dimethylarginine and Cardio-Renal-Syndrome

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Topics: Aorta; Arginine; Autonomic Nervous System Diseases; Bone Diseases, Metabolic; Cardio-Renal Syndrome; Cardiovascular Diseases; Chronic Disease; Endothelium, Vascular; Glycation End Products, Advanced; Humans; Inflammation; Myocardial Infarction; Oxidative Stress; Phosphorus; Renal Insufficiency, Chronic; Toxins, Biological; Tunica Intima; Uric Acid; Vascular Stiffness; Vasculitis

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.

Topics: Anemia; Animals; Arginine; Cardio-Renal Syndrome; Erythropoietin; Homocysteine; Humans; Nitric Oxide Synthase; Vitamin B Complex