Atypical Hemolytic Uremic Syndrome

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Key points

  • Atypical hemolytic uremic syndrome is a rare form of thrombotic microangiopathy resulting from chronic uncontrolled activation of the alternative pathway of complement.

  • Untreated, it carries a high degree of morbidity and mortality.

  • Atypical hemolytic uremic syndrome is associated with nonimmune hemolytic anemia, thrombocytopenia, and renal involvement; it is distinguished from thrombotic thrombocytopenic purpura and Shigatoxin-positive Escherichia coli hemolytic uremic syndrome.

  • Atypical

Epidemiology

The estimated annual incidence of atypical HUS in children less than 18 years of age is approximately 1.0 to 3.3 per million.6, 7, 8 Atypical HUS occurs with equal frequency in boys and girls when onset occurs during childhood. In the global atypical HUS registry of 516 registered patients of all ages, 39% of patients developed the disease before 18 years of age.9 Approximately 44% of children experienced their first episode before the age of 2 years. Atypical HUS may be sporadic or familial,

Clinical presentation

In children, the onset of atypical HUS is usually abrupt, although up to 20% of patients may present with slowly progressive symptoms. In 191 patients registered on the International Registry of Recurrent and Familial HUS/TTP for whom data were available, underlying complement amplifying conditions/diseases were present in 69% of patients (Fig. 3).10 Diarrhea/gastroenteritis and upper respiratory tract infections were associated with atypical HUS in 42% of patients, whereas a variety of other

Pathophysiology

The pathogenesis of atypical HUS stems from genetic or acquired defects in the regulation of the alternative complement pathway. This pathway (Fig. 4) is constitutively active in plasma by the hydrolysis of the reactive thioester bond of C3 to C3(H2O), a process known as the tickover mechanism, where it can bind to Factor B. Factor B when bound to C3(H2O) is a substrate for Factor D, and is cleaved to its fragments Bb, which remains a part of the molecular complex, and Ba. The complex C3(H2O)Bb

Laboratory diagnosis

Laboratory features of atypical HUS are listed in Box 2. Clinically, atypical HUS is characterized by hemolytic anemia and consumptive thrombocytopenia. Endothelial damage and thrombosis in the microvasculature result in abnormally high shear stress leading to platelet aggregation and mechanical (nonimmune) red cell destruction. Thrombocytopenia is modest with platelet counts uncommonly less than 30 × 109/L. Examination of the peripheral blood smear characteristically demonstrates fragmented

Thrombotic Thrombocytopenic Purpura

Atypical HUS can usually be distinguished from TTP based on the clinical presentation and laboratory features. In general, more modest laboratory evidence of renal impairment would be most consistent with TTP, although great caution must be exercised in applying this paradigm because the severity of individual organ system involvement in atypical HUS can vary greatly from patient to patient. An analysis of multiple cohorts of adult patients has yielded the insight that if thrombocytopenia is

Plasma Therapy

There is no evidence that plasma therapy (plasma infusion or plasmapheresis) affects the ultimate outcome of children or adults with atypical HUS. In a large study of more than 270 patients enrolled in an international registry of atypical HUS, plasma therapy was shown to induce hematologic remission in up to 78% of episodes in children and 53% in adults. Nevertheless, at 3 years of follow-up 48% of children and 67% of adults had end-stage renal disease or had died.10 Similarly, in a French

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    Conflict of Interest: Dr R.A. Gruppo has received honoraria for speaking engagements from Alexion Pharmaceuticals. Dr B. Dixon has received honoraria for speaking engagements from Alexion Pharmaceuticals, and has served as a consultant for Alexion Pharmaceuticals and Achillion Pharmaceuticals.

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