Hemolytic Uremic Syndrome

When Gasser et al. first described hemolytic uremic syndrome (HUS) in 1955, it was usually a fatal illness.[1] HUS typically appeared in early childhood and included the combination of Coombs-negative (nonimmune) thrombocytopenic microangiopathic hemolytic anemia and irreversible acute renal failure. Survival greatly improved with the advent and improvement of dialysis and kidney transplantation. However, HUS remains a leading cause of acute renal failure in North American children and is increasingly recognized as a cause of renal failure in adults. Unfortunately, little advance has been made in preventing or acutely reversing this most serious aspect of HUS. HUS accounts for 7% of cases of hypertension in infants younger than 12 months.[2, 3, 4, 5]

Clinical and pathologic similarities between HUS and thrombotic thrombocytopenic purpura (TTP)–the other major thrombotic microangiopathy (TMA)–have long been appreciated. However, certain features have been relied on to distinguish most cases labeled HUS, which is predominantly a disease of children younger than 5 years, from most cases labeled TTP, which is predominantly a disease of adults. Renal manifestations are more prominent than neurologic ones in HUS, whereas neurologic findings are more prominent than renal findings in TTP. In industrialized nations, fever precedes the onset of TTP more commonly than it precedes HUS.[6] In most nonfamilial cases of HUS in industrialized or nonindustrialized nations, dysentery is an important hallmark of HUS.

The HUS label has long been applied to individuals older than ten years of age who have developed thrombotic microangiopathy with manifestations that were predominantly renal. Conversely, thrombotic microangiopathy in small children who have predominantly neurologic manifestations has been labeled TTP. During the early phases of disease recognition, recognition of atypical cases and difficult-to-classify cases eroded confidence that objective criteria other than age could be used to distinguish atypical HUS from atypical TTP.

Two conflicting tendencies followed. The first was awkward expansion of labeled entities within a presumed continuum between classic TTP and classic HUS. The second was the broad application of a single, nonspecific, and unsatisfactory term TTP/HUS to cases of thrombotic microangiopathy associated with renal failure and various degrees of involvement of additional organ systems, particularly the nervous system. The recognition of phenotypic instability in recurrent cases encouraged the tendency to consider HUS and TTP to be due to the same underlying mechanisms though variously manifested in part because of age-related vulnerabilities.[7] An example of this apparent phenotypic instability was a patient who had 5 episodes of the HUS phenotype before the age of 15 years and who had 9 episodes of the TTP phenotype after 20 years of age.[8] However, in 1988 Wardle argued that in most cases, HUS and TTP were separate entities of distinct pathogenesis.[9]

Recent advances in the understanding of the pathogenesis of HUS or TTP have supported Wardle's point of view and have clarified the boundary between these illnesses and produced useful diagnostic tests to identify discrete processes that clearly define a particular pathogenic process. However, such tests do not help in distinguishing some clinical syndromes in the TTP-HUS spectrum. Moreover, the speed of this diagnostic progress has outpaced the establishment of a consensus regarding diagnostic categories and boundaries. Old systems of classification have been variously amended.

Pending the establishment of a widely accepted system of classification, this article considers HUS on the basis of a tentative practical system of classification with reference to areas of overlap with TTP, whereas the subject of TTP and its classification is considered in a separate articles (see Medscape Reference article Thrombotic Thrombocytopenic Purpura).

Retrospective investigations have demonstrated that some and perhaps most fatal cases of HUS and TTP are pathologically distinct entities. Both conditions manifest microangiopathy with thromboses. Immune mechanisms play a role in some instances; however, the microangiopathies of these conditions are primarily the result of different combinations of developmental, toxic, or mechanical and/or rheologic processes rather than primary immune-mediated processes.

Therefore, the arteriolar and capillary microthrombotic process found in most cases of HUS is the result of the activity of specific toxins with ensuing injury to endothelial cells. On the other hand, most cases of TTP are the result of one of several possible abnormalities of platelet function. Microangiopathic anemia is not associated with Coombs positivity in either condition. In both conditions, it is chiefly the result of rheological disturbances produced by clots. In addition, in HUS, an additional effect of vascular endothelial swelling occurs.

Both HUS and TTP are families of illness comprising a large core of typical cases and additional atypical examples mediated by a broad variety of heritable or acquired conditions. Conditions that produce the various atypical forms overlap, and examples of particular stimuli (eg, verocytogenic Escherichia coli gastrointestinal infection) that classically produce HUS in children younger than 5 years are described. However, in adults, some of these conditions may provoke TTP. Therefore, these 2 families of conditions cannot be separated entirely.

In most cases of HUS, the cause is activity of toxigenic proteins that have deleterious effects on endothelial cells, particularly those of colon and kidney. The 2 most important toxins were initially identified in studies of Shigella dysenteriae and therefore named Shiga toxin (Stx), specifically Stx1 and Stx2. Because the assay for these toxins used verocytes, they are also called verocytotoxins (ie, VT-1 and VT-2). In this discussion, these toxins are called Stx1 and Stx2.

Ensuing studies have identified STX (Stx-E coli) as the most important toxic protein in E coli -associated postinfectious HUS (IStx-HUS). The most commonly identified environmental source of Stx-E coli – producing HUS in humans is the stool of various animals, particularly cattle, sheep, goats, horses, dogs, domestic fowl, and wild birds, as well as humans. These bacteria are also found in flies that feed on the feces of these various animals.

Classification

Clinical and laboratory information concerning the presence of infectious agents that may or may not elaborate verocytotoxins, and tests of ADAMTS-13 enzymatic function or other disturbances associated with TTP (when indicated) permit confident diagnosis of most cases of HUS. On this basis, TMAs have been classified in several ways, including the following:

• Hereditary, recurrent TTP - Idiopathic or ADAMTS-13 deficient

• Postinfectious TTP - Acquired, anti-ADAMTS-13 immunoglobulin G (IgG)–mediated

• TTP-like illness without identifiable ADAMTS-13 deficiency

• Postinfectious HUS - Stx-related (IStx-HUS)

• Postinfectious HUS - Non–Stx-related (INon-Stx HUS)

• Sporadic or immunologic HUS - Diarrheal and nondiarrheal

• Familial HUS - H-factor normal or H-factor deficient

• TMA not otherwise specified

As far as HUS is concerned, this classification system is a considerable simplification of old systems of classification. The overwhelming majority of cases of what might be regarded as typical or postinfectious HUS, ie, microangiopathy and renal failure after Stx- or non-Stx–elaborating infectious illnesses, with diarrhea more commonly than without. This simplified scheme readily accommodates these cases, which may be referred to as IStx and non–IStx-HUS. In the venerable Drummond scheme for the classification of HUS, such cases were called classic infantile HUS or postinfectious HUS and subclassified according to whether diarrhea was present.[10]

Sporadic or immunologic cases may or may not be associated with a diarrheal prodrome, and they include acquired transient abnormalities of complement regulation. Clinically defined familial cases are subclassified according to whether the individual is constitutionally deficient in H factor or activity of the third component of complement (C'3). Non-postinfectious HUS illnesses that occur after inflammatory, immunologic, oncologic, endocrine or obstetric, toxic, and other settings are included in the familial category based on clinical grounds. Otherwise, they are placed in the sporadic or immunologic group. Individuals with TMA in association with such presumed provocations are identified as having TTP when the clinical and laboratory syndrome is consistent with that entity. Remaining cases are TMA not otherwise specified.

Stx-related postinfectious HUS, or IStx-HUS

The mechanism of IStx-HUS is increasingly well defined, whereas the mechanisms of INon-Stx HUS is less well understood. Cases in most young children with a respiratory or other presumed viral prodromes to microangiopathic acute renal failure are also readily accommodated, especially because specific testing may help in distinguishing such cases from infantile TTP (see the Medscape Reference articles Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in Emergency Medicine).

Most other cases that are likely to represent forms of HUS may be classified as sporadic or familial HUS. Some mechanisms have been assigned to patients in these groups. Certain provocations associated with HUS are labeled as sporadic or familial. Identification of a family history of similar events has traditionally permitted the diagnosis of familial HUS. Identification of 1 of several known heritable mechanisms for the occurrence of HUS should also permit the diagnosis of familial HUS.

Future identification of additional heritable mechanisms will likely increase the percentage of sporadic cases that are transferred to the heritable category. Individuals with microangiopathic diseases and various combinations of renal, gastroenterologic, neurologic, and other manifestations that cannot be confidently classified as sporadic or clinically familial acute microangiopathic renal disease might be identified as having HUS, TTP, or another microangiopathic entity.

Most cases of HUS arise in previously healthy children younger than 5 years and cause the typical combination of hematologic, gastroenterologic, and renal disease. Most cases occur after an apparently infectious process. Pulmonary findings are not uncommon, and neurologic manifestations arise in approximately one third of all patients with HUS. These problems tend to be mild and transient. Most instances of IStx-HUS are induced by E coli (the most common agent in industrialized nations). Persistent renal disease is unfortunately common and often severe. Outcomes with regard to nonrenal systems are considerably worsened in Streptococcus pneumoniae or S dysenteriae type 1–induced Stx-HUS. Most cases of INon-Stx HUS have a relatively favorable outcome.

In general, the clinical involvement of various organ systems is less widespread in HUS than in TTP. The hemolytic anemia and associated thrombocytopenia of HUS is typically due to a mechanical microangiopathic processes rather than to some directly immune-mediated hemolytic process such as that causing a Coombs-positive hemolytic anemia. Coombs testing is negative in HUS, and the abnormalities of platelet production that characterize most cases of TTP are not found in HUS.

Laboratory testing for heritable or acquired deficiency of ADAMTS-13 activity permits the distinction of most infantile or childhood cases of TTP from HUS, although the boundary between infantile TTP and HUS is occasionally uncertain. HUS in the elderly remains a condition for which additional pathophysiologic characterization is necessary. It may well be a condition that can be differentiated from HUS, the result of unique pathogenicity. HUS-like illness in the elderly tends to be unresponsive to therapies that are usually effective in childhood HUS.[11, 12]

Postinfectious HUS

IStx-HUS is the largest category of HUS, accounting for as many as 60–75% of all cases of HUS.[13, 14] The 2 important varieties of toxins are Stx1 and Stx2. These are also called verocytotoxins (hence, the alternative designations VT-1 and VT-2) because they may be identified by their toxic effects on vero cells. These toxins were initially identified as products of Shigella organisms, hence the term Stx, although in much of the world, verocytotoxin-producing E Coli (VETC) are the most common cause of postinfectious HUS.

The toxins are usually elaborated by toxigenic bacteria that have been ingested and that become transiently established in the colon. In a few cases, other routes of infection (eg, through the respiratory system) establish transient infections with Stx-elaborating pathogens such as S pneumoniae, the cause of some particularly virulent cases of HUS.

Most cases of IStx-HUS occur in children younger than 5 years and are of gastroenteric origin with associated diarrhea. In developed regions of the Western hemisphere and Europe, 60–70% of all cases of HUS are caused by Stx-producing strains of E coli. In nearly 50% of the cases of IStx-E coli HUS, the O157:H7 E coli serotype is found. This particular serotype was termed enterohemorrhagic E coli (EHEC). However, other enterohemorrhagic serotypes have been subsequently identified, including 026 (25%), 0111 (11%), 0145 (11%), and 0103 (6%). Serotypes 055, 086, 0118, and 0120 together account for less than 1%.[14]

In Argentina and Uruguay, where endemicity of Stx-E coli HUS is highest in the world, the 08, 025, 0112, 0103, 0113, 0145, 0171, and 0174 serotypes are most likely to provoke HUS. Approximately 39% of Argentinian beef cattle are chronically colonized by E coli manifesting these various serotypes.[15, 16]

In industrialized nations, toxigenic E coli bacteria are ingested from a variety of sources (chiefly water, milk, or foodstuffs contaminated with fecal material), from contact with animals or their excreta, or from fecal-oral transmission from human to human. An epizootic reservoir for O157:H7 E coli accounts for the high prevalence of that serotype, particularly in cattle herds and hence in undercooked hamburger. These examples are frequently responsible for HUS in North America.[17] Recently, a worrisome trend of increasing prevalence of particularly virulent EHEC has been identified in evolutionary biological studies carried out in Michigan.[18] These findings offer a possible explanation for recent severe spinach-related outbreaks in the United States as well as outbreaks of severe HUS in Japan.

Nonevolutionary changes in bacterial genome must also be considered as an explanation. A dramatic increase in EHEC-related HUS in Sweden was linked to high rates of infection of beef cattle with EHEC. Investigation supported the conclusion that the increase was due to importation of beef cattle harboring EHEC in their guts. The prevalence was 15% in imported cattle as compared with 1% in domestic beef.[19] This suggests the importance of public health measures to identify infections in imported beef.

The finding that as many as 80% of household contacts of children with HUS have circulating Stx supports the feasibility of human-to-human transmission. Factors beyond mere intestinal acquisition of a toxigenic strain of E coli appears to regulate susceptibility to HUS. Shedding of toxigenic E coli may persist for weeks in humans or in animals who have acquired the organism, whether or not they develop diarrhea or other features of HUS.

Ingested toxigenic E coli multiply in the colon. In 38–75% of exposures, cramping and diarrhea ensue after a mean latency of 3 days after ingestion. The diarrhea is initially nonbloody. However, in 70% of patients, it becomes bloody in 1–2 days, and it may be associated with vomiting. Of note, in the remaining cases of HUS associated with Stx-E coli, no premonitory diarrhea is observed. In diarrheal cases, large-bowel inflammation occurs, and submucosal hemorrhages often develop, especially in the ascending and transverse colonic segments. In some instances, toxigenic E coli, particularly the O157:H7 serotype, may induce hemorrhagic colitis without ensuing HUS.[13, 20, 21]

Particular proteins play roles in establishing intestinal infection and in ensuing inflammation, entry into the bloodstream, adhesion to circulating cells, and transition to binding at the sites of intimal injury in the kidney and elsewhere. E coli O157:H7 produce an adhesion intimin in addition to Stx1 and Stx2. Intimin mediates attachment of the ingested organism to colonocytes. Stx2, in turn, mediates attachment to cell surface globotriaosylceramide (Gb3) receptors of other cells, specifically those of polymorphonuclear cells (PMNs), monocytes, erythrocytes, platelets, and endothelial cells.

Stx2 is the more toxic of the 2 Stxs, and it is the toxin most likely to account for renal disease. Exposure to the Stx1 toxin alone may provoke diarrhea without associated renal disease. Clinical series show a 55–70% likelihood that acute renal failure will follow E coli verotoxigenic colitis in children.

Attachment to circulating PMNs appears to be especially responsible for distributing the Stx toxins throughout the body, with particular apparent tropism for attachment to endothelial receptors in kidney.[22] Stx2 binding to leukocytes is of relatively low affinity and permits reattachment to other cell surfaces, particularly those of the kidney[23] ; this produces renal dysfunction in susceptible individuals.

Stx2 binding is particularly likely to occur in blood vessels of the distal convoluted tubules, especially those adjacent to glomeruli and collecting ducts. Selection of this site in children but not adults may have something to do with age-related expression of endothelial Gb3 receptors in this particular anatomic location.[24] This particular regional vulnerability may explain the tendency of HUS TMA to manifest limited organ-system confinement compared with TTP.

Stx1 and Stx2 are made of one A and two small B subunits. One of the B subunits mediates binding to bowel, and a Stx B subunit mediates binding to kidney Gb3 endothelial receptors. On binding, the A unit is internalized and disrupts endothelial function by inhibiting protein synthesis. The development and use of specific antibodies to the A subunit to prevent HUS are among areas of considerable research interest. The disruption of cellular function mediated by the A subunit is the likely proximate cause of injury to the colonic wall and the renal glomerular endothelium.[25, 26]

The microvascular injury in the kidney appears to provoke a procoagulant state that may not have resulted merely based on injury to vascular endothelium of the colon. Individuals without substantial renal involvement do not appear to manifest this same procoagulant picture. Onset of the procoagulant state occurs early in the course of HUS and is indicated by marked elevation of serum thrombomodulin.[27] Therefore, this elevation is likely a valuable laboratory indicator of the onset of renal disease. In the converse, decreasing levels of serum thrombomodulin indicate the onset of recovery or renal function.

The marker for the renal phase of HUS pathogenesis is endothelial swelling in the blood vessels of the renal distal convoluted tubules, which is worsened by the accumulation of proteinaceous material and cellular debris in the vascular subendothelial space. Thrombus formation ensues. In Stx-E coli –related HUS, the fibrin deposition in clots is explained by activation of both prothrombin peptide F1+2 and increases the prevalence of the D-dimer before the microangiopathic stage develops.[28]

Flow obstruction likely participates in the formation of the erythrocyte-rich fibrin clots. These clots may entrap some platelets, but the rate of platelet loss due to this mechanism is far lower than in TTP, in which typically defectively cleaved platelets constitute a principle element of clots. The pathologic changes of Stx-E coli HUS are typically confined to capillary subendothelial spaces in the region of the distal convoluted tubules, although in particularly severe cases, thrombi show anterograde propagation into renal arterioles.

These pathogenic events render portions of the nephron ischemic and compromise function. They also produce a rheologically unfavorable situation that promotes red blood cell shearing with schistocyte formation.[29]

HUS-associated thrombi are largely confined to the kidney, although they may be found in liver, lung, heart, or brain. Thrombi in such extrarenal organs tend to produce only mild symptoms. This is unlike TTP, where thrombi are found in heart, pancreas, kidney, adrenal, and brain (in decreasing order of severity) and often produce signs or symptoms of their presence in these various organs.[30]

In the most severe forms of IStx-HUS (eg, S pneumoniae or S dysenteriae–associated Stx-HUS), leukocyte entrapment may be seen. HUS thrombi do not contain the von Willebrand factor (vWF) multimers that are characteristic of ADAMTS-13 deficiency TTP.[31, 30, 12]

Neither inherited or acquired deficiency of ADAMTS-13 activity, the defining pathogenetic basis of a considerable number of TTP cases, is a feature of postinfectious or other forms of HUS.[32, 33, 34] Young children with Stx-E coli–associated HUS may have elevated rates of ADAMTS-13 cleavage of vWF multimers. This, in turn, may result in smaller-than-normal rather than larger-than-normal vWF multimers.

The enhanced cleavage in HUS may be due to increased availability of ADAMTS-13 cleavage-mediating receptor sites on the vWF multimers. This may be the result of abnormal unfolding of the multimer receptor site areas due to the increased sheer stress vWF multimers may experience during circulation through regions containing HUS thrombi and capillary or arterial microangiopathy.[29]

Other incompletely understood elements are likely to play roles in vulnerability to Stx-HUS. As many as 82% of the household contacts of a child with IStx-E coli HUS (many of whom have hemorrhagic diarrhea) have Stx bound to their PMNs. Despite this binding, such individuals often do not have evidence of renal dysfunction. Therefore, an additional mediator is hypothesized to be necessary for the development of Stx-HUS; this is presumed to be a particular lipopolysaccharide.[35] Why the risk for HUS in individuals with sporadic Stx-E coli colitis is only 3–9%, while the risk is as high as 20% is some epidemics is unclear.

The observation that the use of an antimotility agent increases the risk for HUS suggests that prolonged contact of organism with colonocytes or with inflammation-associated PMNs may play an important role in pathogenesis.[21]

The administration of antibiotics, such as trimethoprim sulfa, to children with E coli O157-associated diarrhea may increase their risk for HUS.[36, 21] The importance of this observation with regard to pathogenesis of HUS is not entirely unclear, although the possibility that such treatment may increase risk for HUS and the often questionable role of antibiotic treatment of diarrhea have caused many clinicians to avoid such treatment.

Special circumstances must, however, be considered. In rare instances, individuals may harbor not only Stx-E Coli, but also Clostridium septicum. This situation may arise as the result of dirty lacerations (in which case localized gas gangrene may provide an important sign) but may also arise as gut infection in individuals exposed to sheep or individuals with carcinoma of the cecum. Failure to adequately treat individuals harboring such dual infection has been associated with serious complications including intracranial C septicum infection.[37]

Levels of C'3 complement are low in approximately one half of all cases of diarrheal HUS; this finding suggests that activation of the alternative complement pathway occurs in postinfectious HUS.

Acute renal failure, the second and most serious cardinal manifestation of HUS, develops in 50–70% of patients with Stx-induced hemorrhagic gastroenteritis. Acute renal failure is a potentially life-threatening complication that often leads to permanently impaired renal function, the principal serious consequence of Stx-E coli HUS.

Insofar as the cerebral manifestations of HUS are concerned, E coli Stx2 induced cerebral microcirculatory endothelial injury in piglets, suggesting a particular age-related vulnerability.[38, 39] Both arteriolar and capillary thrombi are seen in the brains of 50–75% of individuals who had fatal HUS, and thrombi are found in their livers and lungs.

In industrialized nations, IStx-HUS tends to occur in mid summer.[40] Undercooked hamburger appears to be a major vehicle for food-borne E coli O157:H7 outbreaks in children. One study accounted for as many as 46% of cases in children and suggested an epizootic reservoir.[17]

The other major agent for inducing IStx-HUS is S dysenteriae type 1. It is the major cause of HUS in most nonindustrialized tropical, subtropical, and some temperate zones of the world. Therefore, it may the most important cause of HUS worldwide, and it is further distinguished as the cause of the most severe form of HUS. It is acquired by ingesting bacteria from the various sources likely to contain E coli.

The mechanisms are likely similar to those of IStx-E coli HUS. To these is added the increased probability for prerenal dehydration or septic shock with Stx-Shig1, which likely worsens glomerular ischemia and which leads to acute cortical necrosis of kidney. In addition, the comparatively poor availability of intensive medical care in regions with a high prevalence of Stx-Shig1 HUS accounts for the high mortality rate of 30% and the morbidity seen in this form of HUS. Septic shock also plays a role in S pneumoniae HUS, which may also produce acute cortical necrosis of the kidney.

Other pathogens are associated with diarrhea-associated postinfectious HUS. Among them are toxin-elaborating bacteria such as Salmonella and Yersinia species. Yersinia organisms may provoke Stx-associated HUS of severity rivaling that due to S dysenteriae or S pneumoniae. Viruses may provoke early-childhood HUS with diarrhea or a respiratory prodrome (ie, an INon-Stx HUS). Examples include echoviruses, adenovirus, HIV, or Coxsackie virus.

INon-Stx HUS corresponds to many cases of HUS that were included under the old category of classic infantile HUS. These cases account for 10% of all cases of HUS in industrialized nations and tend to be infants. A febrile prodrome in the classic cases is associated with the development of diarrhea. However, bacterial blood cultures are negative and a Stx-elaborating pathogen is not identified. A viral pathogen is sometimes isolated from appropriate cultures or identified serologically. In other instances, no associated diarrhea occurs.

Identified viral pathogens include echoviruses or Coxsackie viruses, adenovirus, and HIV. Viruses may directly mediate vascular endothelial injury in the kidney, but the process is little understood. Likewise, whether the peculiar age-related and regional vascular susceptibility has the same basis as that which occurs in IStx-HUS is not fully understood. In most cases, HUS tends to be mild and is likely to have a relatively good prognosis. However, severe cases are described.

In children older than 5 years of age and in adults with HUS, an increased degree of glomerular endothelial abnormality is found with HUS, and necrotizing arterial thrombosis rather than capillary microangiopathy may predominate.[25] The disease also has a peculiar tendency to manifest pulmonary thrombosis, which may be seen in early childhood HUS. This is especially prominent in HUS associated with the use of cyclosporin A or various cancer chemotherapeutic regimens. These thrombi tend to entrap leukocytes and erythrocytes, and they may be associated with regional tissue necrosis.[41]

Of interest, in some individuals (especially adults), Stx-E coli O157:H7 infection provokes a TTP rather than an HUS phenotype.[42] Disease in older individuals with HUS is most likely to fit in the sporadic or familial categories of HUS.

Familial HUS

Familial HUS is clinically defined by the occurrence of HUS in 2 or more family members. The occurrence is not usually associated with diarrhea, although diarrhea-associated cases do occur. Cases of sporadic HUS may be reclassified as familial when the process is identified in other family members, although co-exposure to Stx-expressing bacteria such as EHEC must of course be excluded, in which case diarrhea is usually prominent. The first description of familial HUS was provided in 1956, although the careful studies of Kaplan and associates in 1975 made a considerable additional contribution. Familial HUS is thought to account for 5–10% of HUS cases.

Recognition of this entity is important because mortality is as high as 50%, despite modern management. This rate is much higher than the mortality of postinfectious HUS. Thus, severity provides another distinguishing characteristic that may prompt testing to identify the identification of mutations associated with this form of HUS.

Both autosomal dominant and autosomal recessive patterns of inheritance are described. The pathophysiology of familial HUS is less well understood than that of postinfectious HUS. Familial cases are subclassified by whether they manifest (D+) or lack (D-) a diarrheal prodrome. Kindreds may contain individuals who manifest TTP rather than HUS.

Approximately 10–20% of familial or sporadic (D-) cases are associated with mutations in a region of chromosome 1 that encodes for various complement regulatory proteins. Some familial cases have heritable deficiencies of C'3. Others involve deficiencies of liver-synthesized complement factor H (HF1).[43, 44] Cases are subclassified according to whether an identifiable defect in HF1 expression is present. Patients with HF1 mutations tend to have low C'3 levels as well with a mutation in MCP, a surface-bound complement regulator. Factor H deficiency is associated with type II mesangiocapillary glomerulonephritis, a particular type of kidney disease, that may develop with or without an HUS presentation.[45, 46] Defective HF1 expression may be found in affected individuals whose families pass on the disease trait in either autosomal dominant or autosomal recessive patterns of inheritance.

Individuals with either of these deficiencies tend to have HUS of greater-than-average severity. A missense mutation in the gene that encodes factor H was identified in some cases of familial HUS,[43]  with the subsequent demonstration of genetic heterogeneity in affected individuals. Furthermore, mutations of this same gene may be associated with familial or sporadic forms of HUS (defined by the absence of family history) without diarrheal prodrome.[47]

Factor H is a fluid-phase regulator of the activation of the alternative complement pathway, which plays a critical role in regulating the discernment of host from foreign tissues. The various missense mutations associated with HUS result in abnormalities in the carboxy terminal of factor H, a region important for binding to C'3 complement receptors and cell-surface polyanionic structures. Early procoagulant activation is hypothesized to occur, as in diarrheal cases, because of injury to the endothelial cells. Dysregulation of the alternative complement pathway, due to abnormal binding function of factor H, then prolongs the abnormal procoagulant state. How defective HF1 expression participates in HUS (or TTP) pathogenesis is not really understood.

Patients with HUS usually have normal levels of factor H with normal or low levels of complement or C'3.[48, 49] A normal factor H level does not exclude mutation of the factor H gene. How many cases of (D-) HUS have demonstrable abnormalities in the factor H gene is unclear. One recent extensive literature review of found factor H gene abnormalities in less than 15% of all nondiarrheal cases of severe HUS in which a renal transplant was required.

C'3 levels are inversely associated with disease severity and outcome in both (D+) and (D-) sporadic or familial HUS.[50, 51, 52] Although HUS occurs in individuals with specific abnormalities of only the carboxy terminus of factor H, complete absence of factor H in pigs, mice, and even humans is not associated with increased susceptibility to HUS. Rather, it portends the possibility of developing mesangiocapillary glomerulonephritis.[53]

Sporadic HUS

A wide variety of stimuli can provoke endothelial injury with an HUS phenotype. Adults, particularly the elderly are at higher risk for sporadic HUS than children. Sporadic HUS includes examples of the former immunologic HUS category that are nonfamilial. It includes HUS with an acute acquired decrease in the concentration of C'3 or a deficiency of H factor activity.[43, 54] A confusion is that some authorities include some individuals who harbor GI Stx-E coli infections[14] or some who have diarrheal prodromes in the sporadic category.

However, most cases in the sporadic category do not have an infectious diarrheal prodrome. Among the most common provocative illnesses are noninfectious vasculitic and inflammatory illnesses, such as Henoch-Schönlein syndrome, systemic lupus erythematosus (SLE), scleroderma, polyarteritis nodosa, and Wegener granulomatosis. In some individuals, these illnesses may provoke TTP rather than HUS. In others, they may result in rapidly progressive vasculitic glomerulonephritis rather than the peculiar glomerulopathies of HUS or of TTP. The elderly are at higher risk for HUS due to these provocations than children perhaps because of an prevalence of these illnesses and their treatments. However, other age-related factors may also be at work.

Other provocations of sporadic HUS are malignant hypertension, kidney irradiation, bone marrow transplantation, immunosuppressants (cyclosporine, tacrolimus, methylprednisolone), snake-venom or diethylene glycol intoxication, and chemotherapy drugs (eg, mitomycin).[55]

Sporadic HUS due to these stimuli usually occurs without a diarrheal prodrome. The identification of additional individuals in a kindred who develop HUS due to these or some other provocations listed causes their HUS to be reclassified as familial rather than sporadic. The reclassification is also true of kindreds in whom familial factor H deficiency is identified.

Tacrolimus-associated HUS, for which renal transplant patients are at risk, tends to arise in adults rather than children. This is consistent with the general rule that HUS tends to be more severe and difficult to treat in adults than children. Tacrolimus-associated HUS occurs idiosyncratically slightly more often in men than women and has a mean onset at about 40 years of age or at about 7 months after receipt of renal allograft. Only 45% of patients improve with various combinations of anticoagulation, use of antiplatelet agents, dialysis, and plasma exchange.

After HUS develops, tacrolimus is usually replaced with cyclosporine. However, in some instances, an initial dose reduction of tacrolimus is tried. Graft loss occurs in 25% of patients. Without successful retransplantation, 100% of patients die. Even with transplantation, approximately one third of patients die. If associated liver failure occurs, 60% die.[56]

The immunologic form of HUS is associated with a decrease in serum concentration C'3, an event that can be detected only after presentation. Other secondary forms of HUS include those associated with SLE, scleroderma, malignant hypertension, kidney radiation, immunosuppression, snake-venom intoxication, diethylene glycol intoxication, or chemotherapy with mitomycin or cyclosporin. Endocrine provocations for HUS include pregnancy and use of oral contraceptives.

Sporadic HUS tends to be associated with greater rates of recurrence and greater prevalence of kidney failure. It is also associated with an increased risk for seizures and other neurologic complications. It tends to be a severe disease and the response to supportive therapy may be poor. Hypertension may be severe in affected individuals. Transplantation after sporadic HUS may be followed by recurrence.

United States

The annual incidence of hemolytic uremic syndrome in the United States is approximately 2.2 cases per 100,000 population. The highest incidence in the United States is in children younger than 5 years. Incidence as high as 6.1/100,000 population per year has been estimated for children 5 years of age or younger, although an estimate as low as 1.08/100,000 children less than 5 years of age has been provided.[57] The incidence tends to decline with age, with lowest incidence in adults aged 55–59 years (0.5/100,000 population per year). HUS may be an under-reported disease. In one study, only 43% of identified cases had been reported to public health agencies. This California study additionally found that despite strenuous public health measures, the prevalence of STEC-associated HUS had not changed from the 0.67/100,000 rate.[58]

HUS is associated with verotoxigenic E coli O157:H7, which accounts for nearly half of childhood cases of HUS. This form tends to occur in midsummer, with most cases occurring between June and September. Summertime predominance is likely to be found in most other developed nations located in temperate climates.

Undercooked hamburger is a particularly important source of verotoxigenic E coli O157:H7. Undercooked ground meats processed by using insufficiently cleaned grinders in which beef was previously ground are another course of infection. Milk, water (from drinking, swimming, or tooth brushing), cider, juices, vegetables washed in water, and human excreta are additional important sources of infection. Other sources include deer, sheep, goats, horses, dogs, and birds.

Of note, several population-based studies showed that the prevalence of HUS substantially increased in the 1980s in the United States on the West Coast; this observation may also be true in other developed nations.[59, 13] However, this suggestion was not supported in one careful study.[57]

When these data are considered with the 40-year increasing prevalence of other autoimmune diseases (eg, juvenile rheumatoid arthritis, asthma, SLE, multiple sclerosis in women) in industrialized nations, one might conclude that a common set of influences is disturbing the development of immunoregulation and tolerance. Current research into the genetic and immunoexperiential factors that determine the competence of immunoregulatory T cells is likely to prove relevant to these worrisome observations.

International

E coli-related HUS

Data concerning the prevalence of HUS in many parts of the world are incomplete. Consumption of improperly stored or prepared meats and other foodstuffs in warm seasons or warm climates increases the risk of exposing individuals, especially children, to Stx-producing E coli. This risk is greatest where sanitation is poor.

• Verotoxigenic E coli, particularly the O157:H7 strain, accounts for at least 75% of all cases of postinfectious Stx-HUS in Western Europe, where the incidence may be on the order of 0.5 case per 100,000 population per year. Incidences in Scandinavia, Switzerland, and perhaps other individual countries may be lower than this.

• The largest ever outbreak of E coli-related HUS in Romania occurred from December 2015 to September 2016. The O26:H11 strain was the most common responsible subtype for this outbreak. Among 32 children who sufferred from HUS, three of them was died.[60]

• In Japan, the O157:H7 Stx strain of E coli is the most important cause of postinfectious HUS.

• The incidence of postinfectious HUS prevalence is approximately 5-fold higher in Argentina and Uruguay, at 10.5 cases per 100,000 population per year, than in the United States. This high prevalence is ascribed to an epizootic reservoir in Argentine beef, though the manner in which beef is handled and cooked must also play a role in this high incidence.

• Stx-E coli are found in approximately 0.6–1.4% of diarrheal stool samples in individuals from Calcutta. However, these organisms are found in as many as 50% of raw-beef samples from the region. They are overwhelmingly non-O157:H7 strains. In such tropical regions, S dysentaeriae is a more important cause of infectious HUS. However, sometimes individuals with diarrheal HUS who are found to have Stx-elaborating Shigella in stool have that organism as well as E coli in blood.

S dysenteriae-related HUS

Data concerning the incidence of S dysenteriae -related postinfectious Stx-HUS is limited. However, in developing nations a very large number of cases of Shigella Stx-HUS likely occur, with an appalling fatality rate. Shigella Stx-HUS may or may not be associated with diarrhea, however. One careful study of tropical Shigella -Stx HUS noted diarrhea in 68% of cases and similar rates of mortality (55%) whether or not diarrhea was present. Among individuals with diarrhea, 16% had neurologic abnormalities. Shigella Stx-HUS without diarrhea tends to have lower hemoglobin and platelet counts than Shigella Stx-HUS with diarrhea.[61]

• In developing nations, approximately 10 million cases of diarrhea occur in children younger than 5 years. About 1 million of these children develop dysentery (bloody diarrhea), and approximately 100,000 of these children have Shigella infection. How many of these children develop postinfectious HUS is unknown.

• Travelers' diarrhea particularly occurs in individuals who have visited tropical countries. Travelers' diarrhea represents an important potential source of sporadic outbreaks of postinfectious Shigella Stx-HUS when these individuals travel to developed nations.

• Between 1993 and 1998, about 5% of individuals returning to Barcelona with traveler's diarrhea harbored enterotoxigenic Shigella species, chiefly Shigella flexneri or Shigella sonnei. In approximately 20%, the Shigella organism could elaborate Stx1, the toxin most likely to produce severe dysentery, bacteremia, shock, disseminated intravascular coagulation (DIC), or HUS. Clustered cases of Shigella Stx-HUS traceable to an index case of traveler's Shigella dysentery appear to be largely due to person-to-person (fecal-oral) transmission.

• North Africa is a region where the risk for severe Shigella Stx-HUS, Stx-sepsis, and shock is increased in children younger than 5 years.

Mortality

When originally described, the mortality rate of menolytic uremic syndrome (HUS) was 50% or greater. Improved supportive therapy, including transfusion; dialysis; and careful management of fluids, electrolytes, and hypertension, where such approaches are readily available, have significantly reduced the high mortality rate for children with HUS.

Since the 1970s, the acute case-mortality rate of HUS (including all subtypes) in developed nations has been approximately 5–10%. A California study of patients hospitalized with HUS showed an acute phase mortality of 2.7%.[58] Comparable data on children with familial HUS shows an acute phase mortality rate of 5% or higher. The mortality rate for early childhood Asian or African S dysenteriae HUS may be as high as 30–55%. Severe hyponatremia was identified as a factor predictive of higher mortality in the Kenyan series.[61] Non–Stx-HUS may have an acute mortality risk as high as 25%, even in developed nations.

Mortality and morbidity rates are distinctly greater in children who develop HUS after a prodromal respiratory illness without GI disturbance than in those who develop HUS after a diarrheal prodrome. Children who have neurologic signs in association with HUS are most likely to die or to have residual hypertension or chronic renal dysfunction.

Adults account for a large percentage of non–Stx-HUS cases. They are most likely to have HUS as a secondary complication of a serious underlying systemic disease; for this reason, the adult case-mortality rate remains higher than that for children.

In tacrolimus-associated HUS, which is chiefly a disease of adults with kidney allografts, graft loss occurs in 25% of all patients. Without successful retransplantation, 100% of these individuals die. Even with successful retransplantation, approximately one third die. If associated liver failure is present, 60% die.[56]

Morbidity

The chief morbidity of HUS is chronic renal failure. In the United States, HUS is the leading cause of acquired renal failure in children. Various degrees of permanent renal injury occur in approximately one third of all cases of HUS. Individuals, usually children, who develop HUS after an S pneumoniae or S dysenteriae infection are most likely to develop severe kidney dysfunction and end-stage renal disease due to the renal necrosis and severe glomerulosclerosis.

Only 45% of adults with tacrolimus-associated HUS improve, despite treatment with various combinations of anticoagulation, antiplatelet agents, dialysis, and plasma exchange. Graft loss occurs in 25% of patients.

HUS accounts for approximately 7% of all cases of hypertension in infants younger than 12 months.

Demographics

No definite racial predilection for HUS has been identified beyond the elevated risk sustained by individuals of particular ancestry whose standard of living or place of residence may account for that elevated risk. One study found that white individuals were more likely than black individuals to be hospitalized for their HUS.[57]

Some data suggest that girls are at greater risk for sporadic postinfectious HUS than boys are. One study found that among children younger than 5 years, girls are more likely to be hospitalized for HUS than boys are.[57]

Predominantly an adult disease, tacrolimus-associated HUS occurs slightly more often in men than in women.

HUS can occur at any age.[62]  However, two thirds of all cases occur in children younger than 3 years, and few cases occur after 5 years of age.[14] HUS occurs less commonly in neonates than in children.

HUS may occur in adults (especially in elderly adults), usually as the result of an identifiable provocation.

Tacrolimus-associated HUS has a mean onset at about 40 years of age or about 7 months after the receipt of a renal allograft. Other factors governing this apparently idiosyncratic medication reaction are not well understood.

In the elderly, the pathogenesis of HUS usually differs from that of HUS in childhood. Elderly individuals respond relatively poorly to support and management that are effective in childhood cases.[11, 12]

Hemolytic uremic syndrome (HUS) may arise as a familial or an idiopathic illness, and it may or may not be associated with an identifiable prodrome or provocation.

Postinfectious HUS is more common than heritable forms of HUS. Postinfectious HUS may occur after infections by viruses or bacteria, and the prodromal manifestation often includes diarrhea.

Viruses isolated in cases of HUS include echoviruses, adenoviruses, and coxsackieviruses. Identified bacterial organisms include Salmonella, Shigella, Streptococcus, and Yersinia species.

In some instances, the presence of an exanthem or enanthem may assist in identifying a particular infectious agent. An example is a coxsackie rash associated with fever and diarrhea before the onset of renal failure.

Diarrhea-associated postinfectious HUS is most likely to occur in children younger than 5 years. It represents what Drummond called "classic infantile" cases. Children uncommonly have a nondiarrheal prodrome, usually as a respiratory infection or sepsis.

In industrialized nations, verotoxigenic E coli O157:H7 appears to be the most important cause of postinfectious HUS. This is usually heralded by the development of hemorrhagic colitis. In one study, this particular serotype of E coli was identified in 46% of children with classic infantile postinfectious HUS.

• HUS due to this agent has a distinct midsummer seasonal predilection.

• A history of consuming undercooked cooked ground beef is the most important risk factor with E coli O157:H7 infection; this finding suggests an epizootic reservoir.

• Relatively uncommon routes of acquisition include exposure to contaminated water or milk and fecal-oral routes from human or animal sources.

Various degrees of cramping abdominal pain precede the onset of diarrhea by days to weeks.

Vomiting occurs in 30–60% of patients.

Diarrhea is usually non bloody at the outset. However, in approximately 38-70% of cases involving E coli O157:H7, the diarrhea becomes hemorrhagic within 1–2 days. Approximately 3–9% (up to 20% in some epidemics) of children who have this course develop overt HUS.

A history of using antibiotics, such as trimethoprim sulfa or antimotility agents, increases the risk of HUS with verotoxigenic colitis.

Abdominal pain and fever may be severe. Severe abdominal tenderness or prolonged vomiting may suggest pancreatitis, and a surgical abdomen suggests the possibility of bowel infarction.

In nonindustrialized nations, the most important cause of hemorrhagic enterocolitis is Shigella dysentery type 1.

Patients may have a history of residing in or traveling to areas where S dysenteriae or Yersinia infections is endemic.

Patients may have a history of having contact with another person, particularly a child, who traveled from an endemic area and who developed dysentery.

Dysentery due to S dysenteriae or Yersinia organisms may be severe.

Children without diarrhea may have had a prodromal respiratory illness or sepsis; these children have a prognosis distinctly worse than that of patients with a diarrheal prodrome.

Patients may have a history of severe fever.

A variety of noninfectious processes may precede sporadic cases of HUS. Many of these processes arise more commonly in adults than in children. Patients may have a history of the following:

• Henoch-Schönlein purpura

• HIV infection or AIDS

• Systemic lupus erythematosus (SLE)

• Antiphospholipid antibody syndrome

• Scleroderma

• Polyarteritis nodosa

• Wegener granulomatosis

• Malignant hypertension

• Kidney radiation

• Bone marrow or stem cell transplantation

• Various organ allograft kidney transplantations, usually more than 7 months before HUS

• Immunosuppression with cyclosporin, tacrolimus, or methylprednisolone (Tacrolimus-associated disease is usually seen in individuals older than 40 years, more commonly in men than in women.)

• Pancreatic cancer treated with gemcitabine

• Cancer treated with mitomycin or other chemotherapy drugs

• Snake envenomation

• Diethylene glycol exposure

• Pregnancy or use of oral contraceptives

Familial and sporadic forms of HUS need not be preceded by diarrhea or another definable illness (other than fatigue, irritability, and lethargy).

Physical findings depend on the nature of the prodromal illness and the degree to which various organ systems are involved in the HUS phase.

Fever may be present.

Skin changes include the common finding of pallor. The patient's skin may be dry or doughy if they are dehydrated, and mucous membranes may be dry in such patients.[63]

Pulmonary findings may reflect a respiratory prodromal illness to postinfectious HUS, or it may be the consequence of renal failure or CNS, cardiac, or pulmonary involvement in HUS.

Postinfectious HUS with diarrheal prodrome may produce abdominal tenderness.

Colonic ischemia may be severe enough to represent a surgical emergency.

Abdominal tenderness is occasionally due to the development of pancreatitis.

Patients develop acute renal failure and enter a catabolic state with acidemic uremia and hypertension.

Neurologic manifestations, most commonly behavioral changes, motor seizures, and encephalopathy, are seen in 30–40% of children with classic postinfectious HUS with a diarrheal prodrome. Such manifestations are more common in familial cases.

Blindness, ataxia, hemiparesis, coma, and decerebrate rigidity are reported. Neurologic findings such as these indicate a poorer prognosis.

Whether neurologic changes are the result of cerebral microangiopathy or secondary to metabolic disturbances and hypertension is not always clear.

The various known causes of HUS are also discussed in the Pathophysiology and Clinical sections.

In brief, postinfectious HUS is due to viruses (eg, echoviruses, adenoviruses, coxsackieviruses) and bacteria (eg, Salmonella, Shigella, Streptococcus, and Yersinia species, as well as verotoxigenic E coli O157:H7).

In one study, the O157:H7 serotype of E coli was identified in 46% of patients. Undercooked hamburger appears to be a major vehicle for food-borne E coli O157:H7 outbreaks in children, suggesting an epizootic reservoir. Several adult cases of TTP have been associated with the same pathogen, though this association is less common in adults than in children. Use of an antimotility agent or trimethoprim-sulfamethoxazole (TMP-SMX) appears to increase the risk for HUS. Data from preliminary studies suggest that the use of SYNSORB-pk may be effective in absorbing verotoxin in the intestine, preventing HUS.

The immunologic form of HUS is associated with a decrease in serum concentrations of C'3, an event that can be detected only after presentation. Other secondary forms of HUS include those occurring in association with SLE, scleroderma, malignant hypertension, kidney radiation, immunosuppression, snake-venom intoxication, diethylene glycol intoxication, or chemotherapy with mitomycin or cyclosporin.

Endocrine causes include pregnancy and use of oral contraceptives.

Hemolytic uremic syndrome (HUS) is fundamentally a microangiopathic nonimmune hemolytic anemia associated with a variety of complications. Microangiopathic Coombs-negative hemolytic anemia and acute renal failure with microscopic hematuria and proteinuria (1–2 g/dL) abruptly mark the onset of HUS in nearly all patients.

Hematologic and associated serologic findings of HUS thrombotic microangiopathy (TMA) (and thrombotic thrombocytopenic purpura [TTP]) include the following:

Anemia is an invariable finding and usually severe, whether HUS occurs after postinfectious verocytotoxin-related colitis (eg, due to E coli or S dysenteriae) or in HUS without a diarrheal prodrome (eg, related to S pneumoniae pneumonia or sepsis).

Platelet counts tend to be somewhat higher in HUS TMA than in TTP because they are not consumed quickly by clot formation. However, in some cases of HUS, thrombocytopenia may be severe. 

• The microcirculatory clots of TTP are formed in large part from platelets, whereas those that develop in HUS consist chiefly of red blood cells. The HUS clots are fibrin rich but contain relatively few platelets.

• Severe HUS GI bleeding is associated with consumptive thrombocytopenia.

• Platelet survival time is shortened in HUS.

• Platelet counts may be < 80 X 109/L (< 80,000/mm3).

Additional findings include the following:

• Microangiopathic changes occur in RBCs.

• The peripheral blood smear reveals fragmented RBCs (eg, schistocytes, spherocytes, segmented RBCs, burr cells, helmet cells).

• Reticulocytosis (proportional to hemolysis) and circulating free hemoglobin may be found, though not when bone marrow response to anemia is impaired.

• Increased serum thrombomodulin levels may be found and are a marker for endothelial injury in HUS.

• Leukocytosis may be found.

• In postdiarrheal cases, moderate leukocytosis typically develops and may be an indicator of renal failure.

• In cases arising after a respiratory prodrome or S pneumoniae sepsis, early and marked leukocytosis may be found with abundant immature forms.

• Because hemolytic anemia is nonimmune, results of Coombs testing is negative.

• HUS is more likely than TTP to manifest changes consistent with disseminated intravascular coagulopathy (elevated fibrin split products, prolongation of the activated partial thromboplastin time, and low antithrombin III levels).[65]

• ADAMTS13 activity now becomes the hallmark for diagnosis of TTP. Very low, less than 10%, ADAMTS13 activity is usually considered as TTP rather than HUS. ADAMTS13 activity can be reduced in aHUS, however, it is not quite often below 10%.[66, 67]

• Full-blown disseminated intravascular coagulation (DIC) is especially likely in S dysenteriae –related postinfectious HUS.

• Of interest, TTP occurring after verotoxigenic E coli O157:H7 infection in adults may provoke changes consistent with DIC.

• Fibrinogen levels may be normal or increased.

• Because of intravascular hemolysis, direct bilirubin values are elevated, where haptoglobin levels are usually low.

• The most sensitive indicator of ongoing intravascular hemolysis is an elevated serum lactate dehydrogenase (LDH) level, and tissue ischemia may further elevate the value.

• Evidence of inflammatory changes may be found in blood and urine.

• Diminished serum concentrations of C'3 is found in approximately half of all cases of verotoxigenic E coli –related HUS.

• In the acute situation, the extent to which low levels of C'3 reflect a heritable defect of complement C3 or factor H may not be clear.

• Elevated concentrations of alpha-1 and beta-2 microglobulins may be found in the urine.

• In HUS with a diarrheal prodrome, bacterial or viral stool cultures may yield verotoxigenic E coli, S dysenteriae, coxsackie virus, echovirus, Salmonella enteritis, or Yersinia species.

• In North America or Europe, at least 70% of all cases of postinfectious HUS with diarrheal prodrome are due to E coli enteritis. This can be confirmed with stool cultures, and the specific serotype may be identified. Most of these cases occur in children younger than 5 years.

• O157:H7 is the most common Stx-elaborating serotype of E coli. Absence of sorbitol fermentation of the subcultured E coli is a strong indication of this serotype, which may be confirmed with specific serotyping.

• The relatively uncommon O26, O103:H2, O111:H8, O121, O145, and other serotypes have been identified as Stx+ E coli.

Culture and other findings

• In Asia, North Africa, and many developing nations in tropical or temperate zones, cultures may demonstrate enteric infection with Stx-elaborating S dysenteriae. Serotype 1 is by far the most common cause of HUS.

• Stx+ S dysenteriae –related HUS more commonly occurs in children younger than 5 than in adults.

• Associated bacteremia is not uncommon.

• Throat cultures may yield S pneumoniae or adenovirus in individuals with a respiratory prodrome.

• Blood cultures may yield S pneumoniae in infants presenting with nondiarrheal sepsis.

• Infants or young children presenting with S dysenteriae postdiarrheal HUS are sometimes septic.

• Stx may be identified in stool in postinfectious HUS with diarrheal prodrome.

• Hematochezia is common in verotoxigenic HUS (related to E coli or especially S dysenteriae), particularly when consumptive coagulopathy is severe. This enteric bleeding is presumably due to the microangiopathy with associated thrombosis of enteric circulation.

• Because of the particular predilection for involvement of renal microvascular circulation, acute renal failure is routinely found in Stx+ or non-Stx HUS with resulting elevation of blood urea nitrogen (BUN) and creatinine levels.

• Microscopic hematuria and proteinuria of 1–2 g/dL develop abruptly as consequences of renal failure in 25% or more of patients with HUS.

• Alpha1- and beta2-microglobulins may be found in the urine of individuals with HUS-associated renal failure.

• The mean glomerular filtration rate for classic Stx-E coli HUS is less than 80 mL/min/1.73 m2 body surface area.

• Marked acidemic uremia may result from the combination of acute renal failure and catabolic state. Approximately one third of these patients become anuric.

• Hypertensive cardiac failure may add prerenal kidney failure to renal failure.

• HUS associated with illnesses other than verotoxigenic infections, sepsis, or other infectious processes may provide additional clues to the pathogenesis. However, many patients with such symptomatic have a premorbid history of such conditions.

• Malignancies associated with the development of sporadic HUS may produce various diagnostically significant changes in the appearance of the blood film and blood counts.

• HUS associated with the use of antineoplastic or immunosuppressive agents may provoke marked leukocytopenia.

• Particularly low platelet counts may be seen in HUS associated with the use of immunosuppressive or antineoplastic drugs.

• Strikingly low platelet counts may be seen in pregnant women with hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome

• Biochemical changes reflecting the hepatopathy that is another cardinal feature of HELLP may also be found.

• Among non-Stx (sporadic) cases of HUS, immune-mediated forms are associated with a decrease in the serum concentration of C'3 at the onset of disease. This decrease may be particularly striking when HUS occurs in association with an identifiable systemic inflammatory disease, such as SLE or scleroderma.

• Various laboratory abnormalities are seen in cases of HUS that involve the liver. These represent dysfunction associated with hepatic microvascular disease.

• Hypercalcemia is common in HUS.

• Familial non-Stx HUS accounts for less than 3% of all cases of HUS and tends to produce particularly severe microangiopathy and renal failure.

• Remarkably low levels of C'3 may be found. This deficiency may persist during remissions of HUS.

• Any of more than 50 mutations of the HF1 (factor H) gene (on chromosomal region 1q32) may be found in up to 40% of all cases of familial non-Stx HUS and in as many as 13–17% of all cases of sporadic non-Stx+ HUS. In the latter case, it probably occurs as an acquired autoimmune HF1 defect due to anti–factor H antibodies.

• Factor H is an important regulator of the alternative pathway of complement. It is a cofactor for the cleavage of C3b by C3b convertase. Of interest, defects in HF1 are observed in some cases of thrombotic TTP.

Other causes of non-Stx+ (sporadic) HUS that can be diagnosed with various laboratory tests. These causes include S pneumoniae (40% of all cases of non-Stx+ HUS), Neisseria meningitidis, and other bacteria. Systemic viral infections may be diagnosed by using blood, oropharyngeal, or rectal cultures and/or viral titers.

Particular tests may reveal non-Stx (sporadic) HUS due to systemic autoimmunity. Important examples are SLE, antiphospholipid antibody syndrome, and scleroderma.

Other conditions that may provoke the development of non-Stx (sporadic) HUS are usually identified based on the clinical history. These conditions may have their own associated clinical or laboratory changes or abnormalities in addition to those characteristic of HUS. These conditions include the following:

• Pregnancy, particularly in individuals with preeclampsia or the syndrome of hemolysis, elevated liver-enzyme levels, and low platelet count (HELLP syndrome)

• Diethylene glycol intoxication

• Use of anticancer drugs (eg, cisplatin, mitomycin, bleomycin, gemcitabine)

• Use of immunomodulatory drugs (eg, cyclosporine, quinidine, interferon, tacrolimus, OKT3)

• Use of antiplatelet drugs (eg, ticlopidine, clopidogrel)

Overview

The organs and system most likely to show imaging changes in association with HUS are the kidneys and the GI tract.

Patients with neurologic abnormalities may or may not have imaging abnormalities initially, though initial or follow-up studies may show a variety of changes.

Abnormalities in organs other than the kidneys and those of the GI tract may be observed initially, during acute illness, or with delayed onset during the recuperative period.

Enteric abnormalities

Marked thickening of the intestinal wall may be observed during the enteritic, or especially the enterohemorrhagic, phase of illness, which usually precedes acute renal failure.

Such changes are usually observed when serious enteropathy is initially suspected and when the diagnosis of HUS or related entities is considered. At this time, typically 4-6 days after the onset of diarrhea, initial enteric imaging is usually undertaken.

Abdominal imaging with barium enema may show thumb-printing of the large bowel due to the combination of edema of the bowel wall and submucosal hemorrhage. These changes are usually most striking in the ascending or transverse colon.

HUS rarely occurs after Clostridium perfringens sepsis with multiple organ failure, in which case imaging abnormalities are particularly severe and fulminant. In such cases, imaging findings may suggest regional enteritis of the Crohn type.

Renal findings

At the onset of acute renal failure, which occurs in 55-70% of cases of HUS, a variety of imaging techniques may be used to evaluate the etiology and nature of renal impairment. Most abnormalities observed are not specific for HUS; hence, considering the changes observed in the context of the case history and available laboratory results is important.

Increased brightness of the kidney may be detected on renal ultrasonography.

In patients with HUS, ultrasonography combined with Doppler imaging may demonstrate the association of 2 findings: diminished parenchymal perfusion and an increased resistance index (RI). This combination is found not only in HUS but also in TTP, panarteritis nodosa, and other vasculitic nephropathies.[68]

Cortical necrosis of the kidney is observed in many instances of severe HUS, as seen in association with S dysenteriae or S pneumoniae infections.

Neurologic findings

In patients with neurologic manifestations associated with HUS, various abnormalities may be observed on brain images.

In North America and in Europe, most patients with clinical and radiographic abnormalities involving the nervous system will have had verocytogenic E coli HUS. Approximately one third of these patients have serious neurologic symptoms or signs.

MRI of the brain may reveal focal areas of infarction with swelling and, in some cases, hemorrhage, especially in areas such as the internal capsule and deep gray nuclei. Whether changes observed on images are due to cerebral microangiopathy or hypertension and metabolic disarray is not always clear.

Limited evidence shows that approximately 60% of patients with chiefly verotoxigenic E coli and clinically significant neurologic findings have abnormalities on brain CT or MRI during the acute phase. However, in 40% of patients, CT and MRI images are entirely normal.

The most common sites of abnormality on CT or MRI during the acute phase of HUS are the thalami, brainstem, or cerebellum. In one series, 1 or more of these locations were involved in 60% of cases of HUS with MRI abnormalities. In approximately 20%, abnormalities were in 1 or both thalami; in 20%, in the cerebellum; and in 10%, in the brainstem. In some instances, lesions contained hemorrhage.[69]

In 1 small series, all abnormalities resolved in nearly one half of all children with good clinical outcomes after verotoxigenic E coli HUS; slightly more than one half had partial resolution at the time of imaging follow-up.[69]

Favorable clinical and imaging improvement may be seen, even in patients with severe initial clinical and imaging abnormalities. On follow-up imaging, a hemorrhagic component in an area of acute abnormality may be the best predictor of a residual imaging abnormality.

The prevalence of neurologic involvement with associated imaging abnormalities is clearly lower in HUS after verotoxigenic E coli enteritis than after the comparatively rare HUS related to S pneumoniae infection.

Although little pertinent information is available, imaging techniques are least likely to show improvement in HUS after verotoxigenic S dysenteriae enteritis among all types of postinfectious HUS.

Verotoxigenic S dysenteriae HUS is by far the most prevalent type of HUS in developing nations, where CT and MRI may not be readily available.

In S pneumoniae–related HUS, the risk for CNS involvement is high. MRI is more sensitive than CT for detecting brain abnormalities. The findings are usually associated with acute bacterial meningitis, which is the cause of death in most patients with S pneumoniae–related HUS. Examples of such findings include the following:

• MRIs obtained with a long repetition time (TR) and a short echo time (TE) (intermediate) show abnormal hyperintensity in the brain cisterns and near the base of the brain.

• On fluid-attenuated inversion recovery (FLAIR) imaging, increased signal intensity throughout the subarachnoid spaces is due to increased cellular and protein content in CSF.

• On FLAIR imaging, contrast enhancement in the meninges is due to leak of contrast agent from inflamed blood vessels.

• Abnormalities of the cerebral parenchyma subadjacent to the meninges may be due to inflammation or infarction.

• Subdural effusions may be observed.

Pulmonary findings

Several types of lung abnormalities have been described in individuals with HUS.

Acute pneumonia is commonly found in patients with non-Stx (sporadic) HUS related to S pneumoniae.

One 20-month-old Italian infant developed pulmonary hemorrhage after the acute phase of postdiarrheal HUS, although he had greater degrees of thrombocytopenia and coagulative abnormality during the acute phase that had resolved.

In kidney biopsy specimens obtained from patients with acute Stx+ HUS, the predominant finding is in the glomerular tuft. These changes apparently develop early in the course of illness. Changes include microvascular endothelial swelling with an accumulation of proteinaceous material and cellular debris in the subendothelial layer (between the inner endothelial cell membrane and the subadjacent basement membrane).

Microthromboses may be found in the involved microcirculation of the kidney near the glomerular tuft. These microthromboses include fibrin thrombi that may occlude the glomerular tuft. In some instances thrombi extend likely because of retrograde propagation of clot into the arterioles.

Renal cortical ischemic disease may be found in severe cases of Shigella dysenteriae or HUS related to S pneumoniae.

Management of HUS is supportive and chiefly involves dialysis for individuals with renal failure. Acute medical issues involve the management of renal failure and hypertension, the maintenance of fluid status in the face of renal failure, and the treatment of fever and catabolic status. Adult HUS and its underlying illnesses respond poorly to various forms of medical therapy.

Among the therapeutic options considered in adults are anticoagulation; antiplatelet or antioxidant agents; fibrinolytics; thrombolysis (with streptokinase); plasmapheresis and plasma exchange; and infusions of plasma, prostacyclin, or gamma globulin.[70, 71, 72] None of these approaches has been proven effective beyond excellent supportive care. Plasma manipulations do not appear to have the same degree of benefit in HUS as such manipulations have shown in TTP.[73] Among other forms of therapy that have been tried in adults, prednisone, azathioprine, vincristine, and intravenous immunoglobulin (IVIg) are the medications for which the evidence of efficacy is strongest.

Eculizumab

Eculizumab (Soliris) is the first treatment approved by the US Food and Drug Administration (FDA) (September, 2011) for adults and children with atypical hemolytic uremic syndrome (aHUS). Approval was based on data from adults and children who were resistant or intolerant to, or receiving, long-term plasma exchange/infusion. Data also included children (aged 2 mo to 17 y) who received eculizumab with or without prior plasma exchange/infusion. Eculizumab demonstrated significant improvement in platelet count from baseline (P = .0001). Thrombotic microangiopathy events were reduced, and maintained or improved kidney function was also reported.[74, 75, 76, 77]

Ravulizumab

Another monoclonal antibody against C5 component of the complement system is ravulizumab. In October 2019, FDA approved ravulizumab (Ultomiris) for the treatment of aHUS to inhibit complement-mediated thrombotic microangiopathy (TMA) in adult and pediatric patients aged 1 month and older.

Approved was based on data from 2 single-arm open-label studies that evaluated the efficacy of ravulizumab in patients with aHUS. Both ongoing pediatric (n=13) and adult (n=56) studies evaluated efficacy based on complete TMA response during the 26-week initial evaluation period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Findings from each study demonstrated a complete TMA response in 71% of children and 54% of adults during the initial 26-week treatment period. Additionally, ravulizumab treatment resulted in reduced thrombocytopenia in 93% of children and 84% of adults; reduced hemolysis in 86% of children and 77% of adults; and improved kidney function in 79% of children and 59% of adults.[78]

Antibiotics

The value of antibiotics has been debated. Antibiotics may be required where sepsis or lung infections complicate HUS, as in HUS associated with S pneumoniae infection. In 1 study, antibiotic treatment in the acute enteric stage of E coli enteritis increased the risk for HUS 17-fold.[36] A meta-analysis did not show such an effect. In 1 adult with E coli O157:H7 bacteremia and urinary tract infection who developed HUS, both renal and hematologic abnormalities promptly improved with antibiotic treatment. Antibiotics may be lifesaving in patients with S dysenteriae–related HUS if started early enough. The treatment of sepsis associated with S pneumoniae HUS is similarly important.

Transfusion

Blood transfusion is required in as many as 70–90% of children with postinfectious HUS, particularly those with hemorrhagic colitis. Platelet transfusion is necessary in about 30% of children with HUS.

Although some regard platelet transfusions as dangerous in TTP, as many as 30% of patients with HUS receive platelet transfusions in addition to other supportive therapies.

Management of blood pressure

Blood pressure support is required for individuals who develop septic shock. Shock occurs in more than 30% of individuals with S dysenteriae–related HUS and in some patients with sepsis due to S pneumoniae–related HUS.

Arterial hypertension develops in two thirds of patients and is often severe. Arterial hypertension may lead to cardiac failure and pulmonary edema.

Management with antihypertensives may be important in the management of HUS-associated posterior leukoencephalopathy.

Plasma treatment

Plasma administration and manipulations appear to be less beneficial in HUS than in TTP.

Plasma treatment has been particularly advocated in HIV-associated HUS and in HUS occurring as a postpartum complication. It has been used in sporadic idiopathic non–Stx-HUS; HUS as a complication of antineoplastic, antiplatelet, or immunosuppressive drugs; and in sporadic or familial HUS associated with abnormalities of complement pathway regulatory proteins, such as factor H, membrane cofactor protein (MCP), and factor I.

Anticoagulation

Anticoagulation, which is sometimes attempted in adults with HUS, entails risk in children because childhood HUS is frequently complicated by both bleeding and hypertension. Where tried, anticoagulation does not appear to be beneficial, even when combined with oral antiplatelet agents. Indeed, heparin therapy may significantly increase mortality;[79, 80] therefore, this approach is probably contraindicated.

Adsorption

Investigations have been undertaken to evaluate the effectiveness of administering preparations containing inert adsorptive surfaces that can bind circulating verocytotoxin and thereby prevent their attachment to endothelial surfaces, where they can cause injury. SYNSORB-pk ingestion was among the first approaches tried.[21] Despite initial enthusiasm, this approach appears to have been abandoned. Other similar preparations have also been evaluated, but none have been effective.[81]

About one third of patients become anuric. In combination with their catabolic state, severe acidemic uremia may develop. Renal failure usually persists for several weeks, and 30–50% of patients require dialysis.

Angiotensin-converting enzyme (ACE) inhibitors used in the treatment of hypertension appear to have a beneficial effect on renal outcomes of postinfectious Stx–E coli HUS.[82]

Other medical therapies

Trials of gamma globulin are under way, with promising preliminary results. Findings suggest the possibility of some benefit in children.

Azathioprine and vincristine are potent drugs with potential benefit in the management of HUS. Their use falls beyond the scope of this review. Oncologists or others familiar with the use of these drugs should be consulted to review the emerging data about safety and efficacy in HUS and to discuss the risks and principles of management before these agents are administered.

About 25% of patients with HUS who develop neurologic complications (eg, seizures, stroke, coma) may require intensive care.

A small study in Germany used immunoadsorption to rapidly ameliorate severe neurological complications in patients with E Coli 0104:H4-induced HUS.[83] Of the 12 patients enrolled, 10 had total neurological and renal function recovery.

Anticonvulsant therapy may be required to control seizures.

HUS occurring in association with tacrolimus occasionally responds to lowering the dose.

Pediatric or adult renal specialists should be consulted to manage renal failure.

Pediatric or adult rheumatologists should be consulted in cases of HUS associated with neoplasia.

Pediatric or adult hematologists may be consulted for the diagnosis and management of hematologic aspects of HUS.

Pediatric infectious disease specialists may be consulted for the diagnosis and management of associated infectious illnesses.

Pediatric gastroenterologists may be consulted for the management of associated gastroenterologic disease.

Special dietary consultation may be necessary to manage renal or gastroenterologic manifestations of HUS. In patients with renal failure, early reduction in protein intake appears to improve long-term renal outcomes.

Individuals who are shedding infectious agents that elaborate Stx or who may spread other contagions should be restricted, as appropriate for the particular infectious agent.

No other specific limitations on activities are needed, except as indicated by the severity of disease and the patient's need for support. Therefore, activities should be advanced as tolerated.

Monoclonal antibodies (eg, eculizumab, ravulizumab) have been approved by the FDA for treatment of aHUS to inhibit complement-mediated thrombotic microangiopathy. These agents have been shown to reduced thrombocytopenia and hemolysis, and to improve renal function.

Class Summary

Monoclonal antibodies that target C5 result in preventing formation of complement complex C5b-9, thereby preventing RBC hemolysis.

Eculizumab (Soliris)

Indicated for treatment of aHUS to inhibit complement-mediated thrombotic microangiopathy; effectiveness based on the effects on thrombotic microangiopathy and renal function.

Ravulizumab (Ravulizumab-cwvz, Ultomiris)

Indicated for treatment of aHUS to inhibit complement-mediated thrombotic microangiopathy; effectiveness based on the effects on thrombotic microangiopathy and renal function.

Support groups for individuals with HUS have been formed. A British example is Hemolytic Uremic Syndrome Help (HUSH). This group may be contacted at PO Box 1303, Loxley, Sheffield, England S6 6YL.

E coli–related HUS is a serious but almost entirely preventable disease.

Careful practices in slaughterhouses and the butcher shops can prevent the contamination of meat products.

Washing of other raw foodstuffs should substantially reduce risk of E coli entering the food chain.

Personal sanitation by food handlers reduces the risk of transferring E coli to foodstuffs, particularly raw meat.

Consumption of contaminated meat is the primary route by which children in developed nations acquire the organism.

If the aforementioned safeguards fail, adequate cooking of meat prevents children who are most subject to HUS from acquiring viable organisms.

Meat should be cooked to at least 70°C. Cooking that imparts a gray color to raw hamburger is not adequate.

E coli may also be acquired by bathing in contaminated lakes, rivers, or even swimming pools. This form of exposure may be more common in certain developing or impoverished areas of the world.

Although approximately 80–85% of patients who have acute renal failure with Stx-HUS recover function, 15–20% develop hypertension within 3–5 years after the onset of acute HUS.

Improved supportive therapy, including transfusion, dialysis, and careful management of fluids, electrolytes, and hypertension, has substantially reduced acute mortality from HUS.

Infants and children

The infantile form of HUS preceded by a viral prodrome, and usually associated with diarrhea, has a relatively good prognosis.

Childhood forms of HUS carried a 50% mortality risk half a century ago. Pooled data obtained since 1950 (chiefly consisting of E coli–related HUS) demonstrate that the overall risk for death or end-stage renal disease is about 12%, including 3–5% risk of death in the acute phase of illness. The inclusion of studies from a period prior to the development of current methods of neurologic and renal intensive care likely paint a poorer picture of outcome than is currently enjoyed by individuals with HUS.[84, 85, 3]

In children who develop HUS after a prodromal respiratory illness without GI disturbance, the prognosis is distinctly worse than that of children who develop HUS after a diarrheal prodrome.

Renal transplantation is necessary in severe HUS, which accounts for approximately 25% of all childhood cases.

Adults

Adult mortality in both the acute and chronic phases of illness are high, probably because adult HUS most often occurs as a complication of systemic illnesses that are more severe than those encountered in children with HUS.

Pooled data from 3476 cases of HUS followed up for a mean interval of 4.4 years showed a 12% risk of death or development of end-stage renal disease after the acute phase of HUS.

Risk factors for a worsened long-term outcome, particularly with E coli-related HUS, are the severity of the initial illness, the need for initial dialysis, and the presence of neurologic signs or complications.

S dysenteriae-related HUS poses a considerable risk of bacteremia or septic shock, DIC, and acute cortical necrosis of kidney. The overall mortality rate is at least 30%; the risk for end-stage renal disease is also high.

HUS-associated renal failure usually persists for several weeks.

About 30–50% of patients require dialysis, which indicates a worsened prognosis.[13]

Adult HUS, which constitutes a tiny minority of all cases of HUS, tend to result from a pathogenesis different from that of most childhood cases, and adult HUS may be relatively unresponsive to therapies effective in children.[12, 11]

Prognostic factors

Considerable interest is attached to the identification of reliable prognostic factors early in the course of HUS.

Such factors should be important in stratifying treatment groups to assess the effectiveness of various therapies.

Such factors might also permit the start of aggressive novel strategies early in the course of diseases with the poorest prognoses.

A review of 387 children with HUS greatly contributed to this important objective.[14]

• About 60% of 276 subjects tested had Stx-E coli–related HUS. The age at onset, leukocyte count, and evidence of CNS involvement did not help in predicting the time to recovery.

• The combined absence of prodromal diarrhea and/or of Stx toxin in stool was associated with worsened outcome. Only 34% of individuals who lacked both features recovered normal renal function, as compared with 65-76% of those who had 1 or both features.

• For 118 patients followed up after postdiarrheal HUS with kidney transplantation, the recurrence rate was 0.8%; recurrence caused graft loss in a single patient.

• Stx-E coli–related HUS had the lowest risk for graft loss of any HUS associated with end-stage renal disease.

• For 63 patients with nondiarrheal HUS who had a kidney transplant without factor H deficiency, 21% had recurrence with graft loss.

• Nearly 30% of 7 transplanted nondiarrheal cases with factor H gene mutations recurred.

In transplanted cases without factor H deficiency or genetic defect, low C3 levels may enhance risk for recurrence with graft loss.

Tacrolimus-associated HUS improves in only 45% of patients despite their receiving various combinations of treatment, including anticoagulation, antiplatelet therapy, dialysis, or plasma exchange, even when tacrolimus is replaced with cyclosporine.

Graft loss occurs in 25% of such cases and even in cases that receive a new allograft, HUS-related death occurs in approximately one third. If associated liver failure is present, 60% die.[56]

As disappointing as the various statistics might be, they are better than the recurrence risk for heritable adult HUS, which is about 60% for both autosomal recessive and autosomal dominant forms.

In nonindustrialized nations, dysentery due to S dysenteriae distinctly worsens the patient's prognosis for ensuing HUS. However, in industrialized nations, HUS occurring after a respiratory prodrome (which is often due to Diplococcus pneumoniae infection) distinctly worsens the prognosis.

Education about risks associated with exposure to Stx-elaborating infectious agents, such as E coli or S dysenteriae should reduce the risk for postinfectious HUS.