Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in 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 of 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 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.
van Guldener
Coen
C
Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands. cvguldener@amphia.nl
Nanayakkara
Prabath W B
PW
Stehouwer
Coen D A
CD
D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood*; D014652:Vascular Diseases / Q000097:blood*
C487735:dimethylarginine; D006710:Homocysteine; D001120:Arginine