Excerpt from Hemolytic-Uremic Syndrome

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Background

Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive renal failure associated with microangiopathic (nonimmune, Coombs-negative) hemolytic anemia and thrombocytopenia.

HUS is the most common cause of acute renal failure in children and increasingly recognized in adults. Thrombotic thrombocytopenic purpura (TTP), childhood HUS, and adult HUS differ in their clinical presentations but have many common features. Gasser et al first described HUS in 1955. In 1988, Wardle described HUS and TTP as different entities, but in 1987, Remuzzi suggested that these 2 conditions are various expressions of the same entity. With the recent discovery of von Willebrand factor–cleaving metalloprotease ADAMTS-13, HUS and TTP are clearly different diseases despite their clinical similarities.

Pathophysiology

Damage to endothelial cells is the primary event in the pathogenesis of HUS. The cardinal lesion is composed of arteriolar and capillary microthrombi (thrombotic microangiopathy [TMA]) and RBC fragmentation.

Classification

HUS is classified into 2 main categories depending on whether it is associated with Shiga-like toxin.

The first category is Shiga-like toxin (Stx)–associated HUS (Stx-HUS). This is the classic or typical, primary or epidemic form of HUS. Stx-HUS is largely a disease of children younger than 2-3 years and often results in diarrhea (denoted D+HUS). One fourth of patients present without diarrhea (denoted D-HUS). Acute renal failure occurs in 55-70% of patients, but they have a favorable prognosis, and as many as 70-85% of patients recover renal function.

The second category is non-Stx–associated HUS (non-Stx-HUS), which can be sporadic or familial. As the name implies, infection by Stx-producing bacteria is not the cause, and disease may occur year round without a gastrointestinal prodrome (D-HUS). Overall, patients with non-Stx-HUS have a poor outcome, and as many as 50% may progress to ESRD or irreversible brain damage. Up to 25% of patients die during the acute phase. The familial form is associated with genetic abnormalities of the complement regulatory proteins.

Recent concepts in the pathogenesis of HUS

Stx–associated HUS

In North America and Western Europe, 70% of cases are secondary to Escherichia coli serotype O157:H7. Other E coli serotypes are O111:H8, O103:H2, O121, O145, O26, and O113. In Asia and Africa, it is often associated with Stx-producing Shigella dysenteriae serotype 1. Regarding Stx associated with E coli, Stx-1 is almost identical to Stx associated with S dysenteriae type 1, differing by a single amino acid. Stx-1 is 50% homologous with Stx-2. Stx-2 is associated with severe disease.

After ingestion, Stx-E coli closely adheres to the epithelial cells of the gut mucosa by means of a 97-kD outer-membrane protein (intimin). The route by which Stx is transported from the intestine to the kidney is debated. Recent studies highlight the role of polymorphonuclear neutrophils (PMNs) in the transfer of Stx in the blood because Stx rapidly and completely binds to PMN when incubated with human blood. However, the receptor expressed on glomerular endothelial cells has 100-fold higher affinity than of PMN receptors; in this way thereby transfer the Stx-ligand to glomerular endothelial cells.

The binding of Stx to target cells depends on B subunits and occurs by means of the terminal digalactose moiety of the glycolipid cell-surface receptor globotriaosylceramide Gb3. Both Stx-1 and Stx-2 bind to different epitopes on the receptor with different affinities. Stx-1 binds to and detaches easily from Gb3, whereas Stx-2 binds and dissociates slowly, causing more severe disease than that due to Stx-1.

Data from recent studies suggest that Stx favors leukocyte-dependent inflammation by altering endothelial cell-adhesion properties and metabolism, ultimately resulting in microvascular thrombosis. Findings from earlier studies suggested that fibrinolysis is augmented in Stx-HUS, but results of more recent studies revealed higher-than-normal levels of plasminogen-activator inhibitor type 1 (PAI-1), indicating that fibrinolysis is substantially inhibited.

Non-Stx–associated HUS

Non-Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. It may occur at all ages, but it is most frequent in adults and occurs without prodromal diarrhea (D-HUS). Patients have an unfavorable prognosis. Stx-HUS can occur in sporadic cases or in families.

Sporadic non-Stx–associated HUS

In sporadic non-Stx-HUS, various triggers have been identified: nonenteric infections, viruses, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions (rare, eg, antiphospholipid syndrome [APL], systemic lupus erythematosus [SLE]), among others.

Streptococcus pneumoniae infection accounts for 40% of all causes of non-Stx-HUS and 4.7% of all causes of HUS in children in the United States. Bacterial neuroaminidase removes sialic acids and thus lyses cell-surface glycoproteins and exposes Thomsen-Friedenreich antigen to preformed circulating immunoglobulin M (IgM) antibodies. These bind to the neoantigen on platelets and endothelial cells and cause polyagglutination and damage to endothelial cells. On clinical examination, the disease is usually severe and causes respiratory distress, neurologic involvement, and coma, with a mortality rate of up to 50%.

Familial non-Stx–associated HUS

Familial non-Stx-HUS accounts for <3% of all cases of HUS. Both autosomal dominant and autosomal recessive forms of inheritance are observed. Recent data suggest genetic abnormalities in the complement regulatory proteins. Autosomal recessive HUS often occurs early in childhood. The prognosis is poor, recurrences are frequent, and the mortality rate is 60-70%. Autosomal dominant HUS often occurs in adults, who have a poor prognosis. The risk of death or ESRD is 50-90%.

Factor H

Factor H (HF1) consists of 20 homologous units called short consensus repeats (CSRs) and plays an important role in the regulation of the alternative pathway of complement. HF1 also serves as a cofactor for the C3b-cleaving enzyme factor I in the degradation of newly formed C3b molecules. It controls the decay, formation, and stability of C3b convertase (C3bBb), and it protects glomerular endothelial cells and the basement membrane against complement attack by binding to the polyanionic proteoglycans on the surface of endothelial cells and in the subendothelial matrix.

Fifty HF1 mutations have been described in 80 patients who had familial (36 patients) and sporadic (44 patients) forms of non-Stx-HUS. The mutation frequency is 40% in familial form and 13-17% in sporadic form.

Patients with HF1 mutations have partial HF1 deficiency that causes a predisposition to the disease rather than the disease itself. Mutant HF1 has normal cofactor activity in the fluid phase, but its binding to proteoglycans is reduced because the mutation affects the polyanion interaction at the C-terminus of HF1. Suboptimal HF1 activity is often enough to protect the patient from complement activation in physiologic conditions. However, activation of complement pathways results in higher-than-normal concentration of C3b, and its deposition on vascular endothelial cells cannot be prevented because of the inability of mutant HF1 to bind to polyanion proteoglycans.

Two thirds of patients with non-Stx-HUS have no HF1 mutation, though as many as 50% have overactivity of the alternative complement pathway. This observation suggests that uncommon polymorphic variants of the gene for HF1 may be responsible for the disease in patients without an HF1 mutation.

Abnormalities in genes encoding for complement modulatory proteins (MCP gene) have recently been shown to predispose people to non-Stx-HUS.

Frequency

United States

Stx-HUS occurs with a frequency of 0.5-2.1 cases per 100,000 population per year, with a peak incidence in children younger than 5 years, in whom the incidence is 6.1 cases per 100,000 population per year.

Non-Stx-HUS accounts for 5-10% of all cases of HUS, and the incidence in children is about one tenth that of Stx-HUS. This rate corresponds to about 2 cases per 100,000 population per year.

International

In children younger than 15 years, typical HUS occurs at a rate of 0.91 cases per 100,000 population in Great Britain, 1.25 cases per 100,000 population in Scotland, and 1.44 cases per 100,000 population in Canada.

Seasonal variation occurs, with the disease peaking in the summer and fall.

Mortality/Morbidity

• Stx-HUS: Acute renal failure occurs in 55-70% of patients and up to 70-85% recover renal function.
• Non-Stx-HUS: Patients have poor outcomes, with up to 50% progressing to ESRD or irreversible brain damage. As many as 25% die during the acute phase.

Race

HUS occurs infrequently in blacks.

Sex

Both sexes are affected equally.

Age

Disease occurs mainly in young children; however, adolescents and adults are not exempt.

• In young children, spontaneous recovery is common.
• In adults, the probability of recovery is low when HUS is associated with severe hypertension.

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