Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease
Author:
El Chamieh Carolla1ORCID, Larabi Islam Amine23, Alencar De Pinho Natalia1ORCID, Lambert Oriane1, Combe Christian45ORCID, Fouque Denis67, Frimat Luc89, Jacquelinet Christian110, Laville Maurice7, Laville Solène1112, Lange Céline1, Alvarez Jean-Claude23, Massy Ziad A113ORCID, Liabeuf Sophie1112ORCID, Hannedouche T, Moulin B, Klein A, Combe C, Bourdenx J P, Keller A, Delclaux C, Vendrely B, Deroure B, Lacraz A, Lobbedez T, Landru I, Massy Z, Lang P, Belenfant X, Thervet E, Urena P, Delahousse M, Vela C, Essig M, Clément D, Sekhri H, Smati M, Jamali M, Hacq B, Panescu V, Bellou M, Frimat Luc, Kamar N, Noël C, Glowacki F, Maisonneuve N, Azar R, Hoffmann M, Hourmant M, Testa A, Besnier D, Choukroun G, Lambrey G, Burtey S, Lebrun G, Magnant E, Laville M, Fouque D, Juillard L, Chazot C, Zaoui P, Kuentz F,
Affiliation:
1. Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin , Villejuif , France 2. Department of Pharmacology and Toxicology, Raymond Poincaré Hospital, AP-HP , Garches , France 3. UVSQ, Université Paris-Saclay, Inserm U1018, CESP, Équipe MOODS , MasSpecLab, Montigny-le-Bretonneux , France 4. Service de Néphrologie Transplantation Dialyse Aphérèse, Centre Hospitalier Universitaire de Bordeaux , Bordeaux , France 5. INSERM, U1026, University Bordeaux , Bordeaux , France 6. Nephrology Dept, Centre Hospitalier Lyon Sud, Université de Lyon , Carmen, Pierre-Bénite , France 7. Université de Lyon, CarMeN INSERM 1060 , Lyon , France 8. Nephrology Department, CHRU de Nancy , Vandoeuvre-lès-Nancy , France 9. Lorraine University, APEMAC , Vandoeuvre-lès-Nancy , France 10. Biomedecine Agency , Saint Denis La Plaine , France 11. Pharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Center , Amiens , France 12. MP3CV Laboratory, Jules Verne University of Picardie , Amiens , France 13. Department of Nephrology, Ambroise Paré University Hospital, APHP , Boulogne-Billancourt , France
Abstract
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
Of the 2406 included patients (median age: 68 years; median eGFR: 25 ml/min/1.73 m2), 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.
Publisher
Oxford University Press (OUP)
Subject
Transplantation,Nephrology
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