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  • Epoetin Alfa Resistance: Valuation of a Management Algorithm: DISCUSSION


The algorithm developed to guide the investigation and management of chronic dialysis patients with ssuspected epoetin alfa resistance was successfully used to manage 16 patients who did not achieve a target hemoglobin of 110 g/L with epoetin alfa for 3 consecutive months. With the use of the algorithm, these patients were managed in 1 of 5 ways. Patients with iron deficiency received intravenous iron or an increase in the oral iron dose. Dialysis efficiency was improved in patients receiving inadequate dialysis. Patients with a subcutaneous epoetin alfa dose greater than 300 IU kg-1 week-1 were investigated for possible causes of epoetin alfa resistance, such as hyperparathy- roidism, aluminum toxicity, infection, or inflammation. Patients with a subcutaneous epoetin alfa dose less than 300 units kg-1 week-1 were eligible for an increased dose with a standard epoetin alfa-dosing protocol.

The most commonly identified causes of epoetin alfa nonresponse included iron deficiency, a low epoetin alfa dose, and epoetin alfa resistance caused by hyperparathyroidism, chronic infection, inflammation, or dialysis inadequacy. Many patients had more than one suspected cause of nonresponse.

Although the algorithm was useful for guiding the investigation and management of the patients in the project, the following changes would improve the usefulness of the algorithm for patients who are nonresponsive to epoetin alfa. First, the distinction between epoetin alfa nonresponse and resistance is arbitrary. The KDOQI guidelines do not consider iron deficiency a cause of epoetin alfa resistance and imply that patients should receive subcutaneous epoetin alfa doses greater than 300 IU kg-1 week-1 for 4 to 6 months before other causes of resistance are investigated. Since iron deficiency seems to affect response at any epoetin alfa dose, this philosophy seems inappropriate. Second, since iron deficiency was the most common cause of epoetin alfa nonresponse in the patients in this project, its prominence in the algorithm should be increased. Finally, although dialysis inadequacy was frequently identified in the study patients, its importance in the algorithm should be reduced since it can be dealt with easily at the same time as other suspected causes of epoetin alfa nonresponse.
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Although the majority (62%) of patients were receiving intravenous iron, the most commonly identified cause of nonresponse to epoetin alfa was iron deficiency. The findings of this study concur with those of other studies that the most common cause of epoetin alfa nonresponse or resistance is iron deficiency. Since the KDOQI definition of epoetin alfa resistance was used, iron deficiency was not categorized as resistance. Iron deficiency in patients on chronic hemodialysis is characterized by ferritin concentrations less than 100 pg/L or transferrin iron saturation of less than 20%. Ferritin is also an acute-phase reactant and its concentration is elevated in patients with infection and inflammation. Therefore, under these circumstances, the use of ferritin to evaluate iron stores may be misleading. Iron supplementation is required in up to 90% of those treated with epoetin alfa. Use of oral iron salts, such as ferrous sulfate, in doses of 200 mg/day of elemental iron is recommended for initial therapy. For many patients, intravenous iron supplementation may be required.17 Iron, total iron-binding capacity, and iron saturation were assessed every 3 months in this study, and intravenous iron dextran or sucrose was actively prescribed for patients who did not respond to oral iron salts. Despite this, it seemed that many of the patients in the current study were still not receiving inadequate iron supplementation. This suggests that patients may rapidly develop iron deficiency, either because of inadequate supplementation or increased demand from erythropoiesis. More frequent assessment and evaluation of iron stores are likely required to identify and manage iron deficiency in these patients.

The benefits of intravenous iron include optimization of hemoglobin concentrations, reductions in epoetin alfa dose, and subsequent cost savings. However, the use of intravenous iron includes the risk of adverse effects such as hypotension, flushing, dizziness, fever, back pain, headache, myalgia, arthralgia, lymphadenopathy, iron overload, infection, and, rarely, anaphylaxis. The possible link between the use of intravenous iron and infection remains controversial. It has not been systematically examined. A retrospective review of United States Medicare claims from approximately 20 000 hemodialysis patients showed that patients receiving more than 17 vials (1700 mg) of iron dextran during a 6-month period had a significantly higher risk of death because of infection than those who did not receive iron. At the hemodialysis unit at St Paul’s Hospital in Saskatoon, Saskatchewan, patients are frequently given an iron-loading dose of 1 g, plus 5 monthly maintenance doses of 100 to 200 mg or maintenance doses greater than 300 to 400 mg monthly. These patients could be at risk for exacerbation of infection. Iron is believed to exacerbate infection by providing a substrate for bacterial growth and by inhibiting the optimal function of leukocytes. Until further evidence is available, it would be prudent to avoid giving intravenous iron to patients with chronic infections, such as osteomyelitis or tuberculosis, when recovery is expected to take several months. kamagra oral jelly 100mg

Localized or systemic infection and inflammation also indirectly cause epoetin alfa resistance by reducing iron delivery from reticuloendothelial cells. Reticuloendothelial blockade is likely caused by increased circulating levels of acute-phase reactants and cytokines such as C-reactive protein, tumour necrosis alfa, ferritin, and interleukins. Inflammatory and infectious disease processes that elicit an acute-phase response will result in reticuloendothelial block and decrease response to epoetin alfa. Hypoalbuminemia, a marker of poor nutritional status, is also a marker of the acute-phase response. In a study by Gunnell and others,29 hypoalbuminemia and elevated C-reactive protein were the most important predictors of epoetin alfa resistance in well-dialysed patients who were iron-replete. Until chronic infectious or inflammatory processes resolve, patients will exhibit epoetin alfa resistance. Therefore, for these patients, increasing the epoetin alfa dose is not recommended.

Hyperparathyroidism also seems to play a role in epoetin alfa resistance. Serum erythropoietin levels increase and the epoetin alfa dose decreases after subtotal parathyroidectomy in hemodialysis patients with severe secondary hyperparathyroidism. Epoetin alfa resistance in patients with secondary hyperparathyroidism seems to be related to bone marrow fibrosis. Although no correlation between epoetin alfa requirements and parathyroid hormone concentrations seems to exist, a correlation between the osseous effects of excess parathyroid hormone and epoetin alfa requirements has been demonstrated. Further, parathyroid hormone suppression with intravenous calcitriol results in improved response to epoetin alfa among patients with hyperparathyroidism.

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