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Abstract: SA-PO275

Endothelin Receptor Antagonists (ERAs) May Protect Against Rapid Kidney Function Decline: A Drug-Target Mendelian Randomization Study

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Ma, Yixin, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Xu, Lubin, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Zhao, Ruohuan, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Chen, Limeng, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
Background

Currently, the efficacy of ERAs to treat kidney disease is being tested in randomized controlled trials, positive effect in reducing albuminuria, preserving eGFR, and lower blood pressure has been reported. However, evidence from large randomized controlled trials comprehensively comparing the long-term renal effects of ERAs is lacking.

Methods

We applied a two-sample Mendelian Randomization approach to evaluate the causal effect of genetically mimicked ERA-induced blood pressure lowering on a series of kidney outcomes. Endothelin receptor (EDNR) SNPs associated with blood pressure and EDNR expression level were selected using GWAS summary data from the International Consortium of Blood Pressure (ICBP) and GTEx. GWAS summary statistics on kidney outcomes, including eGFR, proteinuria, and rapid kidney function decline, were drawn from CKDGen. We use fixed effects inverse variance weighted (IVW) meta-analysis of SNP-specific Wald estimates for primary analysis,the weighted median and MR-Egger methods for sensitivity analysis.

Results

Four EDNRA SNPs and no EDNRB SNPs met the inclusion criteria. Genetic mimicry of EDNRA blockage was associated with a lower risk of rapid kidney function decline (OR = 0.39, 95% CI = 0.20-0.79 for eGFR decline>25%, OR = 0.57, 95% CI = 0.36-0.92 for eGFR decline>3 unit per year) and a higher eGFR based on creatinine (β = 0.02, 95% CI = 0.01-0.04). Despite the significant proteinuria-lowering effect reported in clinical trials, we do not observe a causal effect for EDNRA inhibition on UACR, in the general population or the population with diabetes at baseline.

Conclusion

Mendelian randomization study suggests ERAs may protect against rapid kidney function decline through the blood pressure-lowering effect induced by EDNRA blockage.

A: Study Design. B: The OR and 95% CI indicate the effect estimates of decrease in disease risk per 10 mmHg lowering of SBP via EDNRA inhibition.

Funding

  • Government Support – Non-U.S.