Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease.
BACKGROUND
The pathogenesis of hyperhomocysteinemia in end-stage renal disease (ESRD) is unclear. Folic acid lowers, but does not normalize, the plasma homocysteine level in patients with ESRD, but its effect on whole body metabolism of homocysteine is unknown.


METHODS
We studied the effect of 3 weeks of oral treatment with 5 mg folic acid per day on homocysteine metabolism in six chronic hemodialysis patients and six healthy controls. Primed, continuous infusions with [(2)H(3)-methyl-1-(13)C] methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation, and homocysteine transsulfuration. Metabolic homocysteine clearance was defined as the ratio of transsulfuration and plasma homocysteine level.


RESULTS
Folic acid treatment lowered plasma homocysteine significantly by 39% (95% CI 5 to 73) in the ESRD group, but plasma homocysteine remained higher than baseline values in the control group. In ESRD patients, homocysteine remethylation and methionine transmethylation rate increased by 34% (95% CI 5 to 62) and 22% (95% CI 5 to 39), respectively (i.e., levels that were similar to the baseline values of the control group). Transsulfuration rate and metabolic homocysteine clearance were not significantly altered by folic acid treatment in both the ESRD and the control group.


CONCLUSIONS
In ESRD patients, folic acid treatment lowers, but does not normalize plasma homocysteine, whereas homocysteine remethylation and methionine transmethylation increase to levels found in untreated healthy controls. These findings indicate a persistent, folate-independent, defect in metabolic homocysteine clearance in ESRD.
Stam
Frank
F
Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. f.stam@vumc.nl
van Guldener
Coen
C
Ter Wee
Piet M
PM
Jakobs
Cornelis
C
de Meer
Kees
K
Stehouwer
Coen D A
CD
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000628:therapy; D007700:Kinetics; D008297:Male; D008715:Methionine / Q000378:metabolism*; D008745:Methylation; D008875:Middle Aged; D006435:Renal Dialysis
D006710:Homocysteine; D005492:Folic Acid; D008715:Methionine