Plasma Soluble Urokinase Plasminogen Activator Receptor (suPAR) and CKD Progression in Children

Abstract

Rationale & objective: Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker associated with incident chronic kidney disease (CKD) and has been identified as an independent risk factor for CKD progression in children, although these findings remain preliminary, limited to a single point in time, and unreplicated in pediatric cohorts.

Study design: Prospective longitudinal cohort study.

Setting & participants: 565 participants aged 1 to 16 years enrolled in the Chronic Kidney Disease in Children (CKiD) Study.

Exposure: Plasma suPAR levels, categorized by quartiles, measured at study entry and a 6-month follow-up interval.

Outcome: CKD progression, defined as the initiation of kidney replacement therapy (dialysis or transplantation) or >50% decline in estimated glomerular filtrate rate (eGFR).

Analytic approach: Associations between plasma suPAR quartiles and risk for CKD progression were estimated using lognormal survival models, adjusting for potential confounders.

Results: Participants in the highest suPAR quartile experienced 54% faster progression compared with the lowest quartile after adjustment for demographic and traditional CKD risk factors (P < 0.001). Addition of eGFR to the model attenuated the risk, although those in the highest quartile experienced 33% faster progression compared with the lowest quartile (P = 0.008). Plasma suPAR levels showed little change over 6 months.

Limitations: Potential for residual confounding, reliance on observational data, relatively fewer patients with higher eGFRs for subgroup analysis.

Conclusions: Higher suPAR levels are associated with shorter time to kidney replacement therapy or halving of eGFR in children with CKD. This association is attenuated slightly with inclusion of eGFR in regression modeling but remains a significant association for participants with the highest suPAR levels.

Keywords: Soluble urokinase plasminogen activator receptor (suPAR); biomarker; children; chronic kidney disease (CKD); eGFR decline; end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR); pediatric; progression; renal failure.

Figure 1.

Unadjusted nonparametric Kaplan-Meier curves of progression to the composite event of either kidney replacement therapy or >50% eGFR decline, by baseline plasma suPAR quartiles. Solid line represents Quartile 1 (< 2,627 pg/mL); dashed line represents Quartile 2 (2,267 to <3,204 pg/mL); dot-dashed line represents Quartile 3 (3,204 to <3,785 pg/mL; and two-dashed lines represents Quartile 4 (≥3,785 pg/mL). The lognormal fit is shown as an overlay (gray lines).

Figure 2.

Relative times (95% confidence intervals) of SuPAR quartiles to composite event of kidney replacement therapy or >50% decline in eGFR. Each grouping of relative times are from lognormal parametric survivals models among participants who have eGFR > the cut off displayed on the x-axis. The N’s and number of events (E) in each eGFR cut off group are shown at the bottom of the figure. Circles represent relative times of SuPAR Quartile 4 compared to Quartile 1. Gray symbols are adjusted relative times from model 2 (adjusting for age, sex, race, ethnicity, hypertension (systolic BP percentiles), antihypertensive use, BMI, proteinuria, glomerular diagnosis) and black symbols are the adjusted relative times of SuPAR from model 3 (also adjusting for eGFR).

Figure 3.

Scatterplot and Bland-Altman plot comparing the plasma SuPAR concentration distributions at baseline visit and the second visit, six months later. There are 2 points in the visit 2 distribution >13000 pg/mL that are not shown. In the first panel, the solid line indicates the identity line and the dashed line indicates the regression line between SuPAR concentration at baseline visit and the second visit. In the second panel, the dashed-dotted lines indicates the regression line while the dashed lines represent the 95% confidence limits (+/− 1.96 standard deviations).