Cardiovascular morbidity and endothelial dysfunction in chronic haemodialysis patients: is homocyst(e)ine the missing link?

Kunz, Kristian; Petitjean, Philippe; Lisri, Mohamed; Chantrel, Frances; Koehl, C.; Wiesel, Marie-Louise; Cazenave, Jean‐Pierre; Moulin, B.; Hannedouche, Thierry

doi:10.1093/ndt/14.8.1934

Cited by 59 publications

(50 citation statements)

References 40 publications

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“…Hyperhomocysteinemia has been shown to be another risk factor for thrombosis and cardiovascular problems, but its specific role in the pathogenesis of thrombotic complications remains unknown [36]. Our results are consistent with these previous findings and suggest that hyperhomocysteinemia may contribute to hypercoagulability in children undergoing dialysis.…”

Section: Discussionsupporting

confidence: 92%

A prospective study of the prevalence of heparin‐induced antibodies and other associated thromboembolic risk factors in pediatric patients undergoing hemodialysis

et al. 2006

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Heparin, which is used at high doses in hemodialysis patients, may induce antibodies favoring thromboembolic complications. We prospectively investigated the prevalence of heparininduced platelet-reactive antibodies in a cohort of 38 pediatric hemodialysis patients, by means of heparin/platelet factor 4 (H/PF4) ELISA and heparin-induced platelet activation assay (HIPA). We also assessed other acquired and congenital hypercoagulable states. Heparin-induced antibodies were detected in 13 and 21% of patients with HIPA and ELISA, respectively. Anti-H/PF4 antibodies were negatively correlated with the number of hemodialysis sessions. These antibodies disappeared after a median time of 6 months despite continuing heparin treatment. The prevalence of antiphospholipid antibodies was 21% (anticardiolipin 10.5%, anti-b2GPI 13%, and lupus anticoagulant 5%). Blood levels of homocysteine, factor VIII, and fibrinogen were significantly higher and factor II levels were significantly lower in hemodialysis patients than in controls, whereas factor VII, factor IX, and natural coagulation inhibitor levels were similar in patients and controls. Overall, 26 of 38 patients had at least one biomarker of hypercoagulability, but only 1 patient, without anti-H/PF4 antibodies, presented with thrombosis. In conclusion, heparin induces the transient production of anti-H/PF4 antibodies in children undergoing hemodialysis, but other abnormalities probably contribute to hypercoagulability. These findings may help to improve the diagnosis and management of thrombotic events in hemodialysis patients. Am. J. Hematol. 81:328-334, 2006. V V C 2006 Wiley-Liss, Inc.

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Section: Discussionsupporting

confidence: 92%

A prospective study of the prevalence of heparin‐induced antibodies and other associated thromboembolic risk factors in pediatric patients undergoing hemodialysis

et al. 2006

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“…Evidence to support this assertion also comes from in vitro data, which show that free homocysteine species inactivate NO, promote the generation of oxygen-derived free radicals, induce tissue factor release, and cause endothelial cell injury. 10,12,13,32 Our observations of improved vascular function after B vitamin supplementation in patients with established atherosclerosis are in contrast with previous findings in patients with end-stage renal disease 25 and in animal models of atherosclerosis. 21,33 The lack of improvement in endothelial function despite reduced homocysteine concentrations in these studies may be explained by the failure of folate supplementation to lower plasma homocysteine concentrations Ͻ20 mol/L in patients with end-stage renal disease 25 and the concurrent administration of an atherogenic diet in primates, 21 factors that may have a continuing effect on endothelial function.…”

Section: Chambers Et Al Free Homocysteine and Endothelial Function 2481contrasting

confidence: 99%

“…Studies investigating the effects of lowering homocysteine concentrations on vascular endothelial function have yielded conflicting results. [21][22][23][24][25][26][27] In primates, folate supplementation is reported to reduce plasma homocysteine concentrations but not to affect vascular function. 21 In healthy human subjects, folate supplementation is associated with reduced homocysteine concentrations and improved vascular endothelial function, 22,23,26 although in these studies, there was no relationship between homocysteine concentrations and endothelial function, implying that the effects of B vitamins on endothelial function may not be mediated through homocysteine lowering.…”

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confidence: 99%

Improved Vascular Endothelial Function After Oral B Vitamins

et al. 2000

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Background-Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD. Methods and Results-We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow-mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B 12 (1 mg) daily (nϭ59) or (2) 001).In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (rϭϪ0.26, Pϭ0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B 12 . Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo. Conclusions-Folic acid and vitamin B 12 supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.

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“…It has been proposed that this high prevalence of hyperhomocysteinemia in dialysis patients is one of the main reasons for the high rate of cardiovascular events and poor clinical outcome in these individuals (5-9). Although some studies reported positive correlations between increased tHcy and higher rate of mortality in dialysis patients (7)(8)(9), other studies failed to show such an association (39,40) or found paradoxically reversed correlations (10 -12). Sirrs et al (10) examined the association between tHcy and vascular access complications in 96 MHD patients and did not find any correlation between them.…”

Section: Discussionmentioning

confidence: 99%

A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor Outcome in Hemodialysis Patients

Kalantar-Zadeh

Block

Humphreys

et al. 2004

Journal of the American Society of Nephrology

153

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Abstract. An increased level of total plasma homocysteine (tHcy) is a risk factor for poor cardiovascular outcome in the general population. However, a decreased, rather than an increased, tHcy concentration may predict poor outcome in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse epidemiology. Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization and mortality in 367 MHD patients, aged 54.5 Ϯ 14.7 (mean Ϯ SD) years, who included 199 men and 55% individuals with diabetes. tHcy was 24.4 Ϯ 11.8 mol/L, and 94% of the patients had hyperhomocysteinemia (tHcy Ͼ13.5 mol/L). tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition (serum albumin, prealbumin, creatinine, and urea nitrogen) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines (IL-6 and TNF-␣).During 12 mo of follow-up, 191 MHD patients were hospitalized, 37 died, nine underwent renal transplantation, and 38 transferred out. Hospitalization rates were significantly higher in patients with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was significantly higher compared with other three quartiles (6.5 to 9.8%; Kaplan-Meier P ϭ 0.04). Relative risk of death for the lowest tHcy quartile, even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence interval, 1.14 to 4.53; P ϭ 0.02). Hence, tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures. Despite a very high prevalence of hyperhomocysteinemia in MHD patients, lower values of tHcy are paradoxically associated with increased hospitalization and mortality. The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia. The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome.In the general population, an increased level of total plasma homocysteine (tHcy) is a risk factor for increased cardiovascular events and mortality (1-4). In maintenance hemodialysis (MHD) outpatients, however, the association between tHcy and clinical outcome is inconsistent and even paradoxical. Some studies have shown a poor outcome in MHD patients with hyperhomocysteinemia (5-9). However, a few recent studies have suggested that a decreased, not an increased, tHcy concentration is related to a higher prevalence of cardiovascular disease and poor outcome in these individuals (10 -12). This seems to be due to the empirical association between a low tHcy and protein-energy malnutrition, which is per se a known risk factor for poor clinical outcome in dialysis patients (11,13,14). This recently described paradoxical association between tHcy and clinical outcome in dialysis patients has now been referred to as a possible component of the reversal of the cardiovascular risks (15-17). It is believed that both inflammation and protei...

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Cardiovascular morbidity and endothelial dysfunction in chronic haemodialysis patients: is homocyst(e)ine the missing link?

Cited by 59 publications

References 40 publications

A prospective study of the prevalence of heparin‐induced antibodies and other associated thromboembolic risk factors in pediatric patients undergoing hemodialysis

A prospective study of the prevalence of heparin‐induced antibodies and other associated thromboembolic risk factors in pediatric patients undergoing hemodialysis

Improved Vascular Endothelial Function After Oral B Vitamins

A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor Outcome in Hemodialysis Patients

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