Urine Metabolite Levels, Adverse Kidney Outcomes, and Mortality in CKD Patients: A Metabolome-wide Association Study

Abstract Rationale & Objective Mechanisms underlying the variable course of disease progression in patients with chronic kidney disease (CKD) are incompletely understood. The aim of this study was to identify novel biomarkers of adverse kidney outcomes and overall mortality, which may offer insights into pathophysiological mechanisms. Study Design Metabolome-wide association study. Setting & Participants 5,087 CKD patients enrolled in the observational German Chronic Kidney Disease study. Exposure(s) Measurements of 1,487 metabolites in urine. Outcome(s) Endpoints of interest were time to kidney failure (KF), a combined endpoint of KF and acute kidney injury (KF+AKI), and overall mortality. Analytical Approach Statistical analysis was based on a discovery-replication design (ratio 2:1) and multivariable adjusted Cox regression models. Results After a median follow-up of 4 years, 362 patients died, 241 experienced KF, and 382 KF+AKI. Overall, we identified 55 urine metabolites whose levels were significantly associated with adverse kidney outcomes and/or mortality. Higher levels of C-glycosyltryptophan were consistently associated with all three main endpoints (KF: hazard ratio 1.43, 95% confidence interval [1.27;1.61], KF+AKI: 1.40 [1.27;1.55], death: 1.47 [1.33;1.63]). Metabolites belonging to the phosphatidylcholine pathway showed significant enrichment. Members of this pathway contributed to the improvement of the prediction performance for KF observed when multiple metabolites were added to the well-established kidney failure risk equation. Limitations Findings among CKD patients of European ancestry may not be generalizable to the general population. Conclusions Our comprehensive screen of the association between urine metabolite levels and adverse kidney outcomes and mortality identifies metabolite that predict KF and represents a valuable resource for future studies of biomarkers of CKD progression.