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Obesity as a cause of kidney disease - insights from Mendelian randomisation studies

Objective: To examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease. Design: Conventional observational and Mendelian randomisation study. Setting: UK Biobank and international genome-wide association studies. Participants: 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. Main outcome measures: Estimated glomerular filtration, blood urea nitrogen, kidney health index, chronic kidney disease, hypertensive renal disease, renal failure, acute renal failure, other disorders of kidney and ureters, IgA nephropathy and diabetic nephropathy. Results: The Mendelian randomisation analysis indicated that increasing values of genetically predicted body mass index (BMI) and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration and increased blood urea nitrogen in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals. 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{middle dot}86 ; 95%CI: 0{middle dot}82-0{middle dot}92 ; P=9{middle dot}18x10-6 for BMI and OR=0{middle dot}82 ; 95%CI: 0{middle dot}75-0{middle dot}90 ; P=2{middle dot}12x10-5 for waist circumference, respectively). 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 and diabetic nephropathy. Conclusions: 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.