By Jay Wish, MD
Patients with Chronic Kidney Disease (CKD) are at high risk for developing anemia. This article will help you understand what anemia means, why it is important to you, and what can be done to treat it most effectively.
What Is Anemia?
The blood contains two types of cells, white blood cells and red blood cells. White blood cells are involved in protecting the body against infection, and red blood cells carry oxygen from the lungs to the tissues throughout the body. The protein in red blood cells which combines with the oxygen and releases it to the tissues is called hemoglobin (hee-mah-globe-in). Anemia is a condition characterized by a decreased number of red blood cells below normal, leading to a decrease in the hemoglobin available to carry oxygen to the tissues. The amount of red blood cells present in the blood is typically measured by a test called the hematocrit (hee-mat-o-crit), which represents the percentage of volume of the blood that is occupied by the red blood cells. In other words, if 40 percent of one ounce of blood is occupied by red blood cells, then the patient is said to have a hematocrit of 40 percent. A better index of anemia is the hemoglobin level, which refers to the number of grams of hemoglobin that are present in 100 ml (about 1/10th of a quart) of whole blood. A general rule of thumb is that the hematocrit is approximately three times the hemoglobin level. A normal hematocrit level is 36 percent to 51 percent, and a normal hemoglobin level is 12 to 17. Normal men tend to have higher hematocrit levels than normal women because women have regular blood loss due to their menstrual cycles. Male hormones stimulate the bone marrow to produce more red blood cells than do female hormones. Anemia is defined as a hematocrit less than 42 percent or a hemoglobin level less than 14 in an adult man and a hematocrit less than 36 percent or a hemoglobin level less than 12 in an adult woman.
Red blood cells are produced in the bone marrow mainly under the influence of a hormone called erythropoietin (eh-rith-row-poy-eh-tin) (EPO). EPO is made primarily in the kidneys. When you develop kidney disease, the production of EPO by your kidneys goes down, leading to a decrease in the production of red blood cells by the bone marrow and resulting in anemia. As a rule, the severity of this anemia increases the more your kidney function declines, but there is a tremendous variability from patient to patient in terms of how severe their anemia is at any given level of kidney function (as measured by serum creatinine (cree-at-eh-nen) level or glomerular (glo-mer-yoo-lar) filtration rate). Once your kidney function falls below about one-third of normal (glomerular filtration rate less than 30 ml/min), it is very likely that you will develop some degree of anemia. The degree of anemia that you develop with chronic kidney disease may also be influenced by nutritional factors (adequate intake of the vitamins and minerals that are necessary for red blood cell production), blood loss (due to heavy menstrual periods, surgery, or other reasons), and other illnesses which may also contribute to anemia (such as lupus, HIV, and other chronic infections).
How Can I Tell If I Have Anemia?
Because your anemia tends to develop gradually as your kidney function declines, the symptoms of anemia may not be as noticeable compared to a patient with an equivalent degree of anemia whose hematocrit or hemoglobin has dropped suddenly. This is because the body tends to adapt to the anemia over time with changes in the ease with which hemoglobin releases oxygen to tissues and also changes in the circulatory system. As the rate of delivery of oxygen to the tissues falls with the lower hemoglobin level, the heart has to work harder in order to pump blood more rapidly to the tissues so that oxygen demands can still be met. Although this increase in blood pumping by the heart may delay the onset of symptoms related to the anemia, the muscle of the heart wall actually thickens in response to this increased strain, resulting in a condition called left ventricular hypertrophy (LVH). Studies have shown a high correlation between the presence of LVH in patients with CKD and subsequent outcomes such as hospitalization and mortality. Almost 80% of patients with CKD have LVH at the time that they start dialysis. Major risk factors for LVH are anemia and high blood pressure, so it is essential that, as a patient with CKD, you receive effective treatment for anemia and high blood pressure to minimize the risk of developing LVH.
The symptoms that you may develop as a result of anemia will depend upon the severity of the anemia, the severity of your kidney disease and the presence or absence of other illnesses. The most common symptoms of anemia are fatigue and a decreased ability to carry out physical activities. This usually starts as inability to perform activities which require heavy exertion, and then progresses such that even minimal physical activity produces fatigue. You may also notice that you become increasingly short of breath with heavy exertion, moderate exertion, and then with even minimal exertion. You may notice difficulty concentrating, inability to perform mental tasks that you were able to do in the past, or problems with your memory. You may lose interest in sex and have difficulty with sexual performance. If you already have heart disease, anemia may make the heart disease symptoms worse.
If any of these symptoms develop, you should contact your physician and request that a complete blood count be obtained if this has not already been done in the recent past. Since the cardiac complications of anemia may develop long before the you experience symptoms of the anemia, it is recommended that you have you blood counts monitored periodically so that the anemia can be diagnosed and treated before LVH develops and symptoms occur.
What Should Be Done Once the Diagnosis of Anemia is Made?
The first step in the evaluation of a patient with CKD and anemia is to determine whether the anemia is due to the kidney disease or due to something else. The most common cause of anemia in patients with CKD other than EPO deficiency is iron deficiency. A major source of dietary iron is red meat. Many patients with CKD avoid red meat for a variety of reasons and therefore may develop iron deficiency on that basis. Iron deficiency may also occur because of blood loss through menstrual periods, surgery, or gastrointestinal disease. Therefore, your iron levels should be checked with two laboratory tests called transferrin (trans-fair-in) saturation (TSAT) and ferritin (fair-it-in). If either of these is low, then your anemia may respond to oral or intravenous iron supplements. The most common oral iron supplement is ferrous (fair-us) sulfate, which must be given three times daily in order to provide an adequate dose to overcome iron deficiency.
Additional tests to evaluate anemia include reticulocytes (rye-tick-u-low-sites), B12, and folate levels. B12 and folate are two vitamins that are required for the production of new red blood cells and which may become deficient in patients with CKD if they do not eat a balanced diet. These vitamins can be supplemented if their levels are low. The reticulocyte test determines the percentage of young red blood cells in your blood, which can sometimes distinguish whether the anemia is due to inadequate production or the loss of red blood cells from the body. Most CKD patients will have a low reticulocyte count, reflecting a low production rate of red blood cells due to the deficient production of EPO by the diseased kidneys.
Since the major cause of anemia in CKD is EPO deficiency, it would make sense that the primary treatment for this condition is to administer EPO. Like insulin, EPO is a protein hormone and cannot be administered by mouth; it has to be given by an injection under the skin. One of the EPO products that is administered as a drug for patients with anemia due to CKD is chemically identical to the EPO that normal kidneys make, and its brand name is PROCRIT®. In most patients with anemia due to CKD, PROCRIT® can be administered as a single injection once every one to two weeks. More recently available is a newer EPO-like drug called Aranesp™, which represents a modification of the EPO molecule that appears to give it a longer duration of action, allowing some patients to require an injection of the drug less frequently. If you require the administration of EPO or an EPO-like drug to treat your anemia, you should discuss with your doctor whether PROCRIT® or Aranesp™ would be best for you.
What About Medical Insurance Coverage?
Because PROCRIT® and Aranesp™ are very expensive drugs (typical cost $100 per week or $400 per month), insurance reimbursement is often complicated. Medicare does not pay for prescription drugs except when administered in a healthcare facility. If you have Medicare coverage only, you will need to go to your doctor’s office or another type of healthcare facility in order to get EPO-type drug injections. Medicare requires that a patient have a hematocrit less than 33 or hemoglobin less than 11 and laboratory evidence of kidney disease before it will provide reimbursement for EPO-type drugs. In some states, Medicare also requires laboratory documentation of a decreased plasma EPO level before a CKD patient will qualify for EPO-type drug reimbursement. If you have medical insurance that includes coverage for prescription drugs, most plans including Medicaid, will reimburse for EPO-type drug administration in the home. You can learn how to inject the EPO yourself or the EPO can be administered by another trained individual. Most of these prescription plans require prior authorization to qualify for EPO-type drug reimbursement. This means that your physician’s office will need to complete some forms documenting your medical condition and need for EPO therapy before the insurance company will provide reimbursement to your pharmacy for the EPO. Many medical insurance plans will require that you have a blood test obtained monthly to confirm that your hematocrit and hemoglobin levels have not increased above the limit for EPO-type drug reimbursement. Ortho Biotech Products, L.P., the maker of PROCRIT®, maintains a “hot line” through which your healthcare provider can obtain information regarding insurance reimbursement for PROCRIT® therapy. The staff at the “PROCRITline” can verify whether your specific insurance plan provides coverage for PROCRIT® therapy and can identify alternate reimbursement sources as well. If your healthcare provider has concerns regarding your insurance coverage for PROCRIT® therapy, you should have the provider call the PROCRITline at 1-800-553-3851.
The target hematocrit range for CKD patients being treated with EPO-type drugs is 33 to 36. The target hemoglobin range is 11 to 12. Raising your hematocrit or hemoglobin from an anemic level requires the synthesis of new hemoglobin molecules which contain iron. Even if you are not iron deficient when you start EPO therapy, you may become iron deficient as your iron stores are depleted by the addition of your iron into new hemoglobin molecules. Therefore, most patients receiving EPO will require simultaneous iron therapy. In most patients with CKD, an oral iron supplement such as ferrous sulfate 325 mg three times daily is sufficient to meet the iron demands of new hemoglobin synthesis. However, in some CKD patients, the oral iron is poorly tolerated because of side effects or is ineffective in maintaining adequate body stores of iron. In such cases, intravenous iron administration may be required. If you are receiving EPO therapy, it is recommended that your iron levels be checked three or four times every year and you should discuss with your doctor whether you are receiving adequate amounts of iron supplements.
Summary
Most patients with CKD will develop anemia at some point as their kidney disease progresses. Many patients will not feel symptoms of anemia until well after it has been present long enough to cause LVH of the heart, which is an important risk factor for subsequent hospitalizations and mortality. Early treatment of anemia is recommended to prevent the development of LVH, minimize the development of anemia symptoms and improve your quality of life. In most patients with CKD, the anemia is due to EPO deficiency, and can be treated effectively with EPO-type drugs and iron supplements. As a patient with CKD, you should expect your doctor to obtain blood tests periodically to assess for the presence and severity of anemia, and you should discuss with your doctor the significance of those test results and the implications for therapy. Anemia is a complication of CKD that can be easily diagnosed and effectively treated. If you do develop anemia, treatment to maintain your hematocrit and hemoglobin within the target range will improve your quality of life for years to come.
Jay Wish, MD is a Professor of Medicine in the Division of Nephrology at the University Hospital in Cleveland . He is also a member of the AAKP Medical Advisory Board.
This article originally appeared in the March/April 2003 issue of Kidney Beginnings: The Magazine, Vol. 2, No. 1.
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