Haemolytic and Uremic Syndrome clinical trials

Azithromycin in Post Diarrheal Haemolytic and Uremic Syndrome

Post diarrheal hemolytic and uremic syndrome (D+HUS) is the first etiology of acute renal failure in children less than 5 years old in France. Previous works highlighted a mortality rate of 2 % and a prevalence of renal sequelae at one year after D+HUS onset in 25 % of patients D+HUS is a consequence of a gastrointestinal infection with shiga toxin (Stx) producing E.coli (STEC). The most frequent straight is E.coli O157H7. The sequence of STEC induced HUS is now well known. Typically, digestive symptoms appear five days following STEC ingestion. STEC colonize the intestinal mucosa, adhere to the enterocyte and cause a typical attaching/effacing lesion and inflammation. Then, diarrhea and vomiting occurred. D+HUS occurs in about 10% of patients and is a consequence of Stx systemic absorption. Indeed, Stx are released in the gastrointestinal tract, then after transferred to the systemic circulation. At the cellular level, Stx binds the globotriosylceramide (Gb3Cer) localized at the surface of the endothelial and epithelial cells of target organs. Following binding to Gb3Cer, the A subunits of Stx are internalized and trigger the activation of the apoptotic program leading to cell death. In addition, Stx are also able to enhance the production and the release of pro inflammatory factor (IL-1, TNFα, IL-6). Cytokines locally produced by Stx-stimulated cells can amplify the inflammatory processes and the prothrombotic state leading to the constitution of the microangiopathic lesions of HUS. To this day, management of D+HUS involves supportive care mainly based on fluid management, dialysis and red blood cells transfusions. Specific therapies used in D+HUS (plasma infusion, antithrombotic and anti inflammatory agents) failed to improve the course of D+HUS. The use of antibiotics remains not recommended while meta-analysis clearly showed that the use of bactericidal antibiotics could worse the course of D+HUS. In vitro experimentations highlighted that some classes of antibiotics like fluoroquinolones dramatically increase the production and the release of Stx before bacterial lysis and worsen the outcome of D+HUS in animal models. By contrast, azythromycin, a bacteriostatic antibiotic of the macrolides family blocking the protein synthesis in bacteria, has a strong inhibitory effect on Stx production and release by STEC as well as it inhibits the in vitro growth of STEC strains. In addition, azithromycin is able to inhibit the Stx-induced production of inflammatory cytokines which are considered to be essential for the development of D+HUS. Consistently the use of azithromycin in animal models of D+HUS dramatically improved the survival rate. Preliminary data on humans with D+HUS treated with azithromycin highlighted a lower prevalence of severe gastrointestinal involvement than in control patients. All these data supported the hypothesis that azithromycin should have a beneficial effect on D+HUS and should improve the short and long term outcome and deserves to be formally demonstrated in human with D+HUS.