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.¹

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

Functional iron deficiency may be important, particularly among patients receiving recombinant human erythropoietic-stimulating agents (ESAs).  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 >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 iron deficiency is essential in order to understand iron indices in patients with chronic kidney disease 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 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-Dialysis 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.²  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.  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 erythropoeisis. 
• 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.

Assessing Iron Status
Iron status must be assessed to exclude iron deficiency, the most common cause of inadequate response to ESA therapy.

• In ESA-treated patients, if TSAT levels are below 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 above 20%.
• In CKD patients with ferritin values <200 ng/mL (hemodialysis) or <100 ng/mL (non-dialysis or peritoneal dialysis), 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 (hemodialysis) or >100 ng/mL (non-dialysis or peritoneal dialysis), 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 iron therapy
  • Correction of a less-than-target Hb level during ongoing ESA therapy
  • Recent bleeding
  • After surgery or hospitalizaiton
  • Monitoring response after a course of IV iron
  • Evaluation for ESA hyporesponse

Target Level

• The selected Hb target should generally be in the range of 11.0 to 12.0 g/dL.  In dialysis and non-dialysis patients with CKD receiving ESA therapy, the Hb target should not be greater than 13.0 g/dL. 
• To achieve target Hb with optimum erythropoietin doses, provide sufficient iron to maintain TSAT >20% and ferritin >200 ng/mL (hemodialysis) or >100 ng/mL (non-dialysis or peritoneal dialysis).

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 Hemodialysis Dependent-CKD (HD-CKD) on 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 Peritoneal Dialysis (PD-CKD) or Non-Dialysis CKD (ND-CKD).

Venofer^® (iron sucrose injection, USP) is the only first-line injectable iron product FDA approved for HD-CKD, PD-CKD, and ND-CKD.


Oral Iron

• Daily dose of elemental oral iron is approximately 200 mg in adults.
• 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 click here for complete Venofer ^® dosing information.

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 management 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. ⁴

The KDOQI 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

 



IMPORTANT SAFETY INFORMATION
Venofer ^® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ^® or any of its inactive components, and in patients with anemia not caused by iron deficiency.  Hypersensitivity reactions have been reported with IV iron products.  Hypotension has been reported frequently in hemodialysis dependent-CKD patients receiving IV iron, and has also been reported in non-dialysis dependent and peritoneal dialysis dependent-CKD patients receiving IV iron.  Hypotension following administration of Venofer ^® may be related to rate of administration and total dose delivered.

In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%), whether or not related to Venofer^® administration, were hypotension, cramps/leg cramps, nausea, headache, graft complications, vomiting, dizziness, hypertension, chest pain and diarrhea.  In post-marketing safety studies in hemodialysis dependent-CKD patients (N=1051), the most frequent adverse events reported (>1%) were congestive heart failure, sepsis and taste perversion.  In multi-dose efficacy studies in non-dialysis dependent-CKD patients (N=91), the most frequent adverse events (≥5%) whether or not related to Venofer ^® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.  In the study of peritoneal dialysis dependent-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer^®, reported by ≥5% of these patients were diarrhea, peritoneal infection, vomiting, hypertension, pharyngitis, peripheral edema and nausea.

Please click here for Venofer ^® Full Prescribing Information.

References

1. Danielson BG, Geisser P, Schneider W [eds]. Iron Therapy with Special Emphasis on Intravenous Administration. Switzerland: Vifor (International) Inc. Publisher 1st Edition. 1996.
2. National Kidney Foundation.  KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.  Am J Kidney Dis 47:S1-S146, 2006 (suppl 3).
3. NKF-DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure. New York, National Kidney Foundation, 1997;15-32.
4. Van Wyck DB. Lessons from NKF-DOQI: Iron Management. Seminars in Nephrology. 2000;20:330-334.