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Serum Indoxyl Sulfate Is Associated with Vascular Disease and Mortality in Chronic Kidney Disease Patients

Fellype C. Barreto^*,, Daniela V. Barreto^*,, Sophie Liabeuf^*,, Natalie Meert, Griet Glorieux, Mohammed Temmar, Gabriel Choukroun^*,, Raymond Vanholder, Ziad A. Massy^*,,, and on behalf of the European Uremic Toxin Work Group (EUTox)

^* INSERM ERI-12 (EA 4292), Amiens, France; Clinical Research Centre, Division of Clinical Pharmacology, Amiens University Hospital, and the Jules Verne University of Picardy, Amiens, France; Nephrology Section, Department of Internal Medicine, University Hospital, Gent, Belgium; and Division of Nephrology, Amiens University Hospital, Amiens, France

Correspondence: Dr. Ziad A. Massy,INSERM ERI-12, Divisions of Clinical Pharmacology and Nephrology, Amiens University Hospital, Avenue Rene Laennec, F-80054 Amiens, France. Phone: + 33-322-455788; Fax: +33-322-455660; E-mail: massy{at}u-picardie.fr

Background and objectives: As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients.

Design, setting, participants, & measurements: One-hundred and thirty-nine patients (mean ± SD age: 67 ± 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled.

Results: Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 ± 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification.

Conclusions: The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.