Prospective Cohort Study of Soluble Urokinase Plasminogen Activation Receptor and Cardiovascular Events in Patients With CKD

Abstract

Introduction: Soluble urokinase plasminogen activation receptor (suPAR) is an immune-derived pathogenic factor for kidney and atherosclerotic disease. Whether the association between suPAR and cardiovascular (CV) outcomes is dependent on the severity of underlying kidney disease is unclear.

Methods: We measured serum suPAR levels in 4994 participants (mean age 60 years; 60% men; 36% with diabetes mellitus; mean estimated glomerular filtration rate (eGFR) 49 ml/min per 1.73 m², SD 18) of the German Chronic Kidney Disease (GCKD) cohort and examined its association with all-cause death, CV death, and major CV events (MACE) across the range of eGFR and urine albumin-to-creatinine ratio (UACR).

Results: The median suPAR level was 1771 pg/ml (interquartile range [IQR] 1447-2254 pg/ml). SuPAR levels were positively and independently correlated with age, eGFR, UACR, and parathyroid hormone levels. There were 573 deaths, including 190 CV deaths and 683 MACE events at a follow-up time of 6.5 years. In multivariable analyses, suPAR levels (log₂) were associated with all-cause death (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.21-1.53), CV death (HR 1.27, 95% CI 1.03-1.57), and MACE (HR 1.13, 95% CI 1.00-1.28), and were not found to differ according to diabetes mellitus status, baseline eGFR, UACR, or parathyroid hormone levels. In mediation analysis, suPAR's direct effect on all-cause death, CV death, and MACE accounted for 77%, 67%, and 60% of the total effect, respectively; whereas the effect mediated through eGFR accounted for 23%, 34%, and 40%, respectively.

Conclusion: In a large cohort of individuals with chronic kidney disease (CKD), suPAR levels were associated with mortality and CV outcomes independently of indices of kidney function, consistent with its independent role in the pathogenesis of atherosclerosis.

Keywords: biomarkers; cardiovascular outcomes; cohort; eGFR; suPAR; uACR.

Graphical abstract

Figure 1

Estimated glomerular filtration rates (eGFR) and urine albumin-to-creatinine ratio (UACR) stratified by suPAR quintiles. Box plots depicting the distribution of eGFR and UACR stratified by suPAR quintiles. Panel A shows the distribution of eGFR across suPAR quintiles. Panel B shows the distribution of UACR across suPAR quintiles. The box represents the interquartile range (IQR), with the line inside the box indicating the median value. Whiskers extend to 1.5 times the IQR. suPAR, soluble urokinase plasminogen activation receptor

Figure 2

Cumulative incidence of outcomes stratified by suPAR quintiles. (a) shows the cumulative incidence of all-cause death according to suPAR quintiles. (b) shows the cumulative incidence of cardiovascular death according to suPAR quintiles. (c) shows the cumulative incidence of MACE according to suPAR quintiles. MACE, major adverse cardiovascular events; suPAR, soluble urokinase plasminogen activation receptor.

Figure 3

Forest plots depicting the association between suPAR levels and outcomes. 3-panel forest plot depicting the hazard ratios and 95% confidence interals of the association between each quintile of suPAR (the reference being quintile 1), and (a) all-cause death, (b) cardiovascular death, and (c) major adverse cardiovascular events. Model 0 included suPAR alone; model 1 included suPAR in addition to demographics and CV risk factors: age, gender, body mass index, current smoking, hypertension, diabetes mellitus, LDL, and HDL. In model 2, we added coronary artery disease, stroke and PAD. Model 3 included indices of kidney function eGFR and UACR. Lastly, model 4 included phosphate and iPTH levels. CV, cardiovascular; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; iPTH, intact parathyroid hormone; LDL, low-density lipoprotein; PAD, peripheral artery disease; suPAR, soluble urokinase plasminogen activation receptor; UACR, urine albumin-to-creatinine ratio.