Abstract: TH-OR47
Urinary Clusterin as a Pharmacodynamic Response Biomarker for the Endothelin Receptor Antagonist Atrasentan
Session Information
- Diabetic Kidney Disease - Clinical: Novel Insights into Precision Medicine
October 24, 2024 | Location: Room 33, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: Diabetic Kidney Disease
- 702 Diabetic Kidney Disease: Clinical
Authors
- Ju, Wenjun, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Nair, Viji, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Vart, Priya, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
- Smeijer, Johannes David, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
- Larkina, Maria, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Shedden, Kerby, University of Michigan Department of Statistics, Ann Arbor, Michigan, United States
- Lee, Edmond, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Hartman, John R., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Bitzer, Markus, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Duffin, Kevin L., Eli Lilly and Company, Indianapolis, Indiana, United States
- Gomez, Maria F., Lunds universitet Institutionen for kliniska vetenskaper Malmo, Malmo, Sweden
- Alpers, Charles E., University of Washington School of Medicine, Seattle, Washington, United States
- Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Heerspink, Hiddo Jan L., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
Group or Team Name
- SONAR.
Background
Endothelin-1 pathway activation in the kidney is associated with progressive kidney injury and GFR decline. The endothelin-1 receptor antagonist atrasentan reduces the risk of kidney failure in patients with diabetic kidney disease (DKD) in the phase 3 SONAR clinical trial. However, the individual patient’s response varies. This study aimed to identify biomarkers predictive of atrasentan response and its underlying molecular mechanisms.
Methods
SOMAscan was used to discover urinary biomarkers associated with atrasentan response in 180 patients from the SONAR trial. Logistic regression was used to identify markers whose change from baseline to 6 weeks of treatment are predictive to response. Top candidate markers were validated using ELISA. Biomarker concentration was normalized by urine creatinine. Transcriptomic data from patients with DKD and atrasentan-treated DKD mouse model were analyzed for mechanistic insight. The top candidate biomarker was validated in the remaining SONAR cohort using a Cox proportional hazard regression model.
Results
Putative biomarkers predictive of atrasentan response were identified. Of these, urinary clusterin (uCLU) emerged as the top candidate and was further evaluated. Kidney transcriptomic data revealed that CLU is upregulated in DKD in mice and humans, and correlated with an endothelin activation score, generated from atrasentan-treated BTBR ob/ob mice using DKD-associated endothelin 1 pathway genes that are reversely regulated by atrasentan. Higher uCLU at baseline is significantly associated with an increased risk of a composite endpoint of kidney failure or 57% eGFR decline [HR1.09 (95% CI 1.03, 1.16; p=0.005)] in the SONAR clinical trial (N=3060). Atrasentan reduced uCLU during six weeks treatment by 42.6% and this early change in uCLU was independently associated with a lower risk of the composite kidney endpoint after adjustment for all covariates [HR 0.90 (95% CI 0.84, 0.97); p=0.009].
Conclusion
Our study identified and validated uCLU as a promising pharmacodynamic biomarker for assessing treatment response to atrasentan. This calls for further clinical evaluation and implementation, and fosters indivdualized treatment through molecular stratification.
Funding
- NIDDK Support