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Overview of hemolytic uremic syndrome in children

Overview of hemolytic uremic syndrome in children
Literature review current through: Jan 2024.
This topic last updated: Dec 01, 2022.

INTRODUCTION — The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury [1]. It is one of the main causes of acute kidney injury in children. Although all pediatric cases exhibit the classic triad of findings that define HUS, there are a number of various etiologies of HUS that result in differences in presentation, management, and outcome.

This topic will provide an overview of the different causes, evaluation, and initial management of HUS in children. HUS in adults is discussed separately. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

DEFINITIONS

Thrombotic microangiopathy describes a specific pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. It includes several primary disorders including thrombotic thrombocytopenic purpura, Shiga toxin-mediated HUS and complement-mediated HUS or TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Classification — In the past, HUS had been divided into diarrhea-positive and diarrhea-negative HUS. The former, also referred to as typical HUS, primarily resulted from Shiga toxin-producing Escherichia coli (STEC) infections, and less frequently from Shigella dysenteriae type 1 infection. All other causes of HUS were referred to as atypical HUS or assigned to the diarrhea-negative HUS, even though some patients with non-STEC-associated HUS also presented with diarrhea.

However, ongoing research has provided a better understanding of the underlying causes of HUS, especially those due to genetic mutations in the alternative pathway of complement [2,3]. As a result, the following classification has been developed based on pathophysiological considerations and triggering factors [4]:

Hereditary causes of HUS [5]:

Complement gene mutations (see "Complement-mediated hemolytic uremic syndrome in children")

Inborn errors of cobalamin C metabolism (see 'Cobalamin C' below)

Diacylglycerol kinase epsilon (DGKE) gene mutations (see 'Coagulation pathway' below)

Acquired causes of HUS:

Infection:

-Shiga toxin-producing Escherichia coli (STEC) (see "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children")

-Streptococcus pneumoniae (see 'Streptococcus pneumoniae' below)

-Human immunodeficiency viral infection

Autoantibodies to complement factors

Drug toxicity, particularly in patients with cancer or solid organ transplant recipients

Rare occurrences in pregnant patients or those with autoimmune disorders (eg, systemic lupus erythematous)

EPIDEMIOLOGY — Shiga toxin-producing E. coli hemolytic uremic syndrome (STEC HUS) is the most common cause of pediatric HUS, accounting for 90 percent of cases [6]. It primarily affects children under the age of five years. In the United States and Western Europe, the reported annual incidence of STEC HUS is approximately two to three per 100,000 children less than five years of age [1]. The remaining childhood HUS cases are generally divided into primary HUS caused by complement dysregulation, with an estimated prevalence of seven per one million children in Europe [7], and secondary HUS caused by pneumococcal infection [8,9].

HEREDITARY HUS

Complement gene mutations — Complement-mediated hemolytic uremic syndrome (HUS) is primarily due to mutations in the genes for complement proteins C3, CD46 (previously known as membrane cofactor protein [MCP]), and complement factors H, B, and I. It is estimated that approximately 50 percent of non-Shiga toxin-producing E. coli (STEC) cases result from mutations in these genes [10,11]. The clinical manifestation, diagnosis, evaluation, and management of complement-mediated HUS are discussed in detail separately. (See "Complement-mediated hemolytic uremic syndrome in children".)

Mutations in non-complement genes

Coagulation pathway — Mutations in genes coding for proteins involved in the coagulation pathway have been reported in patients with atypical HUS.

DGKE mutations – Recessive mutations in DGKE (encoding diacylglycerol kinase epsilon) were identified in nine unrelated kindreds with atypical HUS [12]. The authors suggest loss of DGKE function results in a prothrombotic state as DGKE inactivates arachidonic acid-containing diacylglycerols (DAG), an activator of protein kinase C, which promotes thrombosis. In one consanguineous family with a novel truncating mutation in DGKE (p.K101X), patients showed significant complement activation and low C3 levels. Aggressive plasma infusion therapy controlled systemic symptoms and prevented renal failure [13]. Another study of four patients with DGKE mutations found that three of them also carried heterozygous mutations in thrombomodulin (THBD) or C3 [14]. Plasma therapy was effective in two patients with DGKE and THBD mutations, while plasma infusions and eculizumab were effective in the patient with DGKE and C3 mutations.

PLG mutations – A comprehensive genetic analysis of complement and coagulation genes in patients with atypical HUS detected not only mutations in complement regulatory genes in over one-half of the patients, but also novel mutations in several genes in the coagulation system, particularly ones in the PLG gene, which encodes plasminogen [15]. Plasminogen deficiency results in a decreased degradation of thrombi, promoting thrombosis. The authors speculate that thrombi in small vessels cause mechanical damage to erythrocytes, releasing peptides (such as heme), or overexpression of other unidentified factors that activate the complement system, resulting in endothelial cell damage and HUS.

Thrombomodulin mutations – Thrombomodulin is a cofactor in the initiation of the protein C anticoagulant pathway, which accelerates the inactivation of C3b by factor I. In a study of 152 patients with atypical HUS (ie, non-Shiga toxin-producing E. coli [STEC]-HUS), seven patients had six different heterozygous mutations of the THBD gene [16]. In vitro studies demonstrated that the mutated THBD gene resulted in dysregulation of the complement system because it was less effective than normal thrombomodulin in converting C3b to its inactive form iC3b. (See "Complement-mediated hemolytic uremic syndrome in children".)

Cobalamin C — A majority of patients with mutations in the MMACHC (MethylMalonic ACiduria and Homocystinuria type C) gene, which results in methylmalonic aciduria and homocystinuria, are diagnosed with atypical HUS. Mutations of MMACHC result in functional cobalamin (vitamin B12) deficiency. Cobalamin is a cofactor for both methionine-synthase, which transforms homocysteine to methionine, and methyl-transferase, which is involved in the conversion of methylmalonyl CoA to succinyl CoA [17]. As a result, patients with CblC mutations have a functional defect of both methylmalonyl CoA mutase and methionine synthase resulting in methylmalonic acidemia with homocystinuria.

Clinical manifestations are characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and a diagnosis of atypical HUS in a majority of patients [18]. The first symptoms, which are nonspecific, may occur in the neonatal period and consist of anorexia, vomiting, failure to thrive, hypotonia, seizures, and lethargy [19,20]. In these patients, symptoms of HUS are typically severe and observed beyond infancy. The prognosis is poor due to multiorgan failure. Later-onset forms presenting with psychiatric/behavior problems and myelopathy have been reported with better prognosis [21-23]. The diagnosis, which should be suspected in the presence of megaloblastosis, is made by amino acid and organic acid chromatography that reveal a marked increase of homocysteine and a low level of methionine in the plasma, and very high rates of urinary excretion of homocysteine and methylmalonic acid and by genetic testing of the MMACHC gene. Therapy should be started as soon as possible and includes parenteral administration of hydroxocobalamin, betaine, carnitine supplements, and leucovorin calcium, as early initiation of treatment improves prognosis [20,24,25]. (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia'.)

ACQUIRED INFECTIOUS-INDUCED HUS

Shiga toxin-producing E. coli (STEC) — As noted above, Shiga toxin-producing E. coli (STEC) hemolytic uremic syndrome (HUS) accounts for over 90 percent of cases of HUS in children. It is generally preceded by a prodromal illness with abdominal pain, vomiting, and diarrhea, which is usually bloody (figure 1). The clinical manifestations, diagnosis, evaluation, and management of STEC HUS are discussed in detail separately. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

Streptococcus pneumoniae

Epidemiology — Pneumococcal-associated hemolytic uremic syndrome (HUS) has been reported in 5 to 15 percent of all childhood cases of HUS, and in 40 percent of non-STEC HUS cases [8,9]. Pneumococcal-associated HUS occurs mainly in infants and young children, and rarely affects adults. The incidence of HUS after pneumococcal disease is about 0.5 percent. An analysis of the Kids' Inpatient Database reported pneumococcal-associated HUS accounted for 4.6 percent of all HUS discharges, 0.7 percent of all invasive pneumococcal disease discharges, and 3 percent of all discharges for complicated pneumonia in the United States in 2009 [26].

After the introduction of the seven-valent pneumococcal conjugate vaccine (PCV) in 2000, the incidence of cases due to serotypes 3, 6A, 12F, and 19A, which were not covered in the vaccine, has increased [9,27-29]. In one retrospective review from a tertiary center in Australia of cases from 1997 to 2016, pneumococcal infection was identified in 11 of 66 cases of HUS, and 19A serotype was detected in six of the patients including those who received the 13-valent PCV, which covers 19A serotype [28]. In the United Kingdom, the incidence of pneumococcal-associated HUS decreased since the 2010 introduction of the 13-valent pneumococcal vaccine and cases were more likely to be due to serotypes not covered in the 13-valent pneumococcal vaccine [29]. (See "Streptococcus pneumoniae: Microbiology and pathogenesis of infection".)

Pathogenesis — Although the pathogenesis of pneumococcal-associated HUS is uncertain [30]. Proposed mechanisms include:

Increased expression of the pneumococci surface proteins (PspC) that bind plasminogen. This results in plasmin generation resulting in fibrinogen degradation and complement activation and leads to endothelial cell damage [31].

Complement-mediated HUS – Case reports found complement activation and consumption in some children with pneumococcal-associated HUS [32,33]. Further evaluation identified risk haplotypes and, in one individual, a pathologic complement variant that may have contributed to development of HUS triggered by pneumococcal infection in these susceptible individuals. (See "Complement-mediated hemolytic uremic syndrome in children".)

An older hypothesis centered on a role for N-acetyl neuraminidase (sialidase) released during pneumococcal infection, which cleaves sialic acid on the cell glycocalyx. It has been proposed that desialylation by neuraminidase results in exposing Thomsen-Friedenreich antigen (T antigen) on red blood cells, platelets and glomeruli resulting in polyagglutination of patients' red cells and hemolysis [34]. However, subsequent observations argue against a pathogenetic role for the T antigen [34,35]. An alternative proposal is desialylation by neuraminidase disrupting complement factor H (complement regulatory protein) binding sites, which would result in the inability of complement factor B to bind with C3 convertase resulting in unregulated complement activation similar to what is seen in patients with hereditary HUS due to complement gene mutations. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Pathogenesis'.)

Clinical manifestations — Patients with pneumococcal-associated HUS typically present with pneumonia (70 percent), which is usually accompanied by empyema or effusion [9,36]. Meningitis is the second most common presentation, occurring in approximately 20 to 30 percent of cases. Other pneumococcal infections associated with HUS include isolated bacteremia, sinusitis, and otitis media.

Children with pneumococcal-associated HUS compared with those with STEC HUS are younger (median age between one and two years of age), have more severe initial disease with longer duration of oliguria and thrombocytopenia, and require more transfusions [37]. In two case series, 70 to 80 percent of patients underwent dialysis therapy [9,36]. Extra-renal complications are also common and include pancreatitis, purpura fulminans, cholecystitis, thrombosis, cardiac dysfunction, and hearing loss [36,37].

Management — The management of pneumococcal-associated HUS is generally supportive (see 'Treatment' below). In addition, empiric antibiotic therapy for invasive pneumococcal disease should be initiated while awaiting culture results and sensitivities. Because of the increasing prevalence of antibiotic-resistant strains of pneumococcus, and generally due to the severity of the underlying infection, coverage should include both vancomycin and a broad-spectrum cephalosporin (eg, cefotaxime or ceftriaxone). (See "Pneumococcal pneumonia in children", section on 'Empiric therapy'.)

Many experts in the field avoid plasma infusion or plasmapheresis because of concerns that plasma, which contains natural IgM class antibodies to the T antigen, may aggravate hemolysis. However, this has not been proven, and seems unlikely given that these antibodies are active at 4°C and not at 37°C (body temperature). It has also been suggested that blood products should be washed to prevent administration of additional anti-T antigen antibodies [37].

It is uncertain whether eculizumab, a monoclonal antibody C5 inhibitor, is beneficial. In one of the previously mentioned case reports of complement activation in children with pneumococcal-associated HUS, eculizumab appeared to be beneficial in two of the three patients who received this therapy [33]. In the third patient, eculizumab was discontinued due to severe infection. The use of eculizumab in patients with complement-mediated HUS is discussed separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)'.)

Outcome — Patients with pneumococcal-associated HUS have a higher mortality and long-term morbidity rate than those with STEC disease. In a review of the literature of pneumococcal-associated cases of HUS through 2008, the mean mortality rate was 12 percent, 10 percent of patients progressed to end-stage renal disease (ESRD), and 16 percent survived with chronic kidney disease [38].

The cause of death is typically due to the underlying infection. In a case series of 43 patients from the United Kingdom, there were five deaths that were due to meningitis (n = 3), sepsis (n = 1), and pulmonary emboli while on hemodialysis (n = 1) [9].

HIV infection — HUS or thrombotic thrombocytopenic purpura (TTP) has been observed in patients, including children, with human immunodeficiency virus (HIV) infection [39]. The majority of affected patients progress to end-stage renal disease (ESRD). The incidence of HUS associated HIV infection has decreased after the introduction of retroviral therapies. HIV-associated TTP and HUS are discussed separately.

H1N1 influenza A — Several case reports have been published concerning the development of HUS in patients with H1N1 influenza A infection [40-48]. However, it should be remembered that Streptococcus pneumoniae infection is a frequent secondary bacterial infection during influenza A infections. Thus, HUS may have resulted from pneumococcal disease rather than influenza infection [49]. In some patients, an underlying complement defect was observed and infection due to influenza A was considered a trigger for complement-mediated HUS [45,48,50]. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Pathogenesis'.)

HUS has also been reported in association with Entamoeba histolytica intestinal infection and with mycoplasma pneumoniae infections [51,52].

ACQUIRED NON-INFECTIOUS CAUSES — Non-infectious secondary causes of hemolytic uremic syndrome (HUS) have been reported in the following settings [53]:

Antibodies to complement factors

Adverse effects of medications

Complications of specific conditions including pregnancy, systemic lupus erythematosus and antiphospholipid syndrome

Antibody to complement factors — Antibodies to complement factors B and H have been implicated as an acquired cause of HUS. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement antibodies'.)

Medications — Several medications have been implicated as causes of acquired thrombotic microangiopathy.

Calcineurin inhibitors – HUS has occurred in solid organ transplant recipients treated with calcineurin inhibitors (ie, cyclosporine or tacrolimus). Thrombotic microangiopathy (TMA)/HUS usually occurs during the first few months post-transplantation, a time when high doses of calcineurin inhibitors are being administered. Thrombotic microangiopathy with multiorgan injury may occur after hematopoietic stem cell transplantation [54,55]. (See "Thrombotic microangiopathy after kidney transplantation", section on 'Epidemiology of de novo TMA'.)

Cytotoxic drugs – Among children with cancer who are treated with cytotoxic drugs, such as mitomycin, bleomycin, gemcitabine, or cisplatin. Vascular endothelial growth factor (VEGF) inhibitors used as antiangiogenic therapy may be responsible for thrombotic microangiopathy/HUS [55,56]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

Others – Other implicated medications include quinine, interferon beta, and oral contraceptives. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Quinine'.)

Other conditions — TMA/HUS has been reported in patients with the following conditions:

Antiphospholipid syndrome – In children with systemic lupus erythematosus and those with a severe antiphospholipid syndrome. (See "Antiphospholipid syndrome and the kidney", section on 'Kidney manifestations of antiphospholipid syndrome'.)

Pregnancy – Pregnancy-HUS occurs mainly in the postpartum period and is most likely due to complement-mediated HUS triggered by pregnancy [57-59]. Its treatment therefore should include the use of the anti-C5 humanized monoclonal antibody eculizumab [60]. (See "Thrombocytopenia in pregnancy", section on 'Thrombotic microangiopathy (TMA)' and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Other disorders that present with MAHA and thrombocytopenia'.)

DIAGNOSIS — The diagnosis of hemolytic uremic syndrome (HUS) is clinically based on the presence of the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, which is established by laboratory tests that include a complete blood count (eg, hemoglobin and platelet count) and peripheral blood smear, renal functions studies, and urinalysis.

Hemolytic anemia – The microangiopathic hemolytic anemia is established by a hemoglobin level less than 8 g/dL with a negative Coomb's test and a peripheral blood smear demonstrating a large number of schistocytes (up to 10 percent of red cells) and helmet cells (picture 1 and picture 2). (See "Overview of hemolytic anemias in children" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Microangiopathic hemolytic anemia (MAHA)'.)

Thrombocytopenia – Thrombocytopenia is characterized by a platelet count below 140,000/mm3 and is usually approximately 40,000/mm3. Despite the low platelet count, there is typically no purpura or active bleeding. The degree of thrombocytopenia is unrelated to the severity of renal dysfunction.

Acute kidney injury − The severity of renal involvement ranges from hematuria and proteinuria to severe renal failure (usually identified by abnormally elevated serum creatinine and blood urea nitrogen [BUN] levels) and oligoanuria. Severe renal failure occurs in one-half of cases. Hypertension is common, particularly after the administration of excess fluids or blood transfusions. Most patients have microscopic hematuria on urinalysis, although macroscopic hematuria may be observed. Red blood cell casts are occasionally seen, but are not a typical feature.

Further evaluation including additional laboratory tests is needed to determine the underlying cause of HUS and to differentiate HUS from other disorders [5]. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential for hemolytic uremic syndrome (HUS) includes several conditions that may also present with concomitant findings of anemia, thrombocytopenia, and acute kidney injury.

Disseminated intravascular coagulation (DIC) – DIC is distinguished from HUS by the presence of abnormal coagulation studies, including prolonged prothrombin time and activated partial thromboplastin time, and elevated levels of fibrin degradation products and D-dimer. In general, DIC occurs in pediatric patients who are seriously ill, such as those in septic shock or who have undergone massive tissue injury or breakdown. (See "Disseminated intravascular coagulation in infants and children".)

Thrombotic thrombocytopenic purpura (TTP) – TTP is due to deficient activity of the Von Willebrand factor cleaving protease caused by mutations of the ADAMTS13 gene or to the presence of acquired anti-ADAMTS13 antibodies. Pediatric TTP is rare, and affected children usually present at birth with hemolytic anemia and thrombocytopenia. Renal involvement often occurs later in life and has a progressive course. TTP is distinguished from HUS by abnormally low ADAMTS13 activity. (See "Diagnosis of immune TTP", section on 'Reduced ADAMTS13 activity'.)

Systemic vasculitis – Patients with vasculitis typically have other systemic symptoms (such as arthralgias and rash) and do not have a prodromal diarrheal illness. In addition, the characteristic neurologic involvement in patients with vasculitis is peripheral (eg, mononeuritis multiplex) rather than central.

EVALUATION TO IDENTIFY UNDERLYING ETIOLOGY — Once the diagnosis of hemolytic uremic syndrome (HUS) is made, evaluation is focused on identifying the underlying cause of HUS and also differentiating HUS from other conditions that have similar presentations, as this may affect management decisions.

Historical clues include the following:

Concurrent history of HUS in a family member is suggestive of an infectious etiology, especially Shiga toxin-producing E. coli (STEC) HUS.

Past (noncurrent) history of HUS in a family member is suggestive of a genetic complement-mediated cause of HUS. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Clinical manifestations'.)

Previous episode of HUS is suggestive of complement-mediated HUS. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Clinical manifestations'.)

History of possible exposure to STEC is suggestive of STEC HUS. This includes ingestion of undercooked ground beef or other foods that may be fecally contaminated by cattle, swimming in a potentially contaminated lake or pool, or contact with farm animals. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Transmission'.)

Review of current medications to identify any drug that may be associated with HUS. (See 'Medications' above.)

Review of other medical conditions that may be associated with HUS (eg, solid organ recipient, malignancy, or pregnancy). (See 'Medications' above and 'Other conditions' above.)

The following laboratory studies are often obtained at the same time as initial testing, which establishes the diagnosis of HUS (ie, complete blood count and peripheral smear, renal function studies, and urinalysis). (See 'Diagnosis' above.)

Coagulation studies including prothrombin time, and activated partial thromboplastin time to distinguish HUS from disseminated intravascular coagulation (DIC).

Screening for Shiga toxin-producing bacterial strains to differentiate STEC HUS from other forms of HUS. This includes testing for Shiga toxins (eg, ELISA) in the stool, stool cultures, and serologic testing for IgM and anti-lipopolysaccharide antibodies against the most frequent STEC serotypes. In addition, polymerase chain reaction (PCR) testing for Shiga toxin genes can also be performed. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Testing for STEC infection'.)

In the setting of concurrent serious infection, cultures of blood, and other tissues/organs as clinically indicated (eg, sputum, urine, stool, and cerebral spinal fluid), may detect an underlying infectious etiology for HUS, such as pneumococcal-associated HUS. In addition, critically ill patients from septic shock may also develop DIC, which may present with similar manifestations to HUS.

Based on the above evaluation, the underlying cause of HUS may be apparent. However, in some cases, further evaluation may be needed to identify the underlying cause and also to differentiate HUS from other conditions with similar manifestations [5].

Initial complement studies include measuring complement factors 3 and 4 (C3 and C4). Low serum C3 and C4 may indicate complement-mediated HUS. However, missense mutations of complement proteins typically result in functional impairment without affecting complement protein levels. Other complement studies include serum levels of thrombomodulin and complement factors H, B, and I; CD46 leukocyte expression; and testing for antibodies to complement factor H. Definitive diagnosis of genetic complement-mediated HUS requires complement genotyping. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Diagnosis'.)

Serology for human immunodeficiency virus (HIV), and testing for systemic lupus erythematous (antinuclear antibodies and antiphospholipid antibodies). (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Diagnosis' and "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Diagnostic test performance in early HIV infection'.)

In some patients, in whom the diagnosis is uncertain, a renal biopsy may be performed. Renal histology typically demonstrates glomerular thrombotic microangiopathy in patients with STEC HUS, characterized by a thickening of the capillary walls, with a double-contour appearance due to a widening of the subendothelial space. In patients with complement-mediated HUS, the renal histological lesion is most often arteriolar thrombotic microangiopathy, perhaps accounting for the markedly increased blood pressure seen in these [61].

Screening for defective cobalamine metabolism in neonates who present with HUS. (See 'Acquired non-infectious causes' above.)

Assessing ADAMTS 13 function to differentiate HUS from thrombotic thrombocytopenic purpura (TTP). (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Thrombotic thrombocytopenic purpura'.)

TREATMENT

Supportive care — The initial management of hemolytic uremic syndrome (HUS) is supportive and is based on observational data from studies of patients with Shiga toxin-producing E. coli (STEC) HUS. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Supportive therapy'.)

Red blood cell transfusions for anemia when clinically indicated (eg, hemoglobin level reaches 6 to 7 g/dL or hematocrit <18 percent).

Platelet transfusion for patients who have significant clinical bleeding.

Appropriate fluid and electrolyte management to maintain adequate intravascular volume and correct/avoid electrolyte abnormalities.

Stopping nephrotoxic drugs or those that are implicated in the etiology of HUS.

Initiation of dialysis therapy in patients with symptomatic uremia, azotemia (defined as a blood urea nitrogen >80 mg/dL [29 mmol/L]), severe fluid overload, or electrolyte abnormality that is refractory to medical therapy.

Provision of adequate nutrition.

Additional measures — The use of other interventions is dependent on the underlying cause of HUS and is discussed separately.

STEC HUS (see "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Directed intervention for STEC-hemolytic uremic syndrome')

Complement-mediated HUS (see "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment')

Pneumococcal-associated HUS (see 'Management' above)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemolytic uremic syndrome in children" and "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)f

SUMMARY AND RECOMMENDATIONS

Introduction – Hemolytic uremic syndrome (HUS) is defined by the concurrent characteristic triad of HUS: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Although all pediatric cases exhibit the classic triad of findings that define HUS, there are a number of various etiologies of HUS that result in differences in presentation, management, and outcome.

Classification – A classification system is used to describe the different etiologies of HUS and is divided into primary and secondary causes. (See 'Classification' above.)

Primary causes include disorders that result in complement dysregulation and rarely mutations of proteins in the coagulation pathway and cobalamin metabolism (See 'Hereditary HUS' above.)

-Complement-mediated HUS accounts for 5 to 10 percent of HUS pediatric cases and is primarily due to mutations in the genes for complement proteins C3, CD46 (previously known as membrane cofactor protein [MCP]), and complement factors H, I, and B. The clinical manifestations, diagnosis, evaluation, and management of complement-mediated HUS are discussed in detail separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Genetic variants' and "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement antibodies'.)

Secondary causes include infectious etiologies (eg, Shiga toxin-producing Escherichia coli [STEC] and Pneumococcus). Other rare causes include antibody formation due to complement proteins, drug toxicity in pediatric solid organ recipients and children with cancer; adverse effect of quinine, and oral contraceptives; and complications seen in patients with systemic lupus erythematosus and antiphospholipid syndrome, or pregnancy. (See 'Acquired infectious-induced HUS' above and 'Acquired non-infectious causes' above.)

-Shiga toxin-producing Escherichia coli (STEC) HUS accounts for over 90 percent of pediatric HUS cases. It is generally preceded by a prodromal illness with abdominal pain, vomiting, and diarrhea (figure 1). The clinical manifestations, diagnosis, evaluation, and management of STEC-HUS are discussed in detail separately. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

-Pneumococcal-associated HUS is the second most common infectious cause of HUS. It occurs mainly in young children and infants who usually present with pneumonia. Most patients undergo dialysis treatment, and extra-renal complications are common. There is approximately a 10 percent mortality rate, and another 10 percent of patients with pneumococcal-associated HUS progress to end-stage kidney disease (ESKD). (See 'Streptococcus pneumoniae' above.)

Diagnosis – The diagnosis of HUS is clinically based on the presence of the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The diagnosis is established by laboratory tests that include a complete blood count (eg, hemoglobin/hematocrit and platelet count) and peripheral blood smear, renal functions studies (serum creatinine), and urinalysis. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis for HUS includes conditions that present with concomitant findings of anemia, thrombocytopenia, and acute kidney injury. These include disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and inborn errors of vitamin B12. (See 'Differential diagnosis' above.)

Evaluation – Further evaluation is needed to determine the underlying cause of HUS and to differentiate HUS from other disorders. (See 'Evaluation to identify underlying etiology' above.)

History – Historical clues are useful in suggesting STEC disease (history of STEC exposure or concurrent episode of HUS in family member), complement-mediated HUS (noncurrent family history of HUS or previous history of HUS), or a secondary cause (eg, history of a predisposing medical condition or drug).

Laboratory testing – Additional laboratory studies include coagulation studies, screening for STEC, cultures of blood and other pertinent bodily fluids, complement studies, and cobalamin studies.

Treatment

Supportive care – The following supportive measures are provided to all children with HUS based on observational data from studies of patients with STEC-HUS (See 'Supportive care' above.)

-Red blood cell transfusions for anemia when the hemoglobin level reaches 6 to 7 g/dL or hematocrit <18 percent.

-Platelet transfusion for patients who have significant clinical bleeding or if an invasive procedure is required.

-Appropriate fluid and electrolyte management to maintain adequate intravascular volume and correct/avoid electrolyte abnormalities.

-Stopping nephrotoxic drugs or those that are implicated in the etiology of HUS.

-Initiation of kidney replacement therapy in patients with symptomatic uremia, azotemia (defined as a blood urea nitrogen >80 mg/dL [29 mmol/L]), severe fluid overload, or electrolyte abnormality that is refractory to medical therapy. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy".)

-Provision of adequate nutrition.

Additional measures – The use of additional interventions is dependent on the underlying cause of HUS. (See 'Additional measures' above.).

STEC HUS. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Directed intervention for STEC-hemolytic uremic syndrome'.)

Complement-mediated HUS. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Treatment'.)

Pneumococcal-associated HUS – We suggest initial empiric antibiotic therapy in patients with pneumococcal-associated HUS (Grade 2C). Due to the increasing prevalence of antibiotic-resistant strains of pneumococcus, we suggest that coverage should include both vancomycin and a broad-spectrum cephalosporins (eg, cefotaxime or ceftriaxone) while awaiting culture results and sensitivities (Grade 2C). (See 'Management' above.)

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Topic 89549 Version 38.0

References

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