Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations

Background. Hyperhomocysteinemia is a risk factor for atherosclerosis that is common in chronic renal failure (CRF), but its cause is unknown. Homocys teine metabolism is linked to betaine-homocysteine methyl transferase (BHMT ), a zinc metalloenzyme that converts glycine betaine (GB) to N,N dimethylg lycine (DMG). DMG is a known feedback inhibitor of BHMT. We postulated that DMG might accumulate in CRF and contribute to hyperhomocysteinemia by inhi biting BHMT activity. Methods. Plasma and urine concentrations of GB and DMG were measured in 33 dialysis patients (15 continuous ambulatory peritoneal dialysis and 18 hemo dialysis), 33 patients with CRF, and 33 age-matched controls. Concentration s of fasting plasma total homocysteine (tHcy), red cell and serum folate, v itamins B-6 and B-12, serum zinc, and routine biochemistry were also measur ed. Groups were compared, and determinants of plasma tHcy were identified b y correlations and stepwise linear regression. Results. Plasma DMG increased as renal function declined and was twofold to threefold elevated in dialysis patients. Plasma GB did not differ between groups. The fractional excretion of GB (FEGB) was increased tenfold, and FE DMG was doubled in CRF patients compared with controls. Plasma tHcy correla ted positively with plasma DMG, the plasma DMG:GB ratio, plasma creatinine, and FEGB and negatively with serum folate, zinc, and plasma GB. In the mul tiple regression model, only plasma creatinine, plasma DMG, or the DMG:GB r atio was independent predictors of tHcy. Conclusions. DMG accumulates in CRF and independently predicts plasma tHcy concentrations. These findings suggest that reduced BHMT activity is import ant in the pathogenesis of hyperhomocysteinemia in CRF.