Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease

Abstract

Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD.

Indoxyl Sulfate, a Uremic Endotheliotoxin

“…One of the recent major contributions in the understanding of cardiovascular complications in patients with CKD is the involvement of the aryl hydrocarbon receptor (AhR) pathway [91][92][93][94]. AhR is a transcription factor involved in biologic detoxification.…”

Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery

“…[29][30][31] Later, hyperpolarization in the vascular smooth muscle is preferentially evoked through myoendothelial gap junctions by the passage of a current or diffusion of a factor such as K + through gap junctions. 23,32,33) Despite the imbalanced signaling among three EDRFs in disease states and/or other physiological differences, including aging and sex differences, 6,30,[33][34][35] the determinant and altering causal factors, such as such signaling, remain unknown.…”

Internal Jugular Vein Thrombosis due to Chronic Kidney Disease: A Case Report

“…CKD leads to the accumulation of uremic toxins, which exert toxic effects on blood and the vessel wall. 8 The risk of venous thromboembolism is increased across the spectrum of CKD, including mild and more advanced CKD, nephrotic syndrome, end-stage renal disease, and after kidney transplant. This increased risk may be due to underlying hemostatic derangements, including activation of procoagulants, decreased endogenous anticoagulants, enhanced platelet activation and aggregation, and decreased fibrinolytic activity.…”