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Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). This disease can be divided into three major subtypes: typical HUS, atypical HUS (aHUS), and DEAP-HUS (deficiency of CFHR plasma proteins and autoantibody positive HUS). Typical HUS makes up the majority of cases in children (90%) and is associated with bloody diarrhea caused by infection with Shiga-like toxin-producing Escherichia coli (typical HUS; STEC-HUS). aHUS (non-STEC HUS) accounts for 5%–10% of cases and is a heterogeneous disorder that often occurs in the absence of diarrhea and is associated with a wide variety of conditions, namely genetically defined complement dysregulation. A third type is DEAP-HUS, which accounts for about 1% of cases, and is characterized by the presence of autoantibodies directed to complement factor H (CFH).
Pathophysiology
TMA in HUS results in endothelial cell damage, accumulation of platelet thrombi, and vessel obstruction. Red blood cells (RBC) are then destroyed in these vessels, causing schistocyte formation ( Fig. 106.1 ). These vascular abnormalities are most evident in the renal glomeruli.
Hemolytic Uremic Syndrome
Approximately 15% of children with E. coli O157:H7 infections develop HUS within 1 week of onset. STEC infections occur after ingestion of contaminated fruits/vegetables, undercooked meat, or nonpasteurized milk. Bacteria invade colonic mucosal epithelial cells, and then the toxin migrates into the bloodstream and binds to platelets, monocytes, and neutrophils. These aggregates circulate to target organs, such as the kidneys, and induce cytotoxic effects on glomerular cells.
Renal glomerular endothelial cells express glycolipid Gb3, the predominant membrane receptor for the Shiga toxin, making them primary targets. The injured cells expose collagen and ultralarge VWF, causing platelets aggregation. Additionally, exposure of tissue factor activates the coagulation cascade, leading to vessel microthrombosis.
Atypical Hemolytic Uremic Syndrome
aHUS is not associated with STEC infection and is caused by many etiologies that lead to TMA. The pathophysiology of complement-mediated HUS is that a trigger causes uncontrolled continuous activation of the alternative complement pathway in a susceptible individual with either gene mutations or antibodies to complement proteins, which results in renal endothelial damage and leads to TMA. The genetic causes for complement alternative pathway dysregulation are identified in about 60% of cases. The most common mutations affect CFH, membrane cofactor protein (MCP, CD46), factor I, factor B, C3 convertase, thrombomodulin, and other CFH-related proteins.
aHUS also occurs secondary to infections with Streptococcus pneumoniae or HIV. Children with Streptococcus -associated aHUS usually present with pneumonia and/or bacteremia. Neuraminidase is proposed to expose the Thomsen–Friedenreich antigen and lead to complement fixation.
Drug-induced TMA has been reported with exposure to numerous medications, including antineoplastic (cisplatin, bleomycin, gemcitabine), immunosuppressive (cyclosporine, tacrolimus), antiplatelet (ticlopidine), and other agents (quinidine, interferon).
DEAP-HUS
DEAP-HUS is a rare and newly identified form of HUS characterized by deletion of genes coding for CFH-related proteins and the presence of anti-CFH antibodies. These autoantibodies result in a dysregulation of the alternative complement pathway and cell damage. These patients have poorer outcomes compared with patients with STEC-HUS, being more likely to progress to end-stage renal disease (ESRD) and death.
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