Hyperhomocysteinemia and its relationship to cardiovascular disease in ESRD: Influence of hypoalbuminemia, malnutrition, inflammation, and diabetes mellitus

Abstract

Background: In the general population, a mildly elevated plasma total homocysteine (tHcy) level is an independent and graded risk factor for cardiovascular disease (CVD). In patients with end-stage renal disease (ESRD), CVD is highly prevalent and a major cause of premature mortality, and plasma tHcy levels are as much as three to four times greater than in the general population. Several other risk factors, such as diabetes mellitus (DM), inflammation, and malnutrition, also are prevalent and contribute to CVD in patients with ESRD, and there are strong associations between inflammation, malnutrition, and hypoalbuminemia in these patients. Several investigations in patients with ESRD have shown the important role of vitamin status for plasma tHcy, but little attention has been given to the influence of nutritional status. However, it is obvious that hypoalbuminemia is of interest because a substantial fraction of tHcy (>70%) is protein bound, mainly to albumin. Results: In studies of patients with ESRD in whom the prevalence of hyperhomocysteinemia was very high (>90%), tHcy level was strongly related to serum albumin level, and patients with malnutrition had lower levels of both tHcy and serum albumin than those with normal nutritional status. Furthermore, inflammation, DM, and CVD are associated with hypoalbuminemia and therefore a lower degree of hyperhomocysteinemia. In our studies, in different groups of patients with ESRD, we showed that greater tHcy levels were associated with lower CVD mortality. However, this apparently paradoxical association between lower CVD mortality and lower plasma tHcy levels (although still abnormally high) does not refute the concept that hyperhomocysteinemia is a risk factor for CVD because almost all patients may have had long-standing elevated plasma tHcy levels within a range that makes them prone to develop atherosclerosis. Instead, a potentially detrimental effect of hyperhomocysteinemia on CVD in patients with ESRD may be obscured by the influence of hypoalbuminemia, whatever the cause, because hypoalbuminemia and its causes are strong predictors of mortality. Conclusion: Our findings imply that nutritional status and serum albumin level, as well as the presence of inflammation and DM, should be taken into consideration when evaluating tHcy as a risk factor for CVD in patients with ESRD. Am J Kidney Dis 41(S1):S89-S95. © 2003 by the National Kidney Foundation, Inc.