At the start of treatment, patients receiving erythropoietin require fairly close monitoring every 2–4 weeks. As a minimum, the hemoglobin should be measured, there should be an assessment of iron status, and blood pressure should be checked.
HEMOGLOBIN
The desired rate of rise in hemoglobin should be of the order of 1 g/dL/month or 0.25 g/dL/week. Increments lower than this will result in excessively long periods for correction of the anemia, and rates faster than this may compromise patient safety in terms of adverse events. Ideally, the hemoglobin should be measured every 2 weeks until some idea of the rate of response is obtained; thereafter it is probably acceptable to monitor this every 4 weeks.
IRON STATUS
Research is still in progress and there is controversy over which tests of iron status should be used in patients receiving erythropoietin. Many such tests exist, all of which assess different parts of the iron metabolic pathway, and no one single test can be used to give a global picture of iron status. Thus, the serum ferritin gives an approximate indication of iron stores, the transferrin saturation assesses how much iron is circulating in plasma relative to the total iron-binding capacity (transferrin), and the percentage of hypochromic red cells has been advocated as the best means of assessing how much iron is being incorporated into the red cell. Iron stores are said to be normal or near-normal when serum ferritin maintained above 100 µg/L, the transferrin saturation above 20%, and the proportion of hypochromic red cells below 10%.
Iron deficiency is found in up to 40% of renal failure patients with erythropoietin therapy. There are two conditions representing inadequate iron status, namely absolute iron deficiency and functional iron deficiency. Absolute iron deficiency is present when the total body iron stores are inadequate, as judged by a low serum ferritin. Functional iron deficiency exists when there are ample or even increased iron stores, but these stores are unable to release their iron rapidly enough to satisfy the demands of the bone marrow for erythropoiesis. Both conditions will result in a suboptimal response to erythropoietin and will require aggressive iron supplementation. Renal failure patients require high iron availability to maximize use of exogenous erythropoietin and maintain satisfactory hematocrit.
Administration of oral iron is often inadequate in hemodialysis and peritoneal dialysis patients, and intravenous iron is often required. There are several IV iron preparations available, differing in molecular weights, degradation kinetics, availability profiles, and adverse effects, and various dosing regimens have been suggested. Frequent ‘‘low-dose’’ administration of 20–60 mg every dialysis session has been advocated in hemodialysis patients, but this is impractical for peritoneal dialysis patients who neither have ready vascular access nor are attending hospital regularly. In this latter group, larger infusions of 300–1000 mg of IV iron can be given every month or so. If constipation is seen in CAPD patients oral iron to be avoided and most patients suffer gastrointestinal side effects with oral iron supplementation.
BLOOD PRESSURE
Approximately 20–30% of patients receiving erythropoietin will develop hypertension requiring antihypertensive medication. Severe hypertension, resulting in seizures or encephalopathy, which was seen in the early days of erythropoietin use, is now very rare since lower-dosage regimens have been advocated. It is, however, still important to monitor blood pressure regularly aiming to keep this below 140/90 if possible. Fluid removal on dialysis and/or standard antihypertensive medication may be used for this purpose. It is unusual to have to stop erythropoietin therapy because of hypertensive problems, and this should be avoided if possible.
OTHER TESTS
- Monitoring of the reticulocyte count; allows a rapid and convenient way of assessing marrow erythropoietic activity.
- Measurements of serum CRP provide a guide to the degree of inflammatory activity, which can potently inhibit the response to erythropoietin.
- Monitoring serum PTH may help in assessing the severity of secondary hyperparathyroidism, which can also cause resistance to erythropoietin.
- In patients with the homozygous sickle-cell disease, HbS and HbF levels should be measured to reduce the risk of precipitating a sickle-cell crisis with overstimulation of the marrow.
POOR RESPONSE TO ERYTHROPOIETIN
More than 90% of dialysis patients will respond to erythropoietin with a hemoglobin rise of >1 g/dL/ month and an EPO dose of <200 U/kg/week. Patients failing to achieve this hemoglobin response and/or requiring higher doses of EPO are classed as ‘‘poor responders,’’ and many causes of resistance to erythropoietin. These include major factors, such as iron deficiency, blood loss, and infection/inflammation, as well as minor factors such as hyperparathyroidism (with marrow fibrosis), aluminum toxicity, Infection/Inflammation , vitamin B12/folate deficiency, hemolysis, marrow disorders, hemoglobinopathies, underdialysis, carnitine deficiency, poor nutrition, obesity/poor subcutaneous absorption, ACE inhibitors/angiotensin II blockers and erythropoietin antibodies.
- Patients with the inflammatory disease have increased activation of proinflammatory cytokines, such as IL-1α, TNF-α, and IFN-1γ, which have a suppressive effect on erythroid progenitor cell proliferation.
- Hyperparathyroidism has also been shown to inhibit erythropoiesis, there is some debate about whether this is a direct inhibitory effect of PTH on CFU-E growth or whether this is mediated via increased marrow fibrosis.
- Aluminum toxicity causes a microcytic anemia and erythropoietin resistance by inhibiting heme synthesis and iron utilization.
- Vitamin B12 and folate deficiencies are much less common than the iron deficiency in dialysis patients receiving erythropoietin, but both conditions are easily detected and treated.
- Hemolysis is often harder to detect, although a clue may be a high reticulocyte count in the absence of any rise in hemoglobin.
- Marrow conditions causing dyserythropoiesis, such as aplastic anemia or myelodysplastic syndrome, often cause a true resistance to erythropoietin, even at high doses.
- It is very difficult to obtain a rise in hemoglobin in homozygous sickle-cell patients receiving erythropoietin, the problem here is excessive hemolysis but patients show evidence of greatly enhanced erythropoiesis as measured by the reticulocyte count and HbS levels.
- Patients with other hemoglobinopathies such as α-thalassemia trait and β- thalassemia may also show a degree of resistance to erythropoietin, although this is usually not nearly as marked as in sickle-cell disease.
- More recently, underdialysis has been suggested as a cause of poor response to erythropoietin, and indeed increasing the dialysis prescription improved the hemoglobin response.
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