Conventional and genetic evidence on the association between adiposity and chronic kidney disease

Background: The size of any causal contribution of central and general adiposity to chronic kidney disease (CKD) risk and the underlying mechanism of mediation are unknown. Methods: 281,228 UK Biobank participants were included in estimates of the relevance of waist-to-hip ratio and body-mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses employed Mendelian Randomisation and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes and blood pressure [BP]) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (i.e. multivariable MR). Results: 18,034 (6.4%) participants had evidence of CKD. Each 0.06 higher measured waist-to-hip ratio and 5 kg/m2 were associated with a 69% (odds ratio 1.69, 95%CI 1.64-1.74) and 58% (1.58, 1.55-1.62) higher odds of CKD. In analogous MR analyses each 0.06 genotype-predicted higher waist-to-hip ratio was associated with a 29% (1.29, 1.20-1.38) increased odds of CKD, and each 5 kg/m2 genotype-predicted higher BMI, a 49% increased odds (1.49, 1.39-1.59). After conventional models were adjusted for diabetes mellitus and measured BP, 2 values for associations for waist-to-hip ratio and BMI reduced by 56%. In contrast, mediator adjustment using multivariate MR found 83% and 69% reductions in 2 values for genotype-predicted waist-to-hip ratio and BMI models, respectively. Conclusions: Genetic analyses suggest conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP and their correlates. Genetic approaches suggest these mediators explain the majority of adiposity-CKD associated risk.