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Updated: Aug 23, 2025
Assessment of Vascular Function in Patients With Chronic Kidney Disease
Published on: June 16, 2014
Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses
Liam Gaziano1,2,3, Luanluan Sun1,2, Matthew Arnold
1Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (L.G., K.C., R.J.S., D.C.P., P.S., J.J., J.P.C., J.M.G.).
Insights
Mild-to-moderate kidney dysfunction causally increases coronary heart disease (CHD) risk in individuals without prior cardiovascular disease or diabetes. This finding emphasizes the importance of kidney function preservation for cardiovascular health.
Area of Science:
- Nephrology
- Cardiology
- Genetics
Background:
- End-stage renal disease (ESRD) is a known risk factor for cardiovascular events.
- The causal relationship between mild-to-moderate kidney dysfunction and coronary heart disease (CHD) or stroke remains unclear.
Purpose of the Study:
- To investigate the causal link between estimated glomerular filtration rate (eGFR) and the risk of incident CHD and stroke.
- To determine if impaired kidney function, even in its early stages, contributes to cardiovascular disease development.
Main Methods:
- Utilized individual-level data from four large population studies (Emerging Risk Factors Collaboration, EPIC-CVD, Million Veteran Program, UK Biobank).
- Conducted Mendelian randomization analyses using a genetic risk score for eGFR in over 413,000 participants.
- Analyzed incident CHD and stroke events over 6.8 million person-years of follow-up.
Main Results:
- Observational analyses revealed U-shaped associations between eGFR and cardiovascular risk.
- Mendelian randomization showed a 14% increased CHD risk per 5 mL·min⁻¹·1.73 m⁻² lower genetically predicted eGFR in participants with eGFR <60 mL·min⁻¹·1.73 m⁻².
- No significant association was found for eGFR >105 mL·min⁻¹·1.73 m⁻²; stroke results were nonsignificant but consistent.
Conclusions:
- Mild-to-moderate kidney dysfunction is causally associated with an increased risk of CHD in individuals without pre-existing cardiovascular disease or diabetes.
- These findings underscore the significance of maintaining and managing kidney function as a preventive strategy for cardiovascular health.
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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