KDOQI Update 2000





A NORMOCYTIC, normochromic anemia is present in the majority of patients who have a reduction in kidney function.3 The same pathophysiology underlies this anemia in all such patients. In these guidelines, the term "chronic kidney disease" (CKD) is used to describe patients with chronically reduced kidney function, including those with chronic allograft dysfunction, and those in kidney failure who are dialysis dependent (administratively termed ESRD). When untreated, the anemia of CKD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization,4-8 increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure,9-14 decreased cognition and mental acuity,15 altered menstrual cycles,16-18 decreased nocturnal penile tumescence,19 and impaired immune responsiveness.20,21 In addition, anemia may play a role in growth retardation and decreased intellectual performance in pediatric patients.22,23 These abnormalities reduce quality of life24 and opportunities for rehabilitation of CKD patients and decrease patient survival.25

The primary cause of anemia in patients with CKD is insufficient production of erythropoietin (EPO) by the diseased kidneys.26 Additional factors which may cause or contribute to the anemia include: iron deficiency,27 either related to or independent of blood loss from repeated laboratory testing, needle punctures, blood retention in the dialyzer and tubing, or gastrointestinal bleeding; severe hyperparathyroidism28; acute and chronic inflammatory conditions29; aluminum toxicity30; folate deficiency31; shortened red blood cell survival32; hypothyroidism33; and hemoglobinopathies such as α-thalassemia.33 These potential contributing factors, if relevant, should be considered and addressed.

Recombinant human erythropoietin (rHuEPO) has been used in the treatment of the anemia of CKD since 1986.34,35 This recombinant hormone has been referred to by several names, including rHuEPO, EPO, Epoetin, Epoetin alfa, Epoetin beta, and erythropoietin. Epoetin alfa (manufactured by Amgen Inc, Thousand Oaks, CA; distributed in the United States as Epogen by Amgen, Inc, and as Procrit by Ortho Biotech, Johnson & Johnson) is the only approved recombinant human erythropoietin (rHuEPO) product available in the United States. In addition to Epoetin alfa, Epoetin beta, another rHuEPO product with similar pharmacologic effects, is available in other countries but not the United States. Clinical trials with both Epoetin alfa and Epoetin beta have been performed within and outside of the United States, and the clinical response to both has been similar. These guidelines for the management of anemia are based upon available literature for both products. Since these guidelines may be used outside as well as within the United States, the term "Epoetin," when used throughout the guidelines, should be assumed to apply to both Epoetin alfa and beta. Situations that apply only to Epoetin alfa are clearly indicated.

A new erythropoietin-like molecule, called NESP, or novel erythropoietic stimulating protein (manufactured by Amgen, Inc), is being used in clinical trials and as of July 2000 is being reviewed by the FDA. NESP is a glycoprotein similar to erythropoietin, but has 5 additional amino acids in its primary sequence and two extra N-linked carbohydrate side chains, giving it a longer plasma half-life. There have been no peer-reviewed clinical studies published about this molecularly engineered hormone prior to January 2000 when the structured literature review of this update was closed.

Iron is also essential for hemoglobin formation. The iron status of the patient with CKD must be assessed and adequate iron stores should be available before Epoetin therapy is initiated. Iron supplementation usually is essential to assure an adequate response to Epoetin in patients with CKD because the demands for iron by the erythroid marrow frequently exceed the amount of iron that is immediately available for erythropoiesis (as measured by percent transferrin saturation) as well as iron stores (as measured by serum ferritin). In most cases, intravenous iron will be required to achieve and/or maintain adequate iron stores. In the United States as of July 1999, the commercially available intravenous iron preparations consist of iron dextran, manufactured as INFeD by Watson Pharmaceutical, Inc, Nephrology Division (formerly Schein Pharmaceutical, Inc.) and as Dexferrum by American Regent Laboratories Inc and sodium ferric gluconate complex in sucrose (referred to in this text as iron gluconate), manufactured as Ferrlecit by R & D Laboratories and marketed by Watson Pharmaceutical, Inc, Nephrology Division (formerly Schein Pharmaceutical, Inc.). An additional intravenous iron preparation, iron sucrose (Venofer, manufactured by American Regent Laboratories, Inc), was approved by the FDA in November 2000. The molecular weights of the two iron dextran compounds differ, and they will be considered different compounds.

Effective treatment of the anemia of CKD improves survival,36 decreases morbidity,37,38 and increases quality of life.24,39 These 27 clinical practice guidelines, which cover the diagnosis, work-up, and management of the anemia of CKD, as well as possible sequelae related to its therapy, provide information that will help caregivers accomplish these goals. Unless otherwise specified, these guidelines, and their rationales, apply to all age groups.

The potential impact of these guidelines on aggregate use of Epoetin is unknown. For example, these guidelines recommend a higher target Hgb/Hct than is used in current practice and than has been recommended on the basis of an evaluation of evidence performed by Canadian nephrologists.40 All other things being equal, this recommendation would increase the amount of Epoetin required. On the other hand, the guidelines also have recommended maintenance of iron stores for the support of erythropoiesis that are greater than those maintained in current practice. This recommendation should produce an Epoetin-sparing effect. In addition, the guidelines recommend that Epoetin be administered by the subcutaneous (SC) route to most patients. This should provide an improved Hgb/Hct response for the same Epoetin dose, again producing an Epoetin-sparing effect. The likely net impact of these different effects is difficult to predict.

Some of the practices recommended in these guidelines are at variance with current policy of the Health Care Financing Administration (HCFA) and with information contained in the package inserts for Epoetin (Guideline 25) and iron dextran (Guideline 9). In these instances, the Anemia Work Group believes there is sufficient published scientific data to justify its recommendations. In most circumstances, recommendations contained in this document are based on evidence from the medical literature.

When recommendations are based on evidence, a rationale and supporting literature references are indicated. When recommendations are based on opinion in the absence of published evidence, the rationales for the recommendations are described. In some instances, however, recommendations are based in whole or in part on the opinion of the Work Group members. The evidentiary basis (published evidence, opinion, or both) for all recommendations is clearly indicated, along with the rationale (chain of reasoning) for each recommendation.

© 2001 by the National Kidney Foundation, Inc.





© 2001 National Kidney Foundation, Inc

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