Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses
Authors: Gaziano Liam , Sun Luanluan , Arnold Matthew , Bell Steven , Cho Kelly , Kaptoge Stephen K. , Song Rebecca J. , Burgess Stephen , Posner Daniel C. , Mosconi Katja , Robinson-Cohen Cassianne , Mason Amy M. , Bolton Thomas R. , Tao Ran , Allara Elias , Schubert Petra , Chen Lingyan , Staley James R. , Staplin Natalie , Altay Servet , Amiano Pilar , Arndt Volker , Ärnlöv Johan , Barr Elizabeth L.M. , Björkelund Cecilia , Boer Jolanda M.A. , Brenner Hermann , Casiglia Edoardo , Chiodini Paolo , Cooper Jackie A. , Coresh Josef , Cushman Mary , Dankner Rachel , Davidson Karina W. , de Jongh Renate T. , Donfrancesco Chiara , Engström Gunnar , Freisling Heinz , de la Cámara Agustín Gómez , Gudnason Vilmundur , Hankey Graeme J. , Hansson Per-Olof , Heath Alicia K. , Hoorn Ewout J. , Imano Hironori , Jassal Simerjot K. , Kaaks Rudolf , Katzke Verena , Kauhanen Jussi , Kiechl Stefan , Koenig Wolfgang , Kronmal Richard A. , Kyrø Cecilie , Lawlor Deborah A. , Ljungberg Börje , MacDonald Conor , Masala Giovanna , Meisinger Christa , Melander Olle , Moreno Iribas Conchi , Ninomiya Toshiharu , Nitsch Dorothea , Nordestgaard Børge G. , Onland-Moret Charlotte , Palmieri Luigi , Petrova Dafina , Garcia Jose Ramón Quirós , Rosengren Annika , Sacerdote Carlotta , Sakurai Masaru , Santiuste Carmen , Schulze Matthias B. , Sieri Sabina , Sundström Johan , Tikhonoff Valérie , Tjønneland Anne , Tong Tammy , Tumino Rosario , Tzoulaki Ioanna , van der Schouw Yvonne T. , Monique Verschuren W.M. , Völzke Henry , Wallace Robert B. , Wannamethee S. Goya , Weiderpass Elisabete , Willeit Peter , Woodward Mark , Yamagishi Kazumasa , Zamora-Ros Raul , Akwo Elvis A. , Pyarajan Saiju , Gagnon David R. , Tsao Philip S. , Muralidhar Sumitra , Edwards Todd L. , Damrauer Scott M. , Joseph Jacob , Pennells Lisa , Wilson Peter W.F. , Harrison Seamus , Gaziano Thomas A. , Inouye Michael , Baigent Colin , Casas Juan P. , Langenberg Claudia , Wareham Nick , Riboli Elio , Gaziano J.Michael , Danesh John , Hung Adriana M. , Butterworth Adam S. , Wood Angela M. , Di Angelantonio Emanuele , Koettgen Anna , Shaw Jonathan , Atkins Robert , Zimmet Paul , Whincup Peter , Willeit Peter , Willeit Johann , Leitner Christoph , Casiglia Edoardo , Tikhonoff Valérie , Tybjaerg-Hansen Anne , Schnohr Peter , Afzal Shoaib , Pablos David Lora , Arriscado Cristina Martin , Ferreiro Carmen Romero , Wallace Robert B. , Stocker Hannah , Schöttker Ben , Holleczek Bernd , Chetrit Angela , Welin Lennart , Svärdsudd Kurt , Welin Lennart , Svärdsudd Kurt , Lissner Lauren , Hange Dominique , Mehlig Kirsten , Nagel Dorothea , Norman Paul E. , Almeida Osvaldo , Flicker Leon , Hata Jun , Honda Takanori , Furuta Yoshihiko , Iso Hiroyasu , Kitamura Akihiko , Muraki Isao , Salonen Jukka T. , Tuomainen Tomi-Pekka , van Zutphen E. M. , van Schoor N. M. , Donfrancesco Chiara , Lo Noce Cinzia , Palmieri Luigi , Cushman Mary , Kronmal Richard , Koenig Wolfgang , Meisinger Christa , Lappas Georg , Nilsson Peter M. , Melander Olle , Hedblad Bo , Nitsch Dorothea , Cooper Jackie A. , Shaffer Jonathan , Schwartz Joseph , Shimbo Daichi , Sato Shinichi , Iso Hiroyasu , Hayama-Terada Mina , Jassal Simerjot , Aspelund Thor , Thorsson Bolli , Sigurdsson Gunnar , Chaker Layal , Ikram Kamran M. , Kavousi Maryam , Tunstall-Pedoe Hugh , Woodward Mark , Völzke Henry , Can Günay , Yüksel Hüsniye , Özkan Uğur , Nakagawa Hideaki , Morikawa Yuko , Ishizaki Masao , Ärnlöv Johan , Arndt Volker , Feskens Edith , Geleijnse Johanna M , Kromhout Daan 
Published: October 2022

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.