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NDT Advance Access published online on February 20, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn040
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2–4 chronic kidney disease

Prabath W. B. Nanayakkara1,2, Jessica C. Kiefte-de Jong3, Coen D. A. Stehouwer4, Frans J. van Ittersum2,5, Margreet R. Olthof3, Rob M. Kok6, Henk J. Blom6, Coen van Guldener7,8, Piet M. ter Wee2,5 and Yvo M. Smulders1,2

1 Department of Internal Medicine 2 Institute for Cardiovascular Research, VU University Medical Center 3 Institute of Health Sciences, Faculty of Earth and Life Sciences, VU University, Amsterdam 4 Department of Internal Medicine, University Hospital Maastricht, Maastricht 5 Department of Nephrology 6 Department of Clinical Chemistry 7 The Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam 8 Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands

Correspondence and offprint requests to: Prabath W. B. Nanayakkara, Department of Internal Medicine, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel: +31-204444444 (Ext. 986791); Fax: +31-204440505; E-mail: p.nanayakkara{at}vumc.nl



  Abstract

Background. Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD. The aims of this study in patients with stage 2–4 CKD were (1) to assess the association between renal function and DNA methylation, (2) to assess the association between DNA methylation and two markers of atherosclerosis [common carotid intima-media thickness (CCA-IMT)] and brachial artery endothelium-dependent, flow-mediated dilatation (BA-FMD) and (3) to examine the effect of a multi-step treatment strategy on DNA methylation.

Methods. In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study (ATIC-study), 93 patients with stage 2–4 CKD were included. In a randomized, double-blind, placebo-controlled design, the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months. DNA methylation was assessed using tandem mass spectrometry. CCA-IMT and BA-FMD were assessed using B-mode ultrasonagraphy.

Results. At baseline, global DNA methylation was not associated with the estimated glomerular filtration rate (P = 0.32) or with CCA-IMT (P = 0.62) or BA-FMD (P = 0.51). No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function.

Conclusion. In patients with stage 2–4 CKD, global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD. A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients. These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2–4 CKD.

Keywords: Atherosclerosis; chronic kidney disease (CKD); common carotid intima-media thickness (CCA-IMT); DNA methylation; homocysteine

Received for publication: 11.11.07
Accepted in revised form: 21. 1.08


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