Kidney Week

Abstract: TH-OR16

Identification of Noninvasive Biomarkers Reflecting Cellular Mechanisms of Endothelin A (ETA) Receptor Activity and Atrasentan Response in CKD

Session Information

• CKD Mechanisms: Prediction, Propagation, and Prevention
  November 02, 2023 | Location: Room 119, Pennsylvania Convention Center
  Abstract Time: 05:15 PM - 05:24 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Olson, N. Eric, Chinook Therapeutics Inc, Seattle, Washington, United States

N. Eric Olson, PhD

• Bohnenpoll, Tobias, Evotec International GmbH, Gottingen, Germany

Tobias Bohnenpoll,

• Ragan, Seamus, Chinook Therapeutics Inc, Seattle, Washington, United States

Seamus Ragan,

• Lo, I-Ju, Evotec International GmbH, Gottingen, Germany

I-Ju Lo,

• Badal, Shawn S., Chinook Therapeutics Inc, Seattle, Washington, United States

Shawn S. Badal,

• Cox, Jennifer H., Chinook Therapeutics Inc, Seattle, Washington, United States

Jennifer H. Cox,

• Radresa, Olivier, Evotec International GmbH, Gottingen, Germany

Olivier Radresa,

• Andag, Uwe, Evotec International GmbH, Gottingen, Germany

Uwe Andag,

• King, Andrew J., Chinook Therapeutics Inc, Seattle, Washington, United States

Andrew J. King,

Background

Endothelin pathway activation contributes to disease progression across multiple CKD etiologies. Atrasentan is a potent and selective endothelin A receptor (ET_A) antagonist that has demonstrated rapid and sustained reductions in proteinuria, preservation of kidney function and improved kidney outcomes in diabetic kidney disease patients. Single cell transcriptomic characterization of a preclinical mouse model of IgA nephropathy revealed specific ET_A activity and atrasentan responses associated with proximal tubular failed repair (FR-PTs). We conducted an analysis of patient-matched kidney biopsies and biofluids from the NURTuRE cohort with the aim to identify non-invasive biomarkers associated with specific cellular responses that will enable precision treatment in CKD.

Methods

Serum (n= 99) and urine samples (n= 22) from the NURTuRE biobank were assayed using Olink and SomaScan proteomics platforms, respectively. Patient-matched kidney biopsies for each sample were analyzed by RNA-Seq and scored for a gene signature reflecting atrasentan responses in the gddY mouse model. Correlation analysis of biofluid protein abundance with kidney mRNA expression and atrasentan response scores suggested candidate non-invasive biomarkers for further validation (r ≥ 0.4 and p ≤ 0.05).

Results

Proteomic analysis identified 173 serum and 174 urine proteins significantly correlated with atrasentan response score in CKD patients. Strong positive correlation of 16/173 serum and 12/174 urine proteins with kidney mRNA expression suggests these proteins could originate from the kidney. Importantly, the majority of the respective genes were expressed by FR-PTs or immune cells, likely reflecting mechanisms of ET_A activation and atrasentan response in the kidney inflammatory and fibrotic microenvironment.

Conclusion

This study identified potential biomarkers reflecting cellular mechanisms of ET_A activation and atrasentan response in the NURTuRE CKD cohort. These biomarkers may be useful in assessing and differentiating cellular responses in atrasentan-treated CKD patients. To validate these initial findings, serum and urine collected at baseline and following treatment in the AFFINITY IgAN cohort are currently being analyzed.

Funding

• Commercial Support – Chinook Therapeutics, Evotec SE