? Diarrhea-positive Hemolytic Uremic Syndrome (D+ HUS) is a serious disease in children that causes hemolytic anemia, thrombocytopenia, and acute renal failure. In fact, it is the most common cause of acute renal failure in children. During the acute phase of the HUS, some 3 to 5% of patients die, while as many as 25% also suffer stroke, seizures, and/or coma. At present this condition has little established pathophysiology, aside from an association with shiga toxin produced by strains of Escherichia coli and the presence of plasma markers indicative of a prothrombotic state. We have previously demonstrated that shiga toxin significantly increases the expression of functional tissue factor (TF) by TNF-alpha-activated human glomerular endothelial cells (HGECs). Therefore, we hypothesize that increased TF activity plays an important role in the pathophysiology of HUS. Through this grant we aim 1) to demonstrate that kidney sections from a rabbit model of HUS are prothrombotic as compared to control kidney tissue; 2) to demonstrate that sera from patients with HUS augment the expression of TF, while the blood of these patients contains TF-positive circulating endothelial cells and microparticles; and 3) to use monolayers of HGECs, patient platelet adhesion/aggregation in flowing blood, and kidney from the rabbit model to test inhibitors of the TF pathway as potential therapies for HUS. These inhibitors include recombinant-TF pathway inhibitor, an antibody directed against activated factor X, recombinant-activated protein C, and active site-inhibited r-factor VIIa. A confirmation that shiga toxin and cytokines present in patient sera augment the TF pathway in our model system coupled with a demonstration that pharmacologic interruption of this pathway is both effective and feasible, will help to develop a novel, effective therapy for childhood HUS, where at present only supportive care is available. A key additional feature of this proposal is the use of our newly formed collaborative group of pediatric nephrologists to facilitate patient recruitment ? ?
| Nestoridi, Eirini; Kushak, Rafail I; Tsukurov, Olga et al. (2008) Role of the renin angiotensin system in TNF-alpha and Shiga-toxin-induced tissue factor expression. Pediatr Nephrol 23:221-31 |
