Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.
;
Kelly Cho;
Stephen K Kaptoge;
Rebecca J Song;
Stephen Burgess;
Daniel C Posner ;
Katja Mosconi;
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Cassianne Robinson-Cohen;
Amy M Mason ;
Thomas R Bolton;
Ran Tao;
Elias Allara ;
Petra Schubert;
Lingyan Chen;
James R Staley;
Natalie Staplin ;
Servet Altay;
Pilar Amiano;
Volker Arndt ;
Johan Ärnlöv ;
Elizabeth LM Barr ;
Cecilia Björkelund;
Jolanda MA Boer ;
Hermann Brenner ;
Edoardo Casiglia ;
Paolo Chiodini ;
Jackie A Cooper;
Josef Coresh ;
Mary Cushman ;
Rachel Dankner;
Karina W Davidson ;
Renate T de Jongh ;
Chiara Donfrancesco;
Gunnar Engström ;
Heinz Freisling;
Agustín Gómez de la Cámara ;
Vilmundur Gudnason ;
Graeme J Hankey ;
Per-Olof Hansson ;
Alicia K Heath ;
Ewout J Hoorn ;
Hironori Imano ;
Simerjot K Jassal;
Rudolf Kaaks;
Verena Katzke ;
Jussi Kauhanen;
Stefan Kiechl ;
Wolfgang Koenig ;
Richard A Kronmal ;
Cecilie Kyrø ;
Deborah A Lawlor;
Börje Ljungberg ;
Conor MacDonald ;
Giovanna Masala ;
Christa Meisinger;
Olle Melander;
Conchi Moreno Iribas;
Toshiharu Ninomiya ;
Dorothea Nitsch ;
Børge G Nordestgaard ;
Charlotte Onland-Moret ;
Luigi Palmieri ;
Dafina Petrova;
Jose Ramón Quirós Garcia;
Annika Rosengren ;
Carlotta Sacerdote;
Masaru Sakurai;
Carmen Santiuste;
Matthias B Schulze ;
Sabina Sieri ;
Johan Sundström ;
Valérie Tikhonoff ;
Anne Tjønneland;
Tammy Tong ;
Rosario Tumino;
Ioanna Tzoulaki ;
Yvonne T van der Schouw ;
WM Monique Verschuren;
Henry Völzke;
Robert B Wallace;
S Goya Wannamethee ;
Elisabete Weiderpass ;
Peter Willeit ;
Mark Woodward ;
Kazumasa Yamagishi ;
Raul Zamora-Ros ;
Elvis A Akwo;
Saiju Pyarajan;
David R Gagnon ;
Philip S Tsao ;
Sumitra Muralidhar;
Todd L Edwards ;
Scott M Damrauer ;
Jacob Joseph ;
Lisa Pennells ;
Peter WF Wilson;
Seamus Harrison;
Thomas A Gaziano ;
Michael Inouye;
Colin Baigent;
Juan P Casas;
Claudia Langenberg ;
Nick Wareham ;
Elio Riboli;
J Michael Gaziano;
John Danesh;
Adriana M Hung ;
Adam S Butterworth ;
Angela M Wood;
Emanuele Di Angelantonio ;
Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Pro;
(2022)
Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.
Circulation, 146 (20).
pp. 1507-1517.
ISSN 0009-7322
DOI: 10.1161/CIRCULATIONAHA.122.060700
BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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subject - Accepted Version
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