Association between obesity and chronic kidney disease: multivariable Mendelian randomization analysis and observational data from a bariatric surgery cohort

Obesity is postulated to independently increase chronic kidney disease (CKD), even after adjusting for type 2 diabetes (T2D) and hypertension. Dysglycemia below T2D thresholds, frequently seen with obesity, also increases CKD risk. Whether obesity increases CKD independent of dysglycemia and hypertension is unknown and likely influences the optimal weight loss (WL) needed to reduce CKD. T2D remission rates plateaus with 20-25%WL postbariatric surgery (BS) but further WL increases normoglycemia/normotension.

We undertook bidirectional inverse variance weighted Mendelian randomization (IVMR) to investigate potential independent causal associations between increased BMI and CKDeGFR (estimated glomerular filtration rate, eGFR < 60 ml/min1.73m2) and microalbuminuria (MA). In 5337 BS patients, we assessed whether WL influences >50% decline in eGFR (primary outcome) or CKD hospitalization (secondary outcome) using <20% WL as a comparator.

IVWMR suggests increased BMI increases CKDeGFR (beta=0.13, p=1.64×10-4), Odds ratio, OR (95% confidence interval, CI)=1.14(1.07-1.23) and MA (b=0.25, p=2.14 x 10-4,OR(95%CI)=1.29(1.13-1.48). After adjusting for hypertension and fasting glucose, increased BMI did not significantly increase CKDeGFR (b=-0.02, p=0.72), OR(95%CI)=0.98(0.87-1.1) or MA (b=0.19, p=0.08, OR (95%CI)=1.21 (0.98, 1.51).

Post-BS WL significantly reduced the primary outcome with 30-<40%WL (Hazard ratio HR=0.53, 95%CI=0.32-0.87), but not 20-<30%WL (HR=0.72, 95%CI=0.44-1.2) and ≥40%WL (HR=0.73, 95%CI=0.41-1.30). For CKD hospitalization, progressive reduction was seen with increased WL which was significant for 30-<40%WL (HR=0.37, 95%CI=0.17-0.82) and ≥40%WL (HR=0.24, 95%CI=0.07-0.89), but not 20-30%WL (HR=0.60, 95%CI=0.29-1.23).

The data suggests obesity is likely not an independent cause of CKD. WL thresholds previously associated with normotension and normoglycemia, likely causal mediators, may reduce CKD post-BS.