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Endothelial Dysfunction Contributes to Renal Function–Associated Cardiovascular Mortality in a Population with Mild Renal Insufficiency: The Hoorn Study

Frank Stam^*,, Coen van Guldener^*,,, Annemarie Becker^*,, Jacqueline M. Dekker, Robert J. Heine^*,, Lex M. Bouter and Coen D.A. Stehouwer^*,,,||

^* Department of Internal Medicine, Institute for Cardiovascular Research, and Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam; and Department of Internal Medicine, Amphia Hospital (Langendijk), Breda, ^|| Department of Internal Medicine, Academic Hospital Maastricht, and Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Address correspondence to: Dr. Coen D.A. Stehouwer, Department of Internal Medicine, Academic Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: +31-20-433877006; Fax: +31-20-433875006; E-mail: csteh{at}sint.azm.nl

Received for publication August 9, 2005. Accepted for publication November 21, 2005.

Mildly impaired renal function is associated with cardiovascular morbidity and mortality. There are indications that endothelial dysfunction and/or chronic inflammation, which play an important role in atherothrombosis, are present in early stages of renal insufficiency. This study investigated whether and to which extent endothelial dysfunction and inflammation were related to renal function and contributed to renal function–associated cardiovascular mortality in a population-based cohort (n = 613), aged 50 to 75 yr, that was followed with a median duration of 12.5 yr. During follow-up, 192 individuals died (67 of cardiovascular causes). At baseline, renal function was estimated with serum creatinine, the Cockcroft-Gault formula, and the Modification of Diet in Renal Disease equation of GFR (eGFR). Endothelial function was estimated by plasma von Willebrand factor, soluble vascular cell adhesion molecule-1, and the urinary albumin-creatinine ratio. Inflammatory activity was estimated by plasma C-reactive protein and soluble intercellular adhesion molecule-1. Renal function was mildly impaired (mean eGFR 68 ± 12 ml/min per 1.73 m²) and independently associated with von Willebrand factor (standardized –0.09; 95% confidence interval [CI] –0.18 to –0.002; P < 0.05), soluble vascular cell adhesion molecule-1 (standardized –0.14; 95% CI –0.22 to –0.05; P < 0.01), and albumin-creatinine ratio (standardized –0.15; 95% CI –0.23 to –0.08; P < 0.001) but not with markers of inflammatory activity. Renal function was inversely associated with cardiovascular and all-cause mortality. The relative risk for cardiovascular mortality but not all-cause mortality associated with renal function decreased from 1.22 to 1.12 per 5 ml/min per 1.73 m² decrease of eGFR after adjustment for markers of endothelial dysfunction. In conclusion, endothelial dysfunction was related to renal function and contributed to the excess in cardiovascular mortality in this population-based cohort with mild renal insufficiency.

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