Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease

Abstract

N 1969, MCCULLY 1 PROPOSED THAT high plasma total homocysteine concentration caused severe atherothrombotic disease and death in adolescents with homocystinuria. Folic acid, vitamin B 6 , and vitamin B 12 play critical rolesinthemetabolismofhomocysteine. 2 Treatment with large doses of folic acid, pyridoxine hydrochloride (vitamin B 6 ), and cyanocobalamin (vitamine B 12 ) lowered the homocysteine levels and dramatically reduced mortality in these patients. 3 In the last 30 years, numerous case-control and prospective studies have extended these findings to the general population and shown that high levels of homocysteine-albeit an order of magnitude lower than those in homocystinuria-are associated with vascular disease. [4][5][6][7] On a parallel track, laboratory researchhasdemonstratedthathomocysteine causes oxidative stress, injures vascular endothelium, and stimulates formation of thrombi in vitro and in vivo. 1,[8][9][10] Although epidemiologic studies have confirmedtheassociationbetweenhomocysteineandcardiovascularrisk,interven-tional studies designed to lower homocysteine levels have not shown a consistent benefit on clinical outcomes. Several randomized controlled trials of lowering homocysteine with folic acid and B vitamins failed to find a reduction of major See also p 1212 and Patient Page.

Homocysteine-lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta-analysis of randomised, controlled trials

“…2 -5. As noted, Jamison et al (20) reported myocardial infarction as the cardiovascular event. The RR estimated were not statistically significantly different for any outcomes.…”

“…For example, the plausibility of a link between the levels of Hcy and the risk of CVD was supported by a number of studies. (12) Folic acid: 5 mg/d or 5 mg, every other day 35·0 13·1 2 15·1 2 49·3 Righetti et al (14) Folic acid: 15 mg/d 27 13·0 2 2·4 2 8·9 Vianna et al (17) Folic acid: 10 mg, three times a week 23·5 15 2 10·5 2 44 Jamison et al (20) Folic Vit, vitamin.…”

“…Also, to the best of our knowledge, there are no studies that have determined a threshold value for Hcy level for effective prevention of cardiovascular events in the general population or in patients with CKD. Observational data in a meta-analysis show that a 25 % reduction in Hcy was associated with a 32 % lower risk of CVD among Study Righetti et al (16) Wrone et al (13) Righetti et al (14) Zoungas et al (12) Jamison et al (20) Nanayakkara et al (18) Vianna et al (17) Mann et al (19) House et al (21) Heinz et al (22) Overall 0·074931 …”

“…Wrone et al (13) Zoungas et al (12) Righetti et al (14) Jamison et al (20) Heinz et al (22) House et al (21) Overall 0·021215 women and a 15 % lower risk among men (29) . However, the reported decreases in Hcy levels vary substantially; and the ten papers in our meta-analysis reported a wide range of Hcy-lowering from 8·9 % to 53·8 %, which is consistent with the observed range of decrease in patients without CKD.…”

“…It has been proposed that the mutant TT genotype at nucleotide 677 of the gene regulating methylenetetrahydrofolate reductase activity is associated with increased Hcy levels and increased mortality in general and CKD populations. In the methylenetetrahydrofolate reductase TT group, the greatest reductions of Hcy concentration after folate Study Wrone et al (13) Righetti et al (14) Zoungas et al (12) Jamison et al (20) Mann et al (19) House et al (21) Heinz et al (22) Overall 0·297827 Heterogeneity: t 2 = 0·02; c 2 = 5·50, df = 3 (P = 0·14); l 2 = 45% Test for overall effect: Z = 0·87 (P = 0·39) Heterogeneity: t 2 = 0·04; c 2 = 8·75, df = 5 (P = 0·12); l 2 = 43% Test for overall effect: Z = 0·49 (P = 0·62) Heterogeneity: t 2 = 0·01; c 2 = 7·24, df = 6 (P = 0·30); l 2 = 17% Test for overall effect: Z = 1·86 (P = 0·06) Heterogeneity: t 2 = 0·10; c 2 = 5·63, df = 2 (P = 0·06); l 2 = 64% Test for overall effect: Z = 0·83 (P = 0·41) Heterogeneity: t 2 = 0·00; c 2 = 3·47, df = 4 (P = 0·48); l 2 = 0% Test for overall effect: Z = 1·56 (P = 0·12)…”