Proteomic Markers of Dietary Patterns, Chronic Kidney Disease Progression, and Mortality in the CRIC study

Background: Healthy dietary patterns reduce the risk of chronic kidney disease (CKD) progression and mortality in people with CKD. Identifying protein biomarkers of diet, and their associations with these outcomes, can elucidate biological mechanisms through which diet improves prognosis. Methods: Using data from the Chronic Renal Insufficiency Cohort study of adults with CKD (n=2217, mean age 59 years), we examined cross-sectional associations between 4954 plasma proteins and four dietary patterns: Healthy Eating Index-2020, Alternative Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet. Relative values of proteins were determined using an aptamer-based assay. Dietary intake was assessed using a food frequency questionnaire. We used multivariable linear regression to identify proteins associated with diet, and Cox proportional hazards regression to assess longitudinal associations between diet-related proteins, CKD progression, and mortality. Elastic net regression was used to select subsets of proteins that are associated with these outcomes. Results: At a false discovery rate-adjusted P<0.05, 199 proteins were associated with ≥1 dietary pattern and 18 were associated with all patterns. Over seven years median follow-up, 824 CKD progression events occurred. Twenty-one proteins were associated with CKD progression at P<2.5×10 -4 (=0.05/199), of which eight were selected in elastic net regression: follistatin-related protein 3, glutaredoxin-1, asialoglycoprotein receptor 1, extracellular superoxide dismutase [Cu-Zn], zinc-alpha-2-glycoprotein, interleukin-18 receptor 1, ecto-ADP-ribosyltransferase 3, and ephrin type-A receptor 1. All were inversely associated with healthy dietary patterns and associated with higher risk of CKD progression. Thirty proteins were associated with all-cause mortality, of which 14 were selected by elastic net regression. Conclusions: Large-scale proteomics analyses identified potential protein biomarkers of healthy dietary patterns that were associated with CKD progression and mortality in adults with CKD. Their functions, including regulating blood lipids, insulin sensitivity, vascular homeostasis, inflammation and oxidative stress, may represent mechanisms through which diet improves disease course.