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.

L’augmentation de l’insulinorésistance dans le monde est un sujet préoccupant en termes de santé publique, en raison des risques associés de diabète de type 2, de maladies cardiovasculaires, de cancers et, plus récemment, d’augmentation du risque de déclin cognitif. Au cours de la gestation, l’insulinorésistance est un phénomène physiologique qui, lorsqu’elle n’est pas « maîtrisée », peut devenir pathologique, on parle alors de diabète gestationnel (DG). Le lien étroit entre stress oxydant, diabète et DG est clairement admis, résultant d’une hyperproduction radicalaire associée à l’hyperglycémie et à une diminution des défenses antioxydantes. Au cours de cette dernière décennie, une controverse est née sur les risques associés à des apports élevés en fer, en raison de son rôle pro-oxydant et du risque de diabète associé à une ferritinémie élevée. Une relation qui est également décrite dans l’augmentation du risque de DG, et qui doit inciter à évaluer le bénéfice/risque en cas de supplémentation martiale. En effet, un diagnostic biologique fondé uniquement sur une ferritine basse, et en l’absence d’anémie, conduit encore trop souvent à une supplémentation préventive qui ne serait pas dénuée de risque sur l’incidence de DG. Un risque qui justifie que la supplémentation martiale ne soit proposée qu’en cas d’anémie, alors, qu’à l’avenir, le dosage de la ferritine en début de grossesse pourrait devenir un marqueur de risque de DG.The increased insulin resistance (IR) in the world is an issue of concern for public health due to the associated risks of type 2 diabetes, cardiovascular diseases, cancers and more recently increased risk of cognitive decline. During pregnancy, IR is a physiological phenomenon which, when not managed, can become pathological then called gestational diabetes mellitus (GDM). The role of oxidative stress in the pathophysiology of GDM and diabetes is well documented. Studies have shown an increase in oxidative markers with the decreased antioxidant defenses. During the last decade, a controversy rose concerning excess iron due to its prooxidant role and associated diabetes risk. In fact, several observational studies have reported an increased risk of IR in case of high iron status; the relationship is also described in the increased risk of GDM. Iron supplementation based only on low ferritin value without anemia leads too often to preventive supplementation, which is not without GDM risk. Consequently the adaptation of iron dose based on ferritin level in early pregnancy should be reevaluated in terms of risk/benefit and iron supplementation should be offered in cases of documented anemia only.