Hemolytic uremic syndrome (HUS) is the common cause of acute kidney injury in children. It is induced by various clinical situations such as several infections, medications, metabolic disease, bone marrow transplantation, and genetic abnormalities in the complement and coagulation pathway. HUS is characterized by the clinical triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury, and belongs to the subgroup of thrombotic microangiopathy (TMA).^1,2,3)

Shiga toxin-producing Escherichia coli (STEC) is a famous bacterium causing HUS, called STEC HUS, which typically presents after hemorrhagic gastroenteritis. STEC HUS is the most common form of HUS in children. Among the other causes of HUS, complement-mediated genetic HUS, also called as atypical HUS (aHUS), is one of the most important causes and has been extensively studied recently. Thrombotic thrombocytopenic purpura (TTP) is an acquired or congenital disease caused by a severe deficiency (generally below 10%) in plasma ADAMTS13 activity.⁴⁾ TTP is no longer classified as a variant of aHUS; however, clinicians have to distinguish between TTP and aHUS. This review does not include more details on TTP.

Eculizumab is a newly developed drug for blocking the terminal complement pathway, which is generally used in paroxysmal nocturnal hemoglobinuria and aHUS. In this review, aHUS, eculizumab, and the Korean guideline for aHUS will be discussed.

aHUS is a rare, chronic, and devastating disorder caused by uncontrolled complement activation leading to endothelial injury, platelet aggregation, MAHA, and progressive damages to vital organs, leading to stroke, heart attack, renal failure, and death. Initially, aHUS meant any HUS not caused by STEC. However, as several clinical conditions other than STEC, such as pneumococcal infection, cobalamin deficiency, autoimmune disease, and bone marrow transplantation, have been known to lead to HUS, the term aHUS is generally used these days to define HUS without coexisting disease or specific infection, which is mostly a disease of complement alternative pathway overactivation.^5,6) Furthermore, mutations in coagulation pathway genes other than the complement pathway genes have been found to be associated with aHUS. Thus, aHUS can be divided into several groups according to its etiology, including mutations in the complement alternative pathway gene, anticomplement factor H autoantibody, mutations in coagulation pathway genes, and combinations thereof.⁷⁾

Historically, several genes causing aHUS had been identified, including complement factor H (CFH), complement factor B (CFB), complement factor I (CFI), complement 3 (C3), and membrane cofactor protein (MCP). As mentioned before, mutations in coagulation pathway genes such as thrombomodulin (THBD), diacylglycerol kinase-ε (DGKE), and plasminogen (PLG) can induce aHUS.⁷⁾ Generally, genetic abnormalities in aHUS have been detected in about 60% of patients.¹⁾ Anti-CFH antibody production results in an acquired form of aHUS, the pathogenesis of which is a kind of autoimmune disease. Interestingly, production of this autoantibody is associated with genetic susceptibility. Anti-CFH antibody is frequently produced in association with homozygous deletion of CFH-related protein 1 gene (CFHR1), which encodes CFH-related protein 1.⁸⁾ Additionally, 2 cases of anti-CFI antibody in aHUS have been reported; however, its clinical significance needs further investigation.⁹⁾

Recently, a Korean pediatric series of aHUS was published, which investigated 51 patients with aHUS and reported the results of genetic testing. From this multicenter cohort, 15 patients (29.4%) had anti-CFH antibody, which is the most common cause of aHUS. However, in 49% of patients, the investigators failed to find specific genetic mutations. Among the detected mutations, mutations in CFH were the most common (6 of 11 patients, 54.5%). A comparison of etiology in pediatric aHUS between a Korean and a French cohort study, which is one of the largest studies worldwide, is shown in Table 1; however, the French cohort did not include DGKE mutation.^5,7)

Although mortality and renal outcomes in aHUS vary according to the involvement of each gene, about 20% of children progressed to end-stage renal disease (ESRD) or died at the first episode or within 1 month after onset, and 30% within 1 year. Relapse occurred in approximately half of the patients who survived the first episode and did not reach ESRD.^5,10) The mortality rate was significantly higher in children than in adult patients.⁵⁾ Children having CFH mutations demonstrated the most severe manifestations and outcomes, with a risk of death or ESRD of about 30% at the first episode. On the other hand, children with MCP mutations had the best prognosis, with a long-term risk of ESRD of 25% at a median follow-up of 17.8 years despite frequent relapses.^5,11)

Although TMA processes are induced mainly in the kidney, other organs can be involved. That is, aHUS can affect multiple vital organs and tissues besides the kidneys, such as the cardiovascular, gastrointestinal, pulmonary, visual, and central nervous systems. The most common extrarenal involvements during the acute stage is central nervous system involvements, with symptoms such as seizure, decreased mentality, visual problems, and comatose. In a large aHUS registry study in Turkey published in 2017, 42% (61 of 146) of patients had extrarenal manifestations.¹²⁾ aHUS is known to be a microvascular disease. However, macrovascular symptoms including cerebral artery stenosis and peripheral gangrene have been reported.¹³⁾

When children with the clinical triad of MAHA, thrombocytopenia, and acute kidney injury present to the clinic, HUS can be easily diagnosed. Next, differential diagnosis for HUS has very important clinical implications for evaluation, prognosis, and treatment. Through medical history taking and physical examination, HUS secondary to a coexisting condition such as bone marrow transplantation, pneumococcal infection, and other infections can be usually eliminated. Pneumococcal HUS mostly presents with symptoms of invasive infection, including pneumonia with empyema, meningitis, and bacteremia in young children aged <2 years.¹⁴⁾ TTP, which is another group in TMA, can be excluded according to ADMATS13 activity, and cobalamin deficiency can be also ruled out on the basis of serum homocysteine and methionine levels. Blood samples for ADMATS13 activity should be taken before the initiation of plasma therapy.

STEC infection should be excluded as soon as possible in a patient with HUS by means of culture procedures or real-time polymerase chain reaction. Negative results are observed in about 30% of patients who had been clinically classified as having STEC HUS, frequently owing to delayed stool collection.¹⁵⁾ Therefore, it sometimes becomes difficult to diagnose or exclude STEC HUS. Typically, about 80% of children with STEC HUS have bloody diarrhea and STEC HUS accounts for most TMA cases in children. Therefore, STEC HUS should be preferentially presumed in children with common gastrointestinal symptoms.¹⁶⁾

aHUS can be suspected in HUS patients without a history of diarrhea or bloody stool. However, even if children with HUS have gastrointestinal symptoms, aHUS other than STEC HUS should be suspected in the presence of the following conditions: very early onset age (<6 months), no definite onset time, recurrent or familial HUS, and low C3 level.¹⁷⁾

Genetic testing for complement abnormalities is recommended for aHUS patients especially in those with relapse, familial history and de novo posttransplantation HUS, as well as in those scheduled for renal transplantation for aHUS.^17,18) Additionally, confirming aHUS requires genetic testing; however, failing to find causative genetic mutations does not exclude the diagnosis of aHUS because specific genetic mutations still could not be detected in 40%–50% of aHUS patients.

Eculizumab is a humanized monoclonal anti-C5 antibody that inhibits C5 cleavage to C5a and C5b, and ultimately prevents the formation of the membrane attack complex. Therefore, the terminal complement pathway could be blocked (Fig. 1).²⁴⁾ It has been successfully used in paroxysmal nocturnal hemoglobinuria for more than 10 years.²⁵⁾ Theoretically, blocking the terminal complement pathway by using eculizumab can improve aHUS, the pathogenesis of which is based on uncontrolled complement activation; moreover, eculizumab can reduce inflammation, endothelial damage, thrombosis, and kidney injury.²⁶⁾ Several clinical trials from Alexion Pharmaceuticals have shown the efficacy of eculizumab in inducing hematologic normalization, and in improving renal function in adults and children with aHUS.^27,28,29) A recent prospective trial conducted in patients younger than 18 years demonstrated that eculizumab achieved complete TMA response, defined as hematologic normalization (platelet count ≥150×10⁹/L, lactate dehydrogenase levels lower than the upper limit of normal) and renal improvement (≥25% decrease in serum creatinine level from baseline) in 64% of patients after 26 weeks, and was well tolerated. Moreover, most patients showed improvement in all hematologic and renal parameters.³⁰⁾ A retrospective study by Fakhouri et al.³¹⁾ revealed that eculizumab was more effective than plasma therapy used in a historical control group. It is also important that early initiation of eculizumab (within 6 days) improves renal function better than a later initiation. When eculizumab is initiated as soon as possible after aHUS manifestation, greater improvement of renal function can be expected.²⁸⁾

Eculizumab is now officially accepted for the treatment of aHUS in many countries, including European countries, the United States, and Japan. In Korea, very few children with aHUS are treated with eculizumab, although the process of setting health insurance details between pharmaceuticals and the government is yet unfinished. Eculizumab is administered as an intravenous infusion, and the recommended dose and treatment schedule in children with aHUS from the product label is shown in Table 2.

All guidelines recommend urgent eculizumab, if available, as initial therapy, and lifelong eculizumab therapy is generally recommended, especially for kidney transplant recipients with CFH mutation and for those with a <20 mL/min/1.73 m² glomerular filtration rate.^16,17,18) Several trials for the discontinuation of eculizumab have been conducted because lifelong therapy has some problems, including potent serious meningococcal infection, drug adverse reaction, recurrent vascular access, and high cost. However, discontinuation of eculizumab may increase the risk of further clinical manifestation of aHUS and is currently not supported by evidence.^32,33) On the contrary, some authors suggested careful discontinuation with aggressive home monitoring for early detection of relapse, especially in cases with MCP mutations, homozygous CFHR3/R1 deletions, anti-CFH antibodies, no identifiable mutations, and CFI mutations.^34,35)

The major adverse effect of eculizumab is meningococcal infection because defense against this bacterium depends on the lytic terminal complement complex, which is blocked by eculizumab. Therefore, prevention through vaccination and antibiotic administration is essential.¹⁸⁾ All routine vaccinations including live vaccines in children receiving eculizumab can be done as in primary complement deficiency or asplenia.³⁶⁾

Recently, the Korean practical guidelines for aHUS was developed by the Korean aHUS Working Group, which is composed of physicians representing the Korean Society of Pediatric Nephrology, Korean Society of Nephrology, Korean Society of Hematology, and Korean Society on Thrombosis and Hemostasis. All recommendations in this guideline are listed in Table 3.¹⁷⁾

aHUS is a critical disease that leads to irreversible organ damage, especially the kidney, if adequate treatment is not performed. Traditional treatments have not shown sufficient and lasting effectiveness. There are expectations for the newly developed eculizumab, and thus far, eculizumab is giving a lot of hope and further research is needed.