Hemolytic Uremic Syndrome

Abstract

Hemolytic uremic syndrome (HUS) is a disease of nonimmune (Coombs negative) hemolytic anemia, low platelet count, and renal impairment (1). Anemia is severe and microangiopathic in nature, with fragmented red blood cells (schistocytes) in the peripheral smear, high serum lactate dehydrogenase (LDH), circulating free hemoglobin, and reticulocytes. Platelet count is <60,000/mm3 in most cases (1). In children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli (Stx-E. coli) and manifests with diarrhea (D+HUS), often bloody. Cases of Stx-E. coli HUS—approximately 25% (2)—which, however do not present with diarrhea, have also been reported (3). Acute renal failure manifests in 55 to 70% of cases (4–6); however, renal function recovers in most of them (up to 70% in various series) (1,3,6,7). Non–Shiga toxin-associated HUS (non–Stx-HUS) comprises a heterogeneous group of patients in whom an infection by Stx-producing bacteria could be excluded as cause of the disease. It can be sporadic or familial (i.e., more than one member of a family affected by the disease and exposure to Stx-E. coli excluded). Collectively, non–Stx-HUS forms have a poor outcome. Up to 50% of cases progress to ESRD or have irreversible brain damage, and 25% may die during the acute phase of the disease (8–10). Genetic studies have recently documented that the familial form is associated with genetic abnormalities of complement regulatory proteins, and evidence is now emerging that similar genetic alterations can predispose to sporadic cases of non–Stx-HUS as well. Major recent advances in the field of Stx-HUS and non–Stx-HUS are summarized in Table 1. Microvascular lesion of HUS consists of vessel wall thickening with endothelial swelling and accumulation of proteins and cell debris in the subendothelial layer, creating a space between endothelial cells and the underlying basement membrane of affected microvessels (1,3). In Stx-HUS, the lesion is mainly confined to the glomerular tuft and is noted in an early phase of the disease. Examination of biopsies taken several months after the disease onset showed that most glomeruli are normal, whereas 15 to 20% eventually became sclerotic (11,12). Arterial thrombosis does occur but is uncommon and seems to be a proximal extension of the glomerular lesion (11,12). Stx-Associated HUS Epidemiology In 70% of cases in North America and Western Europe, Stx-HUS is secondary to infection with the E. coli serotype O157:H7 (13–19). This serotype has a unique biochemical property (lack of sorbitol fermentation) as to render it readily distinguishable from other fecal E. coli (20). However, many other E. coli serotypes (O111:H8, O103:H2, O121, O145, O26, and O113 [13,16,21–23]) have been shown to cause Stx-HUS. Infection by Stx-producing Shigella dysenteriae serotype 1 has been commonly linked to Stx-HUS in developing countries of Asia (24) and Africa (25) but rarely in industrialized countries (26). After exposure to Stx-E. coli, 38 to 61% of individuals develop hemorrhagic colitis and 3 to 9% (in sporadic infections) to 20% (in epidemic forms) progress to overt HUS (5,27). The overall incidence of Stx-HUS is estimated to be 2.1 cases per 100,000 persons/yr, with a peak incidence in children who are younger than 5 yr (6.1 per 100,000/yr), and the lowest rate in adults who are 50 to 59 yr of age (0.5 per 100,000/yr) (1). The incidence of the disease parallels the seasonal fluctuation of E. coli O157:H7 infections with a peak in warmer months, between June and September. In the United States, approximately 70,000 illnesses and 60 deaths have been attributed annually to Stx-HUS (28). In Argentina and Uruguay, E. coli infections are endemic and Stx-HUS is a common cause of acute renal failure in children (23,29,30), with an estimated incidence rate of 10.5 per 100,000/yr (31). An association between traditional extensive production of cattle with endemic HUS in Argentina has been proposed, as supported by detection of Stx-producing E. coli strains—mainly O8, O25, O103, O112, O113, O145, O171, and O174 serotypes—in stool samples from 39% of Argentine healthy young beef steers (31). Stx-producing E. coli colonize healthy cattle intestine but also have been isolated from deer, sheep, goats, horses, dogs, birds, and flies (1,32). They are found in manure and water troughs in farms, which explains the increased risk for infection in people who live in rural areas. Humans become infected from contaminated milk, meat, and water—water-borne outbreaks have occurred as a result of drinking and swimming in unchlorinated water (21)—or from contact with infected animals, humans, or either’s excreta (27,33,34) and occasionally through environmental contamination (17). Meat is contaminated at slaughter. Internalization of the microorganism during grinding renders it capable of surviving cooking (27). Fruits and vegetables may also be contaminated, including radish sprouts, lettuce, and ap