IRON REQUIREMENTS IN ERYTHROPOIETIN THERAPY

Eschbach JW.

Best Pract Res Clin Haematol 2005 Jun;18(2):347-61.

When erythropoietin (epoetins or darbepoetin) is used to treat the anemias of chronic renal failure, cancer chemotherapy, inflammatory bowel diseases, HIV infection and rheumatoid arthritis, functional iron deficiency rapidly ensues unless individuals are iron-overloaded from prior transfusions. Therefore, iron therapy is essential when using erythropoietin to maximize erythropoiesis by avoiding absolute and functional iron deficiency. Body iron stores (800-1200 mg) are best maintained by providing this much iron intravenously in a year, or more if blood loss is significant (in hemodialysis patients this can be 1-3 g). There is no ideal method for monitoring iron therapy, but serum ferritin and transferrin iron saturation are the most common tests. Iron deficiency is also detected by measuring the percentage of hypochromic red blood cells, content of hemoglobin in reticulocytes, soluble transferrin receptor levels, and free erythrocyte protoporphyrin values, but iron overload is not monitored by these tests. Iron gluconate and iron sucrose are the safest intravenous medications.

In this review article Eschbach examines the role of iron therapy in optimizing epoetin treatment of anemia in patients with chronic renal failure, especially those undergoing hemodialysis (HD), and other settings such as anemic cancer patients, inflammatory bowel disease, rheumatoid arthritis, and chronic heart failure. Most of the available data are related to CRF patients. In HD patients, iron metabolism is affected by significant chronic blood losses and oral iron is inadequate to maintain iron stores. Increased erythropoiesis following epoetin therapy often results in functional iron deficiency; by maintaining adequate iron stores it is possible to prevent both functional and absolute iron deficiency while optimizing erythropoiesis. Eschbach recommends the use of either iron sucrose or iron gluconate in ensuring that functional and absolute iron deficiency are avoided in patients receiving erythropoiesis stimulating agents.

Design: Review article.

Review Overview The production of hemoglobin requires both iron and erythropoietin (EPO). There are approximately 4,000 mg of iron in the human body, 1 mg of which is lost daily through the gastrointestinal tract and 1 mg is absorbed though food (menstruating women lose 1.5 mg daily). Iron is also lost through blood losses (gastrointestinal or surgical). If erythropoiesis is accelerated there is an increased demand for iron. There are several epoetin-responsive anemias that have EPO levels that do not increase in response to anemia; this is the case of the anemia associated with renal disease and chronic renal failure (CRF).

Iron metabolism and the anemia of chronic renal disease: In patients with chronic renal disease, erythroid function varies between one-third and two-thirds normal due to an insufficient EPO production in response to anemia. When anemia worsens, iron stores increase as the iron in senescent red blood cells (RBCs) is sequestered by the reticulioendothelial cells; RBC transfusions would further increase storage iron. Nevertheless, by the time that the chronic renal disease has progressed so that dialysis is needed, iron stores are elevated in most patients, yet one-third of patients are iron deficient undoubtedly due to prior blood losses. Consequently, before epoetin* therapy became standard for the treatment of the anemia of renal disease iron overload was common in these patients due to RBC transfusions and inadequate erythropoiesis. When treating CRF patients it is important to remember that iron metabolism in these patients is affected by the fact that iron losses due to blood losses are high, especially in those undergoing hemodialysis (HD); oral iron is inadequate to maintain iron stores; increased erythropoiesis following epoetin therapy often results in functional iron deficiency; and that by maintaining adequate iron stores it is possible to prevent both functional and absolute (serum ferritin levels [SF] < 100 µg/L) iron deficiency while improving erythropoiesis.

Functional and absolute iron deficiency: Functional iron deficiency occurs when the reticuloendothelial cells are unable to release enough iron to meet the increased demands of the erythroid cells following epoetin administration. In this case, epoetin therapy does not have the desired effect of increasing hemoglobin (Hb) levels in anemic CRF patients undergoing HD. The administration of intravenous (IV) iron appears to enable erythropoiesis to take place.

Inflammation can cause SF to rise while transferrin saturation (TSAT), serum iron and total iron binding capacity (TIBC) decrease (the latter decreasing less than the other parameters). In order to differentiate functional iron deficiency from inflammation serial measurements of TSAT and SF are required.

Epoetin and iron parameters: Epoetin therapy has been used in CRF since 1986, often in conjunction with IV iron therapy. In CRF patients undergoing HD blood losses are high with 5-20 mL of red blood cells remaining in the dialyzer after each dialysis session. Furthermore, functional iron deficiency occurred in the majority of these patients due to insufficient iron supplementation and non-physiological administration of epoetin (bolus injection of rather high doses). By 1997 it was recommended that maintaining SF > 100 µg/L and TSAT > 20% (ideally SF should be > 200 µg/L and TSAT > 25%) enabled easier maintenance of target Hb levels, and optimization of epoetin therapy and minimization of epoetin dose requirements.

Studies by Eschbach et al. (Kidney International 1992;43:407-16) and Rutherford et al. (Am J Med 1994;96:139-45) have shown that the administration of epoetin to normal individuals causes an important change in iron parameters with both SF and TSAT decreasing quickly after epoetin administration. Eschbach et al. showed that the decrease was greater in normal subjects (approx 60% decrease in SF, 57 % decrease in TSAT) than in patients undergoing HD (30% decrease in TSAT and SF) following 600 IU/kg epoetin over 8 days. Rutherford et al. study reported similar results and in addition demonstrated that oral iron was ineffective in maintaining appropriate iron parameters with SF decreasing by 74% and TSAT by approximately 64% following the combined administration of 1,200 IU/kg epoetin over ten days and 300 mg/day of oral iron.

A study by Silverberg (Clinical Nephrology 2001;55:212-9) has also shown that IV iron (five weekly doses of 200 mg) is effective when administered in conjunction with relatively low dose epoetin therapy (2,000 IU/week) in patients with progressive renal insufficiency, causing a rise in Hb from 9.7 to 11.05 g/dL.

Stoves et al. (Nephrol Dial Transplant 2001;16:967-74) reported that oral iron might be as effective as IV iron in raising Hb in pre-dialysis patients. In this study 600 mg of daily oral iron was shown to have the same effect as a monthly 300 mg dose of IV iron sucrose. However, SF was higher in those receiving IV iron (330 µg/L vs. 95 µg/L).

Consequently, IV iron therapy is recommended for all patients undergoing hemodialysis and treated with epoetin, although optimum iron dose will vary among patients. IV iron therapy ensures adequate iron stores so that epoetin therapy is optimized. SF, TSAT and TIBC can be used to monitor iron therapy. SF and TSAT should be used to assess iron stores once IV iron therapy is initiated. SF is directly related to iron stores, while TSAT indicates the iron available for erythropoiesis (in normal healthy individuals SF < 15 µg/L ad TSAT < 16% indicate absolute iron deficiency; however, these values are not referred to in patients with chronic kidney disease receiving epoetin and iron therapy). Once epoetin therapy is initiated, functional iron deficiency may develop and this is difficult to recognize with SF and TSAT unless both parameters decline, with a TSAT of 20-25%. An increase of the percentage of hypochromic red blood cells to > 6-10% indicates functional iron deficiency, even if the SF value indicates appropriate iron stores. Soluble transferrin receptor protein increases in presence of functional iron deficiency but also increases with epoetin therapy; it can suggest functional iron deficiency if Hb concentration remains stable at a stable epoetin dose. Free erythrocyte protoporphyrin measurement has also been considered. . A TSAT > 50-80% indicates iron overload. The K/DOQI guidelines advise that IV iron be stopped if SF > 800 µg/L, while most nephrologists aim for SF 200-500 µg/L. If available, Hb content of reticulocytes should be maintained at > 29 pg.

Intravenous Iron Therapy in Other Settings than CRF: IV iron therapy has also been shown to be effective in patients receiving epoetin therapy for cancer chemotherapy anemia when compared to oral iron or placebo. Functional iron deficiency may occur particularly when large doses of epoetin are administered.

Functional iron can also ensue when epoetin is used to correct anemia related to inflammatory bowel disease (IBD), HIV infection and rheumatic arthritis. IV iron alone or in conjunction with epoetin has been shown to be effective in IBD-associated anemia. IV iron therapy associated with epoetin therapy has also been effective in correcting anemia in patients with severe chronic heart failure, resulting in improved cardiac function and reduced hospitalizations.

Adverse effects of iron therapy:Iron dextran is associated with acute allergic reactions in 1 in 150 people exposed, and serious life-threatening events in 20 per 100,000 doses. Anaphylactic reactions are very rare with iron sucrose and iron gluconate, with one patient out of 2,500 having a life threatening reaction to 125 mg of iron gluconate (Michael et al. Kidney International 2002;61:1830-9), and no anaphylactoid reaction after 1,000 doses of 100 mg of iron sucrose (Van Wyck Am J kidney Disease 2000;36:88-97; Charytan Am J Kidney Disease 2001;37:300-07). Other possible long-term effects of IV iron therapy include increased risk of cardiovascular disease and atherosclerosis, increased infection and increased oxidative stress although empirical data has yet to prove this. Moreover, anemia has been demonstrated to cause oxidative stress and increasing Hb over 11 g/dL decreases this oxidative stress. Regular administration of IV iron also decreases tumor necrosis factor-?, and increases the anti-inflammatory cytokine interleukin-4. Consequently, at present the benefits of improving anemia with erythropoiesis stimulating agents and IV iron outweighs the hypothetic potential for long-term iron toxicity.

Key Points

· The administration of erythropoiesis stimulating agents, such as epoetin, can cause functional iron deficiency in CRF patients.

· Iron therapy, when administered in conjunction with epoetin therapy, enables an optimal iron balance to be maintained to support optimal erythropoiesis and a stable Hb.

· SF, TSAT are the most common tests for monitoring iron therapy; the percentage of hypochromic red blood cells, content of hemoglobin in reticulocytes, soluble transferrin receptor levels, and free erythrocyte protoporphyrin values have also been proposed.

· Inflammation can cause SF to be elevated, and in the instance of functional iron deficiency SF may remain elevated.

· Iron gluconate and iron sucrose are the safest intravenous preparations with the latter having no reported lethal anaphylactoid reactions.

*

Currently, epoetin and darbepoetin are the two erythropoiesis stimulating agents available in clinical practice. Epoetin = recombinant human erythropoietin or rHuEPO (epoetin-? and epoetin-?). The action of epoetin is similar to darbepoetin in erythropoiesis stimulation; however, few data is available on iron requirements during darbepoetin therapy.