Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure

Anemia is associated with exacerbation of both renal and cardiac disease. A considerable proportion of patients whose anemia is treated with erythropoietin do not respond, and the safety and efficacy of this therapy in people that have both chronic heart and kidney disease has not been proven. Overcoming erythropoietin resistance in this population must be predicated on understanding the processes that contribute to this state. These are reviewed here. Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function. Key Points Anemia is common in patients with chronic kidney disease and chronic heart failure, and is associated with a negative outcome Resistance to erythropoietin is a major cause of the anemia that affects patients with both chronic heart failure and chronic kidney disease Inflammation has a key role in resistance to erythropoietin Resistance to exogenous erythropoietin is associated with an increased risk of death in patients with chronic kidney disease