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.126
Iron deficiency is the most common deficiency disease worldwide. More than
one 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. Insufficiency is commonly due
to chronic blood loss, but inadequate iron intake, reduced bioavailability of dietary
iron, and increased utilization of iron may also be seen. Prolonged iron deficiency
leads to iron deficiency anemia, a microcytic, hypochromic anemia characterized by
decreased hemoglobin production and decreased red cell production.126
Functional iron deficiency may be important, particularly among patients receiving
recombinant human erythropoietin. 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 inadequate to support erythropoiesis, as evidenced by a low
transferrin saturation and an increased number of microcytic, hypochromic erythrocytes.
126
Functional iron deficiency has the following characteristics:
• Inadequate hemoglobin (Hb) response to erythropoietin.
• Serum ferritin >100 ng/mL.
• 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 irondeficiency is essential
in order to understand iron indices in chronic kidney disease.
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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 which 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. Venofer® is the only first-line IV iron therapy approved to treat iron deficiency
anemia in all of the following key patient groups with Chronic Kidney Disease (CKD):
Pre-Dialysis, Hemodialysis and Peritoneal Dialysis patients.
Iron Deficiency In Chronic Kidney Disease
The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative
(KDOQI) Clinical Practice Guidelines and Clinical Practice Recommendations for
Anemia in Chronic Kidney Disease (CKD) provides recommendations for optimal clinical
practices. KDOQI Anemia 2006 reviewed 2756 citations, cited 461 publications,
and developed 3 evidence based guidelines and 34 clinical practice recommendations.
127 These guidelines represent the best and most current appraisal of care for
anemia in CKD patients.
The May 2006 supplement of The American Journal of Kidney Diseases represents
the first comprehensive update of the KDOQI guidelines since their original publication
in 1997.128 In 2001, the original DOQI clinical practice guidelines initiative underwent
a minor revision. The most current guidelines reflect a re-analysis of all available
evidence and an expanded scope explicitly addressing all patients with CKD,
including transplant CKD, regardless of etiology, stage, or treatment modality.
Several important issues related to iron deficiency and its management in CKD
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 erythropoiesis-stimulating agents (ESAs).
• In patients using ESA therapy, assuring adequate iron for erythropoiesis is
particularly important.
• Prevention of functional and absolute iron deficiency by regular use of intravenous
(IV) iron improves sensitivity to ESA.
• TSAT, or CHr, are the best indicators of iron availability for erythropoiesis.
• Serum ferritin is the best indicator of tissue iron stores.
• However, in CKD patients, TSAT and ferritin are each unreliable as diagnostic
indices of iron deficiency. Testing of Hb, TSAT or CHr together with ferritin is
recommended because the combination provides important insight into external
iron balance and internal iron distribution.
A brief summary of some of the issues addressed by these guidelines is provided.
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Assessing Iron Status
Iron status must be assessed to determine iron deficiency, the most common cause of inadequate
response to ESA therapy.
• In ESA-treated patients, if TSAT <20%, the likelihood that Hb will rise or ESA doses fall
after IV iron administration is high. Achievement of target Hb levels with optimum ESA
doses is associated with providing sufficient IV iron to maintain TSAT >20%.
• In CKD patients with ferritin <200 ng/mL (HD) or <100 ng/mL (ND or PD), 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
>200 ng/mL (HD-CKD) or >100 ng/mL (ND or PD-CKD), iron stores are thought to be
adequate but unavailable for iron delivery. In this condition, iron deficiency is considered
to be relative or functional.
• No current evidence is available to support the routine treatment of patients with serum
ferritin levels greater than 500 ng/mL. Clinicians should therefore base iron treatment
decisions on the individual patient’s clinical status and ESA responsiveness. When the
serum ferritin is >500 ng/mL and concurrently measured TSAT is <20%, a trial course
of iron therapy may be considered.
• TSAT or CHr 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.
Monitoring Iron Status
Results of iron status tests, Hb, and ESA dose should be interpreted together to guide iron
therapy.
• In the patient initiating ESA 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.
• Clinical settings in which more frequent iron testing may be necessary
- Initiation of ESA therapy
- Correction of a less-than-target Hb level during ongoing ESA therapy
- Recent bleeding
- After surgery or hospitalization
- Monitoring response after a course of IV iron
- Evaluation for ESA hyporesponse
Target Levels
• The target Hb level is >11.0 g/dL (caution when intentionally maintaining Hb >13 g/dL).
• To achieve target Hb with optimum erythropoietin doses, provide sufficient iron to maintain
TSAT >20% and ferritin >200 ng/mL (HD-CKD) or >100 ng/mL (ND or PD-CKD).
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Administration of Supplemental Iron
Supplemental iron should be given to maintain target hemoglobin while
preventing iron deficiency.
IV iron is the preferred route of administration in patients with HD-CKD or ESA therapy.
• Most hemodialysis patients will require repeated IV iron administration, due
to dialysis-associated blood loss resulting in negative iron balance.
The route of iron administration can be either IV or oral in patients with PD or NDCKD.
Oral Iron
• Daily dose of elemental iron in oral iron therapy is approximately 200 mg.
• Oral iron is unlikely to maintain target iron indices in ESA-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
There are 2 widely used and effective approaches to IV iron treatment. These are
outlined in the KDOQI guidelines as follows:
Periodic Iron Repletion: A series of IV iron doses administered episodically to
replenish iron stores whenever iron status tests decrease.
• To correct iron deficiency (TSAT <20%). Administer 1 gram IV iron in divided
doses (e.g., 100 mg doses of Venofer® (iron sucrose injection, USP) on
10 consecutive dialysis sessions). Reassess iron status and repeat if necessary.
Please refer to page 13 for complete Venofer® dosing.
Continuous Maintenance Treatment: Smaller doses administered at regular intervals
to maintain iron status within target. The average IV iron dose needed to maintain
a stable ferritin level appears to be in the range of 22 to 65 mg/week.
• To maintain target iron levels, administer IV iron weekly, monthly, or at each
dialysis session, in doses sufficient to maintain TSAT >20% and ferritin >200
ng/mL (HD-CKD) or >100 ng/mL (PD or ND-CKD).
Successful anemia therapy in patients with CKD requires appropriate targets of
therapy, testing of iron status, and the safe and effective use of iron agents. The
goal of iron therapy is to achieve and maintain target Hb levels, to avoid storage
iron depletion and prevent iron deficient erythropoiesis.129
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