Proteomics of CKD progression in the chronic renal insufficiency cohort

Ruth F. Dubin (), Rajat Deo, Yue Ren, Jianqiao Wang, Zihe Zheng, Haochang Shou, Alan S. Go, Afshin Parsa, James P. Lash, Mahboob Rahman, Chi-yuan Hsu, Matthew R. Weir, Jing Chen, Amanda Anderson, Morgan E. Grams, Aditya Surapaneni, Josef Coresh, Hongzhe Li, Paul L. Kimmel, Ramachandran S. Vasan, Harold Feldman, Mark R. Segal and Peter Ganz
Additional contact information
Ruth F. Dubin: University of Texas Southwestern Medical Center
Rajat Deo: Perelman School of Medicine at the University of Pennsylvania
Yue Ren: University of Pennsylvania
Jianqiao Wang: Harvard T.H. Chan School of Public Health
Zihe Zheng: University of Pennsylvania
Haochang Shou: University of Pennsylvania
Alan S. Go: Division of Research, Kaiser Permanente Northern California, Oakland, the Department of Health Systems Science
Afshin Parsa: National Institutes of Health
James P. Lash: University of Illinois Chicago
Mahboob Rahman: University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine
Chi-yuan Hsu: Division of Research, Kaiser Permanente Northern California, Oakland, the Department of Health Systems Science
Matthew R. Weir: University of Maryland School of Medicine
Jing Chen: Tulane University
Amanda Anderson: Tulane University
Morgan E. Grams: Johns Hopkins University
Aditya Surapaneni: Johns Hopkins University
Josef Coresh: Johns Hopkins University
Hongzhe Li: University of Pennsylvania
Paul L. Kimmel: Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Ramachandran S. Vasan: University of Texas School of Public Health San Antonio and the University of Texas Health Sciences Center in San Antonio. Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine
Harold Feldman: University of Pennsylvania
Mark R. Segal: University of California, San Francisco
Peter Ganz: Division of Cardiology, University of California, San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41642-7

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