Glucagon-like peptide-1 receptor agonists, inflammation, and kidney diseases: evidence from Mendelian randomization.

OBJECTIVE

It has been proved that glucagon-like peptide-1 receptor (GLP1R) agonists have positive effects on renal outcomes in diabetic patients. However, it remains unknown whether GLP1R agonists could provide similar protection against other kidney diseases.

METHODS

We performed two-sample Mendelian randomization (MR) analyses to determine the causal effects of GLP1R agonists on multiple kidney diseases. Exposure to GLP1R agonist was proxied by the available cis-eQTLs for GLP1R. Primary outcomes included the risk assessment for diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute glomerulonephritis, chronic glomerulonephritis and calculus of kidney/ureter. Type 2 diabetes and body mass index were used as positive control. Two-stage network MR analyses were conducted to assess the mediation effect of inflammatory proteins on the relationships between GLP1R agonists and kidney diseases.

RESULTS

After meta-analyses of both discovery and validation cohorts, genetically proxied GLP1R agonist was found to significantly associated with a decreased risk of diabetic nephropathy (OR = 0.72, 95%CI = 0.54-0.97,  = 0.031) and IgA nephropathy (OR = 0.58, 95%CI = 0.36-0.94,  = 0.027). Two-stage network MR revealed that there was an indirect effect of GLP1R agonist on IgA nephropathy through signaling lymphocytic activation molecule family member 1 (SLAMF1), with a mediated proportion of 34.27% (95% CI, 1.47-67.03%,  = 0.041) of the total effect.

CONCLUSIONS

The findings of current study presented genetic proof for the potential protective effects of GLP1R agonists in the development of diabetic nephropathy and IgA nephropathy, offering a novel sight for future mechanistic and clinical applications.