Regular low-dose IV iron treatment is more physiologically appropriate than the intermittent IV iron for anemic hemodialysis (HD) patients. In addition, IV iron has an important role in improving response to treatment with erythropoiesis-stimulating agents (ESAs).

These are some of the conclusions of two nephrologists who spoke at a symposium during the American Nephrology Nurses Association National Meeting in San Diego.  The symposium, sponsored by Watson Pharmaceuticals, was titled “IV iron Practices Today for Improved Outcomes Tomorrow.”

Rajiv Agarwal, MD, Professor of Medicine at the Indiana University School of Medicine in Indianapolis, said regular infusions of low-dose iron enable HD patients to achieve and maintain target hemoglobin (Hb) levels better than IV loading doses, and infusions can reduce ESA requirements.

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Dr. Agarwal cited a study (Am J Nephrol. 2002;22:67-72) in which 26 HD patients received ferric gluconate continuously (6.25-21.3 mg per dialysis session) or intermittently (62.5 mg every one to four weeks). At 16 weeks, the continuous group had a significant increase in Hb levels compared with baseline (11.83 vs. 10.96 g/dL), whereas the intermittent group had no significant change (11.16 vs. 11.14).

Reduce ESA dose

In addition, a number of studies have demonstrated the ESA-sparing effect of regular low-dose iron treatment, Dr. Agarwal noted. One of those studies compared continuous IV iron therapy (iron dextran 25-100 mg every one to two weeks) to maintain transferrin saturation (TSAT) at 30%-50% and intermittent IV iron (iron dextran 100 mg at each of 10 consecutive dialysis sessions) when TSAT was below 20% or serum ferritin was below 200 ng/mL.

Compared with the intermittent group, the continuous maintenance group experienced a significant decrease in the amount of erythropoietin required to maintain Hb levels between 10 and 11 g/dL (Am J Kidney Dis. 1999;34:21-28).

The intermittent strategy repletes iron stores in HD patients with absolute iron deficiency, defined as serum ferritin levels below 200 ng/mL and TSAT below 20% or reticulocyte hemoglobin content [CHr] less than 29 pg/cell. But iron deficiency can return. Moreover, Hb levels can decrease because iron is used continuously for RBC production and HD patients have ongoing blood and iron losses from dialysis, repeated laboratory tests, and other causes. Regular low-dose iron administration ensures a constant supply of iron for RBC production.

Dr. Agarwal pointed out that a mean of 22-65 mg/wk of iron is needed to maintain iron balance and recover iron losses (Am J Kidney Dis. 2006;47[5 suppl 3]:S11-S145). Furthermore, he noted, studies show that even when iron indices appear normal, many HD patients can be very iron-deficient. Consequently, when Hb levels are low, additional iron is required beyond the losses expected during HD.

ESA hyporesponsiveness

In a separate presentation, Amit Sharma, MD, Director of Clinical Research at Boise Kidney and Hypertension Institute in Meridian, Idaho, reviewed strategies for improving response to ESA therapy in HD patients. He pointed out that many CKD and HD patients differ in their response to ESAs; some fail to have an adequate response.  This hyporesponsiveness to ESAs is a clinical challenge in HD units because these patients become more anemic or require higher ESA doses to maintain Hb levels. 

Higher ESA doses without achieving target hemoglobin values may result in poorer outcomes. Inflammation is among the chief causes of ESA hyporesponsiveness, he said. Evidence suggests that patients with elevated markers of inflammation require more ESA.

In one study, Goicoechea et al showed that HD patients with tumor necrosis factor-α levels above 2 ng/mL and interleukin-6 (IL-6) levels above 40 ng/mL required twice as much ESA as patients with lower levels of these markers (Kidney Int. 1998;54:1337-1343). Another study, by Kalantar-Zadeh et al, demonstrated that increasing severity of malnutrition-inflammation complex syndrome is associated with greater ESA requirements in HD patients.

For example, the average ESA dose requirement was 27,495 units/wk for patients whose IL-6 levels were 29.66 pg/mL or for those whose total serum cholesterol levels were 135.9 mg/dL. In contrast, the average ESA dose requirement was 4,954 units/wk for subjects with IL-6 levels of 12.26 pg/mL or for those with total serum cholesterol levels of 152.3 mg/dL (Am J Kidney Dis. 2003;42:761-773).

Dr. Sharma explained that chronic inflammation can lead to iron restriction in the reticuloendothelial (RE) system (inflammation-mediated RE blockade) by increasing levels of hepcidin, a peptide secreted by the liver. Increased hepcidin levels cause a decrease in intestinal iron absorption and an increase in iron sequestration in the RE system. As a result, serum ferritin levels rise and serum iron and TSAT decline.

IV iron, Dr. Sharma said, can help overcome inflammation-mediated RE blockade, as suggested by a study of 134 HD patients randomly assigned to receive ferric gluconate 125 mg with eight consecutive HD sessions or no iron (J Am Soc Nephrol. 2007;18:975-984).

The study, by Coyne et al., included subjects with Hb levels of 11 g/dL or below, ferritin levels of 500-1,200 ng/mL, TSAT of 25% or below, and epoetin dosages of 225 IU/kg per week or higher. Mean TSAT rose from 18.2 at baseline to 25.6 at six weeks in the iron group and from 19% to 21.1% in the control arm. The investigators concluded that administration of IV iron in this patient population overcomes functional iron deficiency/inflammation-mediated RE blockade.

Managing inflammation would be one approach to correcting ESA resistance.

Iron-restricted erythropoiesis

Another possible cause of ESA hyporesponsiveness is iron-restricted erythropoiesis, which is caused by insufficient circulating iron to meet the increased iron demands driven by ESA. As a result, the RE system is unable to release iron quickly enough to match the rate of erythropoiesis. The study by Coyne et al found that CHr decreased in patients who did not receive IV iron but was unchanged in iron recipients.

With respect to predicting hyporesponsiveness to ESAs, Dr. Sharma cited a recent study showing that a TSAT below 20% was associated with 50% lower ESA responsiveness compared with a TSAT of more than 30%. Serum ferritin levels below 200 ng/mL were associated with 23% lower ESA responsiveness compared with levels of 200-500 (Am J Kidney Dis. 2009;75:104-110).

In the context of a trend toward higher ESA doses over the past decade, Dr. Sharma, clinicians should employ strategies that minimize hyporesponsiveness. A potential emerging approach is the use of weekly iron infusion, he said.