Hyperhomocysteinaemia almost invariably occurs in patients with
end-stage renal disease (
ESRD), but there is debate whether, within the group of
ESRD patients, higher or lower plasma
homocysteine concentrations are related to an increased risk of
vascular disease.
Homocysteine is thought to be vasculotoxic in high concentrations, but it may also lead to elevated levels of its precursor,
S-adenosylhomocysteine (AdoHcy), which is a potent inhibitor of the transmethylation pathway, in which
S-adenosylmethionine (
AdoMet) donates its methyl group to a variety of acceptors. Impairment of this transmethylation pathway in
ESRD patients has been suggested by high AdoHcy levels, decreased
AdoMet/AdoHcy ratios, decreased
protein repair requiring
methyltransferases, and by
DNA hypomethylation. Stable
isotope techniques using labelled
methionine have indeed demonstrated a decreased whole body transmethylation flux in
ESRD patients. These studies have also shown that
folic acid treatment is capable of restoring transmethylation rates to normal values. The remaining hyperhomocysteinaemia after
folic acid treatment in
ESRD is probably due to a persistent impairment of
homocysteine clearance through transsulphuration.
DNA hypomethylation with its concurrent alterations in gene expression is largely improved by
folate treatment. The adverse effects of hyperhomocysteinaemia in
ESRD may thus be related to impaired transmethylation. Normalisation of plasma
homocysteine does not seem to be required to restore transmethylation to normal levels in
ESRD patients.