Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease
Carolla El Chamieh, Islam Amine Larabi, Natália Alencar de Pinho, Oriane Lambert, Christian Combe, Denis Fouque, Luc Frimat, Christian Jacquelinet, Maurice Laville, Solène M. Laville, Céline Lange, Jean‐Claude Alvarez, Ziad A. Massy, Sophie Liabeuf, the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) Study Group, Thierry Hannedouche, Bruno Moulin, Armelle Klein, Christian Combe, J P Bourdenx, Arielle S. Keller, C Delclaux, Benoı̂t Vendrely, Benjamin Deroure, Adeline Lacraz, Thierry Lobbedez, Isabelle Landru, Ziad A. Massy, P Lang, Xavier Belenfant, Éric Thervet, Pablo Ureña, Michel Delahousse, C. Vela, Marie Essig, D Clément, H Sekhri, Mustafa Smati, Mohammad Jamali, B Hacq, V Panescu, M Bellou, Luc Frimat, Nassim Kamar, C. Noël, François Glowacki, Nathalie Maisonneuve, Raymond Azar, Maxime Hoffmann, Maryvonne Hourmant, Angelo Testa, Dominique Besnier, G. Choukroun, G Lambrey, Stéphane Burtey, Gaëtan Lebrun, Éric Magnant, M. Laville, Denis Fouque, Laurent Juillard, Charles Chazot, Philippe Zaoui, F Kuentz
Abstract
Background: Kynurenine is a protein-bound uremic toxin. Its circulating levels are increased in chronic kidney disease (CKD). Experimental studies showed that it exerted deleterious cardiovascular effects. We sought to evaluate an association between serum kynurenine levels and adverse fatal or nonfatal cardiovascular events and all-cause mortality in CKD patients. Methods: The CKD-REIN study is a prospective cohort of people with CKD having an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Baseline frozen samples of total and free fractions of kynurenine and tryptophan were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for each outcome. Results: ), 52% had a history of cardiovascular disease. A doubling of serum-free kynurenine levels was associated with an 18% increased hazard of cardiovascular events [466 events, HR (95%CI):1.18(1.02,1.33)], independently of eGFR, serum-free tryptophan level or other uremic toxins, cardioprotective drugs, and traditional cardiovascular risk factors. Serum-free kynurenine was significantly associated with non-atheromatous cardiovascular events [HR(95%CI):1.26(1.03,1.50)], but not with atheromatous cardiovascular events [HR(95%CI):1.15(0.89,1.50)]. The association of serum-free kynurenine with cardiovascular mortality was also independently significant [87 events; adjusted HR(95%CI):1.64(1.10,2.40)]. However, the association of serum-free kynurenine with all-cause mortality was no more significant after adjustment on serum-free tryptophan [311 events, HR(95%CI):1.12(0.90, 1.40)]. Conclusions: Our findings imply that serum-free kynurenine, independently of other cardiovascular risk factors (including eGFR), is associated with fatal or nonfatal cardiovascular outcomes, particularly non-atheromatous cardiovascular events; in patients with CKD. Strategies to reduce serum kynurenine levels should be evaluated in further studies.