The Path physiology of Renal Failure in a Shiga Toxin plus Lipopolysaccharide Induced Murine Model of Hemolytic Uremic Syndrome

Abstract

Hemolytic uremic syndrome (HUS) is the primary cause of worldwide pediatric acute renal failure. The vast majority of HUS is due to gastrointestinal infection with Shiga toxin producing Escherichia coli (STEC), bacteria that produce the ribosomal protein synthesis inhibitor Shiga toxin (Stx). During the diarrheal prodrome, virulence factors lipopolysaccharide (LPS) and Stx cross into the systemic circulation and cause inflammation and apoptosis in many tissues. The multi-organ pathology that results from toxemia consists of microvascular thrombosis and tissue ischemia with parenchymal destruction. The clinical syndrome of HUS typically comprises microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure, a complex inflammatory response, and neurologic dysfunction. The prognosis is variable; however death or significant lasting renal impairment occurs in up to half of cases. Current treatment consists only of supportive care with intravenous fluids and dialysis, and therapeutic advances have been unforthcoming. Due to the infrequent and sporadic nature of HUS, clinical and therapeutic advancement require an appropriate model system that will allow the underlying mechanisms of this disease to be elucidated. Thus far, only expensive and cumbersome large animal models mimic the human disease, and small animal models of HUS are either incomplete or inadequate. This work fully describes the renal failure that occurs in the mouse model of Shiga toxin mediated HUS. Intraperitoneal injection of Shiga toxin 2 (Stx2) plus LPS into mice causes systemic toxemia and results in death over 96 hours. Acute renal failure, thrombocytopenia, inflammation and neurologic dysfunction develop xii Abbreviations A/E Attaching and Effacing ACE Angiotensin Converting Enzyme ADP Adenosine Diphosphate AKI Acute Kidney Injury ARF Acute Renal Failure ß-TG ß-Thromboglobulin BUN Blood Urea Nitrogen CBC Complete Blood Count CCL2 CC Chemokine Ligand 2 (MCP-1) CCL4 CC Chemokine Ligand 4 (MIP-1ß) Cer Ceramide CD 50 50% Cytotoxic Dose CDH Ceramide Dihexoside CMH Ceramide Monohexoside CNS Central Nervous System CXCL1 C-X-C Chemokine Ligand 1 (Gro-α) CXCL5 C-X-C Chemokine Ligand 5 (ENA-78) D+HUS Diarrhea associated Hemolytic Uremic Syndrome DAF Delay Accelerating Factor DB Dutch Belted (Rabbit) Chapter 2: A Murine Model of HUS: Shiga Toxin with Lipopolysaccharide Mimics the Renal Damage and Physiologic Response of Human Disease This chapter was originally published as a co-authorship with Tiffany R. Keepers.