Managing anemia of chronic kidney disease (Proceedings)

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Managing anemia of chronic kidney disease (Proceedings)

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Aug 01, 2010

ANEMIA OF CHRONIC KIDNEY DISEASE

Anemia is a common clinical finding in both human and veterinary patients with chronic kidney disease (CKD). Anemia has been reported as a clinical complication in 80-90% of human dialysis patients,1 and in 32-65% of cats with CKD.2-4 The underlying cause of the anemia of CKD is multifactorial. Although factors such as gastrointestinal blood loss, reduced red blood cell survival, deficiencies in iron and/or folate, cytokines and inflammatory mediators may be involved, the primary contributing factor to the anemia of CKD is an inadequate production of erythropoietin by the kidneys. Erythropoietin is a glycoprotein hormone that regulates red blood cell generation and is produced in the peritubular interstitial cells of the kidney in response to a decrease in tissue oxygenation.

Recombinant human erythropoietin (rHuEPO), epoetin alfa (Epogen®, Procrit®, Eprex®) has been available for the treatment of the anemia of CKD since 1985. In humans with CKD, rHuEPO is an effective and well tolerated treatment for anemia with over 90% of treated patients responding.5 However, a major drawback of treatment with rHuEPO, is its relatively short half –life. Although rHuEPO may be effective in some patients when administered in large dosages once a week, many patients require 3 times a week dosing, often requiring frequent visits to health centers for parenteral administration. The limitations of the short half-life of rHUEPO in human medicine lead to the development of darbepoetin alfa (Aranesp®). Structural differences may make darbepoetin less immunogenic, while the longer half-life means that it may be administered less frequently than rHuEPO while maintaining the same level of clinical effectiveness.

DEVELOPMENT OF DARBEPOETIN

Erythropoietin is a 165 amino acid polypeptide chain that is glycosylated at four positions; with each of the carbohydrate chains terminating in a number of negatively charged sugar molecules (sialic acid). The exact number of sialic acid residues on a molecule of erythropoietin may vary, up to a maximum of 14. As the number of sialic acid residues increases, the affinity for the erythropoietin receptor in vivo decreases. However, increased sialic acid residues also prolongs the terminal elimination half-life, overcoming the lower receptor affinity and resulting in greater biological activity in vivo.

Recombinant human erythropoietin (rHuEPO), epoetin alfa (Epogen®, Procrit®, Eprex®) has been available for the treatment of the anemia of CKD since 1985. In humans with CKD, rHuEPO is an effective and well tolerated treatment for anemia with over 90% of treated patients responding.5 However, a major drawback of treatment with rHuEPO, is its relatively short half –life. Although rHuEPO may be effective in some patients when administered in large dosages once a week, many patients require 3 times a week dosing, often requiring frequent visits to health centers for parenteral administration. The limitations of the short half-life of rHUEPO in human medicine lead to the development of darbepoetin alfa (Aranesp®).

The direct relationship between the degree of sialylation of rHuEPO and its biologic activity lead to the development of several analogs with additional N-linked glycosylation sites. Darbepoetin was one of the few analogs that retained the correct protein conformation for binding and activation of the receptor. The amino acid sequence of darbepoetin differs from that of erythropoietin at 5 sites, allowing for 2 additional N-linked glycosylation sites and up to 8 additional sialic acid residues.6 These additional sialic acid residues confer approximately a 3-fold increase in serum half-life and greater in vivo potency, requiring less frequent administration to obtain the same biological response.