Hyperhomocysteinemia, a new cardiovascular risk factor, occurs in 85–100% of patients with end-stage renal disease. The exact mechanism by which renal function is linked to plasma homocysteine has not been definitively established. There is reasonably good clinical evidence that hyperhomocysteinemia in itself does not cause renal insufficiency. Two, not mutually exclusive, hypotheses are that in renal failure: i) homocysteine disposal is impaired in the kidneys themselves and ii) extra-renal homocysteine metabolism is defective, possibly due to uremic toxins. Several methods have been applied to investigate kidney and whole-body sulfur amino acid metabolism in healthy subjects and in patients with different degrees of renal failure. Arteriovenous extraction studies have not found a significant homocysteine disposal in the human kidney. Methods to study whole-body homocysteine metabolism have included measurement of plasma metabolites, calculation of plasma homocysteine elimination after oral loading and the use of stable isotope techniques with methionine tracers. The results implicate a decreased homocysteine clearance instead of an increased production as the cause of hyperhomocysteinemia in renal failure, but the exact site of the impaired clearance remains controversial.
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