Association of Urinary Dickkopf-3 Levels with Cardiovascular Events and Kidney Disease Progression in Systolic Blood Pressure Intervention Trial

Abstract

Key PointsIn unadjusted analyses, elevated urinary Dickkopf-3 levels were strongly associated with higher risks of cardiovascular disease, ESKD, AKI, and mortality.However, associations were substantially weakened after adjustment for eGFR and albuminuria, suggesting limited prognostic value.BackgroundUrinary Dickkopf-3 (uDKK3) is a tubular epithelial-derived profibrotic protein secreted into the urine under tubular stress. It is associated with kidney disease progression in persons with CKD and diabetes and postoperative and contrast-associated AKI. We explored associations of uDKK3 with cardiovascular disease (CVD), kidney, and mortality outcomes within the subset of Systolic Blood Pressure Intervention Trial participants with nondiabetic CKD.MethodsWe included 2344 participants with eGFR <60 ml/min per 1.73 m2at baseline. We used Cox proportional hazards models to evaluate associations of uDKK3 with CVD (acute decompensated heart failure, myocardial infarction, acute coronary syndrome, stroke, or CVD death), kidney outcomes (incident ESKD, incident AKI, and eGFR decline ≥30%), and all-cause mortality. We used linear mixed models to examine the association of uDKK3 with annual percentage change in eGFR. Models were adjusted for demographic and clinical characteristics, eGFR, and albuminuria.ResultsOver a median follow-up of 3.5 years, there were 292 CVD, 73 ESKD, 183 AKI, 471 eGFR decline, and 228 mortality events. In multivariable models without adjustment for eGFR and albuminuria, uDKK3 was strongly associated with CVD, ESKD, AKI, eGFR decline ≥30%, and mortality. However, after further adjustment for eGFR and albuminuria, uDKK3 was no longer associated with risks for composite CVD (hazard ratio, 1.07; 95% confidence interval, 0.92 to 1.23), ESKD (0.80; 0.62 to 1.02), AKI (1.01; 0.85 to 1.21), eGFR decline ≥30% (0.88; 0.79 to 0.99), or mortality (1.02; 0.87 to 1.20). For the linear eGFR change outcome, higher uDKK3 also had no association in the fully adjusted model (-0.03; -0.41 to 0.36).ConclusionsAmong individuals with hypertension and nondiabetic CKD, higher uDKK3 appeared to have associations with a greater risk of CVD events, incident ESKD, incident AKI, eGFR decline ≥30%, and mortality but these associations were not independent of eGFR and albuminuria.