Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1507-1517
Number of pages11
Issue number20
StatePublished - 15 Nov 2022


FundersFunder number
British United Provident Association UK Foundation
Catalan Institute of Oncology - ICO
Compagnia di SanPaolo
County Councils of Skåne
Department of Epidemiology and Biostatistics
Dutch Prevention Funds
Dutch ZON (Zorg Onderzoek Nederland
German Institute of Human Nutrition PotsdamRehbruecke
Health Data Research UK
Health Research Fund
LK Research Funds
Million Veteran Program
NIHR BTRUBTRU-2014-10024
Netherlands Cancer Registry
National Institute of Environmental Health SciencesP30ES005605
Office of Research and DevelopmentCH/12/2/29428, R01DK122075
Health Services Research and DevelopmentI01-BX003360, BX003362-01, I01-BX004821, CX001897, IK2-CX001780
Kræftens Bekæmpelse
Deutsches Krebsforschungszentrum
Centre International de Recherche sur le Cancer
Wellcome Trust
Seventh Framework ProgrammeHEALTH-F2-2012-279233
Sixth Framework ProgrammeMC_UU_12015/1, LSHM_CT_2006_037197, MC_UU_12015/5
National Research Council
Chief Scientist Office, Scottish Government Health and Social Care Directorate
University of Maryland School of Public Health
Medical Research CouncilMR/L003120/1, MR/M012190/1
Engineering and Physical Sciences Research Council
Economic and Social Research CouncilBCDSA\100005, ES/T013192/1
National Institute for Health and Care Research
British Heart FoundationRG/13/13/30194, SP/09/002, RG/18/13/33946
Department of Health and Social Care
Cancer Research UKC8221/A29017
World Cancer Research Fund
Imperial College London
European Research Council268834
Public Health Agency
Institut national de la santé et de la recherche médicale
Bundesministerium für Bildung und Forschung
Ministerie van Volksgezondheid, Welzijn en Sport
Ligue Contre le Cancer
Instituto de Salud Carlos III
Sixth Framework Programme
Associazione Italiana per la Ricerca sul Cancro
BHF Centre of Research Excellence, OxfordRE/18/1/34212
Deutsche Krebshilfe
Institut Gustave-Roussy
Mutuelle Générale de l'Education Nationale
Consejería de Salud y Familias, Junta de Andalucía
Health and Social Care Research and Development Division
UCLH Biomedical Research CentreBRC-1215-20014
NIHR Imperial Biomedical Research Centre
NIHR Cambridge Biomedical Research Centre


    • cardiovascular diseases
    • coronary disease
    • kidney diseases
    • stroke


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