Association between uremic toxin-anthranilic acid and fibrinolytic system activity in predialysis patients at different stages of chronic kidney disease

Abstract

PurposeChronic kidney disease (CKD) is an estimated risk factor for increased mortality and morbidity due to fibrinolytic system disturbances. Progressive loss of renal function leads to retention of uremic toxins. Anthranilic acid (AA) is a tryptophan-derived uremic toxin with multidirectional properties that can affect the hemostatic system. The goal of this study was to examine the association between AA and the parameters of fibrinolysis at different stages of CKD.MethodsPatients with CKD were divided into two groups: mild-to-moderate (n = 20) and severe-to-end-stage CKD (n = 28). Seventeen healthy volunteers served as an additional control group. Parameters of fibrinolysis, inflammation, and monocytes activation were determined by ELISA immune-enzymatic kits. AA levels were evaluated using high-performance liquid chromatography.ResultsAA concentration and parameters of fibrinolysis: urokinase-type plasminogen activator (uPA), its soluble receptor (suPAR), tissue plasminogen activator (tPA), tissue plasminogen activator inhibitor-1 (PAI-1) and plasmin-antiplasmin complex (PAP) were significantly elevated in the CKD groups compared with the controls. The markers of inflammation, monocyte activation, and impaired kidney function were also increased in those with CKD. AA was positively correlated with the uPA/suPAR system in the early stages of CKD, whereas during severe-to-end-stage CKD, inverse relationships were observed between AA, tPA and PAI-1. Additionally, AA was an independent variable associated with tPA in patients with CKD overall and with uPA levels in the mild-to-moderate CKD group.ConclusionsObtained results suggest for the first time the association between AA and the fibrinolytic system in CKD patients. The distinct relationship between AA and individual parameters of fibrinolysis appears to be dependent on CKD stage.

Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease

“…Kynurenine is positively associated with vWF [ 34 ] and with prothrombin fragments F(1+2), reflecting hypercoagulability in CKD patients [ 35 ]. AA is also significantly associated with TF and prothrombin fragments F(1+2) [ 35 ], and negatively correlated with the fibrinolytic system uPA/uPAR in severe-to-end-stage CKD [ 36 ]. QA is positively associated with vWF [ 34 ], TF, and prothrombin fragments F(1+2) [ 35 ].…”

Association between Soluble Urokinase-Type Plasminogen Activator Receptor Levels and Chronic Kidney Disease: A Systematic Review and Meta-Analysis

“…A total of five studies [23–26, 28] compared suPAR concentrations between CKD patients and normal controls. Of the five studies, four were from Poland and the other [26] was from the United States.…”

How do Uremic Toxins Affect the Endothelium?

“…Fibrinolysis is enhanced in CKD, as demonstrated by higher levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) in this setting compared to healthy controls [ 58 , 73 ]. Likewise, there are also higher serum levels of D-dimer, a product of fibrin degradation, in CKD patients [ 55 ].…”

“…In vivo, Karbowska et al [ 72 ] found increased levels of PAI-1, but not of D-dimer, in rats treated with IS compared to control group. Therefore, both coagulation and fibrinolysis systems are altered in CKD [ 58 , 73 , 74 ].…”