Urinary Biomarkers and Kidney Outcomes: Impact of Indexing Versus Adjusting for Urinary Creatinine

RATIONALE & OBJECTIVE: Urinary biomarker concentrations are frequently indexed to urinary creatinine (Ucr) concentration in spot samples to account for urine dilution; however, this may introduce biases. We evaluated whether indexing versus adjusting urinary biomarker concentrations for Ucr concentration altered their associations with outcomes. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: We analyzed data from 2,360 Systolic Blood Pressure Intervention Trial (SPRINT) participants with estimated glomerular filtration rates < 60 mL/min/1.73 m(2) and urinary albumin (UAlb) and 8 urinary kidney tubule biomarkers measured at baseline. OUTCOMES: The primary outcome was a composite of cardiovascular disease events; secondary outcomes were all-cause mortality and a composite of kidney outcomes (50% estimated glomerular filtration rate decline, end-stage kidney disease, or transplantation). ANALYTICAL APPROACH: We used Cox proportional hazards regression to examine the associations of 1/Ucr with outcomes and compared the associations of UAlb and 8 individual urinary tubule biomarkers with outcomes, analyzed by indexing to Ucr, adjusting for 1/Ucr or the biomarker alone (without Ucr concentration). RESULTS: During a median follow-up of 3.3 years, 307 composite cardiovascular events, 166 deaths, and 34 composite kidney outcomes occurred. After multivariable adjustment, 1/Ucr was significantly associated with cardiovascular events (HR, 1.27 per 2-fold higher; 95% CI, 1.11-1.45), not associated with either mortality (HR, 1.06; 95% CI, 0.87-1.28) or kidney events (HR, 1.49; 95% CI, 0.95-2.35). For UAlb and urinary tubule biomarker concentrations, most risk estimates were not significantly different when indexed to Ucr concentration versus adjusted for 1/Ucr. LIMITATIONS: Cohort excluded patients with diabetes and overall had low levels of albuminuria. CONCLUSIONS: 1/Ucr is independently associated with cardiovascular events in trial participants with chronic kidney disease. Indexing versus adjusting for 1/Ucr does not significantly change the associations of most urinary biomarkers with clinical outcomes.