Viji Nair | PubMed Health

PubMed2026

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.

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.

Humans↗

PubMed2025

Polygenic Risk Scores Predicting Estimated GFR Validated With Iohexol Clearance.

INTRODUCTION: Genome-wide association studies (GWAS) have identified hundreds of single nucleotide variants (SNVs) associated with estimated glomerular filtration rate (eGFR). eGFR has been used as a proxy phenotype because of the complexity and cost of measured GFR (mGFR) in large studies. Because eGFR is influenced by non-GFR factors, these GWAS results may be biased compared with a hypothetical study using mGFR. We aimed to investigate this by comparing aggregate measures of genetic effects on mGFR and eGFR. METHODS: We studied 1492 persons from the Renal Iohexol Clearance Survey (RENIS) cohort, a representative sample of the general population in Northern Norway without preexisting cardiovascular disease, kidney disease, or diabetes. We measured iohexol-clearance, and genotyping was performed with a microarray chip enriched for GFR-related SNVs. We compared the performance of 3 published polygenic risk scores (PGS) developed for creatinine-based eGFR (eGFRcr), narrow-sense heritability (h2) and the mean effect of SNVs on mGFR, eGFRcr, cystatin C-based eGFR (eGFRcys) and eGFRcr-cys. RESULTS: The performance of the PGS differed for mGFR and the 3 eGFRs, with best performance for prediction of eGFRcr (P < 0.05). However, when the beta coefficients of the SNVs in the 3 PGS were estimated in the RENIS-cohort, their magnitude was 11% to 46% greater for mGFR than for the 3 eGFR methods in 8 of 9 comparisons (P < 0.05). mGFR had higher h2 (0.47) than eGFRcr (0.21), eGFRcys (0.37), and eGFRcr-cys (0.42). CONCLUSIONS: SNVs with non-GFR effects on creatinine and cystatin-C influence GWAS results. The results of GWAS using eGFR should be validated using experimental and other more precise methods.

chronic kidney disease↗