Managing Iron Deficiency Anemia

This section gives an overview of the management of iron deficiency anemia in patients with chronic kidney disease —especially those receiving an erythropoietin such as Epogen^® (Amgen), Procrit^® (Ortho Biotech), or Aranesp^® (Amgen).

Topics covered in this section include:

• Benefits of treating anemia and maintaining iron balance in patients with end-stage renal disease (ESRD)
• Current prevalence of uncontrolled anemia and iron deficiency in patients with ESRD
• Highlights of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000
• Available iron replacement therapy options

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• Benefits of anemia control in ESRD
• Guideline highlights for the treatment of anemia of chronic kidney disease

Benefits of Anemia Control in ESRD
Many benefits of controlling anemia in patients with ESRD have been demonstrated, including:

• Increased survival^1,2
• Decreased cardiac complications¹
• Improved quality of life^1,2
• Increased exercise capacity¹
• Decreased hospitalizations^1,2

The decreased morbidity and fewer hospitalizations associated with controlling anemia and with higher hematocrit (HCT) levels may result in cost savings.³

Adequate iron stores and iron availability are important to control anemia and enable patients to benefit from erythropoietin therapy.^4,5 Correction of functional iron deficiency, a condition involving reduced availability of iron, in patients receiving erythropoietin has been shown to⁵:

• Increase the response to erythropoietin therapy
• Reduce the dose of erythropoietin required to achieve hemoglobin (Hb) and HCT target levels (which may translate into cost savings)

NOTE: Although Hb and HCT are both used as markers of anemia, Hb is now the preferred of the two.

Despite the widespread use of erythropoietin, anemia continues to be observed in many patients with ESRD.⁶ Iron deficiency, chronic blood loss related to the hemodialysis procedure, and functional iron deficiency are contributing factors.
Iron deficiency is common in patients with ESRD.^3,7 A study of 7092 adult patients undergoing hemodialysis in centers revealed that 30% had a transferrin saturation (TSAT) below 20%, and 19% had serum ferritin levels below 100 ng/mL.³


Iron deficiency can both exacerbate anemia and reduce the effectiveness of erythropoietin therapy in treating anemia in patients with ESRD.⁴

Because the body can store only about 800 to 1200 mg of iron, iron deficiency can develop easily in hemodialysis patients as a result of ongoing dialyzer-related blood (iron) losses.⁴ Hemodialysis patients commonly lose up to 15 to 25 mL of whole blood at each dialysis session, which can add up to losses of 6 to 8 g of iron each year.⁸

Functional iron deficiency caused by the increased iron demands of erythropoietin is common among patients with ESRD.⁴ Functional iron deficiency is a condition in which there is a failure to release iron rapidly enough to keep pace with the demands of the bone marrow for erythropoiesis⁴ despite adequate total body iron stores.⁵ Also, patients who are already iron deficient often don’t respond to erythropoietin treatment.⁷

Another concern about erythropoietin therapy is that maintenance of near “normal” HCT levels with this treatment may pose increased mortality risks in this patient population. In a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease, maintaining near normal HCT levels with erythropoietin therapy was related to increased mortality, myocardial infarctions, and thrombotic events.⁹

In a randomized placebo-controlled study of patients undergoing coronary bypass surgery who did not have chronic kidney disease, 7 deaths occurred among the 126 patients receiving erythropoietin, including 4 deaths related to thrombosis. There were no deaths among the 56 patients receiving placebo.⁹ The reason for the increased mortality in these studies and the extent of the population that may be affected is not known.⁹

While achieving and maintaining HCT levels of 33% to 36% is beneficial for most chronic kidney disease patients receiving erythropoietin, it is important to be aware of the potential risks for some patients with cardiac-related conditions. For these patients, the benefits of an erythropoietin treatment should be weighed against the risks.

Why are so many patients with ESRD iron deficient? One reason is that some of the available iron supplements may have shortcomings. Tolerance to oral iron supplements is poor, leading to noncompliance and poor outcomes.¹⁰ Clinicians may fail to achieve and maintain iron balance in their patients because of concerns about anaphylaxis, which has been observed with IV iron dextran therapy.³

Anaphylactic reactions occur in 0.7% of dialysis patients taking IV iron dextran, usually within the first few minutes of administration of the test dose.¹¹ The earlier a reaction appears after start of infusion, the more severe it will be.¹² These allergic reactions are generally considered to be type I (Ig [immunoglobulin] E) immune response related. The anaphylactic response to IV iron is a severe allergic reaction, most commonly to dextran.^13,14 Immune defense cells respond by releasing histamine and other inflammatory mediators, causing allergic symptoms. It is not certain why some individuals are more sensitive than others; however, severe reactions are more common in patients with diabetes, heart disease, pulmonary disease, and chronic inflammatory states¹² and in patients with multiple drug allergies.¹⁵ Elderly patients are more likely to develop a severe reaction.¹²

So, while considerable progress has been made during the past decade in the management of anemia and iron balance in patients with ESRD, the pursuit of the ideal therapeutic solution continues.

Guideline Highlights for the Treatment of Anemia of Chronic Kidney Disease
A review of the NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000 appears here. These guidelines include a recommended approach to anemia and iron deficiency management in patients with ESRD that is based on extensive research and the opinion of top medical experts in the field. Because of its length and complexity, only highlights of the guideline are presented here. (The complete guidelines are included in the National Kidney Foundation Web site at http://www.kidney.org.)

(NKF-K/DOQI expands on the Dialysis Outcomes Quality Initiative [DOQI], published in 1997, that addressed the care of dialysis patients alone. Much broader in scope, K/DOQI includes all phases of kidney disease and dysfunction and their monitoring and management.)¹⁶

The NKF-K/DOQI guidelines include specific recommendations for¹:

• An anemia workup
• Target Hb and HCT levels during erythropoietin therapy
• Iron support

Performing an anemia workup
An anemia workup should be performed for patients with chronic renal failure (or chronic kidney disease [CKD] as it’s called in K/DOQI) when Hb levels are below 11 to 12 g/dL and HCT levels are below 33% to 37%. If the workup reveals no other cause of anemia and serum creatinine is ≥2 mg/dL, deficient erythropoietin production is likely.¹ According to NKF-K/DOQI Guideline 5, serum iron, total iron-binding capacity, and serum ferritin levels are the best indicators of the availability of iron for erythropoiesis and iron stores but do not provide definitive criteria for either iron deficiency or iron overload.^1,10

Target Hb/HCT levels during erythropoietin therapy
During erythropoietin therapy, a target Hb level of 11 to 12 g/dL and a target HCT level of 33% to 36% should be maintained in patients with CKD.¹

Iron support
The recommendations for iron support include¹:

• Assessing and monitoring iron status (using serum ferritin and TSAT levels)
• Administering iron replacement therapy

Assessing and monitoring iron status: target serum ferritin and TSAT levels

• The guideline recommends monitoring iron status with TSAT and serum ferritin levels. The target values are serum ferritin ≥100 ng/mL and TSAT ≥20%.¹ Iron overload can be avoided by withholding iron from patients with a TSAT ≥50% and/or serum ferritin ≥800 ng/mL¹

Figure 1: NKF-K/DOQI Recommendations for Assessment of Iron Status and Target Iron Levels¹

To achieve and maintain target Hb/HCT levels, sufficient iron should be administered to maintain a TSAT ≥20% and a serum ferritin level of ≥100 ng/mL.



*A small dose of epoetin is defined as <3000 units/week.¹

 

Figure 2: Monitoring Iron Status¹

Case A: Patient receiving epoetin



*IV iron dextran therapy must be discontinued for 2 weeks prior to performing these measurements of iron status. With ferric gluconate (Ferrlecit^®), these measurements should be performed no sooner than 2 to 7 days after the last dose, depending on the amount of the dose; doses of 100 to 125 mg require 7 days.¹ With Venofer^® (iron sucrose injection, USP), iron indices can be checked 48 hours after the last dose.¹⁷

Administration of iron replacement therapy

• To achieve and maintain target Hb/HCT levels, sufficient iron should be administered to maintain a TSAT level of ≥20% and a serum ferritin level of ≥100 ng/mL¹

A third flowchart (Figure 3) summarizes NKF-K/DOQI recommendations for IV iron administration.

Figure 3: NKF-K/DOQI Recommendations for IV Iron Administration¹



*Oral iron should NOT be given along with IV iron.
^†Other schedules that provide 250 to 1000 mg iron within 12 weeks are acceptable (eg, 3x/week, once every 2 weeks).
^‡Hb/HCT, TSAT, and serum ferritin levels should be measured 2 weeks following the end of an IV iron treatment period. However with Venofer^® (iron sucrose injection, USP), iron can be reliably determined 48 hours after the last dose.¹⁷

Additional Information

Role of oral iron

• If oral iron is given, at least 200 mg of elemental iron daily for adults and 2 to 3 mg/kg daily for children is required¹
• A trial of oral iron is acceptable for the hemodialysis patient, but it is unlikely to maintain target iron and Hb/HCT levels. Most hemodialysis patients with iron deficiency require IV iron on a regular basis¹

Avoidance of iron overload
If TSAT is ≥50% and/or serum ferritin is ≥800 ng/mL, IV iron should be withheld for up to 3 months to prevent risk of iron overload. Iron status should then be reassessed before IV iron therapy is resumed. Because of hemodialysis-associated blood losses, withholding IV iron will result in a decrease in serum ferritin levels.¹

Maintenance iron replacement therapy
Maintenance IV iron needs in patients undergoing hemodialysis may vary from 25 to 125 mg per week. The goal is to provide a dose that will maintain target Hb/HCT levels at a safe, stable iron level. The goal of iron therapy is to improve erythropoiesis, not to attain specific levels of TSAT and/or serum ferritin.¹

Therapeutic options for iron replacement
Iron supplements include oral and IV iron preparations. All iron supplements belong to a therapeutic class called hematinic agents. Hematinic agents improve the quality of blood by increasing the number of red blood cells (RBCs) and/or the Hb concentration.

Oral Iron Supplements
Oral iron supplements include over-the-counter tablets and elixirs containing varying amounts of ferrous iron.¹⁸ Table 1 contains a list of 4 oral iron preparations currently available as tablets and the amount of elemental iron they provide.¹³ Other options—absorption-enhancing formulations (eg, iron–ascorbic acid combinations), delayed-release formulations, and iron complexed to heme—are also available.^3,18

Table 1. Oral Iron Supplements¹³

Adapted from Fishbane et al.¹³


For an adult with moderate to severe iron deficiency anemia, the usual dosage of a standard oral iron supplement, such as ferrous sulfate, is 325 mg or 5 mL (300 mg) 3 to 4 times daily between meals.¹⁸ This dosage provides 200 to 250 mg of elemental iron per day.¹⁸

Patients may fail to respond to oral iron therapy for several reasons, including:

• ESRD¹⁸
• Noncompliance¹⁸
• Persistent blood loss¹⁸
• Chronic inflammation or bone marrow damage¹⁸
• Abnormal iron absorption¹⁸
• Dialysis (erythropoietin use creates iron needs that are greater than the replacement capacity of oral iron)⁴

Factors contributing to noncompliance include gastrointestinal side effects (more than 25% of patients taking three to four 325-mg oral iron tablets daily experience gastrointestinal distress or constipation), inconvenience (must be taken 3 to 4 times daily), and nonreimbursed costs.^13,18

Although associated with gastrointestinal side effects, oral iron supplements are not associated with the anaphylaxis that can occur with parenteral iron dextran preparations.¹⁰ Oral iron therapy is also less burdensome for the nursing and medical staff in dialysis units because it is noninvasive and patients take their own doses at home.

Is there a place for oral iron therapy in chronic kidney disease? Oral iron is frequently used to maintain iron balance in predialysis and continuous ambulatory peritoneal dialysis (CAPD) patients.^10,20 Oral iron may be preferred in these patient groups because¹⁰:

• It is convenient
• No access to the vein is needed
• Less iron is lost on a daily basis than in patients undergoing hemodialysis
• It is relatively inexpensive

Parenteral IronTherapy

Before 1999, the only parenteral iron preparation available in the United States was iron dextran. The first iron dextran on the US market was Imferon^®, manufactured by Fisons Corporation of Rochester, NY.¹⁴ Imferon^® was removed from the market in 1991 because of production irregularities. In 1992, INFeD^®, a similar form of iron dextran, was introduced in the United States by Schein Pharmaceutical, Inc. (Florham Park, NJ), now Watson Pharmaceuticals, Inc. In 1996, Dexferrum^® was introduced in the United States by American Regent Laboratories, Inc., (Shirley, NY), now American Regent, Inc.

In June 1999, Schein Pharmaceutical, Inc., subsequently acquired by Watson Pharmaceuticals, Inc., began marketing Ferrlecit^® (sodium ferric gluconate complex in sucrose injection).¹⁴ The introduction of Venofer^® in 2000 marked the fourth parenteral iron compound to be approved for marketing in the United States.

The parenteral iron compounds available vary in approved usage, polysaccharide content, molecular weight, stability of the complex, rate of iron release, dosage, and adverse event profile. (See Table 2).^{1,14,17,21,22}

Table 2. Parenteral Iron Supplements^{1,14,17,21,22}

Adapted from Matzke et al and Lange et al.^14,21
INFeD and Ferrlecit are trademarks of  Watson Pharmaceuticals, Inc.
*+ = unstable, ++++++ = very stable.
^†A more rapid release of iron possibly leads to a more predictable and manageable availability of iron within bone marrow.<sup>23


‡</sup> Hemodialysis is usually performed 3 times a week.<sup>24

§</sup>There is limited experience with doses of 500 mg of Venofer^® over 3.5-4 hours; hypotension occurred in 2 lf 30 patients treated.

The association between iron dextran and anaphylaxis fueled an interest in developing new parenteral iron preparations, which subsequently led to the clinical study and introduction of Ferrlecit^®, and now Venofer^®, to the US market. Venofer^® has been available in Europe for over 50 years.^14,25

Epogen^® and Aranesp^® are registered trademarks of Amgen, Inc.
Procrit^® is a registered trademark of Ortho Biotech Products, L.P.

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 see Full Prescribing Information .

References

1. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative: clinical practice guidelines for anemia of chronic kidney disease, 2000. Am J Kidney Dis. 2001;37(suppl 1):S182-S238.
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3. Wish JB. Economic issues and future directions in iron management. Semin Dial. 1999;12:267-270.
4. Eschbach JW. Iron therapy and the anemia of ESRD: historical perspective. Semin Dial. 1999;12:212-218.
5. Tarng D-C, Huang T-P, Chen TW, et al. Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. Kidney Int. 1999;55(suppl 69):S-107–S-118.
6. Owen WF, Szczech L, Johnson C, et al. National perspective on iron therapy as a clinical performance measure for maintenance hemodialysis patients. Am J Kidney Dis. 1999;34(suppl 2):S5-S11.
7. Nissenson AR, Strobos J. Iron deficiency in patients with renal failure. Kidney Int. 1999;55(suppl 69):S-18–S-21.
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13. Fishbane S, Mittal SK, Maesaka JK. Beneficial effects of iron therapy in renal failure patients on hemodialysis. Kidney Int. 1999;55(suppl 69):S-67–S-70.
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15. Bailie GR, Johnson CA, Mason NA. Parenteral iron use in the management of anemia in end-stage renal disease patients. Am J Kidney Dis. 2000;35:1-12.
16. National Kidney Foundation announces major expansion of DOQI guidelines [press release]. New York, NY: National Kidney Foundation; January 24, 2000. Available at: http://www.kidney.org /general/news/doqi_expand.cfm. Accessed March 23, 2000.
17. Venofer^® [package insert]. Shirley, NY: American Regent, Inc.; 2007.
18. Hillman RS. Iron deficiency and other hypoproliferative anemias. In: Harrison's Online. Available at: http://www.harrisonsonline.com/server-java/Arknoid /harrisons/1096-7133 /Chapters/ch-106. Accessed April 18, 2000.
19. Proferrin^®-ES [package insert]. Cuzad, Neb: Colorado Biolabs Inc; 2002.
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22. Ferrlecit^® [package insert]. Corona, Calif: Watson Pharmaceuticals, Inc; 2001.
23. Bailie GR, Johnson CA, Mason NA. Parenteral iron products for anemia in end-stage renal disease: comparative considerations. Formulary. 2000;35:498-513.
24. National Institute of Diabetes and Digestive and Kidney Diseases. End-stage renal disease: choosing a treatment that's right for you. Available at: http://www.niddk.nih.gov/health/kidney/pubs/esrd/esrd.htm. Accessed May 10, 2000.
25. Data on file. American Regent, Inc., Shirley, NY.