Proteomics of CKD progression in the chronic renal insufficiency cohort

• Published in: Nature communications Vol. 14; no. 1; p. 6340
• Main Authors: Dubin, Ruth F., Deo, Rajat, Ren, Yue, Wang, Jianqiao, Zheng, Zihe, Shou, Haochang, Go, Alan S., Parsa, Afshin, Lash, James P., Rahman, Mahboob, Hsu, Chi-yuan, Weir, Matthew R., Chen, Jing, Anderson, Amanda, Grams, Morgan E., Surapaneni, Aditya, Coresh, Josef, Li, Hongzhe, Kimmel, Paul L., Vasan, Ramachandran S., Feldman, Harold, Segal, Mark R., Ganz, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/53; 692/4022/272; 692/499; Arteriosclerosis; Atherosclerosis; Bone diseases; Bone morphogenetic proteins; Cohort Studies; Disease Progression; Drug development; Glomerular filtration rate; Humanities and Social Sciences; Humans; Kidney diseases; Kidneys; multidisciplinary; Plasma proteins; Prospective Studies; Proteins; Proteomics; Prothrombin; Renal failure; Renal insufficiency; Renal Insufficiency - complications; Renal Insufficiency, Chronic - metabolism; Risk; Science; Science (multidisciplinary); Statistical analysis; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41642-7

Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression. Progression of chronic kidney disease may lead to kidney failure and cardiovascular, metabolic and bone disease complications. Here, the authors conduct a large-scale proteomic study in patients with chronic kidney disease, identify numerous proteins that predict kidney failure, some of which are likely causal mediators and hence potential therapeutic targets.