Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease.

Laetitia Dou,Stéphane Burtey,Tawfik Addi

doi:10.3390/toxins10100412

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.

Highlights

Chronic kidney disease (CKD) is defined as the occurrence of abnormalities of kidney structure or function, present for >3 months [1]
An important clot formation was observed in primary human vascular smooth muscle cells (vSMC) pretreated with indoxyl sulfate (IS) or indole-3-acetic acid (IAA) when exposed to coronary-like blood flow in an ex-vivo flow loop model [28]
We demonstrated that IAA induces COX-2 expression in cultured endothelial cells via an aryl hydrocarbon receptor (AhR)/p38MAPK/Nuclear Factor kappa B (NF-κB) pathway [25]

Summary

Introduction

Chronic kidney disease (CKD) is defined as the occurrence of abnormalities of kidney structure or function, present for >3 months [1]. The decline of GFR is related to a substantial risk of mortality and cardiovascular disease (CVD) [3,4,5,6]. CKD patients display an increased thrombotic risk, paradoxically associated with a bleeding tendency [8,9]. In CKD, thrombotic events occur in the cerebral, coronary, and retinal arteries, in the deep venous system, heart, and at sites of vascular access in hemodialysis patients [10]. CKD patients display a higher mortality rate than patients with normal kidney function due to pulmonary embolism [8]. In CKD patients, the atrial fibrillation risk is higher and associated with an increased neurovascular risk [13]. Thrombosis can complicate stenosis, leading to access failure [14]

Uremic Toxins from Tryptophan Metabolism

Tryptophan-Derived Uremic Toxins and Thrombotic Events

Thrombotic Mechanisms Induced by Tryptophan-Derived Uremic Toxins

Deregulation of Plasma Coagulation Factors

Platelet Hyperactivity

Endothelial Dysfunction

Decrease in NO Bioavailability

Production of Procoagulant Microparticles

Overexpression of Cell Tissue Factor

Modulation

Results from diet modifications

Conclusions