Plasma Reduced Homocysteine and Other Aminothiol Concentrations in Patients With CKD

Sjöberg, Bertil; Anderstam, Björn; Suliman, Mohamed E.; Alvestrand, Anders

doi:10.1053/j.ajkd.2005.09.032

Cited by 26 publications

(25 citation statements)

References 36 publications

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“…Previous studies showing a lowered reduced-to-total Hcy ratio and an increased percentage of protein-bound Hcy in hemodialysis patients compared with healthy subjects [5, 10, 11] support the above hypothesis. However, a high reduced-to-total Hcy ratio and a low percentage of protein-bound Hcy were recently found in the same patients, the discrepancy with previous data being tentatively ascribed to confounding factors, such as vitamin supplementation or smoking [29]. In any case, whatever the actual thiol/disulfide ratio of Hcy, because the redox status of bulk plasma thiols is definitely altered in hemodialysis patients (this study and [19,20,21]) and membrane proteins may be uniquely sensitive to extracellular thiol redox status [17], an alternative – although speculative – explanation for our findings might be that the thiol-directed pro-oxidant activity of uremic plasma influences the uptake of low-MW aminothiols by affecting the related membrane transport mechanisms.…”

Section: Discussionmentioning

confidence: 45%

Homocysteinemia Correlates with Plasma Thiol Redox Status in Patients with End-Stage Renal Disease

et al. 2008

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Background/Aims: In end-stage renal disease (ESRD), hyperhomocysteinemia is a common finding associated with increased cardiovascular risk. However, the pathogenic role of homocysteine is still unclear. In vitro studies show that thiol redox status affects endothelial cell functions. We therefore investigated the possible association between homocysteinemia and plasma thiol redox status in ESRD patients. Methods: Total plasma homocysteine (Hcy), cysteine (Cys) and free thiols (SH) were measured both before and after a dialytic session in 54 ESRD patients receiving (n = 15) or not receiving (n = 39) folate supplementation, and 17 control subjects. Results: High predialysis levels of both Hcy and Cys were found to be negatively correlated with low SH levels both in supplemented (r = –0.680, p < 0.01 and r = –0.624, p < 0.02, respectively) and unsupplemented (r = –0.698, p < 0.001 and r = –0.445, p < 0.01, respectively) patients. Following dialysis, SH values returned to normal and the above correlations were no longer appreciable. Conclusion: A strong, folate therapy-insensitive association between homocysteinemia and plasma free thiol levels was found in ESRD patients. These results support a role for oxidative stress in ESRD-related hyperhomocysteinemia and suggest the plasma thiol redox status alteration as a possible pathogenic mechanism underlying the cardiovascular toxicity of hyperhomocysteinemia in these patients.

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Section: Discussionmentioning

confidence: 45%

Homocysteinemia Correlates with Plasma Thiol Redox Status in Patients with End-Stage Renal Disease

et al. 2008

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“…This increased cardiovascular morbidity and mortality is present across the whole renal dysfunction spectrum, even in patients with moderate renal insufficiency. The high risk of cardiovascular disease seems to be the consequence of a higher prevalence of risk factors in patients with CKD than in the general population [7,8,24,25,29]. Atherosclerosis is a diffuse arterial disease triggered in response to various insults such as dyslipidemia, which is very prevalent in CKD patients and is the main cause of cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

“…This is mainly characterized both by low levels of HDL and increased levels of triglycerides and LDL [27,28]. Moreover, CKD patients are characterized by high plasma Hcy levels [7,8] which are also linked to a higher cardiovascular disease risk and mortality [8,9]. Hcy is a reactive thiol amino acid and one of the hypothesis (‘molecular target hypothesis’) proposed for Hcy pathogenesis is its ability to bind either to protein Cys residues or cleave accessible protein disulfide bonds, thereby modulating the structure and function of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…In chronic kidney disease (CKD) patients, high plasma homocysteine (Hcy) levels are commonly present [7,8], usually in the moderate-intermediate range, and have been linked to higher cardiovascular disease risk and mortality [8,9]. The possible mechanisms through which increased Hcy levels exert a toxic effect in CKD are as follows: oxidation, nitrosylation and DNA and protein hypomethylation [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

Zinellu

Loriga²,

Scanu³

et al. 2010

Am J Nephrol

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Background: Since low-density lipoprotein (LDL) S-homocysteinylation has been recently reported to enhance atherogenicity of lipoprotein, we have investigated the levels of homocysteine (Hcy) linked to LDL in chronic proteinuric patients in which lipid abnormalities highly contribute to the excess of morbidity and mortality. Methods: We used capillary electrophoresis to measure LDL-bound thiol Hcy, cysteine (Cys), cysteinylglycine (Cys-Gly), glutathione (GSH), and glutamylcysteine (Glu-Cys) in 30 chronic kidney disease (CKD) individuals and 60 healthy volunteers. Results: We found more elevated levels of total plasma Hcy, Cys, GSH and Glu-Cys in patients than in controls and also found that Hcy and Cys bound to LDL were significantly increased in nephropathic subjects. By multiple linear regression, we found that in healthy people, total Hcy was the most important determinant of LDL-bound Hcy and Cys-Gly was negatively associated with apoB-Hcy concentrations. In CKD the most important determinant of homocysteinylation was creatinine while total plasma Hcy is weakly associated with apoB-Hcy. Conclusions: The increased levels in Hcy-LDL observed in CKD patients might account, at least in part, for the excess of cardiovascular risk; thus LDL S-homocysteinylation can be considered a key marker of risk for cardiovascular disease in these individuals.

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“…The free reduced form of homocysteine typically only comprises less than 3% of the total plasma homocysteine level, yet it is likely the component most injurious to endothelium. The ratio of reduced to total homocysteine level increases dramatically in kidney failure and may be a more sensitive measure of effectiveness of homocysteine-lowering therapy and cardiovascular risk (21).…”

Section: Possible Reasons For Lack Of Benefit In Interventional Studiesmentioning

confidence: 99%

Homocysteine lowering and cardiovascular disease risk: Lost in translation

Marcus

Sarnak

Menon

et al. 2007

Canadian Journal of Cardiology

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E levated plasma total homocysteine has been proposed as a risk factor for cardiovascular morbidity and mortality. The public health implications of homocysteine as a cardiovascular risk factor are particularly far-reaching, because homocysteine can be lowered effectively, inexpensively and safely by treatment with folic acid and other B vitamins. In patients with chronic kidney disease (CKD), homocysteine levels rise and cardiovascular risk increases as glomerular filtration rate declines, raising the question of whether hyperhomocysteinemia may be responsible, in part, for the high cardiovascular disease burden in this population. The reasons for increased homocysteine levels in CKD are not entirely understood, but probably relate to decreased renal clearance and metabolism of homocysteine.In the present paper, the following are reviewed: possible biological mechanisms underlying the role for homocysteine as a cardiovascular risk factor; observational studies examining the association between elevated homocysteine and cardiovascular risk in the general population and in patients with CKD; interventional studies of homocysteine-lowering therapy; possible reasons for the largely negative results from these trials; and the ongoing trials of homocysteine-lowering therapy.Pathophysiology of cardiovascular risk from elevated homocysteine levels Hyperhomocysteinemia is believed to promote atherogenesis and atherothrombosis via several mechanisms ( Figure 1) (1).Homocysteine metabolism generates reactive oxygen species that can directly injure the endothelium. Homocysteine has been shown to inhibit nitric oxide synthase activity, leading to endothelial dysfunction. Other proatherogenic mechanisms attributed to hyperhomocysteinemia include dysregulated methylation of proteins and DNA resulting in abnormal vascular smooth muscle cell proliferation, as well as increased lipid peroxidation.Observational studies of homocysteine levels and cardiovascular disease Data from observational studies examining the association between elevated homocysteine levels and cardiovascular morbidity and mortality in the general population have been inconsistent. Homocysteine was an independent risk factor for all-cause mortality in the Physicians' Health Study (2). Male physicians with the highest 5% of homocysteine levels demonstrated a five-year RR of 3.4 for acute myocardial infarction (MI) or death due to coronary disease compared with subjects with the lowest 90% of homocysteine levels. Two meta-analyses of observational data demonstrated a similar association. Wald et al (3) evaluated 20 prospective studies and concluded that lowering homocysteine concentrations by 3 μmol/L decreased the risk of ischemic heart disease by 16% and stroke by 24%. A second meta-analysis of 18 retrospective and 12 prospective studies (4) determined that a 25% reduction in homocysteine Studies of the general population have suggested that high homocysteine levels are associated with cardiovascular morbidity and mortality. In chronic kidney disease, homocys...

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Plasma Reduced Homocysteine and Other Aminothiol Concentrations in Patients With CKD

Cited by 26 publications

References 36 publications

Homocysteinemia Correlates with Plasma Thiol Redox Status in Patients with End-Stage Renal Disease

Homocysteinemia Correlates with Plasma Thiol Redox Status in Patients with End-Stage Renal Disease

Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

Homocysteine lowering and cardiovascular disease risk: Lost in translation

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