Proteins associated with risk of kidney function decline in the general population

Morgan E. Grams, Aditya Surapaneni, Jingsha Chen, Linda Zhou, Zhi Yu, Diptavo Dutta, Paul A. Welling, Nilanjan Chatterjee, Jingning Zhang, Dan E. Arking, Teresa K. Chen, Casey M. Rebholz, Bing Yu, Pascal Schlosser, Eugene P. Rhee, Christie M. Ballantyne, Eric Boerwinkle, Pamela L. Lutsey, Thomas Mosley, Harold I. FeldmanRuth F. Dubin, Peter Ganz, Hongzhe Lee, Zihe Zheng, Josef Coresh

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


BACKGROUND: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD.

METHODS: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR.

RESULTS: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and β-trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2).

CONCLUSIONS: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline.

Original languageEnglish (US)
Pages (from-to)2291-2302
Number of pages12
JournalJournal of the American Society of Nephrology
Issue number9
StatePublished - Sep 2021

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© 2021 by the American Society of Nephrology.


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