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Urinary clusterin as a biomarker of human kidney disease progression and response to the endothelin receptor antagonist atrasentan : An exploratory analysis from the SONAR trial

Ju, Wenjun ; Nair, Viji ; Vart, Priya ; Smeijer, J. David ; Hudkins, Kelly L. ; Moedt, Erik ; Larkina, Maria ; Perco, Paul ; Burdet, Frédéric and Shedden, Kerby , et al. (2026) In Nature Communications 17(1).
Abstract

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... (More)

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) population, 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
17
issue
1
article number
2482
publisher
Nature Publishing Group
external identifiers
  • pmid:41654492
  • scopus:105032325390
ISSN
2041-1723
DOI
10.1038/s41467-026-68973-5
language
English
LU publication?
yes
id
eef2f8d2-cd26-4868-94b5-6fef712b56f8
date added to LUP
2026-04-20 09:22:31
date last changed
2026-05-18 12:35:52
@article{eef2f8d2-cd26-4868-94b5-6fef712b56f8,
  abstract     = {{<p>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) population, 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.</p>}},
  author       = {{Ju, Wenjun and Nair, Viji and Vart, Priya and Smeijer, J. David and Hudkins, Kelly L. and Moedt, Erik and Larkina, Maria and Perco, Paul and Burdet, Frédéric and Shedden, Kerby and Hwang, Michael and Lee, Edmond and O’Connor, Christopher and Hartman, John and Subramanian, Lalita and Bitzer, Markus and Ibberson, Mark and Duffin, Kevin L. and Gomez, Maria F. and Alpers, Charles E. and Kretzler, Matthias and Heerspink, Hiddo J.L.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Urinary clusterin as a biomarker of human kidney disease progression and response to the endothelin receptor antagonist atrasentan : An exploratory analysis from the SONAR trial}},
  url          = {{http://dx.doi.org/10.1038/s41467-026-68973-5}},
  doi          = {{10.1038/s41467-026-68973-5}},
  volume       = {{17}},
  year         = {{2026}},
}