THE UREMIC TOXIN INDOLE-3-ACETIC ACID INDUCES ENDOTHELIAL COX-2 EXPRESSION BY INCREASING OXIDATIVE STRESS

49th Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association (ERA-EDTA), Paris, FRANCE, MAY 24-27, 2012International audienceno abstrac

INDOLE-3 ACETIC ACID PREDICTS CARDIOVASCULAR EVENT AND MORTALITY IN CHRONIC KIDNEY DISEASE PATIENTS: EVIDENCE FOR AN ENDOTHELIAL INFLAMMATORY AND PROOXIDANT EFFECT

51st Congress of the European-Renal-Association(ERA)/European-Dialysis-and-Transplant-Associa tion (EDTA), Amsterdam, NETHERLANDS, MAY 31-JUN 03, 2014International audienceno abstrac

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

International audienceIn 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 mu M) than in the lower IAA group (IAA<3.73 mu M). 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-kappa B 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-kappa B pathway

. Cytomegalovirus and adenovirus infections and diseases among 75 paediatric unrelated allogeneic bone marrow transplant recipients.

Viral infections remain a major complication of allogeneic bone marrow transplantation. A population of children who underwent unrelated allogeneic bone marrow transplantation in a single centre has been followed-up for viral infections and diseases. We describe the detection of cytomegalovirus (CMV) and adenovirus among 75 children transplanted between 1989 and 2000. CMV was detected among 22 patients (29%) and adenovirus among 19 patients (25%); they were associated with clinical diseases in 10 and 8 patients, respectively. Four patients had adenovirus and CMV coinfection. The obvious risk factor for CMV infection is seropositivity of the recipient prior to transplantation. Adenovirus is detected significantly more frequently when conditioning regimen includes anti-thymocyte or anti-lymphocyte globulin. Diseases associated with adenovirus have been correlated with a significantly higher mortality rate, stressing the need for the implementation of a systematic virological survey for this virus and for the evaluation of therapeutic protocols including new molecules. Copyright 2004 Wiley-Liss, Inc

Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease

International audienc

Mechanisms of tissue factor induction by the uremic toxin indole-3 acetic acid through aryl hydrocarbon receptor/nuclear factor-kappa B signaling pathway in human endothelial cells

International audienceChronic kidney disease (CKD) is associated with high risk of thrombosis. Indole-3 acetic acid (IAA), an indolic uremic toxin, induces the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVEC) via the transcription factor aryl hydrocarbon receptor (AhR). This study aimed to understand the signaling pathways involved in AhR-mediated TF induction by IAA. We incubated human endothelial cells with IAA at 50 mu M, the maximal concentration found in patients with CKD. IAA induced TF expression in different types of human endothelial cells: umbilical vein (HUVEC), aortic (HAoEC), and cardiac-derived microvascular (HMVEC-C). Using AhR inhibition and chromatin immunoprecipitation experiments, we showed that TF induction by IAA in HUVEC was controlled by AhR and that AhR did not bind to the TF promoter. The analysis of TF promoter activity using luciferase reporter plasmids showed that the NF-B site was essential in TF induction by IAA. In addition, TF induction by IAA was drastically decreased by an inhibitor of the NF-B pathway. IAA induced the nuclear translocation of NF-B p50 subunit, which was decreased by AhR and p38MAPK inhibition. Finally, in a cohort of 92 CKD patients on hemodialysis, circulating TF was independently related to serum IAA in multivariate analysis. In conclusion, TF up-regulation by IAA in human endothelial cells involves a non-genomic AhR/p38 MAPK/NF-B pathway. The understanding of signal transduction pathways related to AhR thrombotic/inflammatory pathway is of interest to find therapeutic targets to reduce TF expression and thrombotic risk in patients with CKD

Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children.

International audienceWe report the post-transplant lymphocyte subset recovery of 226 children treated with Unrelated Cord Blood transplant (UCBT) (n = 112) or Unrelated Bone Marrow Transplant (UBMT) (n = 114) for malignant or non-malignant diseases. Absolute numbers of natural killer (NK), B and T cells were monitored by flow cytometry up to 5 years post-transplant. Immunological endpoints were: time to achieve a CD3(+) cell count > 0*5 and 1*5 × 10⁹/l, CD4(+) > 0*2 and 0*5 × 10⁹/l, CD8(+) > 0*25 ×10⁹/l, CD19(+) > 0*2 × 10⁹/l, NK > 0*1 × 10⁹/l. These endpoints were analysed through the use of cumulative incidence curves in the context of competing risks. CD8(+) T cell recovery was delayed after UCBT with a median time to reach CD8(+) T cells > 0*25 × 10⁹/l of 7*7 months whereas it was 2*8 months in UBMT (P 0*2 × 10⁹/l of 3*2 months in UCBT and 6*4 months in UBMT (P = 0*03). Median time for CD4(+) T cell and NK cell recovery was similar in UCBT and UBMT. CD4(+) T cells recovery was negatively correlated to age (better reconstitution in younger patients, P = 0*002). CD8(+) T cells recovery was shorter in recipients with a positive cytomegalovirus serology (P =0*001)

Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway

International audienceIn chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a `dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients