Shigatoxin-associated hemolytic uremic syndrome: current molecular mechanisms and future therapies

Abstract

Hemolytic uremic syndrome is the leading cause of acute kidney injury in childhood. Ninety percent of cases are secondary to gastrointestinal infection with shigatoxin-producing bacteria. In this review, we discuss the molecular mechanisms of shigatoxin leading to hemolytic uremic syndrome and the emerging role of the complement system and vascular endothelial growth factor in its pathogenesis. We also review the evidence for treatment options to date, in particular antibiotics, plasma exchange, and immunoadsorption, and link this to the molecular pathology. Finally, we discuss future avenues of treatment, including shigatoxin-binding agents and complement inhibitors, such as eculizumab.

Keywords: Escherichia coli; alternative pathway; complement; diarrhea; eculizumab; hemolytic uremic syndrome; shigatoxin.

Figure 1

Thrombotic microangiopathy. Notes: After infection with a shigatoxin-producing organism, shigatoxin enters the circulation, possibly via Gb4 receptors. On entering the microcirculation, it circulates, probably bound to polymorphonuclear leukocytes. These cells deliver shigatoxin to vulnerable endothelial cells which express Gb3 receptors. There is a higher affinity of shigatoxin for Gb3 receptors and so it dissociates from polymorphonuclear leukocytes. This triggers a proinflammatory and prothrombotic cascade. Endothelial cells express adhesion molecules like P-selectin, which attract neutrophils. They also produce proinflammatory cytokines. There is expression of von Willebrand factor which attracts platelets. Tissue factor, a prothrombotic and proinflammatory molecule, is expressed. There is loss of the thromboprotective receptor, thrombomodulin. The result is thrombotic microangiopathy which is characterized by swelling and detachment of endothelial cells with exposure of the subendothelial matrix. There is accumulation of debris in the subendothelial space. Platelets aggregate and fibrin is deposited. There is partial or complete vessel occlusion with microthrombi formation. Red cells are damaged and fragmented by the vessel occlusion and increased sheer stress.

Figure 2

Alternative complement pathway. Notes: The alternative pathway is triggered by the hydrolysis of C3 which forms C3a and C3b. C3b becomes bound to the cell surface and is then able to interact with factor B, which is cleaved by factor D, creating the Bb fragment which binds to other surface-bound C3b molecules to form C3bBb; the C3 convertase of the alternative pathway triggers an amplification loop, with further hydrolysis of C3. Ultimately, there is further production of C3b which joins with C3 convertase to form C5 convertase which cleaves C5 to C5a and C5b, and this leads to formation of an membrane attack complex.

Figure 3

Regulation of the alternative pathway. Notes: Complement regulators are shown circled in red. These include factor H and factor I and membrane cofactor protein. Each acts to promote inactivation of C3b and prevent further progression of the complement cascade. Factor H binds C3b and works with factor I to inactivate it. Both complement factor H and I are serum-based. Membrane cofactor protein is cell-bound. It also binds to C3b which has become attached to cells and works with factor I to inactivate it. Thrombomodulin is also shown because mutations have been associated with atypical hemolytic uremic syndrome. Thrombomodulin regulates complement by acting to inactivate the proinflammatory mediators, C3a and C5a, and by accelerating factor I-mediated C3b inactivation. Thrombomodulin also plays a role in regulation of local coagulation via its interactions with thrombin.