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Abstract: SA-PO817

A Causal Relationship Between Body Mass Index and AKI Is Mediated by the Metabolome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Triozzi, Jefferson Lorenzo, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Lo, Claire, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Siew, Edward D., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Hung, Adriana, VA Tennessee Valley Healthcare System, Nashville, Tennessee, United States

Group or Team Name

  • Million Veteran Program.
Background

Obesity is a known risk factor for chronic kidney disease, but its association with acute kidney injury is unclear. We investigated the causal relationship between body mass index (BMI), the metabolome, and acute kidney injury (AKI) using a Mendelian randomization (MR) experiment.

Methods

We performed MR using genome-wide association summary statistics of BMI as the exposure (GIANT Consortium, n = 681,275), the metabolome as a mediator (MuTHER Consortium, n = 7,822), and AKI as the outcome (FinnGen Consortium, n = 2,383 cases, n = 212,841 controls). First, a two-sample MR tested the association of AKI on BMI using the inverse variance weighted (IVW) primary analysis, and the weighted median, weighted mode, and MR-Egger regression sensitivity analyses. We then applied multi-step and multivariable MR to integrate the role of the metabolome. In the first step, metabolome-wide MR identified causal relationships between BMI and metabolites. In the second step, univariable MR identified causal relationships between metabolites and acute kidney injury. Finally, multivariable MR assessed the indirect effect of BMI on AKI as mediated by metabolites.

Results

BMI demonstrated a causal relationship with AKI in the IVW (β= 0.56, SE = 0.097, p < 5.85E-09), weighted median (β= 0.55, SE = 0.17, p < 1.17E-03), weighted mode (β= 0.58, SE = 0.28, p = 0.03), and MR-Egger regression analyses (β= 0.617, SE=0.26, p=0.01). There were 14 significant BMI-metabolite relationships (p < 1.11E-04), of which there was 1 suggestive metabolite-AKI relationship (p < 0.05). This yielded a putative pathway between BMI, metabolonic lactone sulfate, and AKI. In the multivariable MR analysis, the indirect effect of BMI on AKI via the metabolome was 0.52925.

Conclusion

The causal relationship between BMI and AKI may be partially mediated by the metabolome, particularly metabolonic lactone sulfate. This metabolite has known associations with cardiometabolic health, with possible influence on blood pressure, lipid metabolism, and insulin resistance. This is the first report connecting this metabolite with AKI. The MR methodology supports a causal relationship and is less susceptible to confounding and reverse causation biases. Mechanisms linking obesity, the metabolome, and kidney outcomes deserve further investigation.

Funding

  • Veterans Affairs Support