Hemolytic uremic syndrome (HUS) refers to thrombotic microangiopathy (TMA) that usually causes oliguric or anuric renal failure in addition to thrombocytopenia and microangiopathic hemolytic anemia. Ingestion of Shiga toxin–producing Escherichia coli (STEC) can cause the most common form of HUS referred to as STEC-HUS, which is usually preceded by bloody diarrhea. Inherited or acquired defects in the regulation of complements in the alternative pathway cause a rare form of HUS referred to as complement-mediated or atypical HUS (aHUS) because it often occurs without a prodrome of bloody diarrhea. HUS must be differentiated from another thrombotic microangiopathy known as thrombotic thrombocytopenic purpura, which is primarily caused by autoantibodies against a disintegrin and metalloprotease with a thrombospondin type 1 motif member 13 (ADAMTS13) or rarely caused by inherited mutations in ADAMTS13. Diagnosis of HUS relies on a distinct clinical feature and laboratory assessment, including the assays for stool Shiga toxins, plasma ADAMTS13 activity, and mutations in the genes related to complement activation and regulatory proteins in the alternative complement pathway. Supportive therapy is usually sufficient for patients with STEC-HUS. Inhibition of terminal complement activation complexes such as the use of eculizumab is required for aHUS. Secondary TMA may occur in association with disseminated malignancy, infections, bone marrow or solid organ transplantation, and certain drugs. These variants of TMA differ in pathogenesis and prognosis but can be difficult to distinguish because their clinical features often overlap.
Acronyms and Abbreviations
ADAMTS, a disintegrin and metalloprotease with thrombospondin repeats; ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif member 13; aHUS, atypical hemolytic uremic syndrome; ANA, antinuclear antibody; APS, antiphospholipid syndrome; aPTT, activated partial thromboplastin time; CFH, complement factor H; CFHR, complement factor H-related protein; DGKE, diacylglycerol kinase ε; D+HUS, diarrhea plus HUS; Gb3, globotriaosylceramide 3; HELLP, hemolysis, elevated liver enzymes, low platelet count; HIT, heparin-induced thrombocytopenia; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MMACHC (methylmalonic aciduria and homocystinuria type C protein); MCP, membrane cofactor protein; PT, prothrombin time; SLE, systemic lupus erythematosus; STEC, Shiga toxin–producing Escherichia coli; Stx, Shiga toxin; TM, thrombomodulin (gene name THBD); TTP, thrombotic thrombocytopenic purpura; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor.
SHIGA TOXIN–PRODUCING ESCHERICHIA COLI–ASSOCIATED HEMOLYTIC UREMIC SYNDROME
DEFINITION AND HISTORY
Hemolytic uremic syndrome (HUS) refers to thrombotic microangiopathy that mainly affects the kidneys and usually causes oliguric or anuric renal failure.1 Ingestion of Shiga toxin–producing Escherichia coli (STEC) causes a HUS that is referred to as STEC-HUS. This type of HUS is usually associated with gastrointestinal (GI) infection that results in a prodrome of diarrhea. Other names in the literature for STEC-HUS include diarrhea-associated HUS (D+HUS)2 and “typical” HUS,3 as opposed to “atypical” HUS (aHUS)3 that results from alternative complement pathway dysregulation, and “secondary” HUS4–7 or secondary thrombotic microangiopathy” caused by various coexisting conditions including disseminated cancer, ...