Causal Effect of Kidney Function on Lipid Metabolism: An Integrated Population-Scale Observational Analysis and...

Additional investigations into the causal effects of kidney function on various metabolites, particularly lipoprotein lipids in detailed subfractions of lipoprotein particles, in the general population are warranted.

Integrated cross-sectional observational and Mendelian randomization (MR) analyses.

We included 157,541 participants aged 40-69 years from the UK Biobank study, a population-scale prospective cohort. Genetic instruments for estimated glomerular filtration rate (eGFR) were developed from the Chronic Kidney Disease Genetics genome-wide association study meta-analysis results, which comprised 567,460 individuals of European ancestry.

eGFR for observational analysis and genetically predicted eGFR for MR analysis.

Each of the 178 metabolites from recently updated metabolomics data, including detailed lipoprotein components within 14 subclasses of lipoprotein particles.

Observational analysis was performed using multivariate linear regression adjusted for various clinicodemographic characteristics. A 2-sample MR analysis was performed using the random-effects inverse-variance weighted method as the main MR method.

In the integrated results of the observational and MR analyses, 25 metabolites were causally associated with eGFR. A lower eGFR causally decreased lipoprotein components of high-density lipoprotein and several of its subclasses, particularly medium-sized high-density lipoprotein. Conversely, a lower eGFR causally increased triglyceride levels in smaller-sized very low-density lipoprotein and intermediate-density lipoprotein, as well as increased lipoprotein particle concentrations and total lipids in small very low-density lipoprotein. Additionally, a lower eGFR causally increased the ratio of monounsaturated fatty acids to total fatty acids and that of apolipoprotein B to apolipoprotein A-1.

Possibility of false-negative findings when integrating observational and MR analyses.

Decreased kidney function causally aggravates lipoprotein lipid profiles; therefore, clinicians should closely monitor the lipid profiles of individuals with impaired kidney function.