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 anaemia. 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 anaemia - a microcytic, hypochromic anaemia 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 anaemia 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 anaemia in chronic renal failure (CRF). The NKF-DOQI Anaemia Work Group reviewed 2 836 publications, cited 349 publications, and developed 28 clinical practice guidelines on the management of erythropoietin and iron in anaemia. (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



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