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Published on: May 2, 2025
Causal Effects From Kidney Function to Plasma Proteome: Integrated Observational and Mendelian Randomization Analysis
Jeong Min Cho1,2, Minsang Kim3, Jaeik Oh1,3
1Department of Translational Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Insights
Reduced kidney function causally impacts 383 plasma proteins, with 381 increasing, particularly those linked to inflammation and apoptosis. Tumor necrosis factor (TNF) pathways are key in chronic kidney disease progression.
Area of Science:
- Proteogenomics
- Systems biology
- Nephrology
Background:
- Chronic kidney disease (CKD) significantly increases morbidity and mortality due to systemic effects like inflammation and apoptosis.
- The precise causal links between diminished kidney function and systemic proteomic changes remain unclear.
Purpose of the Study:
- To investigate the causal relationship between estimated glomerular filtration rate (eGFR) and plasma protein levels.
- To identify specific plasma proteins and pathways affected by reduced kidney function.
Main Methods:
- Integrated Mendelian randomization (MR) and observational analyses.
- Utilized UK Biobank data (50,407 participants) and CKDGen Phase 4 GWAS meta-analysis.
- Analyzed 1815 plasma protein profiles.
Main Results:
- Identified 383 plasma proteins causally associated with eGFR.
- Reduced kidney function increased 381 protein levels (e.g., TNF, IGFBP4) and decreased 2 (NPHS1, SPOCK1).
- Apoptosis pathways were enriched; TNF emerged as a hub protein in inflammation and fibrosis pathways.
Conclusions:
- 383 plasma proteins are causally linked to eGFR.
- TNF-associated pathways are critical in kidney disease progression, systemic inflammation, and organ fibrosis.
- Further research into these pathways is warranted.
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.
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