Applied Evidence

Anemia and chronic kidney disease: What’s the connection?

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References

TABLE
Stages of chronic kidney disease

StageDescriptionGFR (mL/min/1.73 m2)
1Kidney damage with normal or increased GFR≥90
2Kidney damage with mildly decreased GFR60-89
3Moderately decreased GFR30-59
4Severely decreased GFR15-29
5Kidney failure<15 or dialysis
GFR, glomerular filtration rate.
Source: KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007.3

Anemia of CKD: A diagnosis of exclusion

Because anemia can have many causes, other possibilities must be ruled out before a diagnosis of CKD anemia can be made. Testing should be tailored to each individual situation, determined by a thorough history and physical. Steps in the diagnosis are shown in the FLOW CHART. A basic work-up should include complete blood count with differential, iron studies (ferritin, serum Fe, and total iron binding capacity), reticulocyte count, and a guaiac test. Other blood tests, such as thyroid-stimulating hormone (TSH), B12, and folate levels, and a hemolysis panel (lactate dehydrogenase, haptoglobin), should be obtained if the history suggests these disorders. A peripheral blood smear showing normocytic red blood cells with a normochromic pattern would favor the diagnosis of anemia of CKD.

FLOW CHART
A step-by-step guide to CKD anemia diagnosis and treatment


CBC, complete blood count; CKD, chronic kidney disease; ESA, erythropoietin-stimulating agents; R/O, rule out; TIBC/TSAT, total iron-binding capacity/transferrin saturation.

A look at the iron connection

Many patients with CKD anemia have iron deficiency and are unable to produce adequate numbers of red blood cells. Iron deficiency can have many causes: not enough iron-rich food in the diet, chronic bleeding, malabsorption, or an occult gastrointestinal malignancy. Once iron deficiency anemia is diagnosed, a colonoscopy is warranted to rule out occult malignancy. Ferritin, a protein found mostly in macrophages and hepatocytes, stores iron and serves as a marker for total iron stores. Using stored iron requires transferrin, a transporting protein, to shuttle iron from the reticuloendothelial system and gut to the bone marrow. CKD is a pro-inflammatory state that results in a limited ability to use iron stores. For this reason, patients with CKD require higher levels of iron.

Absolute iron deficiency. Iron deficiency in CKD patients with serum ferritin <100 ng/mL and transferrin saturation (TSAT) <20% is characterized as absolute iron deficiency. The TSAT represents the percent of iron bound to transferrin and is a good indicator of the body’s functional capacity to use stored iron.

Relative iron deficiency and iron block. Patients who do not respond to ESA therapy even though they have adequate iron stores are said to have a functional or relative iron deficiency. Iron block is a condition that results in anemia from a chronic inflammatory state such as infection, autoimmune disorders, or malignancies. It resolves once the inflammatory process abates. Both conditions have similar anemia profiles, with a serum ferritin >100 ng/mL and a TSAT <20%. Differentiating between these conditions requires dynamic testing using serial iron studies and observing responses to ESAs and iron supplementation.

Options for correcting iron deficiency

After a thorough history and physical with appropriate screening, you find that Mary has an iron deficiency that must be corrected before her anemia can be treated effectively. Treatment for iron deficiency is usually initiated with oral therapy, at the recommended dose of 200 mg oral elemental iron a day in 3 divided doses.

If the oral therapy does not correct iron deficiency within 3 months, or a patient cannot tolerate the constipation that is often a side effect of this therapy, IV iron administration can be considered. Because CKD patients do not have the ongoing iron losses seen in patients with end-stage renal disease (ESRD), a conservative approach using a single IV dose followed by repeat testing is warranted. The goal is to achieve ferritin levels >100 ng/dL and TSAT >20%. A number of products for IV iron administration are available. The most widely used are iron dextran (INFeD), ferric gluconate (Ferrlecit), and iron sucrose (Venofer).

Iron stores are replenished? Time to treat the anemia

When ferritin levels and TSAT show that iron deficiency has been corrected, ESA treatment for anemia can begin. Two major brands of ESAs currently in use in the United States are a recombinant human erythropoietin (rHuEPO) known as epoetin alfa (Procrit, Epogen), and darbepoetin alpha (Aranesp). Both medications are effective and can be given intravenously or subcutaneously. Subcutaneous darbepoetin alpha has a longer half-life compared with epoetin alpha (70 vs 24 hours), so dosing intervals can be longer.10,11 ESAs should not be started in patients with uncontrolled hypertension until the blood pressure is controlled, or in patients with an active malignancy unless the treatment is directly supervised by an oncologist.

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