Erythropoiesis stimulating agent resistance

Erythropoietin is produced by the kidney and stimulates growth and differentiation of red blood cells. Loss of this hormone production with renal failure is the major mechanism behind anaemia of chronic kidney disease (CKD). Severe anaemia is known to be associated with increased cardiovascular events and mortality in renal failure and thus the development of recombinant erythropoietin revolutionised the management of anaemia in CKD. Erythropoiesis stimulating agent (ESA) administration became widespread without randomised trial data to generate parameters for use. The use of these agents to minimise blood transfusions and correct severe anaemia is appropriate. Although observational data demonstrated that using ESAs to target normal haemoglobin and haematocrit was associated with improved outcomes, four large randomised trials demonstrated harm using these agents to aggressively correct anaemia. Subsequent analyses of these trials revealed that it may not have been the high haemoglobin per se that resulted in high adverse event rates, but rather the high doses of ESA required in a subset of patients. ESA resistance has emerged as an independent risk factor for morbidity and mortality in CKD patients and is an indicator of significant underlying comorbidity. Common causes of ESA resistance include iron deficiency, inflammation, infection, malnutrition, hyperparathyroidism and inadequate dialysis. Erythropoietin resistance as a risk factor for poor outcomes persists into transplantation, and thus the identification of this should prompt investigation and treatment for underlying causes. Treatment with ESA should be individualised to avoid excessive dosing or high haemoglobin. This review discusses the epidemiology, clinical sequelae and causes of ESA resistance. A suggested plan for the investigation and management of such patients is also provided