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

Abstract

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.

Keywords: cardiovascular diseases; coronary disease; kidney diseases; stroke.

Figure 1.

Study design and overview. CHD indicates coronary heart disease; CKDGen, CKD Genetics consortium; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; EPIC-CVD, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease; ERFC, Emerging Risk Factors Collaboration; MVP, Million Veteran Program; NMR, nuclear magnetic resonance; and UKB, UK Biobank.

Figure 2.

Observational associations of eGFR levels with risk of coronary heart disease and stroke (n=648 135). Participants with missing information on age and CVD risk factors (systolic blood pressure, total and high-density lipoprotein cholesterol, body mass index, and smoking status) were excluded from the analyses. Hazard ratios were estimated using Cox regression, adjusting for age and CVD risk factors (systolic blood pressure, total and high-density lipoprotein cholesterol, body mass index, and smoking status), and stratified by sex and study center. The reference point is 90 mL·min^–1·1.73 m^–2. Shaded regions indicate 95% CIs. CVD indicates cardiovascular disease; and eGFR, estimated glomerular filtration rate.

Figure 3.

Associations of genetically predicted eGFR with risk of coronary heart disease and stroke (n=413 718). The reference point is 90 mL·min^–1·1.73 m^–2. Gradients at each point of the curve represent the localized average causal effect on coronary heart disease or stroke per 5 mL·min^–1·1.73 m^–2 change in genetically predicted eGFR. The vertical lines represent 95% CIs. Analyses were adjusted for age, age-squared, sex, study center, and the first 10 principal components of ancestry. eGFR indicates estimated glomerular filtration rate.