McDonnell, Thomas, Onoja, Anthony, Vuilleumier, Nicolas, Banks, Rosamonde E, Cockwell, Paul, Fraser, Simon D.S., Saleem, Moin, Wheeler, David C., Geifman, Nophar, Kalra, Phillip A. and Taal, Maarten W. (2026) Sex associated biomarker differences in CKD progression and mortality. Clinical Journal of the American Society of Nephrology. (doi:10.2215/CJN.0000000979).
Abstract
Background: males with chronic kidney disease (CKD) experience worse outcomes than females, a difference not fully explain ed by comorbidities or sociocultural factors. We explored whether sex-based differences in biomarkers could account for this difference in risk.
Methods: our study included 1,680 male and 1,204 female participants with non-dialysis-dependent CKD and 84 controls from NURTuRE-CKD, a prospective multicentre cohort study. Twenty-one biomarkers relating to kidney injury and fibrosis, inflammation, and cardiovascular stress were measured. Outcomes were kidney failure (estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2 or kidney replacement therapy) and all-cause mortality. Multivariable Cox and Fine and Gray models assessed outcomes by sex. ANCOVA compared biomarker values between males and females adjusted for eGFR and urine albumin to creatinine ratio (UACR).
Results: sex differences in biomarker concentrations were observed in both controls and CKD participants. In male controls, higher levels of urinary Vascular Endothelial Growth Factor, Tissue Inhibitor of Metalloproteinases-1 and blood Neutrophil Gelatinase-Associated Lipocalin, soluble Cluster of Differentiation 40, soluble Cluster of Differentiation 40 Ligand, soluble Tumour Necrosis Factor Receptor 1, Monocyte Chemoattractant Protein-1, and High-Sensitivity Cardiac Troponin T were observed. In males with CKD, additionally higher levels of urine Collagen Type I Alpha 1, blood Kidney Injury Molecule-1, Growth Differentiation Factor-15, and N-terminal pro-B-type Natriuretic Peptide. were noted, while females with CKD showed higher urinary Osteoactivin, KIM-1, Matrix Metalloproteinase-9 and blood Fibroblast Growth Factor-23, concentrations. In Cox proportional hazards models adjusted for demographics, kidney function, comorbidities, social factors, and medications, male sex was associated with a higher risk of kidney failure (hazard ratio (HR) 1.28, 95% confidence interval (CI): 1.09–1.50) and mortality (HR 1.29, 95% CI: 1.05–1.60). Male sex was no longer associated with higher risk after adjustment for biomarker differences, kidney failure (HR 1.18, 95% CI: 0.97, 1.43) and mortality (HR 1.17, 95% CI: 0.98, 1.58).
Conclusions: male sex was associated with a higher risk of kidney failure and mortality, despite adjustment for demographic, clinical, and treatment factors. Males had higher levels of inflammatory and extracellular matrix deposition biomarkers. In contrast, females showed higher levels of matrix turnover and degradation markers. After adjustment for these biomarker differences, the elevated risk associated with male sex was eliminated, suggesting a biological basis for the observed sex difference in outcomes.
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