A Multiomics Study of Circulating Proteins and Kidney Stone Risk

Background: Kidney stones are increasingly recognized as a systemic disorder with a high global prevalence. However, large proteomics studies are lacking. Methods: An individual-level proteomics study with rigorous adjustments was performed on 35,331 UK Biobank participants to uncover the independent associations between 2922 circulating proteins and prevalent kidney stone disease. Mendelian randomization (MR) analysis was utilized to assess causal relationships. Findings were validated using genomic data from the Mayo Clinic Biobank (MCBB, N=43,744), concentration-response analysis, transcriptomics analyses, and additional genome-wide association studies (GWAS). Results: Nine plasma proteins were independently associated with a kidney stone diagnosis, including reduced uromodulin (UMOD; β = -0.10, 95% CI: [-0.15, -0.05]) and elevated scavenger receptor cysteine-rich domain-containing group B protein (SSC4D; β = 0.28, 95% CI: [0.17, 0.38]), and were enriched in extracellular matrix pathways. MR analysis revealed kidney stone presence contributes to elevated levels of matrix metalloproteinase 7. Conversely, lower plasma UMOD (OR = 0.93, 95% CI: [0.90, 0.97]) and higher plasma SSC4D (OR = 1.10, 95% CI: [1.02, 1.18]) were associated with a kidney stone risk. These associations were consistently replicated in the MCBB dataset (UMOD: OR = 0.92, 95% CI: [0.86, 0.98]; SSC4D: OR = 1.13, 95% CI: [1.01, 1.27]) and further validated by a concentration-response analysis. Single-nucleus RNA sequencing and quantitative trait loci analyses confirmed consistent associations between thick ascending limb UMOD expression and stone former status, and with blood and urine UMOD concentrations. GWAS analysis, adjusted for eGFR, suggested that the protective role of UMOD against kidney stones was independent of kidney function. Conclusions: This study highlights significant associations between concentrations of specific blood proteins and a history of kidney stones. Several implicated proteins are related to kidney stone matrix, with UMOD independently associated with lower risk and SSC4D with higher risk of kidney stones.