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Kidney Week

Abstract: TH-PO453

A Metabolome-Wide Association Study of Kidney End Points in CKD Patients: Results from the GCKD Study

Session Information

Category: CKD (Non-Dialysis)

  • 2102 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

  • Steinbrenner, Inga, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Sekula, Peggy, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Schultheiss, Ulla T., Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Schmid, Matthias, University Hospital Bonn, Bonn, Germany
  • Eckardt, Kai-Uwe, Charité – Universitätsmedizin Berlin, Berlin, Germany
  • Oefner, Peter J., University of Regensburg, Regensburg, Germany
  • Kottgen, Anna, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
Background

Chronic kidney disease (CKD) affects >10% of the adult population and is associated with increased risk of end-stage kidney disease (ESKD) and mortality. The underlying mechanisms are incompletely understood. A comprehensive screen of metabolites whose levels in urine are associated with kidney endpoints can identify novel biomarkers for CKD progression and may provide pathophysiological insights.

Methods

We performed Cox Proportional Hazards analyses relating incident kidney endpoints to levels of 1487 urinary metabolites quantified in 5088 participants of the German Chronic Kidney Disease (GCKD) study in a randomly selected discovery (N=3392) and replication (N=1696) sample adjusted for age, sex, eGFR and UACR at baseline. Main endpoints were time to ESKD (dialysis or transplantation) or renal death (“ESKD”, Nevents=241) and a composite endpoint that additionally included acute kidney injury AKIN stage 3 (“Composite”, Nevents=382). Urinary metabolites were measured using the Metabolon HD4 platform, log2-transformed and analyzed when quantified in at least 30 patients with an event. Cause-specific hazard (CSH) regression as well as subdistribution hazard (SH) analyses with death of other causes as a competing event were performed. Statistical significance was defined using a Bonferroni correction for the number of tested metabolites in both the discovery (p≤4e-05) and replication setting.

Results

Median follow-up time was 4.0 years. CSH analyses of the Composite and the ESKD event identified and replicated 20 and 8 significant metabolites, respectively. For the Composite event, there were both protective and harmful metabolites, with cause-specific hazard ratios ranging from 0.63 to 2.75 per doubling of metabolite levels. Many replicated metabolites have not yet been implicated in ESKD. They belong to different biochemical classes, with evidence for enrichment in one sub-pathway. Most associations remained after adjusting for additional clinical covariates. SH analyses showed almost identical results.

Conclusion

We identified 20 urinary metabolites significantly associated with adverse kidney events in a cohort of CKD patients, potentially providing new insights into the mechanisms of kidney disease progression.

Funding

  • Government Support - Non-U.S.