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OBESITY AS A CAUSE OF KIDNEY DISEASE - INSIGHTS FROM MENDELIAN RANDOMISATION STUDIES

Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. We aim to examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease.

We performed conventional observational and Mendelian randomisation (MR) study to examine if modifiable anthropometric indices of obesity exert putatively causal effects on different kidney health and disease-related phenotypes. These analyses were conducted using approximately 300,000 participants of white-British ancestry from UK Biobank and up to 480,000 participants of predominantly European ancestry from genome-wide association studies.

The Mendelian randomisation analysis indicated that increasing values of genetically predicted BMI and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration (P_{eGFRcystatineC}=5.96 × 10^-59 for BMI and P_{eGFRcystatineC}=1.72 × 10^-69 for waist circumference) and increased blood urea nitrogen (P_BUN=2.01 × 10^-10 for BMI and P_BUN=4.54 × 10^-12 for waist circumference) in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals (P_{eGFRcystatineC}=1.47 × 10^-5 for BMI and P_{eGFRcystatineC}=7.63 × 10^-5 for waist circumference; P_BUN=1.96 × 10^-4 for BMI and P_BUN=3.10 × 10^-3 for waist circumference). One standard deviation increase in genetically-predicted BMI and waist circumference decreased the relative odds of kidney health index by 14% and 18% (OR=0.86; 95%CI: 0.82-0.92; P=9.18 × 10^-6 for BMI and OR=0.82; 95%CI: 0.75-0.90; P=2.12 × 10^-5 for waist circumference). Approximately 13-16% of the causal effect of obesity indices on kidney health was mediated by blood pressure. Obesity increased the risk of both acute and chronic kidney disease of several aetiologies including hypertensive renal disease (OR=1.79; 95%CI: 1.14-2.82; P=1.15 × 10^-2 for BMI and OR=2.41; 95%CI: 1.30-4.45; P=5.03 × 10^-3 for waist circumference), renal failure (OR=1.51; 95%CI: 1.25-1.83; P=2.60 × 10^-5 for BMI and OR=1.86; 95%CI: 1.43-2.42; P=4.16 × 10^-6 for waist circumference) and CKD (OR=1.50; 95%CI: 1.16-1.96; P=2.44 × 10^-3 for BMI and OR=1.83; 95%CI: 1.28-2.63; P=9.49 × 10^-4 for waist circumference) and diabetic nephropathy (OR=1.92; 95%CI: 1.44-2.54; P=6.86 × 10^-6 for BMI).

These findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease.