Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.
Gaziano L, Sun L, Arnold M, Bell S, Cho K, Kaptoge SK, Song RJ, Burgess S, Posner DC, Mosconi K, Robinson-Cohen C, Mason A, Bolton TR, Tao R, Allara E, Schubert P, Chen L, Staley JR, Staplin N, Altay S, Amiano P, Arndt V, Ärnlöv J, Barr ELM, Björkelund C, Boer JMA, Brenner H, Casiglia E, Chiodini P, Cooper JA, Coresh J, Cushman M, Dankner R, Davidson KW, de Jongh RT, Donfrancesco C, Engström G, Freisling H, de la Cámara AG, Gudnason V, Hankey GJ, Hansson PO, Heath AK, Hoorn EJ, Imano H, Jassal SK, Kaaks R, Katzke V, Kauhanen J, Kiechl S, Koenig W, Kronmal RA, Kyrø C, Lawlor DA, Ljungberg B, MacDonald C, Masala G, Meisinger C, Melander O, Moreno Iribas C, Ninomiya T, Nitsch D, Nordestgaard BG, Onland-Moret C, Palmieri L, Petrova D, García JRQ, Rosengren A, Sacerdote C, Sakurai M, Santiuste C, Schulze MB, Sieri S, Sundström J, Tikhonoff V, Tjønneland A, Tong T, Tumino R, Tzoulaki I, van der Schouw YT, Monique Verschuren WM, Völzke H, Wallace RB, Goya Wannamethee S, Weiderpass E, Willeit P, Woodward M, Yamagishi K, Zamora-Ros R, Akwo EA, Pyarajan S, Gagnon DR, Tsao PS, Muralidhar S, Edwards TL, Damrauer SM, Joseph J, Pennells L, Wilson PWF, Harrison S, Gaziano TA, Inouye M, Million Veteran Program Million Veteran Program, Baigent C, Casas JP, Langenberg C, Wareham N, Riboli E, Michael Gaziano J, Danesh J, Hung AM, Butterworth AS, Wood AM, Di Angelantonio E, Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program
DOI : 10.1161/CIRCULATIONAHA.122.060700
PubMed ID : 36314129
URL : https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.060700
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.
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.
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·1.73 m, compared with those with eGFR between 60 and 105 mL·min·1.73 m. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min·1.73 m, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min·1.73 m lower genetically predicted eGFR, but not for those with eGFR >105 mL·min·1.73 m. 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.
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.