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

Background Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression ofCKD. Methods Wequantifiedthe associationbetween 4877 plasmaproteins anda composite outcome ofESKDor 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 theseproteins ina subset of4378participants (visit 5),whowerefollowedat a later timepoint, foramedian 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 Inmodels adjusted formultiple covariates, including baselineeGFRandalbuminuria,we identified13 distinct proteins thatwere significantly associatedwith the composite end point in both time periods, including TNF receptor superfamilymembers 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 eachprotein associatedwith higher risk of50%eGFRdeclineorESKD.Wefoundgenetic 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.