & Maesaka, 1997). In a recent study conducted in Taiwan, 51% of HD patients had TSATs less than 30% (Tarng, Huang, Chen, & Yang, 1999). According to the NKF-DOQI, most HD patients receiving EPO therapy will need intravenous iron to avoid functional iron deficiency.

Why was iron overload so common in the pre-EPO era and so uncommon now? In the anemia of chronic renal failure, RBC iron is gradually shifted into storage sites in the reticuloendothelial system (RES), the scavenger system that includes macrophages and other cells, and recycles iron from RBCs at the end of their life cycles (see Figure 1). If not mobilized to correct blood loss, the iron becomes sequestered in the RES, resulting in increased stores and elevated serum ferritin levels. This sequestration does not generally cause organ damage.


Renal failure patients are deficient in EPO, which normally acts to increase the number of cell-surface transferrin receptors in erythroid cells (RBCs and their progenitors) (Weiss et al., 1997). Therefore, without stimulation by erythropoietin, iron uptake by erythroid tissue is reduced, while uptake by nonerythroid tissues is upregulated (Eschbach & Adamson, 1999). In patients who subsequently receive repeat transfusions, iron is delivered from the RES to the liver and other organs such as the heart, leading to iron overload (Eschbach & Adamson, 1999). Biopsies taken from iron-overloaded renal patients in the pre-EPO era showed iron deposits in both hepatocytes of the liver and Kupffer cells of the RES (Eschbach et al., 1967). In the EPO era, fewer patients require transfusions, and EPO administration causes iron to be shifted into the erythroid cells (Eschbach & Adamson, 1999).

Overload in Hemochromatosis and Renal Disease

Much of what we know about iron overload comes from the experience with hemochromatosis. Hemochromatosis is a genetic disease in which excessive iron is absorbed from the gastrointestinal tract, resulting in accumulation of iron in various organs such as the heart, liver, and pancreas (reviewed in Rouault, 1993). The accumulated iron damages the cells, leading to eventual organ dysfunction. Patients with hemochromatosis frequently develop cirrhosis, heart failure, diabetes, impotence, and arthritis (Adamson, Cavill, Fishbane, Petersen, & Wish, 1999; Yang, McDonnell, Khoury, Cono,& Parrish, 1998).

ESRD patients have a different profile than typical hemochromatosis patient (see Table 1). Patients receiving dialysis have shorter life expectancies than those with hemochromatosis. HD patients are losing iron on a chronic basis. Thus, they are at lower risk for developing the chronic iron deposition seen in patients with hereditary hemochromatosis (Adamson et al., 1999). Yet, this profile is changing. In the pre-EPO era, the longer patients survived and were transfused, the greater the likelihood that iron overload would develop. Today, ESRD patients who are potential transplant candidates may have a life expectancy of many years and should be monitored for iron status (Adamson et al., 1999).

Table 1 Comparison of Iron Overload in Renal Patients Versus Typical Hemochromatosis Patients(*)
                    Patient                  Renal Patient

Cause of overload   Increased iron           Multiple transfusions
                    absorption               or parenteral iron
                                             therapy, decreased
                                             iron incorporation
                                             into the erythroid

Where iron          Liver, spleen, heart     Mostly the
accumulates                                  reticuloendothelial

Treatment           Therapeutic phlebotomy   Withholding parenteral
                                             iron, administering
                                             EPO, chelation

(*) EPO indicates erythropoietin.

Manifestations of iron overload in HD patients may be different than those seen in hemochromatosis patients. Dialysis patients appear more likely to deposit iron into the RES than into organs and are less likely to develop organ failure than are hemochromatosis patients (Ali et al., 1980; Henderson & Hillman, 1969). Even when ESRD patients with iron overload deposit iron into tissues such as the liver, the deposition does not usually cause cirrhosis unless the patient has hepatitis (Eschbach & Adamson, 1999). In the past, many ESRD patients received frequent blood transfusions and may have been unwittingly exposed to hepatitis C. This may explain why many ESRD patients who were overly transfused developed cirrhosis (Eschbach & Adamson, 1999). Iron-overloaded ESRD patients may experience a degree of hyporesponsiveness to EPO, suggesting abnormal iron utilization (El-Reshaid et al., 1994). This EPO hyporesponse tends to disappear with continued EPO therapy. It is a reversible condition and may be an example of functional iron deficiency.

While infrequent, hemochromatosis may occur in ESRD patients: 1 in 300 Caucasians are homozygous for the gene for primary hemochromatosis, and 1 in 10 are heterozygous (Bregman et al., 1980). It would seem that such patients would be at increased risk for iron overload compared with other renal patients. Yet, a study of almost 100 patients in Portugal revealed no correlation between hemochromatosis carriage and high serum ferritin levels in ESRD patients. Patients with the hemochromatosis gene were not at risk for development of hemosiderosis when parenteral iron administration and excessive transfusions were avoided (Carrera, Andrade, Silva, & Simoes, 1988).

Parenteral Iron

It is difficult to determine the frequency of iron overload induced by parenteral iron therapy. Most studies of iron overload in dialysis patients were conducted in patients who received both parenteral iron and RBC transfusions (Eschbach & Adamson, 1999). A few reports of iron overload induced by parenteral iron therapy have appeared in the medical literature. A 1984 report in the pre-EPO era indicated that serum ferritin levels were elevated in IV iron-treated patients to a mean of 1373 ng/mL and as high as 3000 ng/mL in one patient (Van de Vyver et al., 1984). These patients also had iron deposition in hepatocytes and Kuppfer cells. Saven and Beutler (1989) showed iron overload was present in a patient who had received 52 g of elemental iron intramuscularly over a 20-year period. The patient had large deposits of iron in the liver, although she did not have cirrhosis.

Now that maintenance iron therapy is used with increasing frequency in conjunction with EPO therapy, many patients are receiving parenteral iron on a long-term basis. A randomized study of 52 hemodialysis patients on long-term EPO therapy showed that iron indices increased progressively, from a mean serum ferritin level of 191 ng/mL to 754 ng/mL and from a TSAT of 23% to 75% in patients receiving maintenance therapy with iron dextran 100 mg twice weekly for 4 months. Whether these indices indicated excessive organ iron accumulation was not determined (Fishbane, Frei, & Maesaka, 1995). Since this report, specific guidelines have been set to help avoid iron overload during maintenance parenteral iron therapy in HD patients. The NKF-DOQI (1997) recommends that laboratory values be assessed every 3 months to individualize dose adjustments during maintenance IV iron therapy. If the patient's TSAT increases to [is greater than] 50% or serum ferritin level increases to [is greater than] 800 ng/mL, then IV iron maintenance therapy should be withdrawn and the iron parameters should be checked again in 3 months.

Laboratory Assessment

Monitoring for iron overload begins with the normal assessment of iron status (serum ferritin and TSAT) as discussed above. Iron overload is unlikely to develop in patients whose TSATs and serum ferritin levels are kept within the NKF-DOQI recommended ranges. It is important to remember that serum ferritin levels may be elevated in a variety of circumstances, including inflammation, infection, and liver disease, so it is not an ideal marker for overload. Indeed, serum ferritin levels have not been found to correlate with bone marrow iron levels, although the levels seem to correlate with degree of iron deposits in the liver and spleen (Ali et al., 1982). Other, direct markers should be considered.

When their serum ferritin levels are markedly elevated or sustained despite withholding IV iron, patients with suspected cases of iron overload may be referred to a hematologist. Although hepatic computed tomography density is more effective than serum ferritin in measuring iron overload, the gold standard remains liver biopsy. This technique not only allows for determination of iron levels within the hepatocytes, it can also be used to distinguish clinically important liver disease (fibrosis and cirrhosis) (Cecchin et al., 1990). Alternatively, bone marrow biopsy can be performed (Rouault, 1993; Simon, 1985; Worwood, 1997).


One treatment for iron overload is to institute EPO therapy with the goal of shifting iron from stores into the erythroid cells. This use of EPO probably received more attention when the medication was first introduced and a greater proportion of ESRD patients had frank iron overload than do today. Several studies have shown that EPO therapy, alone or in conjunction with phlebotomy, relieves iron overload in heavily transfused ESRD patients (Agroyannis et al., 1991; Burghard, Leititis, Pallacks, Scigalla, & Brandis, 1988).

Another way to reduce iron levels is through chelation. An effective chelator must be able to penetrate tissues, bind to the target metal (in this case iron), and form metal complexes that can be eliminated from the body (May & Williams, 1980). Deferoxamine (DFO), which chelates iron, has been used to treat iron overload in ESRD patients. Although DFO is an effective chelator in patients with normal renal function, the removal of chelated iron by modern dialysis membranes is unlikely (Roxe, Krumlovsky, Del Greco, & Fitzsimons, 1990). While some reports from the pre-EPO era have shown this agent effective in the treatment of iron overload in various types of renal patients (Gomez, Campbell, Savory, & Chevalier, 1987), others have found it ineffective (Andreoli & Cohen, 1989; Gokal et al., 1979; Roxe et al., 1990). Side effects of DFO therapy include digestive disorders, cataracts, skin rash, neutropenia, and hypotension (Simon, 1985).

Therapy with DFO is rarely used in ESRD patients with iron overload today. It is usually reserved for patients with aluminum toxicity. A recent consensus panel examining the iron management of chronic renal failure (CRF) patients suggests that DFO is an option for patients with transfusional overload (Adamson et al., 1999). However, the panel did not recommend its use in patients with iron overload due to hemochromatosis or excess parenteral iron administration (see Table 1).

Phlebotomy (therapeutic venesection) has been a standard treatment for hemochromatosis for many years (Bomford & Williams, 1976; Rouault, 1993). The consensus panel examining the iron management of CRF patients suggested that phlebotomy should be used to reduce iron stores to the low normal range in ESRD patients with hereditary hemochromatosis. Phlebotomy should be performed on a weekly or twice-weekly basis (Adamson et al., 1999). However, repeated phlebotomy is impractical for hemodialysis patients not receiving EPO because they have a hypoproliferative anemia (Simon, 1985). Phlebotomy is also not a good option for ESRD patients without hemochromatosis, since the goal is to treat anemia in these patients.

Finally, a treatment is required to relieve iron overload caused by excessive parenteral iron administration. As mentioned previously, parenteral iron administration rarely causes iron overload. If overload does occur, patients should be managed by simply interrupting parenteral iron administration and continuing EPO therapy (Adamson et al., 1999). There is some rationale that such therapy will work. In a study of maintenance therapy with iron dextran, Fishbane and colleagues (1995) found that by withholding IV iron, patients' serum ferritin levels dropped from a mean of 754 ng/mL to 183 ng/mL, and TSAT dropped from 75% to 19% within 4 months. Sunder-Plassmann and Horl (1995) found that withdrawal of iron in patients who had received maintenance iron saccharate therapy led to a reduction in serum ferritin levels from a mean of 836 ng/mL to 477 ng/mL and TSAT from 22% to 16%.


Iron overload is a serious condition that can occur in ESRD patients because of blood transfusions, hemochromatosis, and/or excess parenteral iron therapy. If patients are managed according to the NKF-DOQI guidelines, iron overload is unlikely. When severe or extreme iron overload is suspected, it may be confirmed through liver biopsy. Therapeutic phlebotomy may be initiated in ESRD patients with hemochromatosis. Withholding iron should return iron levels to normal range in patients with parenterally induced iron overload. In conclusion, iron overload is a rare, manageable condition in renal patients in the EPO era.

Note: This article is supported by a financial grant from Schein Pharmaceutical, Inc. This article has undergone peer review. The information in this article does not necessarily reflect the opinions of ANNA or the sponsor.


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Karen C. Robbins, MS, RN, CNN, is a Nurse Educator, Dialysis Services, Hartford Hospital, Hartford, CT; and a past president of ANNA.
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Author:Robbins, Karen C.
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Apr 1, 2000
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