Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients

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Abstract
The role of hyperhomocysteinemia (HHcy) as a risk marker for cardiovascular diseases in renal patients is a matter of controversy. The remethylation of homocysteine (Hcy) to methionine in the kidneys is of great importance for Hcy clearance. Hcy remethylation is markedly decreased in patients on hemodialysis, but transsulfuration remains mostly unaffected. Markedly increased concentrations of methylmalonic acid (MMA), as a metabolic marker of vitamin B12 deficiency, have been found in approximately 70% of renal patients. This is in contrast to normal concentrations of vitamin B12 usually reported in such patients. We demonstrated in cell culture experiments that the uptake of vitamin B12 by mononuclear cells from renal patients was lower than that taken up by cells from controls. The lowering of MMA and Hcy concentrations in renal patients after B12 administration may indicate the presence of intracellular pre-treatment deficiency. We administered folic acid (5 mg) plus vitamin B6 (50 mg) and B12 (0.7 mg) three times per week intravenously to hyperhomocysteinemic dialysis patients. Hcy decreased after 4 weeks by 51%. Hcy was normalized in almost all patients, while serum concentrations of MMA and cystathionine were reduced by 28% and 26%, respectively. Cystathionine, an indicator for the transsulfuration pathway, showed a drastic increase in renal disease and was only slightly lowered by B-vitamin treatment. The increased cystathionine/cysteine ratio in renal patients indicates possible impairment of the catabolism of cystathionine by cystathionase. Moreover, renal failure is associated with severe abnormalities in plasma concentrations of S-adenosyl Hcy (SAH) and S-adenosyl methionine (SAM), as well as the SAM/SAH ratio. This ratio is an indicator of the availability of methyl groups from SAM. Therapeutic doses of B-vitamins in dialysis patients led to a limited improvement in the biomarkers of methylation and probably did not have a significant effect on transmethylation potential in the cells. Furthermore, elevated serum levels of asymmetric dimethylarginine (ADMA) in renal patients, which are associated with a poor outcome for such patients, could be lowered, but this effect was confined to patients who had no anemia. Future studies may consider extending the duration of vitamin treatment, as well as agents that may enhance the hydrolysis of SAH and cystathionine.