Obesity as a cause of kidney disease – insights from Mendelian randomisation studies
Authors: Xu Xiaoguang , Eales James M. , Jiang Xiao , Sanderson Eleanor , Scannali David , Morris Andrew P. , Guzik Tomasz J. , Charchar Fadi J. , Holmes Michael V. , Tomaszewski Maciej 
Published: September 2020

AbstractObjectiveTo examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease.DesignConventional observational and Mendelian randomisation study.SettingUK Biobank and international genome-wide association studies.ParticipantsApproximately 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 measuresEstimated 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.ResultsThe 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=0·86; 95%CI: 0·82-0·92; P=9·18×10-6for BMI and OR=0·82; 95%CI: 0·75-0·90; P=2·12×10-5for 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.ConclusionsThese 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.What is already known on this topic-Several previous studies reported associations between increasing adiposity/obesity and either a decline in kidney function or the increased risk of specific kidney disorders.-High blood pressure and diabetes represent the two most common aetiologies of chronic kidney disease and co-exist with obesity.-It is not clear to what extent these associations may reflect cause-effect relationships.What this study adds-Our results show a consistent pattern of causation between obesity and kidney health and disease, across different biochemical parameters of kidney function and a broad spectrum of kidney health/disease.-We further demonstrate that the causal effect of obesity on kidney health is partially mediated by blood pressure and largely independent of type 2 diabetes.-We provide evidence for a causal relationship between two clinical indices of obesity and specific renal disorders including hypertensive renal disease, acute renal failure, chronic kidney disease and diabetic nephropathy.