Soluble Urokinase Receptor and Chronic Kidney Disease

Abstract

Background: Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease.

Methods: We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m(2) of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables.

Results: A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was -0.9 ml per minute per 1.73 m(2) among participants in the lowest quartile of suPAR levels as compared with -4.2 ml per minute per 1.73 m(2) among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥ 90 ml per minute per 1.73 m(2)) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m(2), the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile.

Conclusions: An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.).

Figure 1. Levels of suPAR and Decline in the eGFR

Shown are data from a statistical model examining the percent change in the estimated glomerular filtration rate (eGFR) over time in 2292 persons, with data stratified according to quartile (Q1 through Q4) of the soluble urokinase-type plasminogen activator receptor (suPAR) level at baseline. The annual change in the eGFR was −0.9 ml per minute per 1.73 m² in Q1 as compared with −4.2 ml per minute per 1.73 m² in Q4 (P<0.001). Q4 had a significantly higher rate of decline than both Q1 and Q2 (P<0.001 for both comparisons); Q3 also had a significantly higher rate of decline than both Q1 and Q2 (P<0.001 for both comparisons). There was not a significant difference in the rate of decline between Q1 and Q2 (P = 0.91) or between Q3 and Q4 (P = 0.08).

Figure 2. The suPAR-Related Decline in the eGFR, According to Subgroup

Panel A shows the suPAR-related change in the eGFR per year during follow-up, stratified according to presence or absence of diabetes, black or nonblack race (race was self-reported), and baseline eGFR (<60 or ≥60 ml per minute per 1.73 m² of body-surface area). Information on diabetes status was missing for 22 patients. CI denotes confidence interval. Panel B shows the suPAR-related change in the eGFR per year, stratified according to baseline eGFR. Patients with an eGFR in the normal range (90 to 120 ml per minute per 1.73 m²) had the largest suPAR-related decline in the eGFR. I bars indicate 95% confidence intervals.

Figure 3. Levels of suPAR and Incident Chronic Kidney Disease

Kaplan–Meier curves show the cumulative incidence of chronic kidney disease, defined as an eGFR of less than 60 ml per minute per 1.73 m², among the 1335 participants who had a baseline eGFR of at least 60 ml per minute per 1.73 m², stratified according to quartile of suPAR level. The shaded areas represent the 95% confidence intervals. The P value is the result of the log-rank test for the overall comparison among the groups.