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

Abstract

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 m2]. 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 m2) 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 (β: −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 (β: 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.

Causal linkage between adult height and kidney function: An integrated population-scale observational analysis and Mendelian randomization study

“…Therefore, MR analysis is widely adopted in the medical literature to investigate causative pathways between complex exposure and outcome traits, also benefiting from the recent availability of large-scale genetic data [14]. MR analysis has also been recently implemented in the field of nephrology to reveal risk factors for CKD [15][16][17][18][19][20].…”

“…Here, we present a cross-sectional observational study and an MR analysis focusing on causal effects of adult height on eGFR in middle-aged to elderly individuals. Along with our recent efforts to identify causative factors for kidney function through MR investigations [15][16][17][18], we hypothesized that a taller adult height, as adjusted for the effects of BMI, would be causally linked to lower kidney function in the middle-aged to elderly population.…”

Nutritional and dietary interventions to prolong renal allograft survival after kidney transplantation

“…A recent observational cohort study mainly based on the UK Biobank utilizing Mendelian randomization analysis demonstrated no association between carbohydrate intake and risk of ESKD in participants with eGFR !60 ml/min/1.73 m 2 [42].…”

“…Kidney injury was resulted in part from tissue lipid accumulation, increased oxidative stress, and mitochondrial dysfunction, which promotes excess programmed cell death [48]. The aforementioned study using two-sample Mendelian randomization showed that increased relative fat intake causally increased the risk of CKD [42].…”

Vexed causal inferences in nutritional epidemiology—call for genetic help

“… 75 Implementing these single nucleotide polymorphisms (SNPs) in a two-sample Mendelian randomization setting, Park et al were able to assess the causal associations of relative macronutrient intake on the risk of chronic kidney disease (CKD). 76 Their results suggested that, for a given level of total calorie intake, the composition of macronutrient intake would causally affect the risk of CKD. Thus, reducing relative fat intake and increasing relative protein intake may causally reduce the risk of CKD in the general population.…”