Enterohemorrhagic Escherichia coli (EHEC) produce ribosome inactivating Shiga toxins (Stx1, Stx2) responsible for development of hemolytic uremic syndrome (HUS) and acute kidney injury (AKI). Some patients show evidence of complement activation during EHEC infection, raising the possibility of therapeutic targeting of complement for relief. Our juvenile non-human primate (Papio baboons) models of endotoxin-free Stx challenge exhibit full spectrum HUS including thrombocytopenia, hemolytic anemia, and AKI with glomerular thrombotic microangiopathy. There were no significant increases in soluble terminal complement complex (C5b-9) levels after challenge with lethal Stx1 (n=6) or Stx2 (n=5) in plasma samples from T0 to euthanasia at 49.5-128 hrs post-challenge. D-dimer and cell injury markers (HMGB1, histones) confirmed coagulopathy and cell injury. Thus, complement activation is not required for the development of thrombotic microangiopathy and HUS induced by EHEC Shiga toxins in these pre-clinical models, and benefits or risks of complement inhibition should be studied further for this infection.
"Proteomic analysis of laser-microdissected glomeruli should confirm these findings. A recent study by Lee et al.  underpins the proposed concept. In the nonhuman primate, HUS induced only by Stx challenge shows the full spectrum of HUS, including glomerular platelet-rich thrombi, but the complement system was not activated. "
[Show abstract][Hide abstract] ABSTRACT: Background/Aims
Diarrhea-associated hemolytic uremic syndrome is associated with the presence of Shiga toxin (Stx1, Stx2 and several variants) in the circulation. The aim of this study is to examine the possible triggering effect of Stx1 on the exocytosis of Weibel-Palade bodies (WPbs).
Cultured human umbilical venous endothelial cells (HUVECs) and glomerular microvascular endothelial cells (GMVECs) were stimulated by thrombin and Stx1 in both static and flowing conditions. The amount of secreted von Willebrand factor (VWF) in the supernatant as well as the remaining intracellular fraction was determined.
In HUVECs and in 2 out of 4 GMVECs, the stimulation of Stx1 in flow at 1 dyne/cm2 resulted in a decrease of intracellular VWF. This is contrary to the results of Stx1 applied in static conditions. At a higher flow rate of 5 dyne/cm2, no effect in GMVECs was observed.
Stx1 can contribute, via an effect on WPbs, to the exocytosis of WPbs in flow conditions in HUVECs and probably in GMVECs. This results in the release of VWF, suggesting an initiating role of the coagulation system in the pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: In the blurring boundaries between clinical practice and scientific observations, it is increasingly attractive to propose shared disease mechanisms that could explain clinical experience. With the advent of available therapeutic options for complement inhibition, there is a push for more widespread application in patients, despite a lack of clinically relevant research. Patients with disseminated intravascular coagulation (DIC) and thrombotic microangiopathies (TMA) frequently exhibit complement activation and share the clinical consequences of thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis. However, they arise from very different molecular etiologies giving rise to cautious questions about inclusive treatment approaches because most clinical observations are associative and not cause-and-effect. Complement inhibition is successful in many cases of atypical hemolytic uremic syndrome, greatly reducing morbidity and mortality of patients by minimizing thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis. But is this success due to targeting disease etiology or because complement is a sufficiently systemic target or both? These questions are important because complement activation and similar clinical features also are observed in many DIC patients, and there are mounting calls for systemic inhibition of complement mediators despite the enormous differences in the primary diseases complicated by DIC. We are in great need of thoughtful and standardized assessment with respect to both beneficial and potentially harmful consequences of complement activation in these patient populations. In this review, we discuss about what needs to be done in terms of establishing the strategy for complement inhibition in TMA and DIC, based on the current knowledge.
[Show abstract][Hide abstract] ABSTRACT: Hemolytic uremic syndrome (HUS) is a disease characterized by hemolysis, thrombocytopenia, and acute kidney injury, although other organs may be involved. Most cases are due to infection with Shiga toxin-producing Escherichia coli (STEC). Early identification and initiation of best supportive care, with microbiological input to identify the pathogen, result in a favorable outcome in most patients. The remaining 10% of HUS cases are classed together as atypical HUS and have a diverse etiology. The majority are due to inherited or acquired abnormalities that lead to a failure to control complement activation. Atypical HUS occurring in other situations (for example, related to pregnancy or kidney transplantation) may also involve excessive complement activation. Plasma therapies can reverse defective complement control, and it is now possible to specifically target complement activation. This has led to improved outcomes in patients with atypical forms of HUS. We will review our current understanding of the pathogenesis of HUS and how this has led to advances in patient care.
F1000 Prime Reports 01/2014; 6:119. DOI:10.12703/P6-119
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