PHYSIOLOGY.

It has long been realized that hypoxia is a potent stimulus to red cell production. In human subjects, within a few hours of exposure to hypoxia, the reticulocyte count increases, denoting the presence of new red blood cells in the circulation; this is followed by an increase in the circulating red cell mass. This response is the result of the increased production of a glycoprotein, erythropoietin. The kidney is the major source of this hormone, although it is also produced in the liver, particularly in fetuses. Day-to-day production of erythropoietin depends on the partial pressure of oxygen (PO₂) of blood perfusing the kidneys. The target cells for erythropoietin are the colony-forming units–erythroid (CFU-E) cells in the bone marrow. Erythropoietin reacts with receptors on CFU-E cells, leading to increased production of proerythroblasts and release of more erythrocytes into the circulation (Fig. 18-1) (Erslev, 1991).

FIGURE 18-1 Feedback circuit that adjusts the rate of red cell production to the demand for oxygen. BFU-E, Burst-forming units–erythroid; CFU-E, colony-forming units–erythroid.

(Erslev AJ: N Engl J Med 324:1339, 1991.)

Healthy adults continuously secrete erythropoietin. Because hypoxia is the most important stimulus to erythropoietin production, a number of pathologic conditions affecting the kidney, particularly those that reduce renal blood flow, may increase the rate of erythropoietin release and inevitably increase red blood cell production. A few cases of erythropoietin-releasing tumors have been described in dogs with severe polycythemia.

One of the explanations for the nonregenerative anemia in dogs and cats with chronic renal failure is a decreased capacity to synthesize erythropoietin because of underlying disease, which results in a loss of erythropoietin-producing cells. The suppressed rate of red blood cell formation caused by lack of renal production of erythropoietin is a major problem in the treatment of patients with severe renal failure. Renal transplantation not only restores renal function to individuals with severe renal failure but also restores normal erythropoiesis.

BENEFITS OF SYNTHETIC ERYTHROPOIETIN.

Human erythropoietin has been cloned and represents one of the most successful products of recombinant deoxyribonucleic acid (DNA) technology. Recombinant human erythropoietin (rHuEPO; epoetin) is available for therapeutic use and has revolutionized the treatment of anemia in humans with chronic renal failure. Epoetin is virtually identical to human urinary erythropoietin; it has the same amino acid sequence but a slightly different glycosylation pattern. Most treated humans have reported dramatic improvement in their quality of life and sense of well-being as a result of correction of anemia. The benefits of improved exercise tolerance, appetite, strength, and cognitive abilities without the need for blood transfusions outweigh some of the risks associated with the use of rHuEPO.

Most experience with the use of rHuEPO in animals has been with epoetin-α (Epogen). Epogen is suspended in human albumin to prevent adherence to glass and does not contain a preservative. The structure of erythropoietin is well conserved across species lines. Both dogs and cats respond appropriately to administration of this synthetic hormone. When given to dogs or cats with chronic renal failure, rHuEPO causes a dose-dependent increase in the hematocrit and corrects anemia (Cowgill, 1990, 1995). A transient, moderate reticulocytosis is initially observed within the first week of therapy in most animals. The bone marrow myeloid:erythroid ratio decreases, illustrating the increased erythropoietic response. Some animals have a transient thrombocytosis during therapy. This response may be seen in some human patients as well, and it is not known whether this is a direct effect of the rHuEPO on megakaryocytes or a secondary effect caused by iron deficiency (Polzin et al, 1995). Correction of the hematocrit to low normal takes about 2 to 8 weeks, depending on the measurement when treatment was initiated and the dose administered. Most clients observe improved clinical status in their pets as the hematocrit increases. These changes include improved appetite, body weight, energy, and sociability (Cowgill, 1990).

DOSAGE AND ROUTE OF RHUEPO ADMINISTRATION.

Both intravenous and subcutaneous routes of administration of rHuEPO have been effective, and no difference has been seen in the percentage of patients that develop antibodies. Plasma concentrations persist longer after subcutaneous administration, which allows lower total doses to be given. Definitive dosing schedules are continuing to evolve. Currently, starting doses of 50 to 150 U/kg given subcutaneously three times per week are recommended (Polzin et al, 1995). Weekly monitoring should continue until a target hematocrit is achieved; that is, a packed cell volume (PCV) of 33% to 40% in dogs and 30% to 35% in cats. If a dog or cat has severe anemia (PCV <14%) but does not require transfusion, daily therapy with 150 U/kg may be preferred for the first week. In hypertensive animals or if the anemia is not severe, 50 U/kg three times weekly may prevent progressive increases in blood pressure or iron-deficient erythropoiesis.

When a hematocrit at the low end of the target range has been achieved, the dosing interval should be decreased to twice weekly. Most animals require 50 to 100 U/kg two to three times weekly to maintain red blood cell counts and PCVs in the target range. The dosage required, however, varies significantly among treated individuals, therefore chronic monitoring of the PCV is necessary for proper adjustment of the dose or dosing interval or both. If a dosage exceeding 150 U/kg three times weekly is required, the animal may have erythropoietin resistance. Because of the time lag between dose adjustment and the effect on the PCV, patience must be exercised so that the dose is not adjusted too frequently, resulting in rather unpredictable changes in the PCV and inability to find a stable dose. Avoiding iatrogenic polycythemia is important.

Because of the high demand for iron associated with stimulated erythropoiesis, patients treated with rHuEPO are at risk of exhaustion of iron stores. Oral iron supplementation, therefore, is recommended for all patients treated with rHuEPO, even if the pretreatment transferrin concentrations are normal.

ADVERSE REACTIONS TO RHUEPO

WHEN TO INITIATE rHuEPO THERAPY.

The prevalence of anti-rHuEPO antibodies in treated dogs and cats makes the decision process regarding when to initiate therapy quite important. Most recommend using the drug only when definitely necessary because once an animal develops the antibodies, the drug no longer has any value to that individual. When the hematocrit values are below 25% in dogs or 20% in cats, anemia probably contributes to the adverse clinical signs associated with chronic renal failure. These PCV guidelines usually can be used to judge the severity of anemia; however, the degree of azotemia, expected progression rate of chronic renal failure, appetite, willingness to eat therapeutic diets, and progression rate of the anemia should all be considered in the risk-benefit analysis of when to start therapy (Polzin et al, 1995). Because many pet owners consider quality of life of prime importance, the advantages and disadvantages of rHuEPO treatment should be discussed with owners when anemia appears to be contributing to the dog’s or cat’s deteriorating quality of life.