Pathogenesis and prevention of cardiovascular disease in patients with chronic kidney disease

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is formed by methylation of arginine residues in proteins and released after proteolysis. In this reaction, S-adenosylmethionine is methyldonor and S-adenosylhomocysteine the demethylated product. ADMA and homocysteine are thus biochemically linked. Both plasma homocysteine and ADMA concentrations are increased in patients with renal dysfunction, probably as a result an impairment in their metabolic, but not urinary, clearance. Hyperhomocysteinemia has been associated with an increased risk of cardiovascular disease in end-stage renal disease, especially in patients without malnutrition and inflammation. Also plasma ADMA levels have been associated with cardiovascular disease in renal failure patients. Both homocysteine and ADMA are thought to mediate their adverse vascular effects by impairing endothelial, nitric-oxide-dependent function resulting in decreased vasodilatation, increased smooth muscle cell proliferation, platelet dysfunction and increased monocyte adhesion. At the same time, it has been shown that the correlation between plasma ADMA and homocysteine is weak and that, in renal patients, the association of plasma ADMA carotid intima-media thickness, cardiovascular events and overall mortality is independent of homocysteine. This indicates that the negative vascular effects of ADMA and homocysteine have a different etiology. Treatment with folic acid treatment substantially lowers homocysteine, but not ADMA concentration. So far, homocysteine-lowering therapy has not been very successful in decreasing cardiovascular disease. In patients with renal failure, ADMA reduction may be an interesting new goal in the prevention of cardiovascular disease. Introduction Cardiovascular disease is the leading cause of death both in the general population as in patients with end-stage renal disease (ESRD). However, mortality rates from cardiovascular disease are 10 to 30 times higher in ESRD than in the general population (1;2), suggesting that atherosclerosis is accelerated in ESRD. More recently, data have shown that patients with milder forms of chronic kidney disease (CKD) with an estimated GFR of 15-60 ml/min, also have an elevated risk of mortality and cardiovascular disease (3;4). The excess of mortality and cardiovascular events in ESRD and CKD patients is independent of traditional risk factors for atherosclerotic disease, such as hypertension, diabetes, smoking and hyperlipidemia (1-4). Alternative risk factors that may contribute to cardiovascular disease in renal failure include hyperhomocysteinemia and elevated plasma levels of asymmetric dimethylarginine (ADMA). Homocysteine Homocysteine is a sulfhydryl amino acid, which is formed by demethylation of methionine. S-adenosylmethionine is the intermediate in this reaction and serves as a universal methyl donor. Homocysteine is either remethylated to methionine or transsulfurated to cysteine. In plasma, about 80 percent of homocysteine is protein-bound. When it was found that patients with extreme hyperhomocysteinemia due to different genetic enzyme defects suffered from premature atherosclerosis and venous thrombosis, it was hypothesized that homocysteine was a direct vasculotoxic agent (5). Subsequently, it was shown that plasma homocysteine is strongly related to renal function and that virtually all ESRD patients have elevated homocysteine levels, probably due to decreased metabolic clearance (6). Pro-