Novel protein biomarkers for risk stratification and personalized medicine

Albuminuria is widely used to monitor chronic kidney disease (CKD) and treatment response but is subject to variability and primarily reflects glomerular injury. Urinary clusterin and epidermal growth factor (uEGF) are associated with tubular injury and repair, respectively, and may serve as mechanism-informed pharmacodynamic biomarkers. We investigated responses of urinary clusterin and uEGF to endothelin receptor antagonists (ERAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), respectively, in CKD.

We evaluated changes in urinary clusterin-to-creatinine ratio (uCLU/Cr) and uEGF-to-creatinine ratio (uEGF/Cr) in two randomized CKD trial populations. Effects of ERA on uCLU/Cr and endothelin-1 (ET-1) were assessed during the atrasentan enrichment phase of SONAR (Study of Diabetic Nephropathy with Atrasentan), and effects of SGLT2i on uEGF/Cr were examined in DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) across different CKD etiologies, diabetes status, and glycemic control. Associations between uEGF/Cr and intrarenal EGF messenger RNA (mRNA) expression were examined using kidney biopsy single-cell RNA sequencing data.

After 6 weeks of treatment with atrasentan, uCLU/Cr decreased by 46.3% (95% confidence interval [CI]: -57.8 to -37.1), while serum ET-1 increased by 23.4% (95% CI 19.2-27.4). There were no effects on serum clusterin and only a numerical decrease in urinary ET-1. Baseline uCLU/Cr correlated significantly with urinary ET-1 (Pearson r = 0.65, P < .0001). In DAPA-CKD, dapagliflozin attenuated the decline in uEGF/Cr over 1 year, with heterogeneity across CKD etiologies. Relative increases were greatest in diabetic kidney disease and absent in glomerulonephritis and hypertensive nephropathy. Similarly, effects were larger in those with type 2 diabetes and higher baseline HbA1c. Tubular EGF mRNA expression correlated positively with uEGF/Cr.

Urinary clusterin and uEGF are mechanism-informed pharmacodynamic biomarkers reflecting distinct intrarenal pathways engaged by ERA and SGLT2i therapy, respectively. These biomarkers complement albuminuria by capturing tubular injury and repair, providing a more comprehensive biological assessment of treatment effects and heterogeneity in CKD.