Urinary Clusterin as a Biomarker of Human Kidney Disease Progression and Response to the Endothelin Receptor Antagonist Atrasentan: An Exploratory Analysis from the SONAR Trail

The endothelin receptor antagonist atrasentan improved kidney outcomes in the SONAR trial for type 2 diabetes and chronic kidney disease (NCT01858532), though individual responses varied. To identify molecular biomarkers of atrasentan response and outcome, we conducted a nested case-control proteomics study (N=180) within the SONAR trial population and identified urinary clusterin (uCLU) as the top candidate. Transcriptomic analyses of human kidney biopsies at tissue and single cell level from independent cohorts revealed higher CLU mRNA levels associated with worse kidney function and outcomes. An endothelin signaling activation score derived from pathway genes was reduced by atrasentan in mice with diabetic kidney disease. In the SONAR trial (N=3,060), higher uCLU predicted worse outcomes, while atrasentan reduced uCLU by 42.6% over six weeks. Early uCLU changes independently predict improved kidney outcomes. In summary, uCLU is associated with kidney disease progression and response to atrasentan treatment, supporting its potential as a pharmacodynamic biomarker to target therapy. Overall design: Bulk RNAseq data obtained from kidney glomerular tissues from wild type (n=5), BTBR ob/ob mice with 6 wk of saline (n=5) or atrasentan (n=7) treatment, respectively