Abstract
Shiga toxin (Stx)-producing Escherichia coli (STEC) infections have become a threat to public health globally because of the severe illnesses that they can trigger, such as hemorrhagic colitis and the post-diarrheal hemolytic uremic syndrome (HUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. Glomerular endothelial cells are primary targets of Stx which, after binding to its specific receptor globotriaosylceramide, upregulates proinflammatory proteins involved both in the recruitment and adhesion of leukocytes and thrombus formation at the site of endothelial injury. In this review, we discuss the role of complement activation in promoting glomerular microvascular dysfunction, providing evidence from experimental models and patients with STEC-HUS. Within the glomerulus, an important target for Stx-induced complement activation is the podocyte, a cell type that is in close contact with endothelial cells and participates in maintaining the filtration barrier. Recently, podocyte injury and loss have been indicated as potential risk factors for long-term renal sequelae in patients with STEC-HUS. Therapeutic approaches targeting the complement system, that may be useful options for patients with STEC-HUS, will also be discussed.
Highlights
Shiga toxin (Stx)-producing Escherichia coli (STEC) infections induce diarrhea, often epidemic, that can results in hemorrhagic colitis and hemolytic uremic syndrome (HUS), a disorder involving microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, which develops mainly in early childhood [1,2,3,4,5]
Stx induces the release of thrombomodulin (TM) from the endothelial cell surface and upregulates the expression of P-selectin (P-sel), which interacts with von Willebrand Factor (VWF), promoting thrombus formation
Recent studies point to glomerular podocytes as a cell population—which is in close proximity to injured glomerular endothelial cells—that is heavily involved in disease progression
Summary
Shiga toxin (Stx)-producing Escherichia coli (STEC) infections induce diarrhea, often epidemic, that can results in hemorrhagic colitis and hemolytic uremic syndrome (HUS), a disorder involving microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, which develops mainly in early childhood [1,2,3,4,5]. In Latin America, STEC infections are endemic, and Argentina has the highest incidence of the disease in the world (10–17 cases per 100,000 children under five years) [8]. In 2011, an unusual E. coli O104:H4 caused a large outbreak of gastroenteritis and HUS in Germany that was associated with, but never conclusively proven to be due to ingestion of raw fenugreek sprouts [11]. Acute mortality outcomes for patients with STEC-HUS have improved from 30% to less than 5% through the use of early dialysis [20] Of those patients who survive the initial insult, up to 25–30% develop renal sequelae or neurological manifestations [21,22]
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