Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study

Mann, Johannes F.E.; Sheridan, Patrick; McQueen, Matthew; Held, Claes; Arnold, Jane; Fodor, George; Yusuf, Salim; Lonn, Eva

doi:10.1093/ndt/gfm485

Cited by 87 publications

(68 citation statements)

References 37 publications

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“…This initial stage of cardiomyopathy was completely prevented by the administration of the superoxide dismutase mimetic tempol, which abrogated oxidative stress. Although administration of folate did not provide benefit as expected on the basis of the hypothetical role of homocysteine (91,92), the issue may not yet be completely settled (93), and more sophisticated and specific medications to reduce oxidative stress remain a high priority.…”

Section: Attractive Areas For Future Investigationsmentioning

confidence: 98%

Cardiovascular Problems on Hemodialysis

Ritz

Bommer

2009

Clinical Journal of the American Society of Nephrology

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Section: Attractive Areas For Future Investigationsmentioning

confidence: 98%

Cardiovascular Problems on Hemodialysis

Ritz

Bommer

2009

Clinical Journal of the American Society of Nephrology

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“…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 …”

Section: Studymentioning

confidence: 99%

“…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)…”

Section: Studymentioning

confidence: 99%

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

et al. 2012

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The efficacy of homocysteine (Hcy)-lowering therapy in reducing the risk of CVD among patients with chronic kidney disease (CKD) remains controversial. We performed a meta-analysis to determine whether pooling the data from the few small randomised, controlled trials that address this topic would improve the statistical power of the analysis and resolve some of the inconsistencies in the results. Randomised, controlled clinical trials (RCT) were identified from MEDLINE, EMBASE, www.clinicaltrials.gov, the Cochrane Controlled Clinical Trials Register Database and Nephrology Filters. Independent extraction of articles was performed using predefined data fields. The primary outcome was relative risk (RR) of CVD, CHD, stroke and all-cause mortality for the pooled trials. A stratified analysis was planned, assessing the RR for cardiovascular events between the patients on and not on dialysis. Overall, ten studies met the inclusion criteria. The estimated RR were not significantly different for any outcomes, including CHD (RR 1·00, 95 % CI 0·75, 1·31, P ¼ 0·97), CVD (RR 0·94, 95 % CI 0·84, 1·05, P ¼ 0·30), stroke (RR 0·83, 95 % CI 0·57, 1·19, P ¼ 0·31) and all-cause mortality (RR 1·00, 95 % CI 0·92, 1·09, P ¼ 0·98). In the stratified analysis, the estimated RR were not significantly different for cardiovascular events regardless of dialysis or in combination with vitamin B therapy or the degree of reduction in Hcy levels. Our meta-analysis of RCT supports the conclusion that Hcy-lowering therapy was not associated with a significant decrease in the risk for CVD events, stroke and all-cause mortality among patients with CKD.Key words: CVD: Chronic kidney disease: Folic acid: Homocysteine-lowering therapy: Homocysteine: Meta-analyses CVD is the leading cause of mortality both among the general population and among patients with chronic kidney disease (CKD). The rate of mortality from CVD among patients on haemodialysis (HD) is 20-fold higher than that among the general population (1) , and impaired renal function per se is a very strong cardiovascular prognostic factor (2,3) . Therefore, much attention has been focused on managing risk factors to attempt to reduce the associated CVD risks, especially among patients with CKD. Elevated plasma total homocysteine (Hcy) has been proposed as a risk factor for cardiovascular morbidity and mortality in patients either with normal renal function or with CKD (4,5) . Among patients with CKD, plasma Hcy levels tend to increase with decreasing glomerular filtration rate (6) ; thus, hyperhomocysteinaemia may potentially further increase the risk of CVD in this special population. In the Cardiovascular Risk Extended Evaluation in Dialysis trial, investigators followed-up on 175 patients with kidney failure for 29 months and found that an increase in Hcy of 10 mmol/l was associated with a 20 % increased risk for CVD events (7) . In another study, Hcy was found to be a strong independent predictor of mortality among patients on HD with a 3 % increase in mortality for each 1 mmol...

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“…94 However, beneficial CV effects of homocysteine-lowering therapy by folate and vitamin B supplementation are still controversial. A metaanalysis has recently reported a 15% CV risk reduction in CKD patients receiving folate treatment (n=3386), 97 but results from other large clinical trials (n=619 and 2056) with folate and vitamin B therapy have been neutral, 98,99 with 1 study even reporting adverse CV outcomes.…”

Section: Evidence Of Adverse CV Effects Of Protein-bound Uremic Toxinsmentioning

confidence: 99%

Cardiorenal Syndrome

Lekawanvijit

Kompa

Wang

et al. 2012

Circulation Research

149

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Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate−induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.

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Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study

Abstract: Active treatment with B vitamins lowered homocysteine levels in participants with CKD but did not reduce cardiovascular risk.

Cited by 87 publications

References 37 publications

Cardiovascular Problems on Hemodialysis

Cardiovascular Problems on Hemodialysis

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

Cardiorenal Syndrome

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