Association of the Urine-to-Plasma Urea Ratio With CKD Progression

The urine-to-plasma ratio of urea ([U/P]urea) is correlated with urine concentrating capacity and associated with progression of autosomal dominant polycystic kidney disease. As a proposed biomarker of tubular function, we hypothesized that [U/P]urea would also be associated with progression of more common forms of chronic kidney disease (CKD).Observational cohort study.3,723 adults in the USA with estimated glomerular filtration rate (eGFR) of 20-70 mL/min per 1.73m2, enrolled in the Chronic Renal Insufficiency Cohort Study.[U/P]urea, calculated from 24-hour urine collections and plasma samples at baseline.Associations of [U/P]urea with eGFR slope, incident end-stage kidney disease (ESKD), and CKD progression, defined as 50% decline in eGFR or incident ESKD.Multivariable linear mixed-effects models tested associations with eGFR slope. Cox proportional hazards models tested associations with dichotomous CKD outcomes.Median (interquartile range) [U/P]urea was 14.8 (IQR, 9.5-22.2). Compared to participants in the highest [U/P]urea quintile, those in the lowest quintile had a greater eGFR decline by 1.06 ml/min per 1.73m2 per year (P<0.001) over 7.0 (IQR, 3.0-11.0) years of follow-up. Each 1 standard deviation decrease in natural log-transformed [U/P]urea was independently associated with CKD progression (HR 1.22, 95% CI 1.12-1.33) and incident ESKD (HR 1.22, 95% CI 1.10-1.33). Associations differed by baseline eGFR (p-interaction=0.009). Among those with an eGFR ≥30 ml/min per 1.73m2, each 1 standard deviation decrease in log-[U/P]urea was independently associated with CKD progression (HR 1.30, 95% CI 1.18-1.45), but this was not significant among those with eGFR <30 ml/min per 1.73m2 (HR 1.00, 95% CI 0.84-1.20).Possibility of residual confounding. Single baseline 24-hour urine collection for [U/P]urea.In a large and diverse cohort of patients with common forms of CKD, [U/P]urea was independently associated with disease progression and incident kidney failure. Associations were not significant among those with advanced CKD at baseline.