KDOQI Update 2000


V. Inadequate Epoetin Response


Ninety-six percent of patients will respond to Epoetin at 450 units/kg/wk IV (a dose expected to produce a comparable response to 300 units/kg/wk administered SC103) within 4 to 6 months, provided that there are adequate iron stores.65 Therefore, an inadequate response to Epoetin therapy is defined as failure to achieve target Hgb/Hct in the presence of adequate iron stores at a dose of 450 units/kg/wk IV or 300 units/kg/wk SC within 4 to 6 months, or failure to maintain target Hgb/Hct subsequently at that dose. However, since there is a wide variability in dose response to Epoetin, an individual patient may respond to as little as 75 units/kg IV (or 50 units/kg SC) per week.


Causes for Inadequate Response to Epoetin

The most common cause of an incomplete response to Epoetin is iron deficiency.

In the iron-replete patient with an inadequate response to Epoetin, the following conditions should be evaluated and treated, if reversible: (Evidence)

1. Infection/inflammation (eg, access infections, surgical inflammation, AIDS, SLE)

2. Chronic blood loss

3. Osteitis fibrosa

4. Aluminum toxicity

5. Hemoglobinopathies (eg, alpha and beta thalassemias, sickle cell anemia)

6. Folate or vitamin B12 deficiency

7. Multiple myeloma

8. Malnutrition

9. Hemolysis

Rationale Iron deficiency has been reviewed in Guidelines 5, 6, 7, and 8. A brief review of the other potential causes of Epoetin resistance outlined above follows. The general approach to treatment of patients refractory to Epoetin should include identification and reversal of potentially treatable causes of resistance. When the cause of Epoetin resistance is untreatable, either progressively increase the Epoetin dose in an attempt to reach or maintain the target Hgb/Hct, transfuse with red blood cells (see Guideline 23: Red Blood Cell Transfusions in Dialysis Patients with Chronic Renal Failure) or accept an Hgb/Hct below the target level.

The nine conditions listed in this guideline have been documented to be potential reasons for inadequate response to Epoetin therapy in the adequately dialyzed, iron-replete patient. Of these, the first four are the most commonly encountered in the dialysis patient. The other five are less common and should be considered only if the first four have been excluded.

1. Infection and inflammation can markedly impair responsiveness to Epoetin; responsiveness is usually restored upon resolution of the underlying problem.29,259,266-270 The differential diagnosis is extremely broad, encompassing all infectious disorders, including access infections, AIDS, rheumatologic disorders, and surgical inflammation (including vascular access surgery). In pediatric patients on CAPD, peritonitis may exert a protracted suppressive effect on the response to Epoetin.270 The pathophysiology of inflammatory reticuloendothelial blockage is gradually being elucidated and may relate to the inhibition of erythropoiesis, mediated by inflammatory cytokines, such as tumor necrosis factor and interleukin-1.267,268 An elevated C-reactive protein level, often associated with inflammation and/or infection, has been a predictor of resistance to Epoetin.271,272

2. Chronic blood loss, regardless of cause, results in iron deficiency and thus impaired Epoetin response.35 Blood loss should always be suspected in patients who require increasing doses of Epoetin to maintain a stable Hgb/Hct, in patients whose Hgb/Hct levels are falling, and in patients with failure to augment iron stores in the face of repetitive intravenous iron loading. The appropriate approach to the evaluation of this problem is addressed in Guideline 6: Target Iron Level, and Guideline 7: Monitoring Iron Status, and Guideline 8: Administration of Supplemental Iron.

3. Osteitis fibrosa impairs response to Epoetin by replacing active marrow erythroid elements with fibrosis. Although the best study does not demonstrate a statistically significant relationship between serum levels of intact parathormone (iPTH) and Epoetin dose, there is a direct relationship between the degree of fibrosis and the amount of Epoetin needed to maintain a stable Hct.273

4. Aluminum intoxication affecting the marrow can either prolong the treatment time required to reach the target Hgb/Hct or necessitate higher Epoetin doses, but has not been shown to cause absolute resistance to therapy.277-279

5. Hemoglobinopathies: Patients with sickle cell disease respond poorly to Epoetin therapy, even when high doses of Epoetin are used over long treatment periods. In hemoglobin SS and SC diseases, Epoetin results in release of reticulocytes containing predominantly hemoglobin S, with little if any increment in the more stable hemoglobin F.280-282 Both alpha and beta thalassemia may respond poorly to Epoetin. Alpha thalassemia is more common among Asians and those of Asian ancestry. Treatment of alpha thalassemia with Epoetin may increase Hgb slowly, with effective therapy usually requiring very high doses over a long period.283,284

6. Folate and vitamin B12 deficiency: Folic acid and vitamin B12 are essential for optimal Hgb synthesis. While most of the available literature suggests that effective Epoetin therapy does not require concomitant vitamin B12 and folate supplementation, the latter is water soluble and dialysate losses may exceed intake in poorly nourished patients. Therefore, loss of responsiveness to Epoetin requires investigation of cofactor adequacy.285-288 One study, however, suggests that concomitant folate administration improves Epoetin response.286 Specifically, this study suggests that even if folate levels are adequate at the inception of Epoetin therapy, macrocytosis and poor response will develop without continuous cofactor replacement.289 The presence of macrocytosis must be interpreted with caution, however, since Epoetin therapy is often associated with macrocytosis, due to shifting of immature (large) reticulocytes into circulation. Iron overload is also associated with macrocytosis.154

7. Multiple myeloma: Reports on the effectiveness of Epoetin treatment in this setting are few, contain small numbers of patients, and have variable results. Poor response (increases in Hgb from 5.9 to 6.2 g/dL) has been reported at doses of 125 units/kg/wk SC to 320 units/kg/wk SC in some patients,290 although others appear not to require transfusions on regimens of 120 to 140 units/kg/wk.291,292 The reason(s) for the varying effectiveness of these dosing schedules is unclear. Several reports have expressed concern over the potential for stimulation of malignant clone proliferation with chronic cytokine therapy (Endnote n).290,293 Despite this potential concern, Epoetin is not contraindicated in the treatment of the anemia of patients with myeloma kidney disease.

8. Malnutrition: Low serum albumin is associated with low Hgb among dialysis patients. About one third of CKD patients have low albumin. While malnutrition is common in this population, any acute or chronic inflammatory condition may result in a low serum albumin.294 The effect of nutritional status on Epoetin responsiveness in ESRD patients has received little attention.295 Theoretically, protein and/or calorie malnutrition may result in the unavailability of needed substrate for protein synthesis in hematopoietic cells.

9. Hemolysis: Dramatic resistance to Epoetin therapy has been documented in anti-Nform hemolysis in the setting of chronic formaldehyde exposure296 and with hemolysis resulting from multiple cardiac valve replacements.296

Other Potential Causes Angiotensin-converting enzyme inhibitors (ACE-I): There was initial concern that ACE-I would worsen the anemia of CKD because of its ability to diminish posttransplant erythrocytosis.297 Subsequent reports provide conflicting information: three suggest that there is no inhibition of Epoetin by ACE-I,298-300 whereas four brief reports and one recent study,305 in which no other cause of Epoetin-resistance could be determined, concluded that ACE-I did inhibit the action of Epoetin.301-304 The mechanism of action of such an effect, if present, is not known, but considerations include interference with native erythropoietin secretion,304 blunting of the effect of Epoetin, or direct inhibition of the erythroid marrow response to Epoetin. Patients receiving ACE-I who are treated with Epoetin should be monitored for possible resistance to therapy and the Epoetin dosage should be adjusted in order to sustain a stable Hgb/Hct. Malignancy may result in anemia. If malignancies other than myeloma (addressed above) develop, and are thought to decrease the efficacy of Epoetin therapy, larger amounts of Epoetin are appropriate, since in general, the anemia of cancer patients (with normal renal function), requires larger doses of Epoetin than the anemia of CKD to obtain an erythropoietic response.124


When to Obtain a Hematology Consultation

If Epoetin resistance occurs in the absence of the conditions listed in Guideline 20: Causes for Inadequate Response to Epoetin, a hematology consultation is recommended. (Opinion)

Rationale If all of the conditions listed in Guideline 20: Causes for Inadequate Response to Epoetin, have been excluded, determination of the cause of Epoetin resistance will likely require the expertise of a specialist in hematology.


Epoetin-Resistant Patients

Anemia in Epoetin-resistant patients should be treated in a manner similar to that in which dialysis patients were treated before recombinant human erythropoietin was available. (Opinion)

Rationale No therapy has been shown to be as effective as Epoetin in the treatment of the anemia of CKD. Other therapies have been shown to be either partially effective or ineffective, and many are associated with unacceptable side effects. While the following therapies have increased erythropoiesis in some dialysis patients not treated with Epoetin, there are insufficient data to support the conclusions that any of these therapies enhances the response to Epoetin when used as adjuvant agents in the Epoetin-resistant patient:

1. Carnitine: Reports suggesting that carnitine improves Epoetin response or permits reduction in its dose are anecdotal and involve only a few patients in each study.306-308 One study comparing the dose-response to Epoetin in carnitine-treated and placebo-treated dialysis patients showed an enhanced response to Epoetin in 7 of 13 carnitine-treated patients,309 whereas another study showed that only 8 of 19 patients might have had potentiation of Epoetin with carnitine administration, but iron supplementation might have been responsible for the improvement.310 More controlled trials are needed with carnitine before definitive recommendations for its use as an adjuvant therapy can be made (see also KDOQI guidelines on Nutrition).

2. Androgens: Studies designed to assess whether androgens enhance response to Epoetin are inconclusive (ineffective,311 effective312). Another recent study indicates that the erythropoietic response to androgens in males over 50 years of age with ESRD is as effective as that to Epoetin (6,000 units/wk) in males under 50 years of age and in females, and is less expensive than Epoetin therapy over 6 months.313 However, although androgen therapy may be less expensive than Epoetin, the risks and side-effects of primary androgen therapy alone,particularly in females, are unacceptable. The absence of convincing evidence of a clinical benefit associated with androgen therapy in combination with Epoetin argues against its use, particularly in light of the side effects.

3. Dialysis prescription; dialysis efficiency; hemodialysis with biocompatible membranes: This literature, too, is inconclusive. One report suggests that an inverse relationship exists between Epoetin dose and dialysis efficiency.314 A recent study reported that a higher delivered dose of dialysis improves Epoetin effectiveness.315 Its findings, however, are not convincing: the independent effects of higher Kt/V (small molecule clearance) on Epoetin response were not separated from those of biocompatible dialyzer membranes, the Epoetin treatment interval was short for the magnitude of response reported, and no control data were provided before the change in dialysis prescription was initiated. Another study reports that middle molecule clearance, not delivered dose measured by urea kinetic modeling, may enhance Epoetin responsiveness.316 Hemodialysis for 445 patients in Tassin, France in which middle and small molecule clearances were greater than that in most dialysis centers (24 hours per week with Kiil dialyzers using cuprophane membranes with a mean Kt/V of 1.67) resulted in a mean Hct of 28.1% in the absence of Epoetin therapy.317 While this is a higher mean Hct than that observed during the pre-Epoetin era in most dialysis centers that provided fewer weekly hours of hemodialysis, there are no data (as yet) showing that these patients now require less Epoetin to achieve higher Hct values than those treated at other dialysis centers. Whether the magnitude of the delivered dialysis dose, dialyzer membrane, or clearance of a specific surrogate solute has an effect on response to Epoetin in the patient who is not severely uremic remains unresolved and needs further investigation.




© 2001 National Kidney Foundation, Inc

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