Multi-omics analyses based identification of therapeutic targets for rapid kidney function decline and chronic kidney disease, a mendelian randomization study

PURPOSE: Rapid kidney function decline and chronic kidney disease (CKD) remain significant threats to global health. Currently, there are no effective therapeutic agents capable of reversing progression of CKD. A two-stage Mendelian randomization (MR) study was conducted to uncover causal therapeutic mechanisms of pQTLs during kidney function decline. METHODS: Exposure data comprised 4,853 distinct proteins and their corresponding protein quantitative trait loci (pQTLs, p < 5×10⁻⁸) sourced from 7 large-scale proteomic datasets. Kidney function decline outcomes of 1,201,909 participants and 337,109 participants were collected as the outcome in the discovery stage and validation stage, respectively. Additionally, single cell sequencing analyses from 64,276 mice cells served as an independent cohort to explore the expression level of these potential therapeutic targets in kidney. Protein-protein and protein-drug association analysis were performed in the STITCH database, with supplementary drug-related data extracted from DrugBank database to explore potential therapeutic options. RESULTS: A total of 37 proteins (p < 1.03×10⁻⁵) were associated with impaired kidney function, among which 7 proteins (IGFBP4, CLMP, FGF5, ANGPTL7, LRRN1, DMKN and CHST11) were validated. Lower IGFBP4 expression level was observed during the rapid kidney function decline in mice. Besides, dbcAMP and pioglitazone emerged as candidate agents with the potential to act through IGFBP4 and CLMP in rapid decline and CKD. CONCLUSION: IGFBP4 and CLMP represent promising therapeutic targets for rapid kidney function decline and CKD. Further investigation is warranted to elucidate the underlying mechanisms and validate their functional roles through larger cohort studies.