Kidney Week

Abstract: FR-PO650

Causal Association between Plasma Oxalate and Kidney Disease: Mendelian Randomization Analysis

Session Information

• Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Bowers, Jade E., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jade E. Bowers

• Triozzi, Jefferson Lorenzo, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jefferson Lorenzo Triozzi, MD

• Sosa, Piera A., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Piera A. Sosa, MD

• Yu, Zhihong, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Zhihong Yu, MS, PhD

• Wilson, Otis D., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Otis D. Wilson

• Wang, Guanchao, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Guanchao Wang, MS

• Hsi, Ryan, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ryan Hsi, MD

• Roumie, Christianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Christianne Roumie, MD

• Hung, Adriana, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Adriana Hung, MD, MPH

Group or Team Name

• Million Veteran Program.

Background

Elevated urinary oxalate contributes to tubulointerstitial fibrosis and kidney disease progression. Plasma oxalate, however, is elevated in patients with kidney disease due to reduced filtration raising the question of whether plasma oxalate is a consequence of kidney disease or a causal factor in its development. This study investigated the potentially causal association between plasma oxalate and kidney disease.

Methods

We performed a mendelian randomization experiment to assess the effect of genetically determined plasma oxalate levels on kidney outcomes within the Million Veteran Program (MVP). The exposure was derived from a genome-wide association study (GWAS) of plasma metabolite levels measured using the Metabolon platform among European ancestry individuals (N = 6,136). The MVP outcomes were derived from GWASs of eGFR (N = 397,650), chronic kidney disease (CKD), and end stage renal disease (ESRD), with an additional urine protein-to-creatinine ratio outcome from the CKDGen Consortium. The mendelian randomization experiment was conducted utilizing the inverse variance weighted (IVW) analyses. Sensitivity analyses were performed in subgroups with or without diabetes mellitus (DM).

Results

In the mendelian randomization IVW analysis, higher genetically determined plasma oxalate levels were associated with increased risk of CKD (OR 1.12, 95% CI [1.03, 1.21], p-value = 0.007). In the sensitivity analyses, the non-DM patients did not show a significant effect but the DM patients showed a significant effect for all outcomes: eGFR (p-value = 0.01), CKD (p-value 0.04), and ESRD (p-value = 0.01).These genetic associations did not show evidence of heterogeneity or directional pleiotropy, supporting a potentially causal relationship.

Conclusion

Our genetic association study supports the hypothesis that increased plasma oxalate levels may increase the risk of kidney disease, especially among patients with DM. Further investigation of the mechanisms underlying this association including but not limited to genetic and dietary contributions.

Funding

• Veterans Affairs Support