NDT Advance Access originally published online on November 26, 2007
Nephrology Dialysis Transplantation 2008 23(3):1069-1071; doi:10.1093/ndt/gfm635
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Reply
E-mail: i.baragetti{at}bassini.hsgerardo.orgWe thank Dr Righetti for his valuable comments and would like to raise some questions about the relationships between vitamins B, homocysteine and cardiovascular risk. We agree with the authors that vitamin B12 is absolutely useful in lowering homocysteine plasma concentrations in dialysis patients. In fact, in a previous study by our group [1], we showed reduced levels of homocysteine plasma levels (by about 58%) in haemodialysis patients treated with an association of folinic acid and vitamin B12. Vitamin B6 is also useful to improve hyperhomocysteinaemia in dialysis patients [2]. In our opinion a combination of folic acid, vitamin B6, vitamin B12 and the dialysis modality could strongly improve hyperhomocysteinaemia in dialysis. Our experience however, suggests that the utility of vitamin B12 in improving cardiovascular mortality and morbidity in dialysis is actually a matter of debate. Righetti et al. [3] obtained an improved cardiovascular outcome by lowering homocysteine plasma levels in a population of haemodialysis patients with a combination of folic acid and both vitamins B12 and B6. In their comments they state that the positive results obtained in this study in reducing cardiovascular risk are due to the association of folic acid with vitamins B, an association which should be more effective than folic acid alone in reducing homocysteine plasma levels. Although suggestive, this hypothesis should be tested in larger, controlled, randomized trials. Clinical trials have raised questions as to whether hyperomocysteinemia is either a contributing risk factor or an innocent bystander of other pathological processes. Several large randomized trials have shown that lowering homocysteine with folic acid does not improve cardiovascular outcomes and treatment with folic acid combined with B vitamins may actually accelerate cardiovascular risk [4,5]. A meta-analysis of 12 randomized trials confirmed that folic acid supplementation did not reduce cardiovascular or all-cause mortality in individuals with pre-existing vascular kidney disease [6]. We found an irrelevant effect of vitamin B12 addiction to folic acid in improving endothelial function in patients on acetate-free-biofiltration dialysis, despite a further lowering effect on homocysteine plasma levels by 26.6% (Figures 1 and 2) [7]; we never found a relationship between homocysteine plasma concentrations and endothelial function [7,8]. On the contrary, we found a positive correlation between intracellular folic acid concentrations and endothelial function [8]. For this reason, we suggested in our recent NDT paper [8] that the pharmacologic effect of 5-metylthetrahydrofolate per se, rather than a lowering effect on homocysteine, could have improved endothelial function. This is in agreement with experimental data showing the peculiar antioxidant and tetrahydrobiopterin-like properties of 5-methyltetrahydrofolate, enhancing endothelial nitric-oxide production and tetrabiopterin stabilization [9]. Previous studies showing an improvement of endothelial function in familial hypercholesterolaemia and coronary artery disease in patients treated with folic acid [10], and also our studies [7,8], showing no relationship between endothelial function and homocysteine, suggest that endothelial dysfunction is the cause of cardiovascular outcome. Homocysteine would be better considered as a predictive marker of endothelial dysfunction and cardiovascular risk. The pivotal aim should then be just to treat endothelial dysfunction rather than hyperhomocysteinemia. Nevertheless, the main aim of all studies performed was to improve cardiovascular outcome with a strong effort to lower homocysteine plasma levels, without convincing and definitive results. Our opinion is that the treatment and the improvement of endothelial dysfunction should be the primary end-point of future studies, independently of homocysteine.
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Conflict of interest statement. None declared.
1 Department of Internal Medicine, Nephrology and Dialysis Unit, Bassini Hospital, Cinisello Balsamo, Milan 2 Department of Pharmacological Sciences, Center for the Study of Atherosclerosis, University of Milan
References
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- Touam M, Zingraff J, Jungers P, et al. Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. Kidney Int (1999) 56:2292–2296.[CrossRef][Web of Science][Medline]
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[Abstract/Free Full Text] - Buccianti G, Raselli S, Baragetti I, et al. 5-Methyltetrahydrofolate restores endothelial function in uraemic patients on convective haemodialysis. Nephrol Dial Transplant (2002) 17:857–864.
[Abstract/Free Full Text] - Baragetti I, Raselli S, Stucchi A, et al. Improvement of endothelial function in uraemic patients on peritoneal dialysis: a possible role for 5-MTHF administration. Ndt Advance Access Published on June 2007 Doi: 10.1093/ndt/gfm/40.
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[Abstract/Free Full Text] - Title LM, Cummings PM, Giddens K, et al. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol (2000) 36:758–765.
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