Soluble Urokinase Plasminogen Activator Receptor (suPAR) and All-Cause and Cardiovascular Mortality in Diverse Hemodialysis Patients

Abstract

Introduction: The soluble receptor of urokinase plasminogen activator (suPAR) is an innate immunity/inflammation biomarker predicting cardiovascular (CV) and non-CV events in various conditions, including type 2 diabetic patients on dialysis. However, the relationship between suPAR and clinical outcomes in the hemodialysis population at large has not been tested.

Methods: We measured plasma suPAR levels (R&D enzyme-linked immunosorbent assay [ELISA]) in 1038 hemodialysis patients with a follow-up of 2.9 years (interquartile range = 1.7-4.2) who were enrolled in the PROGREDIRE study, a cohort study involving 35 dialysis units in 2 regions in Southern Italy.

Results: suPAR was strongly (P < 0.001) and independently related to female gender (β = -0.160), age (β = 0.216), dialysis vintage (β = 0.264), CV comorbidities (β = 0.105), alkaline phosphatase (β = 0.136), albumin (β = -0.147), and body mass index (BMI; β = 0.174) (all P < 0.006). In fully adjusted analyses, suPAR tertiles predicted the risk of all-cause mortality (third tertile vs. first tertile hazard ratio (HR) = 1.91, 95% confidence interval (CI) = 1.47 - 2.48, P < 0.001), CV mortality (HR = 1.47, 95% CI = 1.03-2.09, P = 0.03), and non-CV mortality (HR = 1.94, 95% CI = 1.28-2.93, P = 0.002); these relationships were not modified by diabetes or other risk factors. suPAR added only modest prognostic risk discrimination and reclassification power for these outcomes to parsimonious models based on simple clinical variables.

Conclusion: In conclusion, suPAR robustly predicted all-cause and both CV and non-CV mortality in a large unselected hemodialysis population. Intervention studies are needed to definitively test the hypothesis that suPAR is causally implicated in clinical outcomes in this population.

Keywords: cardiovascular mortality; hemodialysis; mortality; noncardiovascular mortality; soluble urokinase plasminogen activator receptor (suPAR).

Figure 1

Crude and adjusted Cox regression analysis showing the effect of soluble urokinase plasminogen activator receptor (suPAR) on all-cause, cardiovascular, and noncardiovascular mortality, respectively. Variables included are suPAR and all variables listed in Table 1. Survival curves were made to compare the risk of the considered outcome. The association between suPAR and cardiovascular (CV) or non-CV mortality was assessed by using competitive risk regression models (see Materials and Methods for further details). CI, confidence interval; HR, hazard ratio; SHR, subdistribution hazard ratio.

Figure 2

Analysis of the association of soluble urokinase plasminogen activator receptor (suPAR) with all-cause and cardiovascular (CV) mortality by nonlinear models. Models were adjusted for the full list of variables presented in Table 1. Nonlinear associations were assessed by estimating hazard ratios of mortality and CV mortality according to suPAR with its linear spline terms 36 with knots at 5625 and 6999 pg/ml. (See Methods for further details). n = Number of patients corresponding to specific values of suPAR. CI, confidence interval; HR, hazard ratio.

Figure 3

Absence of effect modification attributable to diabetes, body mass index (BMI), dialysis vintage, systolic blood pressure (SBP), albumin, C-reactive protein (CRP), fibrinogen, and Kt/V on the link between soluble urokinase plasminogen activator receptor (suPAR)−considered outcome (all-cause mortality/cardiovascular mortality/noncardiovascular mortality).