Hyperuricemia and Progression of CKD in Children and Adolescents: The Chronic Kidney Disease in Children (CKiD) Cohort Study

Abstract

Background: Hyperuricemia is associated with essential hypertension in children. No previous studies have evaluated the effect of hyperuricemia on progression of chronic kidney disease (CKD) in children.

Study design: Prospective observational cohort study.

Setting & participants: Children and adolescents (n=678 cross-sectional; n=627 longitudinal) with a median age of 12.3 (IQR, 8.6-15.6) years enrolled at 52 North American sites of the CKiD (CKD in Children) Study.

Predictor: Serum uric acid level (<5.5, 5.5-7.5, and >7.5mg/dL).

Outcomes: Composite end point of either >30% decline in glomerular filtration rate (GFR) or initiation of renal replacement therapy.

Measurements: Age, sex, race, blood pressure status, GFR, CKD cause, urine protein-creatinine ratio (<0.5, 0.5-<2.0, and ≥2.0mg/mg), age- and sex-specific body mass index > 95th percentile, use of diuretics, and serum uric acid level.

Results: Older age, male sex, lower GFR, and body mass index > 95th percentile were associated with higher uric acid levels. 162, 294, and 171 participants had initial uric acid levels < 5.5, 5.5 to 7.5, or >7.5 mg/dL, respectively. We observed 225 instances of the composite end point over 5 years. In a multivariable parametric time-to-event analysis, compared with participants with initial uric acid levels < 5.5mg/dL, those with uric acid levels of 5.5 to 7.5 or >7.5mg/dL had 17% shorter (relative time, 0.83; 95% CI, 0.62-1.11) or 38% shorter (relative time, 0.62; 95% CI, 0.45-0.85) times to event, respectively. Hypertension, lower GFR, glomerular CKD cause, and elevated urine protein-creatinine ratio were also associated with faster times to the composite end point.

Limitations: The study lacked sufficient data to examine how use of specific medications might influence serum uric acid levels and CKD progression.

Conclusions: Hyperuricemia is a previously undescribed independent risk factor for faster progression of CKD in children and adolescents. It is possible that treatment of children and adolescents with CKD with urate-lowering therapy could slow disease progression.

Keywords: CKD progression; CKiD (Chronic Kidney Disease in Children); Uric acid; adolescents; children; chronic kidney disease (CKD); disease trajectory; end-stage renal disease (ESRD); glomerular filtration rate (GFR); hyperuricemia; pediatric kidney disease; renal function decline; renal replacement therapy (RRT); risk factor; urate.

Figure 1

Histogram depicting the distribution of serum Uric Acid at the index visit; median=6.5 (interquartile range, 5.4–7.6) mg/dL (N=678)

Figure 2

Kaplan-Meier and conventional generalized gamma survival curves for the composite end-point of >30% decline in GFR or initiation of RRT.