Hyperhomocysteinaemia in chronic kidney disease: focus on transmethylation.
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.
van Guldener
Coen
C
Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands. Cvguldener@amphia.nl
Stam
Frank
F
Stehouwer
Coen D A
CD
D000818:Animals; D002908:Chronic Disease; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000378:metabolism*; D007674:Kidney Diseases / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D008745:Methylation; D014652:Vascular Diseases / Q000378:metabolism