Hemolytic Uremic Syndrome

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 apple cider. Unpasteurized apple juice has been implicated in several outbreaks (35). Person-to-person transmission has been reported in child care and long-term care facilities (27). Clinical Phenotype The disease is characterized by prodromal diarrhea followed by acute renal failure. The average interval between E. coli exposure and illness is 3 d (range, 1 to 8). Illness typically begins with abdominal cramps and nonbloody diarrhea; diarrhea may become hemorrhagic in 70% of cases usually within 1 or 2 d (36). Vomiting occurs in 30 to 60% of cases, and fever occurs in 30%. Leukocyte count is usually elevated, and a barium enema may demonstrate “thumb-printing,” suggestive of edema and submucosal hemorrhage, especially in the region of the ascending and transverse colon. HUS is usually diagnosed 6 d after the onset of diarrhea (1). After infection, Stx-E. coli may be shed in the stools for several weeks after the symptoms are resolved, particularly in children <5 yr of age (1). Diagnosis rests on detection of Stx-E. coli in stool cultures. Serologic tests for antibodies to Stx and O157 LPS can be done in research laboratories, and tests are being developed for rapid detection of E. coli O157:H7 and Stx in stools. Bloody diarrhea, fever, vomiting, elevated leukocyte count, extremes of age, and female gender as well as the use of antimotility agents (37) have been associated with an increased risk of HUS after E. coli infection (27). Stx-HUS is not a benign disease. Seventy-percent of patients who develop HUS require red blood cell transfusions, 50% need dialysis, and 25% have neurologic involvement, including stroke, seizure, and coma (6,27,38). Although mortality for infants and young children in industrialized countries decreased when dialysis became available, as well as after the introduction of intensive care facilities, still 3 to 5% of patients die during the acute phase of Stx-HUS (6). recent of studies of long-term of patients who an of Stx-HUS reported or ESRD in of patients and per in 25% The of acute particularly and the need for dialysis associated with a long-term Stx-HUS that is by dysenteriae infection is by and and acute and renal and has a high mortality rate of a E. coli has been associated with hemorrhagic colitis and including failure. In reported an of diarrhea of infants by a of unique in that from E. coli In the E. coli found in the stools of of infants with epidemic diarrhea but in blood now that diarrhea in and to isolated from the stools of it found that most severe cases of epidemic diarrhea associated with and neurologic thrombosis of and in and as well as glomerular tuft by early taken to that a by the E. coli, hemorrhagic of the the blood thrombosis of and the other in noted that E. coli that isolated from patients with diarrhea a toxin similar to the one of dysenteriae 1 found to cells found an increased Stx in fecal and increased in from children who O157:H7 infection an a of or The Stx associated with E. coli are by a is to Stx from dysenteriae by a and is 50% with similar and cause and of as documented by the of of E. coli that than of that In a recent in children who become infected by Stx-E. coli, E. coli that most commonly associated with whereas most that isolated from children who diarrhea or This is also in and and are that are of a of and It is that a toxin that comprises a and a of has been recently isolated from a E. coli that for an of HUS which may the of a of for HUS associated with of E. coli that do not After Stx-E. coli the and to the cells of the through a membrane Stx are by cells and the by the of which The of of Stx from the intestine to the has been In have shown that Stx can to and However, more recent studies have a for in Stx in the blood Stx and to when with blood Stx to circulating have been in the blood of patients with Stx-HUS The Stx on has a than the on glomerular endothelial In in with Stx the to glomerular endothelial cells that at the of the Stx found on glomerular endothelial cells but more on of Stx to cells is on and occurs the of the cell and to on the and also in and showed that to and from in to which but also on the cells to be The could is more than on endothelial cells in endothelial cells are more to the of Stx than This is with that the of on endothelial cells is than in endothelial cells from In glomerular endothelial and Stx are increased exposure to in by in to Stx the biochemical for the of microangiopathic to renal in HUS in After by Stx are by through the to the the and the is to the and it and also endothelial by the of the family many it that the of Stx the of and of endothelial however, it has been shown that of endothelial cells with of on to increased and of as and and cell a by of of endothelial cells with of Stx and by and for and cell including and and and and are in the and of to a in of cells to the This is supported by that the of that and a of endothelial cells and by of the and of that by endothelial cell and The endothelial cells that which to for of has been in of blood on endothelial to at high that in early platelet and followed by the of on endothelial and a for thrombosis in The could also be taken as a of a between bacteria and and as in the In evidence of in 1 has been found in children who developed HUS E. coli O157:H7 Although early studies that is in Stx-HUS more recent the of of that is (36). for is of and care during the acute phase of the illness is still with as with the is on be to Stx-E. coli showed that at the of infection with Stx-E. coli approximately risk for It that to the membrane the acute of of However, a recent on to a risk for HUS associated with in the by of the patients Although is common in Stx-HUS by dysenteriae 1 and patients eventually progress to are early is found in Stx-HUS by E. coli O157:H7 However, a recent of an with E. coli HUS with and infection showed that early and renal abnormalities the of that in patients with Stx-E. coli infection, be in cases with with an of of linked to the to of including and have been shown to be in in the acute phase of the disease and may be particularly on the for patients who renal disease after an of Stx-HUS. recent in children who renal of HUS and followed for to yr documented that early of proteins and use of may have a on long-term renal as documented by a of in patients In to 15 yr of with after severe Stx-HUS and be as an and for children who progress to the of renal is in children with from to and at yr is than in children who other and a Epidemiology and Clinical is common than Stx-HUS and for 5 to of cases of the disease It may at but is more in to a recent the incidence of non–Stx-HUS in children is approximately one that of Stx-HUS to approximately 2 per with Stx-HUS, is or seasonal The onset may be by of the diarrhea is rarely can occur or in of for sporadic non–Stx-HUS have been including various and other underlying Table Infection by for of non–Stx-HUS and of of HUS in children in the United by by from the cell to circulating which to on platelet and endothelial cells and cause platelet and endothelial The is usually with neurologic involvement, and coma and a mortality rate of 50% of that have been most reported to non–Stx-HUS and and and and agents The risk for developing HUS after is 2 to The onset is 1 yr after The is with to mortality at HUS is being reported with It may for the in patients who the disease or may patients cause of ESRD HUS in HUS occur in patients who renal and other as a of the use of or of It occurs in 5 to of renal patients who and in approximately of who are HUS may occasionally develop as a of patients progress to a of with severe microangiopathic hemolytic anemia, renal and forms are an for that is usually followed by HUS manifests within 3 of in most The is usually with 50 to 60% renal and are the in surviving patients in approximately 50% of cases of sporadic could be found (1). forms for than of cases of and forms of have been noted In the onset is usually early in The is with a mortality rate of 60 to are HUS has an onset in most the is with a incidence of or ESRD of 50 to studies have documented that familial HUS may be by genetic abnormalities of proteins in the of the complement genetic abnormalities have been found in sporadic mainly in forms but also in cases of and HUS HUS and HUS one Genetic serum of the of complement have been reported in familial and sporadic forms of non–Stx-HUS in the than as documented by in glomeruli and of HUS patients and by increased in of the of are usually and found in patients with familial in the an of the complement The complement consists of several and proteins that are in The the and the by on the of result in the of the which The are by and whereas the of the the of but not of low in patients with HUS in the of a of the on which to for by and also to the of the that and of the membrane that cell The complement is as to to cells and of to the of This is on a of and and that that or are by In with HUS and in the affected individuals to the of complement on which for several complement regulatory The in region an association between familial HUS and abnormalities been reported is a that an in the of the of complement It as a for the in the of and and of the consists of The complement regulatory that are to have been within the The of is on the of the of to that for and complement regulatory The in and and in and However, the and the in are the for to of of the of to complement on glomerular endothelial cells and glomerular basement membrane are in on an complement the by a of studies have been by who have to 50 in patients who familial and sporadic forms of non–Stx-HUS In sporadic the from a healthy more cases in the The is to in familial whereas to of sporadic forms in other for complement regulatory proteins could be in to sporadic forms could be by an similar to that in patients with in whom the acute is triggered by antibodies the This is supported by a recently the of antibodies in the of children with The of of in HUS patients are and cause or mainly in the and are commonly associated with This is at with patients with who that cause and studies that proteins that have a to with and with which in a of to endothelial cells and a complement regulatory on the cell membrane In have a to of the complement in as by that a in the of The explains the of patients who have HUS and and serum complement that complement regulatory could be in serum with an hemolytic in which serum from patients with a more severe of than serum from patients could a to patients who have HUS and studies of and other complement regulatory who have a as a result of one and one which more predispose to than cause the disease. The that patients occasionally have from HUS or do not present in In that complement and infections) or by endothelial or the acute in approximately 60% of patients with of the can be by that in the is to the from complement in However, exposure to an that is in and on endothelial cells be as a result of of of This in the of membrane and the of that cause and of endothelial and of increased with and and the of and of a particularly to glomerular which is a and the basement membrane a that is in for which could the renal of of of patients with non–Stx-HUS have that to 50% of them evidence of of the of complement The that uncommon of may to HUS in patients has been recently the of the the of the and the of the found to be more in HUS patients than in healthy and of the overall that individuals who or of the a increased risk for developing HUS The and also have a in the is approximately of the disease in In of individuals who developed HUS an the from one with an at one from the other of the healthy the but in for complement proteins have also been recently in to from a in for membrane a complement in affected individuals of is a that as a for to and on cell has complement that are for followed by a a and a reported a of the in one family and a in of and function on showed that the a and a to complement and a of in in which 50% in on of studies from group on patients with non–Stx-HUS have in familial and in sporadic HUS with a of in familial and in sporadic forms) is in the and could be found on glomerular endothelial cells by It a in glomerular endothelial cells as by that in the of cells by and other in complement on from the cell membrane by approximately and could an of cells complement However, is a complement that for approximately one can that is in the of complement in the of the cell membrane for in predispose than cause exposure to that cause of the complement or and of on glomerular endothelial cells result in an of cells from complement in or in result in complement and HUS that complement do not have and that are to complement in the for have been reported in patients with sporadic non–Stx-HUS which the that HUS is a disease of complement are including and who present with non–Stx-HUS be for serum however, do not a complement could be a in or the of in renal of in serum be to patients who that cause and could be found in but not patients with or be the for in and for be in patients with serum for that non–Stx-HUS has a poor after the mortality rate has from 50 to 25% However, still on is or is not in the of acute and that a of patients with non–Stx-HUS to It has been that be more than it from the may not be the is documented by that in a with of the platelet count by or whereas and with and the platelet However, in as renal or which the of that can be with be as (1). be within of as in may failure. one is per can be by the of The of one is the of for patients to the of (1). for the is 30 to on to per for a of 2 d after is or has been in patients with HUS and with the to the patients with to the genetic patients not at and or developed ESRD or of at to to to in a who and developed an acute of HUS and After 3 of in with the renal dialysis and 1 yr after the and dialysis is in patients with HUS by antibodies the which may the disease. In patients with extensive thrombosis at renal and of when including are not to the disease (i.e., severe and hemolytic has been with in patients including or and have been with (1). who develop HUS with or have to the has been as an in patients with patients with 50% (in sporadic forms) to 60% (in familial forms) progress to ESRD is not an for at with Stx-HUS. approximately 50% of the patients who a renal a of the disease in the occur at a of 30 d after (range, d to is of failure occurs in of patients who or and of who the for not renal also be in that it the risk to the disease onset in the healthy as recently reported in from genetic studies more the risk for In patients with the rate from 30 to to and is than in patients In of the that is a mainly of a does not the genetic and in young children with non–Stx-HUS and with the of the genetic and disease However, for that are and that an increased to or to complement cases that with by irreversible failure. In the a of the by the after the a high of antibodies to In a the child developed and coma that with a The by a of the as a result of a of after triggered severe and complement in the as the result of complement regulatory failure the in the of the genetic and for non–Stx-HUS associated with not be a is at risk for is in patients with as found in patients who a and disease In of the is a that is in the a The on renal endothelial cell be from disease The are at more that may with the cause of in the forms of In Stx-HUS, agents that are at exposure to Stx are In as bacteria that an Stx on the that in the toxin in the have been is to use Stx them is an that can of the which to toxin that has the from microvessels have disease in by of antibodies have on in the with in a of Stx-HUS in on mortality that may be a in the of Stx-HUS. the to the and mortality associated with Stx-E. coli that of Stx-E. coli rate in and a for contaminated and is The of in complement regulatory evidence of the of complement in the of non–Stx-HUS and that complement could a in are a of with complement in or and antibodies that the of complement have been developed of to patients with a disease characterized by a genetic of proteins that cells the by the complement and the need for In a phase of as in patients who and complement and mortality as with the the not by the in studies is on the use of forms of the complement 1 and phase have shown that the and during decreased complement and function in infants who In a in patients who on a of complement within and for 3 d It is that the complement to the be in patients with to during the acute or to after also could be of to in and in patients with genetic HUS associated with with could become a to are also to in which could the with the risk for and It is that advances in and render a for studies on other complement regulatory to the underlying the of non–Stx-HUS and an in the and and of of Shiga-like The of toxin to of on the membrane of glomerular endothelial and The toxin is through the the and and the is to the The by one from the of the complement and (in associated with hemolytic uremic syndrome The the of with the The of the regulatory for and the for and are The of the found in patients with HUS in the of that is for to and to and for the of on cell and for the of and After or infection or endothelial complement is and is In the of is to in the and by In it to that are present on endothelial cell and in the subendothelial of high for it on and with to form the The subendothelial complement and is on to complement also on endothelial cells by to by of found in patients with has a in However, the the at the of that it to on endothelial cell and in subendothelial This in more the cell that is not to complement on the cell In on is not and forms the of the of complement that to also to found in patients with HUS result in a of the or in a of to In cases, is not which to of and on endothelial cells through the of The of to The of and by the of the and that to on cells and them the endothelial The of on endothelial cells is followed by the of the membrane which to and and to membrane to endothelial and of The leukocyte and with the of and that the After endothelial damage, cell and basement In from the and to the Major advances in recent and of forms of This supported by from 30 per from and and from the for with HUS with The