Homocysteine and methionine metabolism in ESRD: A stable isotope study

Background. Hyperhomocysteinemia has a high prevalence in the end-stage ren al disease (ESRD) population, which may contribute to the high cardiovascul ar risk in these patients. The cause of hyperhomocysteinemia in renal failu re is unknown, and therapies have not been able to normalize plasma homocys teine levels. Insight into methionine-homocysteine metabolism in ESRD is th erefore necessary. Methods. Using a primed, continuous infusion of [H-2(3)-methyl-1-C-13]methi onine, we measured whole body rates of methionine and homocysteine metaboli sm in the fasting state in four hyperhomocysteinemic hemodialysis patients and six healthy control subjects. Results. Remethylation of homocysteine was significantly decreased in the h emodialysis patients: 2.6 +/- 0.2 (SEM) VS. 3.8 +/- 0.3 mu mol(.)kg(-1.)hr( -1) in the control subjects (P = 0.03), whereas transsulfuration was not 2. 5 +/- 0.3 vs. 3.0 +/- 0.1 mu mol(.)kg(-1.)hr(-1) (P = 0.11). The transmethy lation rate was proportionally and significantly lower in the ESRD patients as compared with controls: 5.2 +/- 0.4 vs. 6.8 +/- 0.3 mu mol(.)kg(-1.)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 transsulfur ation is not. Decreased remethylation may explain hyperhomocysteinemia in E SRD. This stable isotope technique is applicable for developing new and eff ective homocysteine-lowering treatment regimens in ESRD based on pathophysi ological mechanisms.