Abstract
Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13-16% and 21-26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.
Highlights
Chronic kidney disease (CKD) affects more than 10% of adults worldwide and is predicted to become a global threat to public health.[1]
Further sensitivity analyses confirmed that association estimates between obesity measures and measures of kidney function remained largely unaffected by inclusion/exclusion of genetic variants mapping onto genes related to metabolism of creatinine/cystatin C/blood urea nitrogen (BUN) (TableS3) and that there is no evidence for bidirectional causality between obesity measures and kidney function (TableS8)
The association between body mass index (BMI) and/or waist circumference (WC) and different measures of kidney health and disease have been reported before in observational studies – increasing obesity correlates with increased incidence of CKD,[4–7] end-stage renal disease[8] and a drop in estimated glomerular filtration rate (eGFR) calculated based on serum levels of creatinine[9] or cystatin C.5
Summary
Chronic kidney disease (CKD) affects more than 10% of adults worldwide and is predicted to become a global threat to public health.[1]. MR does not require the resources or time consumed by RCT, is safe and generally robust.[23,24] It relies on randomly assigned (at meiosis) genetic variants as proxies (or instruments) for an exposure (e.g. a modifiable lifestyle factor) to examine its putative causal effect on a clinical outcome. Most recently, based on studies embedded largely in one-sample MR, Censin et al.[30] and Zhu et al.[31] showed that increasing values of BMI/waist-hip ratio were associated with increased risk of renal failure/CKD Using both one-sample and complementary two-sample MR analyses we have shown that obesity-related traits show potentially causally association with many different dimensions of kidney heath and disease – from physiological measures of kidney function to kidney diseases of several aetiologies. Through exploitation of information derived from kidney transcriptome we provide important biological context to statistical findings on hypertension and diabetes as potential mediators of causal associations between obesity and renal health/disease contemplated in this and other publications.[13,31]
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