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Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.
Gaziano, Liam PhD ,,,*; Sun, Luanluan PhD ,,*; Arnold, Matthew PhD *; Bell, Steven PhD; Cho, Kelly MD, MPH; Kaptoge, Stephen K. PhD; Song, Rebecca J. MPH; Burgess, Stephen PhD; Posner, Daniel C. PhD; Mosconi, Katja PhD; Robinson-Cohen, Cassianne PhD; Mason, Amy M. PhD; Bolton, Thomas R. PhD; Tao, Ran PhD; Allara, Elias MD, PhD; Schubert, Petra MPH; Chen, Lingyan PhD; Staley, James R. PhD; Staplin, Natalie PhD; Altay, Servet MD; Amiano, Pilar PharmD, MSc; Arndt, Volker PhD; Arnlov, Johan PhD; Barr, Elizabeth L.M. PhD; Bjorkelund, Cecilia MD; Boer, Jolanda M.A. PhD; Brenner, Hermann MD; Casiglia, Edoardo MD; Chiodini, Paolo PhD; Cooper, Jackie A. MSc; Coresh, Josef MD, PhD; Cushman, Mary MD; Dankner, Rachel MD; Davidson, Karina W. PhD; de Jongh, Renate T. MD, PhD; Donfrancesco, Chiara PhD; Engstrom, Gunnar MD; Freisling, Heinz PhD; de la Camara, Agustin Gomez PhD; Gudnason, Vilmundur MD; Hankey, Graeme J. MD; Hansson, Per-Olof MD, PhD; Heath, Alicia K. PhD; Hoorn, Ewout J. MD, PhD; Imano, Hironori MD; Jassal, Simerjot K. MD; Kaaks, Rudolf PhD; Katzke, Verena PhD; Kauhanen, Jussi MD; Kiechl, Stefan MD; Koenig, Wolfgang MD; Kronmal, Richard A. PhD; Kyro, Cecilie PhD; Lawlor, Deborah A. PhD; Ljungberg, Borje MD; MacDonald, Conor PhD; Masala, Giovanna MD; Meisinger, Christa MD; Melander, Olle MD; Moreno Iribas, Conchi PhD; Ninomiya, Toshiharu PhD; Nitsch, Dorothea MD, PhD; Nordestgaard, Borge G. MD, PhD; Onland-Moret, Charlotte PhD; Palmieri, Luigi PhD; Petrova, Dafina PhD; Garcia, Jose Ramon Quiros PhD; Rosengren, Annika MD; Sacerdote, Carlotta MD; Sakurai, Masaru MD; Santiuste, Carmen MD; Schulze, Matthias B. PhD; Sieri, Sabina PhD; Sundstrom, Johan MD; Tikhonoff, Valerie MD, PhD; Tjonneland, Anne MD; Tong, Tammy PhD; Tumino, Rosario MD; Tzoulaki, Ioanna PhD; van der Schouw, Yvonne T. PhD; Monique Verschuren, W.M. PhD; Volzke, Henry MD; Wallace, Robert B. MD; Wannamethee, S. Goya PhD; Weiderpass, Elisabete PhD; Willeit, Peter MD, PhD; Woodward, Mark PhD; Yamagishi, Kazumasa MD; Zamora-Ros, Raul PhD; Akwo, Elvis A. MD PhD; Pyarajan, Saiju PhD; Gagnon, David R. MD, MPH, PhD; Tsao, Philip S. PhD; Muralidhar, Sumitra PhD; Edwards, Todd L. PhD; Damrauer, Scott M. MD; Joseph, Jacob MD, PhD; Pennells, Lisa PhD; Wilson, Peter W.F. MD; Harrison, Seamus MD, PhD; Gaziano, Thomas A. MD, PhD; Inouye, Michael PhD; Baigent, Colin MD, PhD; Casas, Juan P. MD, PhD; Langenberg, Claudia PhD; Wareham, Nick MD; Riboli, Elio MD; Gaziano, J.Michael MD, MPH ,,+; Danesh, John MD, PhD ,,,,,,+; Hung, Adriana M. MD, MPH ,+; Butterworth, Adam S. PhD ,,,,,+; Wood, Angela M. PhD ,,,,,,+; Di Angelantonio, Emanuele MD, PhD ,,,,,,+; on behalf of the Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program; Koettgen, Anna; Shaw, Jonathan; Atkins, Robert; Zimmet, Paul; Whincup, Peter; Willeit, Peter; Willeit, Johann; Leitner, Christoph; Casiglia, Edoardo; Tikhonoff, Valerie; Tybjaerg-Hansen, Anne; Schnohr, Peter; Afzal, Shoaib; Pablos, David Lora; Arriscado, Cristina Martin; Ferreiro, Carmen Romero; Wallace, Robert B.; Stocker, Hannah; Schottker, Ben; Holleczek, Bernd; Chetrit, Angela; Welin, Lennart; Svardsudd, Kurt; Welin, Lennart; Svardsudd, 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; Volzke, Henry; Can, Gunay; Yuksel, Husniye; Ozkan, Ugur; Nakagawa, Hideaki; Morikawa, Yuko; Ishizaki, Masao; Arnlov, Johan; Arndt, Volker; Feskens, Edith; Geleijnse, Johanna M; Kromhout, Daan
[Article] Circulation. 146(20):1507-1517, November 15, 2022.

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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[middle dot]min-1[middle dot]1.73 m-2, compared with those with eGFR between 60 and 105 mL[middle dot]min-1[middle dot]1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL[middle dot]min-1[middle dot]1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL[middle dot]min-1[middle dot]1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL[middle dot]min-1[middle dot]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.