Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure
Introduction: Recent studies have focused on some uremic toxins, particularly those derived from tryptophan, as potential modifiable risk factors of chronic kidney disease (CKD) progression. The kynurenine pathway is the major enzymatic pathway for sequentially catabolizing tryptophan, resulting in...
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Elsevier
2025-05-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024925001147 |
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| author | Carolla El Chamieh Sophie Liabeuf Islam Amine Larabi Natalia Alencar De Pinho Margaux Costes-Albrespic Luc Frimat Céline Lange Yves-Édouard Herpe Jean-Charles Martin Pierre Letourneau Benoit Bérengère Christophe Soulage Stéphane Burtey Jean-Claude Alvarez Laetitia Koppe Ziad A. Massy Prs T. Hannedouche B. Moulin Dr A. Klein Pr C. Combe Dr J.P. Bourdenx Dr A. Keller Dr C. Delclaux Dr B. Vendrely Dr B. Deroure Dr A. Lacraz Dr T. Lobbedez Dr I. Landru Pr Z. Massy Pr P. Lang Dr X. Belenfant Pr E. Thervet Dr P. Urena Dr M. Delahousse Dr C. Vela Pr M. Essig Dr D. Clément Dr H. Sekhri Dr M. Smati Dr M. Jamali Dr B. Hacq Dr V. Panescu Dr M. Bellou Pr Luc Frimat Pr N. Kamar Prs C. Noël et F. Glowacki Dr N. Maisonneuve Dr R. Azar Dr M. Hoffmann Pr M. Hourmant Dr A. Testa Dr D. Besnier Pr G. Choukroun Dr G. Lambrey Pr S. Burtey Dr G. Lebrun Dr E. Magnant Pr M. Laville Pr D. Fouque L. Juillard Dr C. Chazot Pr P. Zaoui Dr F. Kuentz |
| author_facet | Carolla El Chamieh Sophie Liabeuf Islam Amine Larabi Natalia Alencar De Pinho Margaux Costes-Albrespic Luc Frimat Céline Lange Yves-Édouard Herpe Jean-Charles Martin Pierre Letourneau Benoit Bérengère Christophe Soulage Stéphane Burtey Jean-Claude Alvarez Laetitia Koppe Ziad A. Massy Prs T. Hannedouche B. Moulin Dr A. Klein Pr C. Combe Dr J.P. Bourdenx Dr A. Keller Dr C. Delclaux Dr B. Vendrely Dr B. Deroure Dr A. Lacraz Dr T. Lobbedez Dr I. Landru Pr Z. Massy Pr P. Lang Dr X. Belenfant Pr E. Thervet Dr P. Urena Dr M. Delahousse Dr C. Vela Pr M. Essig Dr D. Clément Dr H. Sekhri Dr M. Smati Dr M. Jamali Dr B. Hacq Dr V. Panescu Dr M. Bellou Pr Luc Frimat Pr N. Kamar Prs C. Noël et F. Glowacki Dr N. Maisonneuve Dr R. Azar Dr M. Hoffmann Pr M. Hourmant Dr A. Testa Dr D. Besnier Pr G. Choukroun Dr G. Lambrey Pr S. Burtey Dr G. Lebrun Dr E. Magnant Pr M. Laville Pr D. Fouque L. Juillard Dr C. Chazot Pr P. Zaoui Dr F. Kuentz |
| author_sort | Carolla El Chamieh |
| collection | DOAJ |
| description | Introduction: Recent studies have focused on some uremic toxins, particularly those derived from tryptophan, as potential modifiable risk factors of chronic kidney disease (CKD) progression. The kynurenine pathway is the major enzymatic pathway for sequentially catabolizing tryptophan, resulting in key metabolites including kynurenine and kynurenic acid (KA) by the aminoadipate aminotransferase. We aimed at evaluating the association of serum KA levels and KA-to-kynurenine ratio (as indicators of aminoadipate aminotransferase activity) with kidney failure. Methods: The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) study is a prospective cohort of patients with CKD having an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2. Baseline samples of uremic toxins were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for our outcome. The kidney gene expression of the kynurenine pathway was evaluated in 5 or 6 nephrectomy CKD mice and adenine-diet CKD mice under nephroprotective low protein diet (5% w/w). Results: Over a median follow-up period of 5 years, 608 out of the 2406 patients progressed to kidney failure. A 2-fold increase in serum KA levels and KA-to-kynurenine ratio were respectively associated with a 22% and 20%-increase in the hazard of kidney failure after multiple adjustments. In the mouse model, positive correlation was found between aminoadipate aminotransferase expression and fibrosis-related genes and kidney fibrosis. A low-protein diet was associated with a decrease in aminoadipate aminotransferase expression in the kidney as well as in inflammatory and fibrosis markers. Conclusion: Our findings suggest that the kynurenine pathway is associated with kidney failure, and that the inhibition of aminoadipate aminotransferase and the subsequent reduction of KA accumulation is a promising target to mitigate kidney disease progression. |
| format | Article |
| id | doaj-art-26c685df441b42e7bd9e2e58325801e8 |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj-art-26c685df441b42e7bd9e2e58325801e82025-08-20T03:45:07ZengElsevierKidney International Reports2468-02492025-05-011051404141410.1016/j.ekir.2025.02.024Uncovering the Link Between Kynurenic Acid Pathway and Kidney FailureCarolla El Chamieh0Sophie Liabeuf1Islam Amine Larabi2Natalia Alencar De Pinho3Margaux Costes-Albrespic4Luc Frimat5Céline Lange6Yves-Édouard Herpe7Jean-Charles Martin8Pierre Letourneau9Benoit Bérengère10Christophe Soulage11Stéphane Burtey12Jean-Claude Alvarez13Laetitia Koppe14Ziad A. Massy15Prs T. HannedoucheB. MoulinDr A. KleinPr C. CombeDr J.P. BourdenxDr A. KellerDr C. DelclauxDr B. VendrelyDr B. DeroureDr A. LacrazDr T. LobbedezDr I. LandruPr Z. MassyPr P. LangDr X. BelenfantPr E. ThervetDr P. UrenaDr M. DelahousseDr C. VelaPr M. EssigDr D. ClémentDr H. SekhriDr M. SmatiDr M. JamaliDr B. HacqDr V. PanescuDr M. BellouPr Luc FrimatPr N. KamarPrs C. Noël et F. GlowackiDr N. MaisonneuveDr R. AzarDr M. HoffmannPr M. HourmantDr A. TestaDr D. BesnierPr G. ChoukrounDr G. LambreyPr S. BurteyDr G. LebrunDr E. MagnantPr M. LavillePr D. FouqueL. JuillardDr C. ChazotPr P. ZaouiDr F. KuentzCentre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, FrancePharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Center, Amiens, France; MP3CV Laboratory, Jules Verne University of Picardie, Amiens, France; Sophie Liabeuf, Service de pharmacologieclinique, Département de recherche clinique, Avenue R. Laennec, Amiens, France.Department of Pharmacology and Toxicology, Raymond Poincaré Hospital, AP-HP, Garches, France; UVSQ, Université Paris-Saclay, Inserm U1018, CESP, Équipe MOODS, Montigny-le-Bretonneux, FranceCentre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, FranceCentre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, FranceNephrology Department, CHRU de Nancy, Vandoeuvre-lès-Nancy, France; Lorraine University, APEMAC, Vandoeuvre-lès-Nancy, FranceCentre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, FranceBiobanque de Picardie, CHU Amiens-Picardie, Amiens, FranceCentre de Recherche Cardiovasculaire et Nutritionnelle (C2VN), INSERM, Institut National pour la Recherche en Agriculture et l’Environnement (INRAE), BioMet, Aix-Marseille Université, Marseille, FranceDepartement of Nephrology, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Bénite, FranceLaboratoire CarMeN, INSERM U.1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre Bénite, FranceLaboratoire CarMeN, INSERM U.1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre Bénite, FranceAix-Marseille University, C2VN, INSERM 1263, Institut National pour la Recherche en Agriculture et l’Environnement (INRAE) 1260, Faculté SMPM, Marseille, France; Aix-Marseille University, Centre de Nephrologie et Transplantation Renale, AP-HM Hopital de la Conception, Marseille, FranceDepartment of Pharmacology and Toxicology, Raymond Poincaré Hospital, AP-HP, Garches, France; UVSQ, Université Paris-Saclay, Inserm U1018, CESP, Équipe MOODS, Montigny-le-Bretonneux, FranceDepartement of Nephrology, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre Bénite, France; Laboratoire CarMeN, INSERM U.1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre Bénite, FranceCentre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, France; Association pour l’Utilisation du Rein Artificiel dans la régionparisienne (AURA), Paris, France; Ambroise Paré University Hospital, APHP, Department of Nephrology Boulogne-Billancourt/Paris, France; Correspondence: Ziad A. Massy, CESP, Université Paris-Saclay, 185 Rue Raymond Losserand, Paris, France.Introduction: Recent studies have focused on some uremic toxins, particularly those derived from tryptophan, as potential modifiable risk factors of chronic kidney disease (CKD) progression. The kynurenine pathway is the major enzymatic pathway for sequentially catabolizing tryptophan, resulting in key metabolites including kynurenine and kynurenic acid (KA) by the aminoadipate aminotransferase. We aimed at evaluating the association of serum KA levels and KA-to-kynurenine ratio (as indicators of aminoadipate aminotransferase activity) with kidney failure. Methods: The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) study is a prospective cohort of patients with CKD having an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2. Baseline samples of uremic toxins were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for our outcome. The kidney gene expression of the kynurenine pathway was evaluated in 5 or 6 nephrectomy CKD mice and adenine-diet CKD mice under nephroprotective low protein diet (5% w/w). Results: Over a median follow-up period of 5 years, 608 out of the 2406 patients progressed to kidney failure. A 2-fold increase in serum KA levels and KA-to-kynurenine ratio were respectively associated with a 22% and 20%-increase in the hazard of kidney failure after multiple adjustments. In the mouse model, positive correlation was found between aminoadipate aminotransferase expression and fibrosis-related genes and kidney fibrosis. A low-protein diet was associated with a decrease in aminoadipate aminotransferase expression in the kidney as well as in inflammatory and fibrosis markers. Conclusion: Our findings suggest that the kynurenine pathway is associated with kidney failure, and that the inhibition of aminoadipate aminotransferase and the subsequent reduction of KA accumulation is a promising target to mitigate kidney disease progression.http://www.sciencedirect.com/science/article/pii/S2468024925001147chronic kidney diseasekidney failurekynurenic acid pathwaykynureninetryptophan |
| spellingShingle | Carolla El Chamieh Sophie Liabeuf Islam Amine Larabi Natalia Alencar De Pinho Margaux Costes-Albrespic Luc Frimat Céline Lange Yves-Édouard Herpe Jean-Charles Martin Pierre Letourneau Benoit Bérengère Christophe Soulage Stéphane Burtey Jean-Claude Alvarez Laetitia Koppe Ziad A. Massy Prs T. Hannedouche B. Moulin Dr A. Klein Pr C. Combe Dr J.P. Bourdenx Dr A. Keller Dr C. Delclaux Dr B. Vendrely Dr B. Deroure Dr A. Lacraz Dr T. Lobbedez Dr I. Landru Pr Z. Massy Pr P. Lang Dr X. Belenfant Pr E. Thervet Dr P. Urena Dr M. Delahousse Dr C. Vela Pr M. Essig Dr D. Clément Dr H. Sekhri Dr M. Smati Dr M. Jamali Dr B. Hacq Dr V. Panescu Dr M. Bellou Pr Luc Frimat Pr N. Kamar Prs C. Noël et F. Glowacki Dr N. Maisonneuve Dr R. Azar Dr M. Hoffmann Pr M. Hourmant Dr A. Testa Dr D. Besnier Pr G. Choukroun Dr G. Lambrey Pr S. Burtey Dr G. Lebrun Dr E. Magnant Pr M. Laville Pr D. Fouque L. Juillard Dr C. Chazot Pr P. Zaoui Dr F. Kuentz Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure Kidney International Reports chronic kidney disease kidney failure kynurenic acid pathway kynurenine tryptophan |
| title | Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure |
| title_full | Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure |
| title_fullStr | Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure |
| title_full_unstemmed | Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure |
| title_short | Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure |
| title_sort | uncovering the link between kynurenic acid pathway and kidney failure |
| topic | chronic kidney disease kidney failure kynurenic acid pathway kynurenine tryptophan |
| url | http://www.sciencedirect.com/science/article/pii/S2468024925001147 |
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