Obesity and Kidney Function: A Two-Sample Mendelian Randomization Study

Abstract

Background Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). Methods Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses. Results One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=−0.032 (95% confidence intervals: −0.036, −0.027) log[eGFR], P = 1 × 10−43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10−6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04–1.28], P = 0.009] and CKD [1.13 (1.07–1.19), P = 3 × 10−6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR. Conclusions Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

The risk for chronic kidney disease in metabolically healthy obese patients: A systematic review and meta‐analysis

“…Obesity has been linked to increased risk for CKD according to multiple large‐scale meta‐analysis study 32,33 ; nevertheless, the risk appears to be directly correlated with metabolic syndrome parameters such as abdominal obesity, hypertriglyceridemia, hypertension and low HDL levels 34 . A meta‐analysis study conducted in 2017 over 630.677 participants with a mean follow‐up period of 6.8 years demonstrated that obesity with or without metabolic abnormalities has been associated with a decline in eGFR and risk of albuminuria, whereas, no such association has been recorded in overweight participants 35 .…”

Early life body mass index trajectories and albuminuria in midlife: A 30-year prospective cohort study

“…Obesity is an established risk factor for hypertension, diabetes, CVD, and CKD. 8 , 9 , 10 , 11 , 12 Many studies have identified an increased risk of albuminuria with higher body mass index (BMI) in the general adult population. 13 , 14 , 15 Obesity begins in childhood, and childhood BMI predicts obesity and other long-term health outcomes in adulthood.…”

Waist–hip ratio measured by bioelectrical impedance analysis as a valuable predictor of chronic kidney disease development

“…However, because of the study design, causality between obesity metrics and eGFR can not be suggested. Kjaergaard et al used Mendelian Randomization method to estimate direct causal effect of BMI and WHR on kidney function [ 31 ]. Kjaergaard et al focused on the verification of causality between specific body composite factor and renal dysfunction, while our study conducted for finding best predictor among body composite metrics of kidney dysfunction.…”