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Non-iron pharmacologic adjuvants to erythropoiesis-stimulating agent therapy in dialysis patients

Jeffrey S Berns, MD
Section Editor
Steve J Schwab, MD
Deputy Editor
Alice M Sheridan, MD


Treatment with recombinant human erythropoietin (rHuEPO; epoetin) or darbepoetin alfa is effective in treating anemia in the vast majority of patients on dialysis. However, some patients are relatively resistant or "hyporesponsive" to epoetin. This may be defined as the failure to reach target hemoglobin (Hgb) or hematocrit (Hct) levels despite epoetin doses greater than 300 to 450 international units/kg/week in the absence of iron deficiency (and equivalent darbepoetin) [1,2]. Iron deficiency, either absolute or functional, and inflammation are the most common causes of an inadequate response to epoetin therapy. (See "Erythropoietin for the anemia of chronic kidney disease among predialysis and peritoneal dialysis patients" and "Erythropoietin for treatment of the anemia of chronic kidney disease in hemodialysis patients" and "Inflammation in renal insufficiency".)

In patients with chronic kidney disease (CKD), absolute iron deficiency is characterized by a serum ferritin concentration <100 ng/mL and transferrin saturation (TSAT) <20 percent. Functional iron deficiency is characterized by ferritin levels that are generally >500 ng/mL but with TSAT that is often <20 percent. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Iron balance in nondialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients".)

Similar iron indices (elevated serum ferritin with a low TSAT) are often also seen in patients with inflammatory processes associated with epoetin hyporesponsiveness. In such patients, other laboratory markers associated with the acute phase response that may be clinically useful include low (or falling) serum albumin levels and elevated level of C-reactive protein (CRP). While a CRP level diagnostic of inflammation-related epoetin hyporesponsiveness in dialysis patients has not been established, a level >20 mg/L would be very suggestive of an active, underlying inflammatory process [3,4]. (See "Inflammation in renal insufficiency" and "Anemia of chronic disease/inflammation".)

This topic review will address pharmacologic therapies other than iron that have been investigated as adjuvants to erythropoiesis-stimulating agent (ESA) therapy to either address epoetin hyporesponsiveness or otherwise enhance the response to epoetin and reduce its economic impact. The effect of dialysis adequacy, hemodialysis membrane composition, and different dialysis modalities will not be discussed herein.


A number of non-iron pharmacologic agents have been evaluated as adjuvants to ESAs. Although some have been suggested for use in patients who are "hyporesponsive" to epoetin, these agents have not been studied in hyporesponsive patients for the most part. These agents include L-carnitine, ascorbic acid, androgens, pentoxifylline, statins, and others.


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Literature review current through: Sep 2016. | This topic last updated: May 11, 2016.
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