What is the clinical evidence from this study?

Study design: Observational. Population: Chronic Kidney Disease. Intervention: Genetically higher body mass index (BMI) vs. Genetically lower BMI. Primary outcome: Chronic kidney disease (CKD) (OR 1.13, 95% CI 1.07-1.19, p=3x10-6).

November 3, 2021Open Access

Obesity and Kidney Function: A Two-Sample Mendelian Randomization Study

Key Result

Genetically higher body mass index (1 SD increase) was associated with decreased estimated glomerular filtration rate and an increased risk of chronic kidney disease (OR 1.13).

Study Design

Type

Observational

Randomization

Mendelian randomization

Multicenter

Yes

Structured PICO

Does genetically predicted higher BMI or WHR cause impaired kidney function?

Population

Individuals of European ancestry and trans-ethnic populations from GIANT, DIAGRAM, and CKDGen consortia

Intervention

Genetically predicted higher body mass index (BMI) and waist-to-hip ratio (WHR)

Comparator

Genetically predicted lower BMI and WHR

Outcome

Kidney function outcomes including eGFRcysC, eGFRcreaCKD-EPI, BUN, annual eGFRcreaMDRD decline, UACR, microalbuminuria, and CKDsurrogate

Genetically predicted high BMI is causally associated with impaired kidney function and increased risk of CKD, driven primarily by adverse obesity.

Main Result

Effect estimate: OR 1.13 (95% CI 1.07-1.19)

p-value: p=3x10-6

Limitations

Inability to investigate potentially nonlinear associations between obesity and kidney function due to the use of summary data.
Substantial overlap of participants in the GWASs included in the two-sample MR, which could have biased the estimates.
Potential bias in the multivariable MR approach due to overlapping samples.
Annual eGFR decline analysis was based on eGFRcrea and a relatively small sample size, particularly for the CKD subpopulation.

Abstract

BACKGROUND: Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). METHODS: Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses. RESULTS: One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR, P = 1 × 10-43], increased blood urea nitrogen (BUN) β = 0.010 (0.005, 0.015) log[BUN, P = 3 × 10-6], increased urinary albumin-to-creatinine ratio β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR), P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria odds ratios (OR) = 1.15 [1.04-1.28, P = 0.009] and CKD 1.13 (1.07-1.19), P = 3 × 10-6. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR. CONCLUSIONS: Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

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