UCSF

Background

Urinary 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 chronic kidney disease (CKD) and diabetes, and post-operative and contrast-associated acute kidney injury (AKI). We explored associations of uDKK3 with cardiovascular disease (CVD), kidney and mortality outcomes within the subset of Systolic Blood Pressure Intervention Trial (SPRINT) participants with non-diabetic CKD.

Methods

We included 2,344 participants with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at 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 end stage kidney disease [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.

Results

Over 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 [HR] 1.07, 95% confidence interval [CI] 0.92-1.23), ESKD (0.80; 0.62-1.02), AKI (1.01; 0.85-1.21), eGFR decline >30% (0.88; 0.79-0.99) or mortality (1.02; 0.87-1.20). For the linear eGFR change outcome, higher uDKK3 also had no association in the fully adjusted model (-0.03; -0.41-0.36).

Conclusions

Among individuals with hypertension and non-diabetic CKD, higher uDKK3 appeared to have associations with a greater risk of CVD events, incident ESKD, incident AKI, eGFR decline ≥30%, and mortality, but was not independent of eGFR and albuminuria.