Sex-Associated Biomarker Differences in CKD Progression and Mortality.

KEY POINTS: A higher risk of kidney failure and mortality persisted in men with CKD, despite adjusting for sociodemographic, clinical, and treatment factors. Differences in biomarkers linked to CKD progression and cardiovascular stress were observed between men and women after adjusting for eGFR and urine albumin-to-creatinine ratio. When adjusting for the differences in the biomarkers, the excess risk of kidney failure and mortality seen in men was eliminated.

BACKGROUND

Men with CKD experience worse outcomes than women, a difference not fully explained by comorbidities or sociocultural factors. We explored whether sex-based differences in biomarkers could account for this difference in risk.

METHODS

Our study included 1680 male and 1204 female participants with non-dialysis-dependent CKD and 84 controls from National Unified Renal Translational Research Enterprise-CKD, a prospective multicenter cohort study. Twenty-one biomarkers relating to kidney injury and fibrosis, inflammation, and cardiovascular stress were measured. Outcomes were kidney failure (eGFR <15 ml/min per 1.73 m 2 or kidney replacement therapy) and all-cause mortality. Multivariable Cox and Fine and Gray models assessed outcomes by sex. Analysis of covariance compared biomarker values between men and women adjusted for eGFR and urine albumin-to-creatinine ratio.

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 tumor necrosis factor receptor 1, monocyte chemoattractant protein-1, and high-sensitivity cardiac troponin T were observed. In men with CKD, additionally higher levels of urine collagen type 1 α 1, blood kidney injury molecule-1, Growth Differentiation Factor-15, and N -terminal pro-B-type natriuretic peptide were noted, while women with CKD showed higher urinary osteoactivin, kidney injury molecule-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, 1.09 to 1.50) and mortality (HR, 1.29; 95% CI, 1.05 to 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 to 1.43), and mortality (HR, 1.17; 95% CI, 0.98 to 1.58).

CONCLUSIONS

Male sex was associated with a higher risk of kidney failure and mortality, despite adjustment for demographic, clinical, and treatment factors. Men had higher levels of inflammatory and extracellular matrix deposition biomarkers. By contrast, women 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 biologic basis for the observed sex difference in outcomes.

CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: NCT04084145 .