Hemolytic Uremic Syndrome: Toxins, Vessels, and Inflammation

Abstract

Hemolytic uremic syndrome (HUS) is characterized by thrombotic microangiopathy of the glomerular microcirculation and other vascular beds. Its defining clinical phenotype is acute kidney injury (AKI), microangiopathic anemia, and thrombocytopenia. There are many etiologies of HUS including infection by Shiga toxin-producing bacterial strains, medications, viral infections, malignancy, and mutations of genes coding for proteins involved in the alternative pathway of complement. In the aggregate, although HUS is a rare disease, it is one of the most common causes of AKI in previously healthy children and accounts for a sizable number of pediatric and adult patients who progress to end stage kidney disease. There has been great progress over the past 20 years in understanding the pathophysiology of HUS and its related disorders. There has been intense focus on vascular injury in HUS as the major mechanism of disease and target for effective therapies for this acute illness. In all forms of HUS, there is evidence of both systemic and intra-glomerular inflammation and perturbations in the immune system. Renewed investigation into these aspects of HUS may prove helpful in developing new interventions that can attenuate glomerular and tubular injury and improve clinical outcomes in patients with HUS.

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

“…More precisely, glomerular endothelial cells in the kidney and microvascular endothelial cells in the brain are preferably targeted by Stx leading to acute renal impairment and cerebral disturbances resulting in severe extraintestinal complications of STEC infections [ 12 , 13 , 38 , 45 , 50 , 125 , 126 ]. Because the renal epithelium may also be involved in the pathogenesis of Stx-mediated HUS, in vitro studies using primary kidney-derived epithelial cells have become increasingly recognized [ 13 , 46 , 127 , 128 ]. Besides the reported sensitivity of Stx to immortal epithelial cell lines of renal origin (not further discussed here), few studies have been performed so far, which provided essential knowledge on Stx-mediated damage of cultured primary human tubular [ 51 , 66 , 67 , 70 , 71 , 72 , 129 , 130 , 131 ] and glomerular epithelial cells [ 68 , 69 ].…”

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

“…Disturbance of the endothelial blood–brain barrier elicits serious cerebral malfunction and neurological complications comprising an array of symptoms of the central nervous system such as altered mental status, seizures, stroke, and coma [ 237 , 242 , 243 , 302 ]. Collectively, although thrombotic microangiopathy mainly affects the microvasculature of the kidneys, vascular beds of other organs are affected as well, and the net result is a multi-organ thrombotic process [ 254 , 397 , 402 ]. A hallmark of thrombotic microangiopathy is the mechanical fragmentation of erythrocytes due to increased vascular stress by the microvascular thrombi, which is a setting event that may then sustain and amplify the microangiopathic process, resulting in hemolytic anemia and hemolysis [ 394 , 396 ].…”

Exosomes released from Shiga toxin 2a–treated human macrophages modulate inflammatory responses and induce cell death in toxin receptor expressing human cells

“…Because localized acute inflammation may be induced at multiple sites of tissue damage following hematogenous dissemination of Stxs (Cheung & Trachtman, 2014; King, 2002), we hypothesised that primary CD14 + hMDM and hPBMC might serve as important cellular sources of Stx2‐Exo during progression of HUS with systemic complications. hMDM produced relatively more Stx2‐Exo than hPBMC (Figure 8).…”