Causal effects of relative fat, protein, and carbohydrate intake on chronic kidney disease: a Mendelian randomization study

Background: The effects of specific macronutrients on kidney function independent of total calorie intake have rarely been studied, although the composition of macronutrient intake has been reported to affect health outcomes. Objectives: We aimed to investigate the effects of macronutrient intake ratios on the risk of chronic kidney disease (CKD) by Mendelian randomization (MR) analysis. Methods: The study was an observational cohort study mainly based on the UK Biobank and including MR analysis. First, we evaluated the relative baseline macronutrient composition-that is, the number of calories from each macronutrient divided by total calorie intake-of the diets of UK Biobank participants, and we used Cox regression to assess the incidence of end-stage kidney disease (ESKD) in 65,164 participants with normal kidney function [estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m(2)]. We implemented a genetic instrument for relative fat, protein, and carbohydrate intake developed by a previous genome-wide association study (GWAS) and performed MR analysis. Two-sample MR was performed with the summary statistics from independent CKDGen GWAS for kidney function traits (n = 567,460), including CKD (eGFR <60 mL/min/1.73 m(2)) and log-transformed eGFR. Results: The median relative macronutrient intake composition at baseline was 35% fats, 15% protein, and 50% carbohydrates. Higher relative protein intake in subjects with normal kidney function was significantly associated with a lower risk of incident ESKD (HR: 0.54; 95% CI: 0.30, 0.95) in the observational investigation. Two-sample MR indicated that increased relative fat intake causally increased the risk of kidney function impairment [CKD (OR: 1.94; 95% CI: 1.39, 2.71); log eGFR (beta: -0.036; 95% CI: -0.048, -0.024)] and that higher relative protein intake was causally linked to a lower CKD risk [CKD (OR: 0.50; 95% CI: 0.35, 0.72); log eGFR (beta: 0.044; 95% CI: 0.030, 0.058)]. Conclusions: A desirable macronutrient composition, including high relative protein intake and low relative fat intake, may causally reduce the risk of CKD in the general population.