The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid
Top Cited Papers
Open Access
- 1 April 2015
- journal article
- Published by Wolters Kluwer Health in Journal of the American Society of Nephrology
- Vol. 26 (4), 876-887
- https://doi.org/10.1681/asn.2013121283
Abstract
In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan–Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 µM) than in the lower IAA group (IAAµM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-κB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-κB pathway.Keywords
This publication has 44 references indexed in Scilit:
- Does the Adequacy Parameter Kt/Vurea Reflect Uremic Toxin Concentrations in Hemodialysis Patients?PLOS ONE, 2013
- Estimated Glomerular Filtration Rate Is a Poor Predictor of Concentration for a Broad Range of Uremic ToxinsClinical Journal of the American Society of Nephrology, 2011
- Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J miceBiological Chemistry, 2010
- ApoA-1 Mimetic Peptide Reverses Uremia-Induced Upregulation of Pro-Atherogenic Pathways in the AortaAmerican Journal of Nephrology, 2010
- Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney diseaseNephrology Dialysis Transplantation, 2009
- Serum Indoxyl Sulfate Is Associated with Vascular Disease and Mortality in Chronic Kidney Disease PatientsClinical Journal of the American Society of Nephrology, 2009
- Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular diseaseKidney International, 2008
- The uremic solute indoxyl sulfate induces oxidative stress in endothelial cellsJournal of Thrombosis and Haemostasis, 2007
- Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-κB and free radical in proximal tubular cellsKidney International, 2003
- Review on uremic toxins: Classification, concentration, and interindividual variabilityKidney International, 2003