Causal Effects From Kidney Function to Plasma Proteome: Integrated Observational and Mendelian Randomization Analysis With >50,000 UK Biobank Participants

ABSTRACT Purpose Chronic kidney disease (CKD) causes detrimental systemic effects, including inflammation or apoptosis, which lead to substantial morbidity and mortality. However, the causal effect of reduced kidney function on systemic proteomic signatures is incompletely understood. Methods We performed an integrated Mendelian randomization (MR) and observational analyses to identify the causal association between kidney function and plasma protein levels, based on 1815 plasma protein profiles in 50,407 UK Biobank participants and the CKDGen Phase 4 genome‐wide association study (GWAS) meta‐analysis for the genetic instruments of eGFR. Results The MR analysis revealed 383 plasma proteins causally associated with eGFR. Reduced kidney function was found to be causally associated with an increase in the plasma levels of 381 proteins, among which TNF and IGFBP4 were increased, while the level of two proteins, NPHS1 and SPOCK1, decreased. Apoptosis‐related pathway was significantly enriched in the gene‐set enrichment analysis. In network analysis, TNF was identified as a hub protein with multiple linkages to molecules included in the TNF‐signaling pathways, involved in inflammation, fibrosis, and apoptosis. Conclusions In this proteo‐genomic analysis, we identified 383 plasma proteins causally associated with eGFR, highlighting TNF‐associated pathways as pathologically relevant processes in kidney disease progression, systemic inflammation, and organ fibrosis, warranting further investigation.