It is estimated that 32% to 65% of cats with CKD develop anemia as their disease worsens, and that as end-stage kidney disease approaches, almost all of these animals will develop anemia.1-3 Chronic anemia affects the body negatively in a number of ways and decreases an animal's quality of life. Thus, it is important to recognize renal anemia in cats and dogs so the appropriate therapy may be implemented and the treatable causes of anemia corrected.
Anemia is defined as a state of deficient mass of circulating red blood cells and hemoglobin that results in reduced oxygen delivery to the body's tissues and organs and leads to a decrease of the body's metabolic functions. Anemia triggers numerous adaptive response mechanisms because of a lack of adequate oxygen delivery to the tissues, some of which may be detrimental in the long term. In people, for example, chronic anemia leads to an increased heart rate and stroke volume with reduced systemic vascular resistance to maintain adequate tissue oxygenation and may ultimately lead to ventricular hypertrophy.4
Erythrogenesis is mainly controlled by the production of the hematopoietic growth factor erythropoietin in response to anemia.5,6 Erythropoietin is produced primarily in the peritubular interstitial cells of the inner renal cortex and outer medulla in the kidney.5-7 The main stimulus for erythropoietin synthesis is renal hypoxia, which stimulates the erythropoietin gene within the kidneys.8-10 The main site of erythropoietin action is the bone marrow, where it binds to its receptor expressed on the surface of red blood progenitor cells and leads to increased production.7
Uremia is known to decrease red blood cell survival, but the pathophysiology is unclear and most likely multifactorial.13 Low-grade hemolysis of red blood cells increases as uremia progresses.14 An unidentified uremic toxin is suspected of affecting the red blood cell lifespan.14 In addition, there may be premature clearance of red blood cells by the reticuloendothelial system.15
Uremia causes a platelet dysfunction that can lead to a bleeding diathesis. Many potential reasons contribute to this platelet dysfunction, including the retention of small substances normally eliminated by functioning kidneys that affect platelet function, vascular abnormalities and damage caused by uremia toxins, changes in platelet responsiveness and function, changes in platelet-endothelial interactions, increased concentrations of nitric oxide (a potent platelet antagonist) in uremic states, and dysregulation of the coagulation factors responsible for normal platelet function.16,17
CKD and uremia also predispose animals to gastrointestinal bleeding, with subsequent blood loss; melena is not always clinically evident when chronic low-grade bleeding is present. Gastrin elimination by the kidneys is decreased as renal disease progresses, resulting in increased hydrochloric acid release and hyperacidity in the stomach. Cats with CKD have elevated serum gastrin concentrations.18
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.
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
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
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.
Iron is necessary for hemoglobin and red blood cell formation and function. It is advisable to administer iron at the start of ESA therapy and with continued ESA usage to ensure adequate response.19 Iron can be supplemented orally or parentally. Oral iron, such as ferrous sulfate compounds, tends to be less effective, is not well absorbed in the gastrointestinal system, and tastes bitter; hence, many animals reject oral iron. Recommended dosages are 100 to 300 mg/day for dogs (providing 20 to 60 mg of elemental iron) and 50 to 100 mg/day for cats (10 to 20 mg of elemental iron). Certain oral liquid multivitamins, such as Pet-Tinic (Pfizer Animal Health), contain about 14 mg of iron per teaspoon. Iron tablets contain anywhere from 35 to 100 mg of iron.
Intramuscular iron dextran given every three or four weeks may be a better alternative. Dosages are typically 50 mg/cat and 10 to 20 mg/kg for dogs. Iron dextran administration may be painful, and iron dextran should not be given intravenously as there is a risk of anaphylaxis. Although intramuscular administration is considered safe, a low risk of anaphylaxis exists with this administration route, as well.33
Iron sucrose is used extensively in people and is given intravenously, but no reports exist of its use in animals.
Patient monitoring during iron therapy. Submit an iron panel (serum iron and ferritin concentrations, total iron-binding capacity, % transferrin saturation) before and one month after starting iron therapy and every three months after that to estimate iron stores and prevent overdosing. The lack of adequate iron stores is an important reason for ESA failure.34 However, aggressive administration of iron products may potentially cause oxidative stress.35 Thus, judicious use is recommended.
Transfusion of whole blood or packed red blood cell preparations is indicated when there is acute blood loss or when a patient demonstrates clinical signs of anemia that require rapid correction. However, disadvantages of blood transfusions include the possibility of immune reactions, incompatibility, the limited availability of blood products, the reduced lifespan of infused blood products in a uremic patient, the associated costs, and the lack of long-term effectiveness of these products.3
Oxyglobin (OPK Biotech) is a hemoglobin-based oxygen carrier used in place of whole blood or packed red blood cells.36 Its main indication is for temporary oxygen-carrying capacity. Oxyglobin must be used with caution as fluid overload is possible because of its high colloid oncotic pressure. The cost is a limiting factor, and the effects are short-lived. Oxyglobin is unavailable at this time, and it is unclear if the product will return to the market.
B vitamins, such as vitamin B12, folic acid, niacin, and vitamin B6, are important for erythrogenesis. Supplementation is recommended in polyuric patients; however, the contribution of vitamin supplementation to the overall correction of anemia is minimal.
The administration of anabolic steroids such as nandrolone or stanozolol is not recommended because of the lack of efficacy for correcting anemia and the high risk of liver toxicosis in cats.37,38
The administration of ESAs can create a number of complications in people, cats, and dogs, such as iron deficiency, hypertension, arthralgia, fever, seizures, polycythemia, and pure red cell aplasia. In people, darbepoetin has a similar adverse event profile to that of recombinant human erythropoietin.28
In people using ESA medications, hypertension is reported in 23%, cerebrovascular disorders in less than 1%, seizures in 2%, and pure red cell aplasia in less than 1%.39 In one study on the use of recombinant human erythropoietin for the management of anemia in cats and dogs with renal failure, hypertension was an adverse event with recombinant human erythropoietin administration in 40% to 50% of dogs and cats.19,40 In our experience, similar percentages are seen in dogs and cats receiving darbepoetin therapy. Hypertension secondary to ESA therapy can be managed with a calcium channel blocker (amlodipine orally at 0.625 mg per cat or 0.1 mg/kg in dogs) or an angiotensin-converting enzyme inhibitor (benazepril or enalapril orally at 0.5 mg/kg once daily). Blood pressure and creatinine concentration should be rechecked one week after starting therapy.
Pure red cell aplasia in people, cats, and dogs is caused by the production of neutralizing antierythropoietin antibodies that cross-react with all ESAs, as well as with endogenous erythropoietin.41 It is characterized by severe, nonregenerative anemia with an almost complete lack of bone marrow red blood cell precursors. The antibodies can remain in the body for more than eight months, and all patients become transfusion-dependent.3 Antierythropoietin antibodies are directed against the protein backbone, so although the amino acid sequence is about 85% identical, the lack of complete homology is thought to be the cause of the increased rate of pure red cell aplasia in animals compared with the rate in people. Pure red cell aplasia seems to occur at an incidence of 25% to 30% in dogs and cats receiving human-derived ESA.40,42 In our experience, the occurrence of pure red cell aplasia seems to be much lower with darbepoetin administration than with recombinant human erythropoietin, with a frequency of less than 10%. Pure red cell aplasia is difficult to treat and can last for many months. Treatment involves stopping therapy with ESAs, administering blood transfusions as needed, and possibly beginning immunosuppressive therapy with prednisone and cyclosporine or other immunosuppressive drugs.43,44
ESA TREATMENT FAILURE
Failure to reach the target PCV with ESA treatment can be caused by a number of factors, such as iron deficiency, anemia of chronic inflammation, concurrent illnesses, infections, hemorrhage from gastrointestinal erosions or ulcers, bone marrow failure or fibrosis, and pure red cell aplasia (Figure 1). Thus, it is important to diagnose and treat concurrent diseases and monitor for evidence of pure red cell aplasia.
Renal disease anemia is multifactorial in its pathogenesis. It is important to recognize it so adequate treatment may be instituted, as quality of life and metabolic function may be decreased as a consequence of worsening anemia. Multiple therapies are available; however, administering ESAs and eliminating other potential causes of anemia seem to be the most efficient long-term therapies.
Serge Chalhoub, DVM, DACVIM*
Cathy Langston, DVM, DACVIM
The Animal Medical Center
510 East 62nd St.
New York, NY 10065
*Dr. Chalhoub's current address is Charleston Veterinary Referral Center, 3484 Shelby Ray Court, Charleston, SC 29414.
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