Hemolytic-Uremic Syndrome

The Swiss pediatric hematologist Conrad von Gasser and colleagues first described hemolytic-uremic syndrome (HUS) in 1955. ^[6] In 1983, Karmali and colleagues reported finding a toxin produced by specific strains of Escherichia coli in the stools of children with HUS. This toxin was lethal to Vero cells (a line of kidney cells isolated from the African green monkey), and so was termed verotoxin. Also in 1983, O’Brien and colleagues purified a lethal toxin from the enteropathogenic E coli O157:H7 strain that structurally resembled that of Shigella dysenteriae type 1, and termed it Shiga-like toxin (both terms honor the Japanese bacteriologist Kiyoshi Shiga, who in 1898 discovered S dysenteriae and its toxin as the cause of dysentery). ^{[7, 8]}

The term Shiga-like toxin was replaced with the term Shiga toxin when the two were found to be identical. E coli strains produce two types of Shiga toxins. Shiga toxin type 1 (Stx1) is identical to the toxin produced by Shigella spp or differs by only one amino acid. Stx2 is structurally and functionally similar to Stx1 but immunologically distinct; it shares approximately 50% homology with Stx1 but the two are not cross-neutralized with heterologous antibodies. Stx2 is strongly associated with hemorrhagic colitis and HUS. In addition, there are 10 subtypes of Stx1 and Stx2, each of which is divided into variants, which have different pathogenicity. The capacity of certain E coli strains to produce Shiga toxins appears to have resulted from transduction of the responsible genes by bacteriophages. ^{[7, 8]}

In 1988, Wardle described HUS and TTP as distinct entities, but in 1987, Remuzzi suggested that these two conditions are varied expressions of the same entity. Confirmation that HUS and TTP are clearly different diseases, despite their clinical similarities, followed the discovery of the von Willebrand factor (vWF)–cleaving metalloprotease ADAMTS13 (A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13). Researchers subsequently recognized the etiologic link between TTP and congenital deficiencies of ADAMTS13 or formation of acquired antibodies to ADAMTS13. ^{[9, 10, 11, 12]}

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

HUS is classified into two main categories, depending on whether it is associated with Shiga toxin (Stx) or not. ^{[13, 14]}  

Typical (Stx–associated) HUS

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

In Asia and Africa, typical HUS is often associated with Stx-producing Shigella dysenteriae serotype 1. In North America and Western Europe, 70% of Stx-associated HUS cases are secondary to E coli serotype O157:H7. Other E coli serotypes implicated include the following ^[15] :

• O111:H8
• O103:H2
• O121
• O145
• O26
• O113
• O104:H4

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

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

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

Atypical (non–Stx-associated) HUS

Non–Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. As the name indicates, non–Stx-HUS does not result from infection by Stx-producing bacteria. Unlike HUS caused by enterohemorrhagic E coli, which occurs principally in summer, atypical HUS may occur year-round without a gastrointestinal prodrome (D- HUS). Atypical HUS is a complement-mediated thrombotic microangiopathy. 

Non–Stx-HUS may occur at all ages but is most frequent in adults and occurs without prodromal diarrhea (D- HUS). It can occur in sporadic cases or in families. The familial form is associated with genetic abnormalities of the complement regulatory proteins.

Overall, patients with non–Stx-HUS have a poor outcome, with as many as 50% progressing to end-stage renal disease (ESRD) or irreversible brain damage. Up to 25% of patients die during the acute phase.

Sporadic non–Stx-associated HUS

Various triggers for sporadic non-Stx–HUS have been identified, including the following:

• Nonenteric infections
• Viruses
• Drugs
• Malignancies
• Transplantation
• Pregnancy ^[16]
• In rare cases, other underlying medical conditions (eg, antiphospholipid syndrome [APL], systemic lupus erythematosus [SLE])

Streptococcus pneumoniae infection accounts for 40% of all causes of non-Stx–HUS and 4.7% of all causes of HUS in children in the United States. The pathogenesis in these cases appears to have several mechanisms. For example, S pneumoniae strains isolated from patients with pneumococcal-induced HUS have been shown to bind high levels of human plasminogen, which when activated to yield plasmin causes damage to endothelial cells, with exposure of the underlying matrix; this leads to thrombosis. ^{[17, 18]} Clinically, pneumococcal-induced HUS is usually severe, with respiratory distress, neurologic involvement, and coma, with a mortality rate of up to 50%.

Familial non–Stx-associated HUS

Familial non–Stx-HUS accounts for less than 3% of all cases of HUS. Both autosomal dominant and autosomal recessive forms of inheritance are observed. Autosomal recessive HUS often occurs early in childhood. The prognosis is poor, recurrences are frequent, and the mortality rate is 60-70%. Autosomal dominant HUS often occurs in adults, who also have a poor prognosis, with a 50-90% risk of death or ESRD.

Data suggest that familial non–Stx-HUS results from genetic abnormalities in the complement regulatory proteins, including C3, factor H, factor B, factor I, and CD46 (membrane cofactor protein, MCP). Factor H appears to be particularly important. ^{[19, 20, 21, 22]}

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

Fifty HF1 mutations have been described in 80 patients who had familial (36 patients) and sporadic (44 patients) forms of non–Stx-HUS. The mutation frequency is 40% in the familial form and 13-17% in the sporadic form. One patient with Stx-HUS who did not recover kidney function was noted to have a mutation in exon 23 of the factor H gene. ^[21]

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

Hemolytic-uremic syndrome (HUS) predominantly occurs in infants and children after prodromal diarrhea. In summer epidemics, the disease may be related to infectious causes.

Bacterial infections may include the following:

• Shigella dysenteriae
• E coli
• Salmonella typhi
• Campylobacter jejuni
• Yersinia pseudotuberculosis
• Neisseria meningitidis
• Streptococcus pneumoniae
• Legionella pneumophila
• Mycoplasma species

Viral infections may include the following:

• Human immunodeficiency virus (HIV)
• Coxsackievirus
• Echovirus
• Influenza virus
• Epstein-Barr virus
• Herpes simplex virus
• Norovirus ^[23]

Fungal infections can include Aspergillus fumigatus.

Vaccinations may include the following:

• Influenza triple-antigen vaccine
• Typhoid-paratyphoid A and B (TAB) vaccine
• Polio vaccine
• mRNA-based COVID-19 vaccine ^[24]

Causes of the secondary or sporadic form may include the following:

• Pregnancy and puerperium
• Cancers (chiefly mucin-producing adenocarcinomas)
• Drugs
• Malignant hypertension
• Collagen-vascular disorder (eg, systemic lupus erythematosus [SLE], antiphospholipid antibody syndrome) - It is possible to have both true HUS and a lupus anticoagulant, but in most patients, the thrombocytopenia, microangiopathic hemolytic, and kidney disease are due to antiphospholipid antibodies rather than true HUS
• Primary glomerulopathies
• Transplantation (eg, of kidney, bone marrow): This can be de novo or recurrent. It occurs in 5-15% of kidney transplant patients who receive cyclosporine and in about 1% of patients who receive tacrolimus.
• Allogeneic hematopoietic stem cell transplantation (HSCT)

Pregnancy-associated HUS occasionally develops as a complication of preeclampsia. Patients may progress to full-blown hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Postpartum HUS usually occurs within 3 months of delivery. The prognosis is poor, with a 50-60% mortality rate, and residual kidney dysfunction and hypertension occur in most patients.

Drugs implicated in causing non–Stx-HUS are as follows:

• Quinine - Most common cause of drug-induced TTP-HUS and has been confirmed to cause recurrent disease with recurrent exposure; chronic kidney disease appears to be common following quinine-induced HUS ^[25]

• Anticancer agents: These include mitomycin, cisplatin, bleomycin, and gemcitabine. The risk for HUS after mitomycin therapy is 2-10%, and onset may be delayed, occurring almost 1 year after the patient starts treatment. The prognosis is poor, with a 75% mortality rate at 4 months.

• Immunotherapeutic agents: Examples are cyclosporine, tacrolimus, OKT3, and interferon.

• Antiplatelet agents: Examples are ticlopidine and clopidogrel.

• Oral contraceptives

Posttransplantation HUS is reported with increasing frequency and may be primary (de novo) or recurrent. It is often a consequence of the use of calcineurin inhibitors or of humoral (C4b positive) rejection. This condition occurs in 5-15% of kidney transplant patients treated with cyclosporine and in about 1% of patients treated with tacrolimus.

An immunodeficiency-related cause includes thymic dysplasia.

Familial causes account for 3% of all cases of HUS, and both autosomal dominant and autosomal recessive forms of inheritance have been reported. Autosomal recessive HUS occurs in childhood, and patients have a poor prognosis with frequent recurrences and a mortality rate of 60-70%. Autosomal dominant HUS occurs mostly in adults, who have a poor prognosis; the cumulative incidence of death or ESRD is 50-90%.

No cause is identified in about 50% of all cases of sporadic non–Stx HUS.

United States

Stx-HUS occurs with a frequency of 0.5-2.1 cases per 100,000 population per year, with a peak incidence in children younger than 5 years, in whom the incidence is 6.1 cases per 100,000 population per year. In 2015, 274 cases of HUS were reported in the United States, 122 of them in children 1-4 years of age. ^[26]

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

International

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

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

Race-, Sex-, and Age-related Demographics

HUS occurs infrequently in blacks. Both sexes are affected equally with HUS.

HUS occurs mainly in young children; however, adolescents and adults are not exempt. In young children, spontaneous recovery is common. In adults, the probability of recovery is low when HUS is associated with severe hypertension.

For Stx-HUS, acute rkidney injury occurs in 55-70% of patients; up to 70-85% recover kidney function.

For non–Stx-HUS, patients have poor outcomes, with up to 50% progressing to ESRD or irreversible brain damage. As many as 25% die during the acute phase.

Complications of HUS may include the following:

• Kidney failure
• Stroke
• Coma
• Seizures
• Bleeding

Schuppner et al reported that in an outbreak of Stx-associated HUS resulting from E coli O104:H4 infections in Germany in 2011, neurological complications occurred in 48-100% of adults in different patient groups. On follow-up conducted 19 months after disease onset in 31 patients, 22 still suffered from symptoms such as fatigue, headache, and attention deficits. On neuropsychological assessment, 61% of patients scored borderline pathological or lower. Secondary decline of cognitive function was found in about one-quarter of the patients. ^[27]

Stx-HUS prognosis is as follows:

• Acute kidney injury occurs in 55-70% of patients, but 85% recover kdiney function with supportive therapy.

• Approximately 15-20% of children may develop hypertension 3-5 years after the onset of disease.

• Recurrence with kidney allografting is 10% or lower.

Ardissino et al developed an early prognostic index for Stx-HUS outcome that uses the combination of hemoglobin (Hb) and serum creatinine (sCr) concentrations at onset of illness. The formula is as follows:

                       Hb (in g/dL) + (sCr [in mg/dL] × 2)

On testing of the index in a cohort of of 197 Stx-HUS patients, 8% of those with a score > 13 died or entered a permanent vegetative state, compared with 0% of those with a score of ≤ 13. ^[28]

Alconcher et al reported that the best independent predictors of mortality in children with Stx-HUS were central nervous system (CNS) involvement, hyponatremia (serum sodium ≤ 128 meq/L) and elevated hemoglobin concentration (≥ 10.8 g/dL). ^[29]

Non–Stx-HUS prognosis is as follows:

• Patients collectively have a poor prognosis, and as many as 50-60% progress to ESRD (50% in those with the sporadic forms and 60% in those with the familial forms) or develop irreversible brain damage. About 25% die during the acute phase.

• The recurrence rate in patients receiving kidney transplants is as high as 50%, with graft loss occurring in more than 90% who have recurrence. Recurrence rates are higher in patients with HF1 mutation.

Factors predictive of poor prognosis are as follows:

• Non–Stx-HUS
• Prolonged oliguria or anuria
• Severe hypertension (especially delayed onset of hypertension)
• Involvement of medium-sized arteries
• Severity of CNS symptoms
• Persistent consumption of clotting factors
• Extensive glomerular involvement (>80%)
• Age older than 5 years

In a retrospective study of 323 adult kidney transplant recipients with HUS and 121,311 transplant recipients with other kidney diseases, Santos and colleagues found that while mortality did not significantly differ between groups in the 5 years following transplantation, death-censored graft loss occurred twice as often (hazard ratio 2.05) in patients whose native kidney disease was HUS than in other transplant recipients. HUS patients with post-transplant recurrence had a 5-year graft loss rate significantly higher than that of patients without recurrence (graft survival 14.7% vs 77.4%, P< 0.001). ^[30]

Advise patients to avoid eating raw or partially cooked meat. Improperly cooked or contaminated meat is a potential source of E coli O157:H7. Educate patients on the proper treatment of drinking water. Communities must make adequate efforts to ensure proper treatment and monitoring of drinking water. Educate patients about proper hygienic measures, especially in cattle fields and farms.

For patient education information, see Blood in the Urine, and Acute Kidney Failure.