Managing anemia in patients with chronic kidney disease - Veterinary Medicine
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Managing anemia in patients with chronic kidney disease
Anemia reduces quality of life in cats and dogs with renal disease. Erythropoiesis-stimulating agents, iron supplementation, gastrointestinal protectants, and other treatments may help.


VETERINARY MEDICINE


MINIMIZING BLOOD LOSS TO HELP PREVENT ANEMIA

The frequent blood sampling of hospitalized patients, especially small pets, can contribute to anemia. Pediatric blood tubes that require a smaller volume of blood for optimal blood-to-anticoagulant ratio may minimize blood loss from sampling.

Treating gastrointestinal ulceration with sucralfate (0.25 to 1 g orally every six to eight hours), histamine-2 receptor antagonists (famotidine at 0.5 mg/kg orally or intramuscularly once a day, or given intravenously over 5 minutes once a day; ranitidine at 1 mg/kg orally, intramuscularly, or intravenously twice a day), or a proton pump inhibitor, such as omeprazole (0.5 to 1 mg/kg orally once a day), may mitigate gastrointestinal blood loss.

TREATING ANEMIA

Erythropoiesis-stimulating agents

Recombinant human erythropoietin can be administered to supplement endogenous erythropoietin to stimulate red blood cell production in patients with kidney disease. An erythropoiesis-stimulating agent (ESA) should be considered when an animal displays clinical signs of anemia (lethargy, decreased appetite, tachycardia, pale mucous membranes) or when its packed cell volume (PCV) or hematocrit decreases below a certain threshold that is considered detrimental to general well-being. At the Animal Medical Center, we consider a PCV < 20% in cats and dogs as a threshold for treatment.

Human erythropoietin is a 30,400-dalton glycosylated protein that contains a 165 amino acid-residue backbone. Erythropoietin has a half-life of about six to 10 hours.19 Recombinant human erythropoietin has an identical amino acid sequence to the natural hormone in people.20,21 Canine erythropoietin shares an 81.3% homology with the amino acid sequence of human erythropoietin, while feline erythropoietin shares an 83.3% homology.22-24 The relative conservation of amino acid sequence allows recombinant human erythropoietin products to have clinical activity in animals.

Recombinant human erythropoietin. Several recombinant human erythropoietin products exist, such as epoetin alpha (Epogen—Amgen, Procrit—Centocor Ortho Biotech, Eprex—Janssen) and epoetin beta (NeoRecormon—Roche), and their degree of glycosylation differs.25 Their glycosylation affects their renal clearance, thus changing the required frequency of administration needed to achieve the same clinical efficacy.19,20


Table 2: Key Points About Erythropoesis-Stimulating Agents
Recombinant human erythropoietin products are typically given three times a week during induction therapy (Table 2) in cats and dogs. Protocols vary, but a starting dose of 100 U/kg per administration is recommended until the PCV reaches the low end of the target range. At the Animal Medical Center, we recommend a target PCV of 25% in cats and 30% in dogs. A response is usually seen within three or four weeks. Once the target range is attained, an average maintenance dose of 50 to 100 U/kg once or twice weekly is adjusted based on PCV monitoring. Iron therapy during recombinant human erythropoietin therapy is also recommended to ensure adequate functioning of the ESA (see "Iron" below).

Darbepoetin alfa. Darbepoetin alfa (Aranesp—Amgen), a hyperglycosylated recombinant human erythropoietin analogue, was developed based on the hypothesis that adding carbohydrate chains would result in a molecule with a longer circulating half-life.26,27 By increasing the half-life, the ESA molecule could be given at a reduced dosing frequency. Preclinical studies of darbepoetin administration in dogs demonstrated a greater than threefold increase in half-life (25 hr vs. 7.2 hr) and a correspondingly reduced mean clearance rate (2.4 ml/kg/hr vs. 8.4 ml/kg/hr) when compared with erythropoietin.28 Extensive studies of people with CKD receiving darbepoetin as therapy to correct renal anemia have indicated effective erythrogenesis.28

Darbepoetin doses of 0.45 and 0.75 μg/kg/week (subcutaneously or intravenously) have been demonstrated to provide optimal responses in 60% to 70% of human patients.28,29 Optimal response is defined as a hemoglobin increase of 1 to 3 g/dl over the first four weeks. No recognized effective dosages are available for companion animals, and to our knowledge, only one veterinary report describing darbepoetin administration in a dog exists.30


1. Algorithm to troubleshoot persistent anemia (below PCV range) while using darbepoetin.
Veterinarians at the Animal Medical Center have been using darbepoetin as the primary ESA therapy for renal disease anemia in dogs and cats for many years with good success. Based on our experience, we recommend a starting dose of 1 μg/kg once a week until the target PCV is attained and then decreasing the frequency of administration to every two or three weeks (Table 2). On average, a response is expected within two to three weeks (Figure 1). Once an administration frequency of every three weeks is achieved, we lower the dose to 0.45 μg/kg every three weeks or the lowest dose that maintains an adequate PCV. In our experience, potential serious adverse reactions seem to occur less frequently with darbepoetin than with human recombinant erythropoietin products.

Canine and feline recombinant erythropoietin. Canine recombinant erythropoietin is a promising molecule for dogs with CKD but, unfortunately, is not commercially available. It has been shown to stimulate erythrocyte production in clinically normal dogs and without the serious adverse effects, such as pure red cell aplasia, seen with the administration of recombinant human erythropoietin products.31 Feline recombinant erythropoietin has also been developed, but recent studies demonstrated that pure red cell aplasia incidence was not significantly reduced compared with the incidence in cats receiving recombinant human erythropoietin.32

Patient monitoring during ESA therapy. We recommend monitoring the PCV at every administration of darbepoetin and at least once weekly in animals receiving recombinant human erythropoietin products (Table 2). PCV monitoring is important for adjusting therapy to avoid overdosing complications, such as erythrocytosis and hyperviscosity. In addition, to ensure adequate bone marrow stimulation, a reticulocyte count should be submitted weekly until the patient is in the maintenance phase of therapy, and then a reticulocyte count should be done monthly. Blood pressure should also be assessed as hypertension is one of the most common side effects of ESA therapy or can be a result of CKD.


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Source: VETERINARY MEDICINE,
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