Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies

Rationale & Objective Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design Prospective cohort (ARIC) and case-cohort (MESA and REGARDS). Setting & Participants Adults with eGFR ≥60 mL/min/1.73m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposure Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1 (KIM-1), epidermal growth factor (EGF), and chitinase-3-like protein 1 (YKL-40). Outcome Incident CKD or ESKD (end-stage kidney disease). Analytical Approach Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all three cohorts. Results 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60±10 to 63±8 years and baseline eGFR ranged from 88±13 to 91±14 mL/min/1.73m2. In ARIC, higher concentrations of urine MCP-1, α1m, and KIM-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of EGF was each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all three cohorts, each two-fold higher α1m concentration was associated with incident CKD (HR=1.19 [1.08, 1.31]). Limitations Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to three cohorts. Conclusions In three combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m was independently associated with incident CKD. Four biomarkers were associated with incident CKD in at least one of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.