Plasma reduced homocysteine concentrations are increased in end-stage renal disease

Background. Plasma total homocysteine (tHcy) concentrations >15 mu mol/L ar e associated with an increased risk of cardiovascular disease. This is espe cially the case in end-stage renal disease (ESRD), in which tHcy concentrat ions commonly range between 20 and 30 mu mol/L. Adverse vascular or prothro mbotic effects associated with hyperhomocysteinemia are assumed to be media ted by the free sulfhydryl (reduced) form of the molecule (rHcy), but data based on fluorescence high-pressure liquid chromatography (HPLC) indicate t hat rHcy concentrations are not increased in ESRD despite two- to threefold elevations in tHcy. Methods. We developed a sensitive method for measuring plasma rHcy concentr ations in which freshly drawn blood is incubated with sodium iodoacetate, a nd the resulting S-carboxymethylhomocysteine is analyzed by gas chromatogra phy mass spectrometry. Results. Unlike with the earlier methodology, we found plasma rHcy concentr ations two to four times higher than normal in ESRD. These concentrations w ere lowered by hemodialysis and were proportional to plasma tHcy over the r ange of tHcy concentrations that has been associated with increased cardiov ascular risk (r(2) = 0.39, P < 0.0001). Conclusions. These results support the hypothesis that homocysteine could d irectly mediate vascular disease through mechanisms related to the reactivi ty of its free sulfhydryl group. It remains to be determined how much of th e variability between plasma tHcy and rHcy is due to analytical variation a nd how much is due to biologic factors that separately influence concentrat ions of the disease marker, tHcy, and its presumed mediator, rHcy.