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; Peter Ganz

doi:10.1038/s41467-023-41642-7

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. VasanHarold Feldman, Mark R. Segal, Peter Ganz

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Article number	6340
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41642-7
State	Published - Dec 2023
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Dubin, R. F., Deo, R., Ren, Y., Wang, J., Zheng, Z., Shou, H., Go, A. S., Parsa, A., Lash, J. P., Rahman, M., Hsu, C. Y., Weir, M. R., Chen, J., Anderson, A., Grams, M. E., Surapaneni, A., Coresh, J., Li, H., Kimmel, P. L., ... Ganz, P. (2023). Proteomics of CKD progression in the chronic renal insufficiency cohort. Nature communications, 14(1), Article 6340. https://doi.org/10.1038/s41467-023-41642-7

Dubin, RF, Deo, R, Ren, Y, Wang, J, Zheng, Z, Shou, H, Go, AS, Parsa, A, Lash, JP, Rahman, M, Hsu, CY, Weir, MR, Chen, J, Anderson, A, Grams, ME, Surapaneni, A, Coresh, J, Li, H, Kimmel, PL, Vasan, RS, Feldman, H, Segal, MR & Ganz, P 2023, 'Proteomics of CKD progression in the chronic renal insufficiency cohort', Nature communications, vol. 14, no. 1, 6340. https://doi.org/10.1038/s41467-023-41642-7

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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.",

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AU - Go, Alan S.

AU - Parsa, Afshin

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AU - Weir, Matthew R.

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AU - Anderson, Amanda

AU - Grams, Morgan E.

AU - Surapaneni, Aditya

AU - Coresh, Josef

AU - Li, Hongzhe

AU - Kimmel, Paul L.

AU - Vasan, Ramachandran S.

AU - Feldman, Harold

AU - Segal, Mark R.

AU - Ganz, Peter

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Proteomics of CKD progression in the chronic renal insufficiency cohort

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