Managing anemia of chronic kidney disease (Proceedings)

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.

Immune Reactions To Epo In Vet Med

Antibody mediated pure red cell aplasia (PRCA) is associated with the production of neutralizing antibodies that rapidly reduce the biologic activity of both endogenous erythropoietin and rHuEPO. Patients that develop this disorder become refractory to exogenous and endogenous erythropoietin and are thus transfusion dependent. PRCA associated with the exogenous administration of rHuEPO is a rare condition in humans, with the exception of an "outbreak" of cases in 1999 in Europe associated with manufacturing changes of a single brand of rHuEPO.

The development of antibodies against exogenously administered erythropoietin is much more common in veterinary medicine; reported in up to 30% of treated patients. The nucleotide identity for erythropoietin is highly conserved among species, but it is not identical.9 Canine erythropoietin maintains an 85.7% homology with the human nucleotide sequence, while feline erythropoietin has an 86.7% homology. Although there is enough similarity to maintain clinical effectiveness, the differences in the amino acid sequence may promote antibody formation. In one study of dogs and cats with naturally occurring CKD, 2 of 3 dogs treated with rHuEPO for >90 days and 5 of 7 cats treated for >180 days developed refractory anemia that was attributed to anti-rHuEPO antibodies.10 A clinically significant immunologic reaction to rHuEPO has been reported to occur in 20-70% of treated veterinary patients.11 In some of the cases, stopping rHuEPO treatment and maintaining the patient with blood transfusions ± immunosuppressive therapy may allow for erythropoietic recovery. Although the antibody levels may decline over 2-12 months and the PCV can return to pre-treatment levels, the financial and logistic factors associated with repeat blood transfusions and persistent anemia often result in the death or euthanasia of the patient.12

Clinically, anti-rHuEPO antibodies should be suspected in any patient with an abrupt decline in PCV that cannot be attributed to blood loss, iron deficiency, vitamin deficiencies, infection or inflammation. There are no commercially available tests for the presence of antibodies, thus diagnosis of anti-rHuEPO antibody mediated anemia must be based on cytologic evaluation of the bone marrow showing a high myeloid:erythroid ratio, and the exclusion of other causes of anemia. Treatment with rHuEPO should be stopped if antibody production is suspected and the patient should be maintained with blood transfusions.

GUIDELINES FOR THE USE OF DARBEPOETIN IN VETERINARY PATIENTS

      1. The recommended dosage for darbepoetin is 0.45µg/kg SQ or IV.

      2. In general, darbepoetin is administered weekly until the target PCV is attained. Once the target PCV has been attained, the frequency of administration may be decreased to every other week, or longer, if the PCV is maintained.

      3. Target PCV's: Dog 30%, Cat 27%

      4. Judicious and frequent monitoring of the PCV is essential when using darbepoetin; it should not be administered to a patient without first checking a PCV.

      5. It is important to note that darbepoetin is supplied in a concentration of µg/ml, while rHuEPO (Epogen and Procrit) is supplied in IU/ml.

      6. As with rHuEPO, darbepoetin should only be used in patients that are iron replete. An iron panel should be checked to determine if iron supplementation is required. Routine supplementation of patients with iron is not recommended unless they are iron deficient due to the potential for oxidative stress associated with iron injections. Oral iron supplementation is seldom effective and should be avoided in dogs and cats due to frequent gastrointestinal upset.

      7. Blood pressure should be carefully monitored in patients treated with any erythropoietic stimulating protein.

      8. Adverse effects attributable to treatment with darbepoetin in humans are similar to those reported with rHuEPO, and include hypertension, pain at injection site, infection, myalgia, headache and GI signs.

REFERENCES

1 NKF, K/DOQI Am J Kidney Disease 2001;37:S182

2 Elliott J, et. al. J Smal Anim Pract 1998;39:78

3 Lulich JP, et. al. Compend Contin Educ Pract Vet 1992;14:127

4 DiBartola SP, et. al. J Am Vet Med Assoc 1987;190:1196

5 NKF, Am J Kid Dis 2001;37:S182-238

9 Wen D. et al. Blood 1993;82:1507

10 Cowgill L, et. al. J Am Vet Med Assoc 1998;212(4):521

11 Langston C et. al. Vet Clin Small Anim 2003 33;1245

12 MacLeod J, et. al. Am J Vet Res 1998, 59(9):114