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The cardiovascular effect of the uremic solute indole-3 acetic acid
Laetitia Dou1, Marion Sallée2, Claire Cerini3
1Aix Marseille University, Inserm, UMR 1076, Marseille, France; laetitia.dou@univ-amu.fr.
Insights
High levels of the uremic solute indole-3 acetic acid (IAA) predict mortality and cardiovascular events in chronic kidney disease (CKD) patients. IAA also promotes inflammation and oxidative stress in endothelial cells.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Biochemistry
Background:
- Uremic solutes in chronic kidney disease (CKD) contribute to endothelial dysfunction, inflammation, and oxidative stress, elevating cardiovascular risk.
- Indole-3 acetic acid (IAA) is a prevalent uremic solute whose clinical significance and biological effects in CKD require further elucidation.
Purpose of the Study:
- To determine if serum IAA levels predict clinical outcomes, specifically mortality and major adverse cardiovascular events (MACE), in patients with CKD.
- To investigate the prooxidant and proinflammatory effects of IAA on human endothelial cells in vitro.
Main Methods:
- Prospective study of 120 CKD patients with median follow-up of 966 days, assessing IAA levels, clinical outcomes, and inflammatory/oxidative stress markers.
- Kaplan-Meier and multivariate Cox regression analyses were used to evaluate IAA as a predictor of mortality and MACE.
- In vitro experiments using cultured human endothelial cells to assess IAA's effects on inflammatory pathways (AhR/p38MAPK/NF-κB) and reactive oxygen species (ROS) production.
Main Results:
- Patients with higher IAA levels (>3.73 µM) exhibited significantly higher rates of mortality and MACE compared to those with lower levels.
- Serum IAA was an independent predictor of mortality and MACE, even after adjusting for numerous clinical factors, cardiovascular risk markers, and other uremic toxins.
- IAA levels positively correlated with C-reactive protein and malondialdehyde, markers of inflammation and oxidative stress, respectively.
- In vitro, IAA activated the inflammatory AhR/p38MAPK/NF-κB pathway, induced cyclooxygenase-2, and increased endothelial ROS production.
Conclusions:
- Serum IAA is a significant and independent predictor of mortality and cardiovascular events in patients with CKD.
- IAA contributes to endothelial inflammation and oxidative stress through the activation of the AhR/p38MAPK/NF-κB pathway, providing a mechanistic link to adverse clinical outcomes.
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 (IAA<3.73 µM). 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.
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