Proteins Associated with Risk of Kidney Function Decline in the General Population

Significance Statement Proteomic profiling may allow identification of plasma proteins associated with subsequent changes in kidney function, elucidating biologic processes that underlie CKD. The authors used large-scale proteomic profiling to evaluate the association of 4877 plasma proteins with the development of adverse kidney outcomes in a cohort of 9406 middle-aged adults with a median follow-up of 14.4 years, and, in a subset of 4378 adults at a later time point, with a median follow-up of 4.4 years. They found 13 proteins for which higher levels were associated with greater kidney risk at both time periods, and 12 replicated in at least one external cohort. Although most proteins appeared to be markers, rather than causes, of kidney damage, genetic evidence suggested a causal role for lectin mannose-binding 2 protein (LMAN2). 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.