Urea levels and cardiovascular disease in patients with chronic kidney disease
Solène M. Laville, A. Couturier, Oriane Lambert, Marie Metzger, Nicolas Mansencal, Christian Jacquelinet, Maurice Laville, Luc Frimat, Denis Fouque, Christian Combe, Bruce Robinson, Bénédicte Stengel, Sophie Liabeuf, Ziad A. Massy, the CKD-REIN study collaborators, Carole Ayav, Serge Briançon, Dorothée Cannet, Christian Combe, Denis Fouque, Luc Frimat, Yves-Édouard Herpe, Christian Jacquelinet, Maurice Laville, Ziad A. Massy, Christophe Pascal, Bruce Robinson, Bénédicte Stengel, Céline Lange, Karine Legrand, Sophie Liabeuf, Marie Metzger, Élodie Speyer, Thierry Hannedouche, Bruno Moulin, Sébastien Mailliez, Gaëtan Lebrun, Éric Magnant, Gabriel Choukroun, Benjamin Deroure, Adeline Lacraz, G Lambrey, Jean Philippe, Bourdenx, Marie Essig, Thierry Lobbedez, Raymond Azar, Hacène Sekhri, Mustafa Smati, Mohamed Jamali, Alexandre Klein, Michel Delahousse, Christian Combe, Séverine Martin, Isabelle Landru, Éric Thervet, Ziad A. Massy, Philippe Lang, Xavier Belenfant, Pablo Ureña, Carlos Vela, Luc Frimat, Dominique Chauveau, Viktor Panescu, Christian Noël, François Glowacki, Maxime Hoffmann, Maryvonne Hourmant, Dominique Besnier, Angelo Testa, F Kuentz, Philippe Zaoui, Charles Chazot, Laurent Juillard, Stéphane Burtey, Adrien Keller, Nassim Kamar, Denis Fouque, Maurice Laville
Abstract
BACKGROUND: Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD. METHODS: CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 < 10.5, T2:10.5 to 15.1, and T3 ≥ 15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or nonatheromatous cardiovascular (CV) events, and all-cause mortality before RRT. The models were adjusted for baseline comorbidities, laboratory data, and medications. FINDINGS: Of the 2507 included patients (median [interquartile range (IQR)] age: 69[61-77]; mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²), 54% had a history of cardiovascular disease. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patient in T1 (n events = 451, HR[95%CI]: 1.93[1.39-2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31[0.97; 1.76] and 1.73[1.22; 2.45] for patients T2 and those in T3, respectively. INTERPRETATION: Our data suggested that urea is a predictor of cardiovascular outcomes beyond CV risk factors including eGFR.