Cardio-renal-anemia syndrome: a link between erythropoietin, dimethylarginine and homocysteine.

Cardio-renal-anemia syndrome is a combination of heart failure, kidney failure, and anemia. Many advanced chronic kidney disease patients have both anemia and chronic heart failure. They have often hyperhomocysteinemia, high dimethylarginine values and low erythropoietin levels. Nephrologists treat advanced chronic kidney disease patients with erythropoiesis stimulating agents to improve anemia, renal and heart disease. Erythropoiesis stimulating agents, though considered essential to improve anemia in chronic kidney disease patients, have shown no significant protective effect on cardiovascular disease when used in large clinical trials targeting normal hemoglobin levels. It is possible that the high amounts of these drugs, given to reach normal hemoglobin values, may have counterbalanced the positive effect on endothelium obtained with low doses. Many studies have shown that erythropoietin improves endothelial function in animals with high dimethylarginine levels, lowering asymmetric dimethylarginine and increasing nitric oxide synthesis. Advanced chronic kidney disease patients have also high homocysteine levels which further reduce endothelial function by increasing asymmetric dimethylarginine. Homocysteine-lowering vitamin B treatment has been associated to a significant reduction of cardiovascular disease in advanced chronic kidney disease patients. Low doses of epoetin and B vitamins may improve cardiovascular morbidity by reducing asymmetric dimethylarginine and by increasing nitric oxide synthase activity. This review analyses the interaction between erythropoietin, dimethylarginine and homocysteine, and their role in cardio-renal-anemia syndrome.