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Hyperhomocysteinaemia in chronic kidney disease: focus on transmethylation
Coen van Guldener1, Frank Stam, Coen D A Stehouwer
1Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands. Cvguldener@amphia.nl
Insights
In end-stage renal disease (ESRD), impaired transmethylation, not just high homocysteine, contributes to vascular disease risk. Folic acid treatment normalizes transmethylation, improving DNA methylation and gene expression in ESRD patients.
Area of Science:
- Nephrology
- Biochemistry
- Vascular Biology
Background:
- Hyperhomocysteinemia is common in end-stage renal disease (ESRD).
- The relationship between plasma homocysteine levels and vascular disease risk in ESRD patients is debated.
- High homocysteine may impair the transmethylation pathway, affecting protein repair and DNA methylation.
Purpose of the Study:
- To investigate the role of impaired transmethylation in vascular disease risk in ESRD patients.
- To determine the effect of folic acid treatment on transmethylation and DNA methylation in ESRD.
Main Methods:
- Utilized stable isotope techniques with labeled methionine to measure whole-body transmethylation flux.
- Assessed plasma homocysteine, S-adenosylhomocysteine (AdoHcy), and S-adenosylmethionine (AdoMet) levels.
- Evaluated DNA methylation status and gene expression alterations before and after folic acid treatment.
Main Results:
- Demonstrated decreased whole-body transmethylation flux in ESRD patients.
- Folic acid treatment restored transmethylation rates to normal.
- DNA hypomethylation and associated gene expression changes were significantly improved by folate therapy.
- Hyperhomocysteinemia persisted after folate treatment, suggesting impaired homocysteine clearance via transsulfuration.
Conclusions:
- Impaired transmethylation, rather than solely elevated homocysteine, may underlie adverse vascular effects in ESRD.
- Folic acid effectively normalizes transmethylation and improves DNA methylation in ESRD patients.
- Normalization of plasma homocysteine levels is not essential for restoring transmethylation function in ESRD.
Abstract:
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.
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