Guidelines for Anemia Management

Iron is an essential nutrient that is needed by every human cell. It plays a valuable role in the transport and storage of oxygen and oxidative metabolism, and in cell growth and proliferation. The most important use of iron is the production of hemoglobin and myoglobin. Iron is very reactive and is needed for many metabolic processes but may also be potentially harmful. It can participate in several reactions that may produce free radicals, which can be damaging to cells. Because of this, both iron deficiency and iron overload are clinically significant. If too little iron is available, deficiency of iron-containing compounds may have deleterious effects on cells and tissues. If iron accumulates, toxicity may lead to organ damage and death.

Iron deficiency is the most common deficiency disease worldwide. More than 1 billion people have iron deficiency, and about 700 million people have iron deficiency anemia. An absolute iron deficiency occurs when an insufficient amount of iron is available to meet the body's requirements. The insufficiency may be due to inadequate iron intake, reduced bioavailability of dietary iron, increased utilization of iron, or chronic blood loss. Prolonged iron deficiency leads to iron deficiency anemia—a microcytic, hypochromic anemia in which there are inadequate iron stores.¹

With the advent of recombinant human erythropoietin therapy, functional iron deficiency has also been described. It is the most common cause of a poor response to erythropoietin therapy. Functional iron deficiency is defined as a condition in which there is a failure to release iron rapidly enough to keep pace with the demands of the bone marrow for erythropoiesis, despite adequate total body iron stores. In these cases, ferritin levels may be normal or high, but the supply of iron to the erythron is limited, as shown by a low transferrin saturation and an increased number of microcytic, hypochromic erythrocytes.¹

Functional iron deficiency has the following characteristics:

• Inadequate hemoglobin (Hb) response to erythropoietin
• Serum ferritin may be normal or high
• Transferrin saturation (TSAT) usually <20%
• Reduced mean corpuscular volume (MCV) or mean corpuscular hemoglobin concentration (MCHC) in severe cases

The differential diagnosis between functional and absolute iron deficiency is essential in order to understand iron indices in patients with chronic renal failure on hemodialysis.

Iron deficiency anemia is a serious public health problem that can impact all aspects of life and social activity. Many patients can be treated with oral iron preparations. However, there are subgroups in whom oral iron is not adequate to treat the iron deficiency. In these clinical situations, intravenous iron therapy is the preferred treatment. Venofer^® (iron sucrose injection, USP) is an alternative to oral or other parenteral iron therapy.

Iron Deficiency in Chronic Renal Disease
The National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) provides recommendations for optimal clinical practices for the treatment of anemia in chronic renal failure (CRF). The NKF-DOQI Anemia Work Group reviewed 2836 publications, cited 349 publications, and developed 28 clinical practice guidelines on the management of erythropoietin and iron in anemia.² These guidelines have become the standard of care for chronic renal failure patients.

The January 2001 issue of the American Journal of Kidney Diseases contains an update of revisions to NKF/DOQI. The DOQI clinical practice guidelines initiative has been expanded to include chronic kidney disease before dialysis arises, when early intervention and prevention measures can delay or prevent the need for dialysis and improve outcomes of patients who develop end-stage disease. The new initiative has been renamed Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI).³

Several important issues related to iron deficiency and its management in chronic renal failure patients receiving erythropoietin therapy should be considered:

• Iron (blood) losses are high, especially in hemodialysis patients
• Oral iron usually cannot maintain adequate iron stores, especially in hemodialysis patients receiving erythropoietin
• Erythropoietin stimulates erythropoiesis to greater than normal levels, often leading to functional iron deficiency
• Prevention of functional and absolute iron deficiency by regular use of intravenous (IV) iron improves erythropoiesis
• TSAT is the best indicator of iron availability for erythropoiesis. Serum ferritin is the best indicator of tissue iron stores. However, both indices lack sensitivity and specificity. Thus, no single value of TSAT reliably distinguishes iron-deficient from iron-sufficient erythropoiesis, and no single value of ferritin distinguishes depleted from adequate iron stores

A brief summary of some of the issues addressed by these guidelines is provided.

Assessing Iron Status
Iron status must be assessed to exclude iron deficiency, the most common cause of inadequate response to erythropoietin therapy (Hb <11.0 g/dL).

• In erythropoietin-treated patients, if TSAT levels are below 20%, the likelihood that Hb will rise or erythropoietin doses fall after IV iron administration is high. Achievement of target Hb levels with optimum erythropoietin doses is associated with providing sufficient IV iron to maintain TSAT above 20%
• In CRF patients with ferritin values below 100 ng/mL, the likelihood that iron stores are depleted is high. If these patients also show TSAT <20%, iron deficiency is considered to be absolute
• In patients with TSAT <20% but ferritin ≥100 ng/mL, iron stores are thought to be adequate but unavailable for iron delivery. In this condition, iron deficiency is considered to be relative or functional
• TSAT levels ≥50%, or ferritin levels ≥800 ng/mL even in the presence of TSAT <20%, are thought to be associated with iron overload

	Absolute Iron Deficiency		Functional Iron Deficiency
	TSAT <20%		TSAT <20%
	Ferritin <100 ng/mL		Ferritin ≥100 ng/mL

The serum iron, total iron-binding capacity, and serum ferritin are the best indicators of iron available for erythropoiesis and iron stores but do not provide absolute criteria of either iron deficiency or iron overload.

Target Iron Level

• The target Hb level is 11.0 g/dL to 12.0 g/dL [hematocrit (HCT) approximately 33% to 36%]
• To achieve target Hb with optimum erythropoietin doses, provide sufficient iron to maintain TSAT ≥20% and ferritin ≥100 ng/mL
• Avoid iron overload by withholding iron for TSAT ≥50% and/or ferritin ≥800 ng/mL
• Provide IV iron by either periodic administration as 1 gram in divided doses or maintenance administration. Maintenance administration refers to fixed IV iron doses given weekly, monthly, or at each dialysis session to maintain iron levels within target range

Monitoring Iron Status

• In the patient initiating erythropoietin therapy, monitor iron indices monthly
• In patients who have achieved target range Hb or are receiving IV iron therapy, monitor TSAT and ferritin levels every 3 months

Administration of Supplemental Iron
Supplemental iron should be given to maintain target hemoglobin while preventing iron deficiency.

Oral Iron

• Daily dose of elemental oral iron is approximately 200 mg of elemental iron in adults
• Oral iron is unlikely to maintain target iron indices in erythropoietin-treated patients
• If oral iron is initiated on trial basis but fails to maintain target iron levels, discontinue oral iron and give IV iron

Intravenous Iron

• Many CRF patients receiving erythropoietin will require IV iron to maintain target iron levels
• Most hemodialysis patients will require repeated IV iron administration, due to dialysis-associated blood loss and resulting negative iron balance
• To correct and prevent iron deficiency, many IV iron dosing protocols have been shown to be effective
• To correct iron deficiency (TSAT <20%), administer 1 gram IV iron in divided doses (for example, 100-mg doses on each of 10 consecutive dialysis sessions). Reassess iron status and repeat if necessary
• To maintain target iron levels in hemodialysis patients, administer IV iron weekly, monthly, or at each dialysis session, in doses sufficient to maintain TSAT ≥20% and ferritin ≥100 ng/mL
• Discontinue iron administration if TSAT ≥50% and/or ferritin ≥800 ng/mL

The NKF-K/DOQI Anemia Management Guidelines have served to enhance current clinical practice. They have also identified areas requiring further investigation. Prospective, controlled trials are needed to determine the comparative safety of periodic and maintenance IV iron protocols and to explore the relationship between IV iron administration, body iron status, and risk of infection and ischemic heart disease.⁴