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

Abstract

Rationale & objectives: The urine-to-plasma (U/P) ratio of 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 the U/P urea ratio would also be associated with progression of more common forms of chronic kidney disease (CKD).

Study design: Observational cohort study.

Setting & participants: 3,723 adults in the United States with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m², enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Exposure: U/P urea ratio, calculated from 24-hour urine collections and plasma samples at baseline.

Outcome: Associations of U/P urea ratio with eGFR slope, initiation of kidney replacement therapy (KRT), and CKD progression, defined as 50% decline in eGFR or incident KRT.

Analytical approach: Multivariable linear mixed-effects models tested associations with eGFR slope. Cox proportional hazards models tested associations with dichotomous CKD outcomes.

Results: The median U/P urea ratio was 14.8 (IQR, 9.5-22.2). Compared with participants in the highest U/P urea ratio quintile, those in the lowest quintile had a greater eGFR decline by 1.06 mL/min/1.73 m² per year (P < 0.001) over 7.0 (IQR, 3.0-11.0) years of follow-up observation. Each 1-SD lower natural log-transformed U/P urea ratio was independently associated with CKD progression (HR, 1.22 [95% CI, 1.12-1.33]) and incident KRT (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/1.73 m², each 1-SD lower in ln(U/P urea ratio) 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/1.73 m² (HR, 1.00 [95% CI, 0.84-1.20]).

Limitations: Possibility of residual confounding. Single baseline 24-hour urine collection for U/P urea ratio.

Conclusions: 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.

Keywords: CKD progression; Index Words: Biomarker; chronic kidney disease (CKD); eGFR slope; end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR); renal function; tubular function; urea; urine solute; urine-concentration capacity.