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Clinical chemistry
03 04, 2022;68 (3): 461-472.

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

Alisa D Kjaergaard, Alexander Teumer, Daniel R Witte, Kira-Julia Stanzick, Thomas W Winkler, Stephen Burgess, Christina Ellervik
Author Information
  1. Alisa D Kjaergaard: Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark. ORCID
  2. Alexander Teumer: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. ORCID
  3. Daniel R Witte: Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
  4. Kira-Julia Stanzick: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
  5. Thomas W Winkler: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
  6. Stephen Burgess: MRC Biostatistics Unit, University of Cambridge, Cambridge, UK. ORCID
  7. Christina Ellervik: Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
PMID: 34922334 DOI: 10.1093/clinchem/hvab249

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.

Keywords

albuminuria blood urea nitrogen body mass index chronic diabetes mellitus glomerular filtration rate kidney function tests mendelian randomization analysis obesity renal insufficiency type 2 waist-hip ratio

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Grants

  1. RG/13/13/30194/British Heart Foundation
  2. 204623/Wellcome Trust
  3. MC_UU_00002/7/Medical Research Council
  4. 204623/Z/16/Z/Wellcome Trust
  5. RG/18/13/33946/British Heart Foundation
  6. CH/12/2/29428/British Heart Foundation

MeSH Term

Albumins
Albuminuria
Body Mass Index
Creatinine
Diabetes Mellitus, Type 2
Genome-Wide Association Study
Humans
Kidney
Mendelian Randomization Analysis
Obesity
Renal Insufficiency, Chronic

Chemicals

Albumins
Creatinine
Journal Article Meta-Analysis Research Support, Non-U.S. Gov't
Article has an altmetric score of 3

Word Cloud

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