Shiga Toxin Pathogenesis: Kidney Complications and Renal Failure

The kidneys are the major organs affected in diarrhea-associated hemolytic uremic syndrome (D+HUS). The pathophysiology of renal disease in D+HUS is largely the result of the interaction between bacterial virulence factors such as Shiga toxin and lipopolysaccharide and host cells in the kidney and in the blood circulation. This chapter describes in detail the current knowledge of how these bacterial toxins may lead to kidney disease and renal failure. The toxin receptors expressed by specific blood and resident renal cell types are also discussed as are the actions of the toxins on these cells. This review provides a detailed view of the current knowledge of Shiga toxin (Stx) actions and host responses that comprise the disease known as diarrhea-associated hemolytic uremic syndrome, D+HUS. Stx2 is the predominant form of Stx produced by clinical isolates of STEC and is considered to be the form of Stx that causes D+HUS in humans. Expression of the Stx receptor, glycosphingolipid Gb3, or a close analog, is required for Stx interaction with eukaryotic cells. Stx targets specific cell types in the kidney and blood circulation causing the cells to either become activated, elicit proinflammatory mediators, or apoptose. The primary target of Stx is thought to be endothelial cells, however, additional Stxsensitive cell types exist in the kidney that are required for normal filtration of the blood (endothelial, podocyte) and fluid balance (tubules). Damage to these cells helps explain how Stx causes proteinuria, dehydration, and renal failure. Stx-sensitive platelets in the blood appear to be central to the renal vascular coagulation and thrombosis of D+HUS. Recent evidence indicates that bacterial lipopolysaccharide (LPS) is required for platelet activation in D+HUS prior to their interaction with Stx. The role of specific cytokines and chemokines in the kidneys and blood circulation remains to be determined for D+HUS. Limited data support the concept that transport of Stx from the colon to the kidneys may involve neutrophils. Although successful delineation of the pathophysiology of D+HUS in humans will continue to depend on animal models of D+HUS, none of the animal models currently available for D+HUS completely recapitulates the disease in humans. 1 Shiga Toxin Interaction With Blood Cells in the Circulation Stx-producing Escherichia coli (STEC) are non-invasive. Stx is released in the intestine and after passing through the intestinal mucosal barrier the toxin circulates in the bloodstream © Springer-Verlag Berlin Heidelberg 2011 Correspondence to: Tom G. Obrig, tobrig@som.umaryland. edu. NIH Public Access Author Manuscript Curr Top Microbiol Immunol. Author manuscript; available in PMC 2013 September 22. Published in final edited form as: Curr Top Microbiol Immunol. 2012 ; 357: 105–136. doi:10.1007/82_2011_172. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript before reaching its target organs. The main target organ is the kidney. How the toxin circulates and whether it is free in the circulation or cell-bound has been addressed in numerous studies. In patients with hemolytic uremic syndrome minimal amounts of Stx were found in the serum (Brigotti et al. 2011) but in mice infected with E. coli O157:H7 Stx was detected in serum 2–5 days after inoculation (Kurioka et al. 1998). The presence of Stx in the circulation in mice but not in humans may reflect the longer time span that elapses from infection to clinical presentation in patients. In addition to free toxin, which may no longer be present in the circulation when HUS develops, studies have shown that toxin may bind to blood cells and thus reach its target organs. Stx is not cytotoxic for neutrophils, monocytes, and certain B lymphocytes (Cohen et al. 1990; van Setten et al. 1996; Liu et al. 1999a; Brigotti et al. 2008). Platelets and red blood cells (RBCs) are presumed to be less sensitive to the cytotoxic effects of Stx as they lack nuclei. Thus binding of the toxin to these blood cells will not destroy the cells.