Conventional and Genetic Evidence on the Association between Adiposity and CKD

Abstract

BackgroundThe size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown.MethodsData from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR).ResultsEvidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively.ConclusionsGenetic analyses suggest that 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 most of adiposity-CKD–associated risk.

Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics

“…with smoking, as reported before. 30,31 However, our further sensitivity analyses, e.g. those based on exclusion of such instruments from genetic scores confirmed the validity of our findings.…”

Body mass index and chronic kidney disease outcomes after acute kidney injury: a prospective matched cohort study

“…Recent evidence which added genetic information to risk models, demonstrates that the independent risk of obesity on CKD outcomes is likely causal, however the associated risk is lower than observational studies using conventional methods suggested [ 40 ]. Furthermore, much of the BMI associated risk for CKD in the genetic models is attributable to diabetes and hypertension [ 40 ].…”

“…Recent evidence which added genetic information to risk models, demonstrates that the independent risk of obesity on CKD outcomes is likely causal, however the associated risk is lower than observational studies using conventional methods suggested [ 40 ]. Furthermore, much of the BMI associated risk for CKD in the genetic models is attributable to diabetes and hypertension [ 40 ]. In longitudinal cohort models such as ours, which included diabetes and hypertension as potential confounders, plus the added insult of AKI, it is possible that the small impact attributable to BMI is made negligible by the AKI, and possibly also by the episode of illness leading to hospitalization, as we also did not find evidence of BMI as a risk factor for CKD in this population, with or without AKI.…”

Causal effects of life course adiposity on chronic kidney disease: a Mendelian randomization study

“…Further explorations were necessary to better understand whether body fat from other parts of the body might influence the risk of CKD. In a similar manner, another study investigated the association between CKD and adiposity measured by BMI and WHR using summary statistics from different GWAS (13). In this study, the author identified causal association between both WHR and BMI with CKD.…”

“…Nevertheless, these observational studies might be influenced by the possibility of selection bias, information bias, confounding factors and reverse causation (11). Two pervious studies investigated the causal association between CKD and obesity traits including BMI and WHR from a genetic perspective (12,13), but no systematic analysis has been conducted to investigate the life course adiposity and CKD. Therefore, whether life course obesity/adiposity, taken as a whole, has a causal effect on the risk of CKD remains largely unknown.…”