The Effect of Homocysteine-Lowering Therapy on Vascular Endothelial Function in Chronic Renal Insufriciency

Homocysteine is a reactive sulfur-containing amino acid formed as an intermediary in the catabolism of the essential amino acid methionine. It has long been known that patients with certain genetic errors in homocysteine metabolism have very high total homocysteine levels (100 450 pinol/L), and that these patients suffer from premature arterio sclerosis and consequent cardiovascular events (1). The role of mild to moderate homocysteine elevation (-15-100 pmol/L) in the pathogenesis of cardiovascular disease in those without such genetic defects remains to be defined. Several large, prospective observational cohort studies have demonstrated that patients with moderately elevated homocysteine levels have an increased risk of cardiovascular disease compared to controls (2,3). This association has been shown, with some exceptions, to be independent of known cardiovascular risk factors and therefore it has been suggested that elevated homocysteine may be a novel risk factor for cardiovascular disease. Indeed, at the cellular level homocysteine has been implicated in endothelial injury, platelet activation, smooth muscle proliferation, oxidative modification of low-density lipoproteins, and in endothelial-leukocyte interactions (4). Large-scale clinical trials are now underway to assess the effect of homocysteine lowering on the primary and secondary prevention of cardiovascular events (5). However, their enrollment has begun in a period where widespread folic acid fortification of cereal grains has been undertaken by the governments of the U.S. and Canada with the intention of preventing neural tube defects in the newborn (6,7). This will almost certainly reduce the statistical power of these studies (10) by diminishing the prevalence of mild hyperhomocysteinemia (>13 ~tmol/L) in the study population by 50% according to one population-based analysis (8). Comparing folate supplementation against a background of population-wide dietary supplementation will make achieving significant homocysteine reductions more difficult as well as make less probable a significant difference in outcomes among treatment arms. Patients with chronic renal insufficiency, end-stage renal disease, and who are recipients of renal transplants compose a population exposed to dietary folic-acid fortification that retain an excess prevalence of hyperhomocysteinemia (9,11). This is a population that is also disproportionately stricken by cardiovascular. disease (11). This "high-risk" group clearly has an excess burden of traditional cardiovascular risk factors (i.e. diabetes, hypertension, dyslipidemia), but this only partially explains their excess prevalence of events (12). Elucidation of the roles of renal-specific cardiovascular risk factors including anemia, proteinuria, elevated thrombogenic factors and homocysteine is an area of active investigation. Confounding the research into a causal role for homocysteine and cardiovascular events in chronic renal failure is that serum total homocysteine levels are inversely proportional to glomerular filtration rate (13), perhaps reflecting renal metabolism rather than excretion (13). Elevated homocysteine in this population m ight be conceived of as a benign epiphenomenon reflecting merely the degree of renal dysfunction rather than an independent risk factor. A large-scale randomized placebo controlled homocysteine lowering trial whose primary endpoint would be cardiovascular events would help resolve this question. Endothelial dysfunction is the primary process in atherogenesis and both in vitro and in vivo studies have suggested that this may be the mechanism of homocysteine-induced vascular injury (4). Hyperhomocysteinernia has been associated with impaired endothelial-dependent vasodilation (14), which is a prevalent finding in chronic renal insufficiency (12), and a recent study of patients with known CAD randomized to homocysteine lowering therapy for 12 weeks had improvement in this parameter (15).