Homocysteine and methionine metabolism in ESRD: A stable isotope study.
BACKGROUND
Hyperhomocysteinemia has a high prevalence in the end-stage renal disease (ESRD) population, which may contribute to the high cardiovascular risk in these patients. The cause of hyperhomocysteinemia in renal failure is unknown, and therapies have not been able to normalize plasma homocysteine levels. Insight into methionine-homocysteine metabolism in ESRD is therefore necessary.


METHODS
Using a primed, continuous infusion of [2H3-methyl-1-13C]methionine, we measured whole body rates of methionine and homocysteine metabolism in the fasting state in four hyperhomocysteinemic hemodialysis patients and six healthy control subjects.


RESULTS
Remethylation of homocysteine was significantly decreased in the hemodialysis patients: 2.6+/-0.2 (SEM) vs. 3.8+/-0.3 micromol. kg(-1)x hr(-1) in the control subjects (P = 0.03), whereas transsulfuration was not 2.5+/-0.3 vs. 3.0+/-0.1 micromol. kg(-1) x hr(-1) (P = 0.11). The transmethylation rate was proportionally and significantly lower in the ESRD patients as compared with controls: 5.2+/-0.4 vs. 6.8+/-0.3 micromol. kg(-1) x hr(-1) (P = 0.02). Methionine fluxes to and from body protein were similar.


CONCLUSIONS
The conversion of homocysteine to methionine is substantially (approximately 30%) decreased in hemodialysis patients, whereas transsulfuration is not. Decreased remethylation may explain hyperhomocysteinemia in ESRD. This stable isotope technique is applicable for developing new and effective homocysteine-lowering treatment regimens in ESRD based on pathophysiological mechanisms.
van Guldener
C
C
Department of Internal Medicine, Vrije Universiteit, Amsterdam, The Netherlands. c.vanguldener@azvu.nl
Kulik
W
W
Berger
R
R
Dijkstra
D A
DA
Jakobs
C
C
Reijngoud
D J
DJ
Donker
A J
AJ
Stehouwer
C D
CD
De Meer
K
K
D000328:Adult; D000368:Aged; D002247:Carbon Isotopes; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology; D016022:Case-Control Studies; D003903:Deuterium; D005260:Female; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D007700:Kinetics; D008297:Male; D008715:Methionine / Q000378:metabolism*; D008745:Methylation; D008875:Middle Aged; D006435:Renal Dialysis; D012307:Risk Factors
D002247:Carbon Isotopes; D006710:Homocysteine; D008715:Methionine; D003903:Deuterium