Homocysteine, a new crucial element in the pathogenesis of uremic cardiovascular complications

Most large observational studies available today establish that moderate hy perhomocysteinemia, either genetically or nutritionally determined, is an i ndependent risk factor for myocardial infarction, stroke, and thromboemboli c disease. This is also true for chronic renal failure patients, who exhibi t a high prevalence of hyperhomocysteinemia (85-100%), which reaches high p lasma concentrations (20-40 mu M, while control values range between 8 and 12 mu M). After a renal transplant, homocysteine levels decrease, but tend to be higher than normal. The cause of hyperhomocysteinemia in renal failur e is still obscure, since recent data have questioned the previous notion t h at a net homocysteine renal extraction and/or excretion take place in man . No matter the cause of its increase, the sulfur amino acid homocysteine i s thought to induce an increment in cardiovascular risk through three basic biochemical mechanisms: (1) homocysteine oxidation, with H2O2 generation; (2) hypomethylation through S-adenosylhomocysteine accumulation, and (3) pr otein acylation by homocysteine thiolactone. The final result is membrane p rotein damage, endothelial damage, and endothelial cell growth inhibition, among other effects. Hyperhomocysteinemia, in general, is susceptible of th erapeutic intervention with the vitamins involved in its metabolism. Depend ing on the cause, vitamin B-6, vitamin B-12, betaine, and/or folic acid can be effectively utilized. Chronic renal failure patients benefit from folic acid in high dosage: 1-2 mg are usually not effective ('relative folate re sistance'), while 5-15 mg reduce homocysteine levels to a 'normative' range (<15 mu M) in a substantial group of patients. Good results are also obtai ned in transplant patients, best with a combination of folic and vitamin B- 6. The results of the interventional trials focusing on the possible reduct ion in cardiovascular risk after homocysteine-lowering therapy, both in the general population and in end-stage renal disease, are expected soon, as w ell as the genetic and biochemical studies in suitable models, with the aim to clarify the cause-effect link suggested by the numerous observational a nd basic science studies.