Kidney Medicine · Published 2026-06-01 · DOI 10.1016/j.xkme.2026.101458
Teresa K. Chen, Aditya L. Surapaneni, Michelle M. Estrella, Lawrence J. Appel, Wassim Obeid, Chirag R. Parikh, Mary R. Rooney, Bing Yu, Eugene P. Rhee, Insa M. Schmidt, Sushrut S. Waikar, Morgan E. Grams
Rationale & Objective: Inflammation is associated with adverse kidney, cardiovascular, and mortality outcomes. Investigation of the metabolic milieu as it relates to inflammation may provide important insights into these disease processes. Study Design: Prospective cohort. Setting & Participants: African American Study of Kidney Disease and Hypertension (AASK), Atherosclerosis Risk in Communities (ARIC) study, and Boston Kidney Biopsy Cohort (BKBC) participants with available metabolomics and inflammatory protein data. Predictors: Baseline blood levels of 718 metabolites. Outcomes: Baseline and longitudinal changes in blood levels of tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins 6, 8, and 10 (IL-6, IL-8, IL-10), uromodulin (UMOD), and epidermal growth factor (EGF). Analytical Approach: Multivariable linear regression and linear mixed-effects models. Results: Among 491 AASK participants (mean age 54 years; 37% women; mean glomerular filtration rate, 45 mL/min/1.73 m2), 367 cross-sectional associations between metabolites and inflammatory proteins were significant after correction for multiple comparisons. The direction of association was mostly positive for TNFR1 (97%), TNFR2 (97%), IL-8 (77%), and IL-10 (100%); negative for UMOD (80%) and EGF (97%); and variable for TNF-⍺, IFN-γ, and IL-6. Pathways were distinct for several inflammatory proteins (eg, tryptophan metabolism for TNFR2). Forty-five associations between metabolites and longitudinal change in inflammatory proteins were identified. Notable metabolites included tigylcarnitine and N2,N5-diacetylornithine, which were associated with 2-year increases in TNFR1 and/or TNFR2, and 1,5-anhydroglucitol, where lower levels were associated with decreases in UMOD. In ARIC (n = 3,773) and BKBC (n = 413), replication of cross-sectional associations was excellent for TNFR1 (ARIC 83%; BKBC 85%) and TNFR2 (ARIC 64%; BKBC 79%) but poor for IL-8 (ARIC 3%; BKBC 3%). Limitations: Metabolite data limited to baseline visit; potential for residual confounding. Conclusions: Using an untargeted approach, multiple metabolites were cross-sectionally and longitudinally associated with inflammatory proteins in persons with chronic kidney disease. Plain-Language Summary: This study examined how small molecules in the blood (metabolites) relate to inflammation in people with chronic kidney disease. Using 3 large US studies, we measured hundreds of metabolites and several inflammatory proteins linked to kidney and cardiovascular risk. There were particularly strong and consistent links between metabolites and key inflammatory markers (TNFR1 and TNFR2) across all 3 studies. Some metabolites also predicted increases in inflammation over time, such as higher tigylcarnitine (a marker of mitochondrial stress) and lower 1,5-anhydroglucitol (a marker of poor glucose control), suggesting potential biological pathways driving disease progression. The findings highlight how metabolic profiling may improve understanding of inflammation and help identify new targets for preventing kidney and heart complications.
Abstract from DOAJ. Public domain (CC0 1.0).
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Chen, T., Surapaneni, A., Estrella, M., et al. (2026). Metabolomic Signatures of Inflammation in Chronic Kidney Disease. Kidney Medicine. https://doi.org/10.1016/j.xkme.2026.101458