Version May 2024
INTRODUCTION — Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury [1]. The most common cause of HUS is due to Shiga toxin-producing Escherichia coli (STEC). Research over the last 20 years has shown that complement dysregulation accounts for most of the non-STEC cases of HUS. This discovery has had a major impact on identifying the underlying cause of familial HUS, and on the management of these patients, who historically have had a poor prognosis.
The clinical manifestation, diagnosis, and management of complement-mediated HUS will be reviewed here. An overview of HUS and topics on the clinical manifestations, diagnosis, and management of STEC-HUS in children are found separately. (See "Overview of hemolytic uremic syndrome in children" and "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".)
Complement-mediated thrombotic microangiopathy is also discussed elsewhere. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Causes of CM-TMA'.)
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 TMA/HUS [5]:
•Complement gene mutations (see 'Genetic variants' below)
•Inborn errors of cobalamin C metabolism
•Diacylglycerol kinase epsilon (DGKE) gene mutations (see "Overview of hemolytic uremic syndrome in children", section on 'Coagulation pathway')
●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 "Overview of hemolytic uremic syndrome in children", section on 'Streptococcus pneumoniae')
-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 erythematosus)
EPIDEMIOLOGY — Complement-mediated HUS is a relatively rare disorder with an estimated prevalence of seven per one million children in Europe [6]. Most complement-mediated HUS cases are due to gene mutations of complement factors [7-9]. Antibodies to complement proteins have been implicated in the etiology of 6 to 10 percent of patients with complement-mediated HUS [10]. In addition, patients may have concurrent genetic mutations and antibodies to complement proteins [11].
Genetic complement disorders — Variants in the following identified genes that encode complement proteins appear to account for at least 50 to 60 percent of non-Shiga toxin-producing E. coli (STEC) HUS cases [7,8,12-15]. The reported relative frequency of each affected gene for non-STEC-HUS cases is also listed:
●Complement factor H (CFH, 20 to 30 percent)
●CD46, previously known as membrane cofactor protein (5 to 15 percent)
●Complement factor I (CFI, 4 to 10 percent)
●Complement factor 3 (C3, 2 to 10 percent)
●Complement factor B (CFB, 1 to 4 percent)
●Thrombomodulin gene (THBD, 3 to 5 percent)
It is likely that the percent of noninfectious HUS cases due to a complement disorder will rise with ongoing research identifying new gene variants. As an example, a genetic analysis of 400 patients with atypical HUS (aHUS) identified VTN, which encodes vitronectin, an inhibitor of the terminal complement pathway, as a novel gene associated with HUS [15].
In addition, a significant number of patients with complement-mediated HUS have variants of more than one complement protein [2,7,10,16]. It is important to stress that the penetrance of the disease is low, as less than 20 percent of family members carrying the same variant as the patient with complement-mediated HUS will be affected with the disease [17]. The risk is higher in the siblings and the offspring of patients than in parents. Moreover, rare variants in the complement genes with minor allele frequencies (MAFs) of <1 and <0.1 percent are present in 12 and 3.7 percent of healthy individuals, respectively. Therefore, genetic counselling in aHUS requires the input of trained geneticists and experts who have a comprehensive view of complement biology [18]. (See 'Factor H' below.)
PATHOGENESIS — The complement proteins associated with complement-mediated HUS are components of the alternative complement pathway. HUS results from a loss-of-function variant in a regulatory gene (CFH, CFI, or CD46) or a gain-of-function variant in an effector gene (CFB or C3). The proposed mechanism for the development of HUS is a trigger event, such as infection or pregnancy, in a susceptible individual with a gene variant(s) or antibodies to complement proteins, which leads to uninhibited continuous activation of the alternative pathway resulting in the formation of the membrane attack complex (MAC) [2,12,19]. This causes renal endothelium damage leading to activation of the coagulations cascade and thrombotic microangiopathy. (See "Complement pathways", section on 'Alternative pathway'.)
Data from an animal study suggest that C5 activation is important in the pathogenesis of HUS, thus supporting the use of eculizumab, a humanized monoclonal antibody to C5 [20]. (See 'Complement blockade (eculizumab)' below.)
COMPLEMENT ANTIBODIES — Complement factor H (CFH) antibodies of the IgG class have been reported in approximately 8 to 10 percent of patients with atypical HUS (ie, non-Shiga toxin-producing E. coli [STEC]-HUS) [21-27]. These antibodies detected by enzyme-linked immunosorbent assay (ELISA) interfere with the binding of CFH to the C3 convertase and are associated with a defective CFH-dependent cell protection [28]. Gastrointestinal symptoms (diarrhea and vomiting) are common as well as relapses, which typically occur within the first two years after initial presentation [21,29].
A study of 308 cases of atypical HUS (Newcastle cohort) reported the presence of CFH antibodies in 13 of 142 screened patients (9.2 percent) [25]. Most of these patients also had homozygous or compound heterozygous deletion of CFHR1 and/or CFHR3 and/or CFHR4 genes, suggesting that this deletion has a pathogenetic role in the development of anti-CFH antibodies [21,23,25,30,31]. Variants in other complement genes (CFH, complement factors I and B, CD46, and C3) also were identified in a minority of patients [25]. These findings suggest that in some patients, multiple "hits" to the complement system may be necessary for the clinical presentation of complement-mediated HUS [25,32].
A study of 186 cases of atypical HUS reported the presence of autoantibodies to factor H of the IgM class in 7 cases (3.8 percent), with a higher frequency in patients with atypical HUS following bone marrow transplantation [33]. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1.
GENETIC VARIANTS
Factor H — Variants of the complement factor H (CFH) gene, which encodes a regulatory protein in the alternative complement pathway, and CFH-related proteins (CFHR) are the most frequently identified genetic abnormalities seen in patients with complement-mediated HUS [9,34]. CFH in conjunction with complement factor I (CFI) competes with complement factor B (CFB) for C3b binding and accelerates C3 convertase decay. Over 100 variants of CFH have been reported, most of which are missense variants. Not all variants affect the levels of CFH and C3 [35]. In these patients, variants generally affect the C-terminal region, which is important for binding to C3b, glucosaminoglycans, heparin, and endothelial cells [36,37]. Other variants are located throughout the gene and are associated with low levels of CFH antigen.
The interpretation of sequence variants (which includes CFH variants) is challenging for clinicians as noted by a joint consensus recommendation of the American College of Medical Genetics (ACMG) and Genomics and the Association for Molecular Pathology [38]. In one report, 105 CFH missense variants were functionally characterized, of which 79 were novel [35]. Almost two-thirds of these novel variants were functionally indistinguishable from wild-type FH protein and therefore were classified as benign according to the ACMG criteria. Most of these benign variants are located in the N-terminal and midregions of FH, whereas most C-terminal variants are pathogenic. In this study, allele frequency was not a useful indicator of pathogenicity since 2.3 percent of the general population bear one rare CFH variant with an allele frequency <0.1 percent. Carriers of pathogenic CFH variants were younger at diagnosis and had more severe aHUS with more frequent recurrences than carriers of benign CFH variants. This study highlights the great value of functional assays to appropriately assess the pathogenicity of CFH variants.
CFH gene variants have been associated with both autosomal recessive and dominant forms of HUS [39-45]. Patients with homozygous variants have very low serum levels of CFH antigen, low serum C3 and CFB antigen levels, and a low CH50. However, most patients are heterozygous for the variant and have normal or only slightly decreased serum CFH and/or C3 levels. As a result, normal factor H and C3 levels do not exclude the presence of a CFH variant. Interestingly, kidney survival is higher in patients with low CFH levels compared with those with normal levels of CFH. (See "Overview and clinical assessment of the complement system".)
Although several studies have reported that HUS associated with CFH variants usually presents during infancy or early childhood [39-41,46-49], results from a French study showed that 25 of 59 patients with CFH variants initially presented after 20 years of age [14]. The disease either may be sporadic or clearly associated with a family history of disease. Severe hypertension is frequently observed. Hemolytic anemia is marked at disease onset and during relapses, with haptoglobin levels remaining low during the course of the disease.
Patients with CFH variants have the worst outcome of all the patients with complement-mediated HUS. The natural course of this disease results in 60 to 70 percent of patients progressing to end-stage kidney disease (ESKD) or death within one year of presentation [34,50]. In addition, there is a high rate of recurrent disease in patients who undergo kidney transplantation. (See 'Kidney transplantation' below.)
CD46 — Variants of the complement regulatory protein CD46 gene, previously known as membrane cofactor protein (MCP) [51], have also been implicated in familial HUS [34,52-54]. CD46 is a cofactor of CFI in the degradation of C3b and C4b. The aberrant protein either results in decreased cell surface levels of CD46 (most common) or an impaired ability to control alternative pathway complement activation on host cells [55]. HUS associated with CD46 deficiency is characterized by onset in early childhood, a favorable kidney outcome in most patients, frequent relapses, and a low rate of recurrence in the kidney allograft [56].
Factor I — Variants of CFI, the cofactor for CD46 and factor H, are also associated with HUS [50,57-59]. CFI is a serine protease, which cleaves C3b and C4b in the presence of CFH and CD46. Most patients have heterozygous CFI variants, which result in either a quantitative or qualitative defect of the protein [57,58]. The prognosis of patients with HUS associated with CFI mutations is intermediate between those with HUS associated with CD46 and those with CFH mutations. As an example, in two cohort studies, 50 to 60 percent of patients progressed to ESKD or died within two years of presentation [50,59], and in one of the studies, 30 percent of patients recovered from the initial presentation without disease recurrences [59]. Of note, in one of the cohort studies, 8 of 23 patients had an additional known genetic risk factor for HUS (ie, variant of CD46, CFH, C3, or CFB) [59]. Recurrent HUS occurs in 45 to 80 percent of patients, resulting in graft loss.
C3 — Heterozygous C3 variants resulting in persistently low C3 levels have been identified in patients with HUS [60-62]. These variants are primarily located in the binding regions of C3b that interact with CFH, CD46, and complement receptor 1, and result in dysregulation of the alternative complement pathway [60]. Patients with C3 variants typically develop severe disease, with one-half to two-thirds of patients progressing to ESKD within the first year following presentation. Recurrent disease is common in patients following kidney transplantation. In addition, there is an increase in the incidence of at-risk CFH and CD46 haplotypes for HUS in these patients.
Factor B — Gain of function variants of CFB, which either enhances the formation or delays the inactivation of C3bBb convertase, have been reported in 1 to 3 percent of cases of complement-mediated HUS [63,64]. Progression to ESKD occurs in 70 percent of patients. In the four reported cases of kidney transplantation, all four reported graft failure because of HUS recurrence.
Thrombomodulin — 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 variants of the THBD gene [65]. In vitro studies demonstrated that the mutated THBD resulted in dysregulation of the complement system because it was less effective than normal thrombomodulin in converting C3b to its inactive form iC3b. (See "Overview of hemostasis", section on 'Activated protein C and protein S'.)
CLINICAL MANIFESTATIONS
Presentation — In all cases of HUS, clinical presentation includes the concurrent characteristic findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury due to complement activation. Other clinical findings include neurologic abnormalities (eg, seizures), gastrointestinal complications (eg, hemorrhage, pancreatitis), respiratory complications (respiratory failure, acute respiratory distress syndrome), and cardiac complications (eg, cardiomyopathy) [66,67].
Data from clinical registries have provided additional clinical information for complement-mediated HUS regarding age of presentation, penetrance of gene mutation for affected families, clinical triggers for acute episodes of complement activation, and complement levels [14,34,50,68]. However, data are often inconsistent as there is heterogeneity in the study population, and in the genes and coding sequences used for screening.
●Adult presentation ‒ Although earlier studies suggested that HUS due to genetic variants of the complement proteins was primarily a pediatric disorder [34,50,68], a French cohort of 214 patients reported that more than half of their cohort presented as adults (58 percent) [14]. In this study, genetic variants were demonstrated in 60 percent of the patients. However, in children with complement-mediated HUS, presentation typically occurred in young patients less than two years of age. Several studies also suggest that patients younger than six months who present with HUS are more likely to have complement-mediated disease than Shiga toxin-producing E. coli (STEC)-HUS.
It remains unclear what effect, if any, specific variants have on the age of presentation. As noted above, initial studies had reported that most patients with complement factor H (CFH) variants present as infants or young children [39-41,46-49]. However, in the French study, 40 percent of patients with CFH variants presented after 20 years of age [14]. It does appear that patients with CD46 variants (complement regulatory protein CD46) are more likely to present during childhood.
●Low penetrance ‒ A family history of HUS is obtained in approximately 20 to 30 percent of patients [1,14]. The penetrance of the disease is only approximately 50 percent, so that only half of the family members with the genetic mutation will manifest the disease. It has been shown that for the disease to manifest itself, other factors, such as a trigger (eg, infection) that activates complement, are typically present [8,34]. In other cases, multiple hits, such as the additional presence of antibodies to complement factor B or another genetic mutation, appear to increase the likelihood of disease expression.
●Antecedent trigger ‒ In most patients (70 to 80 percent), there is an antecedent trigger event that is thought to play a role in complement activation. In most patients, the trigger is an upper respiratory infection, however, a diarrheal prodrome has been observed in approximately one-quarter of patients. Pregnancy has also been reported as a trigger event in adolescents and adult women. (See 'Pathogenesis' above.)
●Previous episode of HUS.
●Severe hypertension.
Clinical course and outcome — The clinical course and outcome vary depending on the affected complement component [34,50]. For example, patients with variants of the gene for CFH have a poor prognosis as most patients with this gene defect progress to end-stage kidney disease (ESKD) or death within the first year of presentation. In contrast, few patients harboring variants that affect CD46 progress to ESKD, although relapse is common [50]. (See 'Genetic variants' above.)
EVALUATION — The diagnostic evaluation that differentiates complement-mediated HUS from other conditions with similar presentations, such as other forms of HUS, thrombocytopenia thrombotic purpura (TTP), and inborn errors of vitamin B12, is discussed in detail elsewhere. (See "Overview of hemolytic uremic syndrome in children", section on 'Evaluation to identify underlying etiology' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
In summary, studies that may differentiate complement-mediated HUS from other disorders include [5]:
●Screening for Shiga toxin-producing E. coli (STEC) to differentiate complement-mediated disease from STEC-HUS includes testing for Shiga toxins (eg, enzyme-linked immunosorbent assays [ELISA]) in the stool, stool cultures, and serologic testing for immunoglobulin M (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 the blood, sputum, or cerebrospinal or pleural fluid may demonstrate an underlying serious pneumococcal infection, which is indicative of a diagnosis of pneumococcal-associated HUS rather than complement-mediated disease. (See "Overview of hemolytic uremic syndrome in children", section on 'Streptococcus pneumoniae'.)
●Complement levels ‒ A combination of abnormal complement tests, especially a decrease in both CFB and CH50 may be an important clue to support the diagnosis of complement-mediated HUS [69]. However, there is considerable overlap with normative values, and complement testing lacks sufficient sensitivity and specificity for diagnostic purposes.
•Patients with C3 and factor B variants and those with antibodies to factor H typically have low plasma C3 levels but normal C4 levels.
•In patients with other variants (eg, variants to factor H, CD46, and thrombomodulin [THBD]), plasma C3 levels may be decreased or remain normal [2,70].
●In some patients, in whom the diagnosis is uncertain, a kidney biopsy may be performed. Complement-mediated HUS is characterized by arteriolar thrombotic microangiopathy (image 1), perhaps accounting for the markedly increased blood pressure seen in some patients [71]. In contrast, most cases of STEC-HUS tend to have more glomerular than arteriolar involvement (image 2).
●Other studies that may be performed include assessing ADAMTS13 function and screening for defective cobalamine metabolism. (See "Overview of hemolytic uremic syndrome in children", section on 'Differential diagnosis' and "Diagnosis of immune TTP", section on 'Reduced ADAMTS13 activity'.)
●Diagnostic testing for complement dysregulation is performed for children with any of the following [5] (see 'Diagnosis' below):
•Previous episode of HUS
•Family history of HUS
•Patient is less than one year of age and without evidence of a secondary cause (eg, pneumococcal or STEC infection)
•Episode of HUS during pregnancy or postpartum without evidence of a secondary cause
DIAGNOSIS — The diagnosis of complement-mediated HUS is based upon the classical triad microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, plus demonstration of complement dysregulation, either due to gene variants of complement proteins or antibodies to complement factors.
●When to perform testing – Diagnostic testing for complement-mediated HUS is appropriate in patients with HUS who have any of the following [5,72]:
•Positive family history of HUS
•Previous episode of HUS
•Early presentation (ie, within the first six to twelve months of age)
•Presentation during pregnancy or postpartum
•Severe clinical course with no identified underlying cause (see "Overview of hemolytic uremic syndrome in children", section on 'Evaluation to identify underlying etiology')
●Tests to perform – Diagnostic testing for complement-mediated HUS includes complement genotyping and testing for antibodies to complement proteins. The minimum set of genes that should be evaluated includes CFH, CD46, CFI, C3, CFB, THBD, CFHR1, CFHR5, and DGKE [2]. Because of the frequent concurrence of genetic risk factors, testing should also include genotyping for the risk haplotypes CFH-H3 and MCP.
Testing for antibodies and genetic variants may not be available in all settings. Laboratories that offer complement genotyping for complement-mediated HUS can be found from the National Center for Biotechnology Information website.
As noted above, although many patients with complement-mediated HUS will have low C3 or C4 levels, normal plasma levels of C3, C4, CFB, CFH, and CFI do not exclude the diagnosis of complement-mediated HUS. (See 'Evaluation' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of complement-mediated HUS includes HUS due to other causes and conditions that also present concomitantly with anemia, thrombocytopenia, and acute kidney injury. Further evaluation including history and additional laboratory tests may differentiate complement-mediated HUS from these other disorders. (See "Overview of hemolytic uremic syndrome in children", section on 'Evaluation to identify underlying etiology' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
Other forms of HUS
●Shiga toxin-producing E. coli (STEC)-HUS accounts for 90 percent of pediatric cases of HUS. It is differentiated from complement-mediated HUS based on demonstrating a recent exposure to STEC. Screening for STEC-HUS is discussed separately. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Testing for STEC infection'.)
●Pneumococcal-associated HUS occurs in a patient with evidence of a pneumococcal infection (eg, pneumonia, sepsis, or meningitis), which is confirmed by a positive culture of blood and/or other pertinent tissues. (See "Overview of hemolytic uremic syndrome in children", section on 'Streptococcus pneumoniae'.)
●Other rare noninfectious secondary causes of HUS include drug toxicity, especially in patients with cancer or in bone marrow or solid organ transplant recipients, or are associated with pregnancy or autoimmune disease. It remains uncertain whether these clinical settings may act as triggers for activation of the complement pathway in susceptible individuals with genetic variants in complement proteins. (See "Overview of hemolytic uremic syndrome in children", section on 'Acquired non-infectious causes'.)
●Inborn error of cobalamin C metabolism is a rare cause of HUS, especially in young infants (one to three months of age). The diagnosis is suggested by amino acid and organic acid chromatography findings of a marked increase of homocysteine and a low level of methionine in the plasma, and a very high urinary excretion of homocysteine and methylmalonic acid. (See "Overview of hemolytic uremic syndrome in children", section on 'Acquired non-infectious causes'.)
Thrombotic thrombocytopenic purpura — Thrombotic thrombocytopenic purpura (TTP) is due to deficient activity of the Von Willebrand factor cleaving protease. Pediatric TTP is rare and is usually due to variants of the ADAMTS13 gene. Affected children usually present at birth with hemolytic anemia and thrombocytopenia. Kidney involvement often occurs later in life and has a progressive course. TTP is distinguished from HUS by abnormally low ADAMTS13 activity. The mainstay of initial treatment for TTP is plasma exchange, as untreated patients progress to kidney failure and further neurologic deterioration, and are at risk for cardiac ischemia and death. (See "Diagnosis of immune TTP", section on 'Reduced ADAMTS13 activity' and "Hereditary thrombotic thrombocytopenic purpura (hTTP)" and "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange'.)
Perhaps a further challenge in differentiating TTP from HUS is that partial ADAMTS13 deficiency may occur in patients with complement-mediated HUS. This was illustrated in a study of patients with complement-mediated HUS based on clinical criteria that reported several of the 13 patients with variant in complement genes also had mild to moderated reduction of ADAMTS13 activity due to single nucleotide polymorphism of the ADAMTS13 gene [73]. The authors concluded that partial ADAMTS13 deficiency may occur in patients with complement-mediated HUS, and ADAMTS13 activity should be evaluated in affected patients.
TREATMENT
Overview — The initial management of complement-mediated HUS is supportive and similar to the approach used for Shiga toxin-associated HUS. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Supportive therapy'.)
In addition to supportive care measures, the management of complement-mediated HUS may include [2]:
●Plasma exchange or infusion
●Eculizumab, a monoclonal antibody to C5 that blocks the terminal complement cascade
●Kidney or combination kidney-hepatic transplantation
The following sections regarding the care of patients with complement-mediated HUS are consistent with a published international consensus approach to the management of complement-mediated HUS in children [5].
Supportive care — Supportive therapy includes [5]:
●Red blood cell transfusions for anemia when clinically indicated (eg, hemoglobin level in children is <6 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 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.
Patients with complement antibodies — The management of patients with Complement factor H (CFH) antibodies is challenging and evolving due to the reported beneficial effects of initial therapy with eculizumab, however limited data are based on small case series [26]. Prior to the introduction of eculizumab, the initial management of patients with CFH antibodies included supportive care with plasmapheresis or plasma exchange, followed by immunosuppressive therapy directed to inhibiting further production of antibodies and preventing relapses.
●Our approach – Based on the available evidence cited below, we begin treatment with plasma exchange to rapidly remove circulating anti-CFH antibodies, followed by immunosuppressive therapy to ensure reduced production of anti-CFH antibodies [29,74-76]. Immunosuppression ensures reduced production of anti-CFH antibodies and includes oral corticosteroids with or without the addition of intravenous (IV) cyclophosphamide, rituximab, or mycophenolate mofetil (MMF).
Although data are limited, plasma exchange plus immunosuppressive therapy have been successful measures in patients with CFH antibodies [21-23,25,75,77]. In contrast, treatment with intravenous immune globulin (IVIG) does not appear to be beneficial [21].
●Immunosuppressive regimens – Protocols following plasma exchange include:
•A regimen that consists of induction therapy of oral prednisone (1 mg/kg per day for four weeks and followed by alternate days for four weeks) with either two to five doses of IV cyclophosphamide or two doses of IV rituximab, and maintenance treatment with tapering doses of prednisone and mycophenolate mofetil or azathioprine for 18 to 24 months [74].
•Use of pulses of cyclophosphamide, oral prednisone, and plasma exchange resulted in sustain remission for three children. Rituximab was also used in one other patient to treat recurrent relapses [75,76]. In these four patients, sustained remission was achieved up to six years. Although anti-CFH Ab titer decreased, it remained detectable during remission.
●Role of eculizumab – Eculizumab may be considered during the acute stage, particularly if plasma exchange is not available, if severe neurologic or cardiac illness is present, or if the patient does not respond to intensive plasma exchange.
Alternatively, eculizumab may be considered as a first-line treatment with the possibility of adding corticosteroids and/or MMF in an attempt to reduce antibody titer. However, the safety efficacy profiles and cost-effectiveness of approaches combining few plasma exchanges and immunosuppressive therapy, or long-term eculizumab therapy, have to be determined.
Support for eculizumab therapy without immunosuppression is based upon case reports and a small case series [26,78,79]. In a series of 17 children with CFH antibodies, including seven who had concomitant HUS genetic variants, immunosuppressive therapy was not given, because of concerns over treatment-associated complications [26]. The outcome varied based on management. All patients who received eculizumab recovered kidney function and achieved sustained remission. Two patients treated only with supportive care developed end-stage kidney disease (ESKD). Four of 11 patients treated with plasma exchange recovered kidney function. The authors concluded that based on these results, their clinical practice is to initiate only eculizumab therapy for treatment of CFH autoantibody-mediated HUS and not include plasma exchange or immunosuppressive therapy.
Eculizumab is discussed in greater detail below. (See 'Complement blockade (eculizumab)' below.)
●Renal transplantation – Although data on the outcome of kidney transplantation is limited in patients with CFH antibodies, one-quarter to one-third of patients have allograft loss due to recurrent disease [74]. The risk of recurrence increases with high antibody titers and if there is a concomitant variant in genes encoding CFH, C3, or CFB. For patients at-risk for disease recurrence (antibody titers >1000 AU/mL and/or variants in these specific complement protein), additional preventive measures (eg, eculizumab or plasma therapy) should be provided prior to transplantation. (See 'Transplantation' below.)
Patients with genetic variants
Complement blockade (eculizumab) — Eculizumab is the first-line treatment for patients with severe forms of compliment-mediated HUS.
Eculizumab a humanized monoclonal antibody that binds to complement protein C5, blocking its cleavage, thereby preventing the production of the terminal complement components C5a and the membrane attack complex (MAC) C5b-9 [80]. This results in reduction of the terminal-complement activation that occurs in patients with complement-mediated HUS, thereby reducing endothelial damage, thrombosis, and subsequent kidney injury. (See 'Pathogenesis' above.)
Indications and timing — We recommend eculizumab in patients in with severe forms of complement-mediated HUS (eg, patients with CFH and complement factor I [CFI] variants). Our strong recommendation despite the lack of prospective clinical trials and despite the known potential for adverse events (ie, severe infections) is based upon observational studies demonstrating a large magnitude of effect in reducing progression to ESKD and death. These data are discussed below. (See 'Efficacy' below.)
Treatment with eculizumab should be started as soon as possible, ideally within the first 48 hours of admission.
Eculizumab may not be available in all settings due to prohibitive cost [81-83]. Plasma therapy is often used in such cases. However, even in resource-limited areas, eculizumab should be considered in patients who fail to respond to plasma therapy, who have life-threatening disease (seizure, heart failure), and serious complications of plasma [83]. (See 'Plasma therapy' below.)
While eculizumab is generally not considered a first-line therapy in patients with CFH antibodies, it is a reasonable treatment option for severely affected patients, as discussed above. (See 'Patients with complement antibodies' above.)
Pretreatment evaluation and vaccination — Testing for anti-CFH antibodies is the only urgent complement investigation required, since other treatment options are available for patients with HUS due to antibodies to CFH [74]. (See 'Complement antibodies' above and 'Plasma therapy' below.)
Patients should receive vaccinations for Neisseria meningitis, S. pneumoniae and Haemophilus influenza type b, since there is a risk of developing serious infections due to these pathogens while on eculizumab. When possible, vaccination should be performed prior to the initiation of eculizumab therapy. However, this may not be possible in some patients due to the severity of the initial presentation. For such patients, vaccination should be administered once the patient is stable. (See 'Prevention of infectious complications' below.)
Dosing — Eculizumab is administered as an intravenous infusion. Induction dosing of eculizumab is based on patient body weight as follows [84]:
●5 to <10 kg – 300 mg, one weekly dose
●10 to <20 kg – 600 mg, one weekly dose
●20 to <30 kg – 600 mg, two weekly doses
●30 to <40 kg – 600 mg, two weekly doses
●≥40 kg – 900 mg, four weekly doses
Maintenance dosing based on patient body weight as follows:
●5 to <10 kg – 300 mg every three weeks, starting week two
●10 to <20 kg – 300 mg every two weeks, starting week two
●20 to <30 kg – 600 mg every two weeks, starting week three
●30 to <40 kg – 900 mg every two weeks, starting week three
●≥40 kg – 1200 mg every two weeks, starting week five
Of note, the doses for young children were calculated from a pharmacokinetic model derived from adult data because there are no data in children. In some children, the above dosing protocol does not completely blocked complement activation, and in these patients, dosing has been increased. If eculizumab is used in young children, complement activity should be assessed by measuring CH50. (See "Overview and clinical assessment of the complement system", section on 'CH50'.)
The use of functional complement testing has been used to monitor and modify eculizumab therapy [85,86].
Monitoring — During initial treatment, monitoring consists of frequent assessment of kidney function (ie, urinalysis, blood urea nitrogen [BUN], creatinine) and hematologic testing (ie, complete blood count [CBC] with platelet count).
In addition, monitoring of complement activity is required during eculizumab treatment [2,86,87]. CH50 should be <10 percent for a complete suppression. However, CH50 cannot be used for patients with complete CFH deficiency. One report demonstrated that using a global complement functional test (Wieslab) and maintaining a complement activity at <30 percent appears to safely reduce the frequency of eculizumab administration while keeping the disease in remission [87].
Although not widely available, eculizumab blood levels appear to be the optimal way to monitor the treatment. Levels at 100 mg/mL or over 100 mg/mL markedly reduce CH50 activity while values less than 50 mg/mL do not [5]. However, interpretation of eculizumab levels is difficult since the assays differ from each other, and all detect both bound and unbound drug [2]. (See "Overview and clinical assessment of the complement system", section on 'Complement measurement' and "Overview and clinical assessment of the complement system", section on 'CH50'.)
The frequency between dosing can be extended if adequate complement blockage is maintained [87].
Adverse effects — Treatment with eculizumab is associated with life-threatening and fatal meningococcal infections with a reported annual rate of 0.5 percent. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Eculizumab'.).
In a report from the Centers for Disease Control and Prevention (CDC), 16 cases of meningococcal disease were identified in eculizumab recipients in the United States between 2008 and 2016, including patients who had received at least one dose of meningococcal vaccine [88]. (See "Epidemiology of Neisseria meningitidis infection", section on 'Use of eculizumab'.)
Other reported serious adverse events in patients with complement-mediated HUS treated with eculizumab include hypertension, asymptomatic bacteremia, influenza, peritonitis, and venous sclerosis at the infusion site [89].
Prevention of infectious complications — Patients should receive vaccinations for Neisseria meningitis and for S. pneumoniae and Haemophilus influenza type b, as they are at risk of developing serious infections due to these pathogens. If therapy is given to an unvaccinated patient, pneumococcal vaccination should be administered as soon as possible, and prophylactic antibiotic coverage given for two weeks. Prophylactic antibiotic coverage should also be given to reduce the risk of Neisseria meningitis B infection while patients are receiving eculizumab, as the currently available Neisseria serogroup B vaccines may not provide adequate protection [90]. Prevention of meningococcal infection, including vaccination and prophylactic antibiotics is discussed separately. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors' and "Prevention of infection in patients with impaired splenic function", section on 'Daily antibiotic prophylaxis'.)
In the United States, prescribers of eculizumab are required to enroll in a registration program to certify that they counsel patients and provide educational materials about the risks of eculizumab and agree to promptly report cases of meningococcal infection. Enrollment and additional information are provided by the manufacturer (1-888-765-4747).
Although vaccination for Neisseria meningitis and for S. pneumoniae and Haemophilus influenza type b are recommended, a review by Health Canada reported an increased risk of hemolytic anemia following receipt of the multicomponent meningococcal serogroup B vaccine (Bexsero, MenB-4C) among patients who were already being treated with eculizumab [91]. To minimize the risk of hemolysis, if possible, vaccination should be performed prior to the initiation of eculizumab therapy. For some patients, this may not be possible due to the severity of their initial presentation. In such cases, vaccination should be administered when patients are stable, and their disease is well controlled. (See "Prevention of Haemophilus influenzae type b infection", section on 'Routine childhood immunization in the United States' and "Pneumococcal vaccination in children".)
Discontinuation — Based on observational studies, it appears that eculizumab therapy can be discontinued in selected patients who have had a favorable response to therapy [92-98]. However, some patients may relapse, so ongoing close monitoring (ie, frequent urinalysis and weekly CBC) is required so eculizumab therapy can be reinitiated as relapsed patients respond to resumption of therapy [3,96,98]. It appears that the risk of relapse after eculizumab withdrawal differs based on the underlying genetic variant with higher relapse rates seen in patients with germline variants for CFH, MCP, CFI and CD46 [94,98].
Further studies are needed to further define the optimal timing of withdrawal of eculizumab therapy and the patient population in whom therapy can be safely discontinued [97,99,100]. Until such data are available, the decision to withdraw eculizumab therapy should be made in conjunction with a clinician with expertise in managing patients with complement-mediated HUS.
Efficacy — Based upon the available observational data, eculizumab therapy is associated with dramatic improvements in kidney function and possible improvement in survival among patients with severe forms of complement-mediated HUS, particularly those with CFH and CFI genetic variants [9,89,101-111].
The US Food and Drug Administration (FDA) granted accelerated approval for the use of eculizumab for the treatment of complement-mediated HUS based on review of two small prospective studies [112]. In both studies, identification of a complement gene variant was not required, but the studies excluded patients with ADAMTS13 activity <5 percent of normal, those who had evidence of STEC-HUS, and those with prior eculizumab treatment. The following findings were noted in these early studies [89]:
●In the first study of 17 pediatric and adult patients who were refractory to plasma therapy, four of five patients who required dialysis at baseline were able to discontinue dialysis therapy while receiving eculizumab and remained off dialysis over the two-year follow-up period. For 10 patients, there was an improvement in kidney function with an increase of at least 15 mL/min per 1.73 m2 in the estimated glomerular filtration rate (eGFR) that was sustained over the two-year follow-up period. Two patients, including one who discontinued eculizumab therapy, progressed to ESKD and began dialysis therapy.
Normal platelet counts and lactate dehydrogenase levels, indicating thrombotic microangiopathy (TMA) event-free status, were observed in 14, 13, and 15 patients at 26 weeks, 1 year, and 2 years of follow-up, respectively. Thirteen patients were found to have complement variants or antibodies to complement factor H. At the end of two years, 11 patients remained on eculizumab therapy.
●The second study involved 20 patients who were maintained on plasma therapy. Administration of eculizumab was associated with a discontinuation of plasma therapy in all patients, normalization of hematological parameters in 18 of the 20 patients that was maintained at two-year follow-up, and improved kidney function in three patients (increase of eGFR >15 mL/min per 1.73 m2). For the two patients who were on dialysis at baseline, there was no improvement, as one remained on dialysis and the other remained on dialysis until undergoing kidney transplantation. In addition, another patient required dialysis during a hospitalization for intestinal hemorrhage, and subsequently died. Fourteen patients were found to have complement variants or antibodies to complement factor H. At the end of two years, 18 patients remained on eculizumab therapy.
Subsequent studies continue to demonstrate the benefits of eculizumab in children and adults with atypical HUS [109,111,113,114]. In the largest study, which included 72 patients with atypical HUS treated with eculizumab, kidney function improved dramatically on treatment (ie, eGFR increased by a median of 74 mL/min/m2; proteinuria resolved in nearly all cases, and the proportion of patients requiring dialysis decreased from 38 to 10 percent) [111]. There was only one death in this cohort over a median follow-up of 21 months (mortality rate 1.4 percent). This is considerably lower compared with studies published before eculizumab was available, in which mortality rates were as high as 40 to 50 percent in some studies, depending upon the specific genetic variants studied. (See 'Clinical course and outcome' above and 'Genetic variants' above.)
Hematologic normalization and recovery of kidney function has been observed in the overwhelming majority of patients treated with eculizumab during their first episode and subsequent episodes of HUS [109,111,113,114], including those who have undergone kidney transplantation [106]. (See 'Kidney transplantation' below.)
Other C5 blocking agents — Ravulizumab is a long-acting C5 inhibitor that was engineered from eculizumab. It has been reported to be effective in the treatment of complement-mediated HUS in adults and small pediatric case series including one report in which patients were switched from eculizumab to ravulizumab [115-118]. In the United States, ravulizumab is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.
Plasma therapy — Plasma therapy as a first-line therapy has largely been replaced by eculizumab. However, plasma therapy is still used in resource-limited areas where eculizumab is not widely available [83].
Plasma therapy appears to be less effective compared with eculizumab; only approximately one-half of patients with complement-mediated HUS respond to plasma exchange with both kidney (normal or improved kidney function) and complete hematologic recovery (ie, no evidence of hemolysis and a normal platelet count) [8]. Thus, even in resource-limited areas, efforts to initiate eculizumab therapy should be made for patients with any of the following [83]:
●Life-threatening complications of HUS (seizures, coma, heart failure)
●Serious complications from plasma therapy, including no vascular access
●No response to plasma therapy within 10 days
●Confirmed diagnosis of a high-risk complement genetic variant (eg, CFH or CFI)
Plasma therapy consists of either plasma exchange (plasmapheresis) or infusion of fresh frozen plasma (FFP). Although clinical trials are lacking, most experts in the field advocate for plasmapheresis rather than FFP infusions as a means to both remove defective mutant proteins and antibodies to CFH, and restore normal functioning complement proteins [9,74]. In addition, plasmapheresis avoids the risk of volume overload and hypertension in patients with acute kidney injury.
Most patients who have responded to an initial treatment with plasma infusions or plasma exchange should be switched to eculizumab for subsequent therapy. This strategy offers the best chance of complete kidney recovery. However, patients who are in full remission and have normal kidney function under plasma therapy without catheter complications nor plasma intolerance may remain on this therapy [5].
The response to plasma treatment varies depending upon the affected complement component [9,34].
●CFH variants – In patients with CFH variants, plasma therapy results in complete or partial remission in approximately two-thirds of patients. This has improved outcome with a decrease in mortality, and if initiated early in the course of the disease, preservation of kidney function over months and years [119-122]. Those who fail to respond generally progress to ESKD. In addition, resistance to long-term plasma therapy has been reported in patients [123]. Maintenance plasma therapy appears to be superior to intermittent plasma therapy given only during acute episodes of recurrent disease. However, the overall rate of complete kidney recovery is only five percent. Because long-term plasmapheresis is expensive and requires central venous access, efforts are underway to develop a purified human plasma-derived CFH concentrate, which can be given in a small volume.
●CFI variants – The response to plasma therapy is often inadequate, with only approximately one-quarter of patients with CFI variants achieving remission.
●CD46 deficiency – Plasma therapy provides no additional benefit in patients with CD46 deficiency, as CD46 is a transmembrane protein, and most of these patients recover fully without plasma therapy [8,50].
●Limited data suggest a positive benefit of plasma therapy in patients with gene variants of C3 and thrombomodulin (THBD). However, data are insufficient to determine whether plasma therapy is beneficial in patients with gene variants of complement factor B (CFB).
Use of plasmapheresis in patients with CFH antibodies is discussed above. (See 'Patients with complement antibodies' above.)
Complications of plasma exchanges include hypotension, catheter-related complications (infection, thrombosis), and anaphylactic reactions to plasma. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)
Transplantation
Kidney transplantation
●Complement genotyping and risk stratification ‒ Patients with HUS prior to transplantation should undergo complement genotyping to determine whether there is an underlying gene variant. In addition, genotyping will identify recipients who are at greatest risk for recurrent disease.
•Patients with variants in genes for CFH, CFI, or C3 who fail to respond to plasma therapy, and/or have relapsing disease are likely to progress to ESKD [34]. In these patients, the outcome of kidney transplantation is poor because recurrence of disease occurs in 50 percent of the transplanted kidneys, and graft failure occurs in 90 percent of those with recurrent disease [9,34,124-126].
•Limited data suggest a more favorable outcome of renal transplantation in patients with variants of CD46 or in those with disease due to antibodies to factor H, provided the autoantibodies to CFH are absent at the time of transplantation [53,54,77,124].
●Living donor evaluation ‒ Genetic testing of the donor is performed to ensure that the same mutation is not present in the potential living donor due to the low penetrance of disease [127,128]. In our practice, a living-related transplantation is only performed if both the donor and the recipient have given informed consent, testing confirms that the donor does not have the underlying gene variant, and for recipients at risk for recurrent disease.
●Prevention of disease recurrence ‒ Patients with a low risk of recurrence do not need a preventive treatment. These include those with isolated membrane cofactor protein or DGKE variants and patients with anti-complement factor H antibodies in whom the level of antibodies decreased to a negative level long-term. (See 'Complement antibodies' above.)
All other patients receive preventive therapy (eg, eculizumab and plasma therapy) at the time of and after transplantation to reduce the risk of disease recurrence.
•Eculizumab – Eculizumab therapy is our preferred intervention to prevent recurrent disease in renal transplant recipients with an identified variant in CFH, CFI, C3, or CFB, or in those with a previous post-transplant episode of recurrent disease [103,113,127,129-131]. Eculizumab may also be an option for patients with a moderate risk of recurrence. However, as noted above, this therapy may not be available in some settings because of the prohibitive cost of eculizumab. Another alternative in patients with complement autoantibodies is the addition of rituximab therapy to the immunosuppressive regimen, which was used successfully in one case report of a patient with CFH antibodies and deletion of CFHR1 and CFHR3 genes [132]. The optimal duration of eculizumab therapy remains unknown.I In our practice, we continue long-term eculizumab therapy in high-risk patients throughout the lifespan of the allograft unless combined liver-kidney transplantation is undertaken. (See 'Combined liver-renal transplantation' below.)
Pregnant women with kidney transplantation for complement-mediated HUS (aHUS) have been successfully managed with eculizumab therapy [133]. In these patients, eculizumab dosing requires adjustment during pregnancy to reach optimal eculizumab levels, which ensure effective complement blockade, and close monitoring of hemolysis biomarkers.
•Plasma therapy– If plasma therapy is used to prevent recurrent disease, the first exchange is performed a few hours prior to transplantation. After transplantation, plasma therapy is initially performed daily followed by decreasing frequency [134]. However, prophylactic plasma therapy may fail to prevent recurrence and may mask clinical signs of recurrence [126].
•Alternative approach using living related donors – In a case series of 17 patients, a strategy employed the use of living kidney donors, low-dose tacrolimus and strict blood pressure control. In this cohort that included 16 patients with a variant in genes encoding complement factors, only one patient had a recurrence of HUS, which was successfully treated with eculizumab [135]. Although the cohort size is limited and the follow-up is short, these results suggest that a rescue approach is a reasonable alternative to the more costly eculizumab prophylactic strategy [136]. Further, studies are needed to determine whether a rescue strategy is a feasible option.
●Management of recurrent disease – Eculizumab has been shown to be beneficial in patients with post-transplant recurrent disease [102,106,107,113,127,137-139]. In contrast, plasma therapy has failed to improve graft survival in renal transplant recipients with recurrent disease.
Combined liver-renal transplantation — Liver transplantation may be a curative intervention for severe complement-mediated HUS for patients with variants of CFH, CFI, CFB, and C3, which are proteins that are synthesized in the liver. In addition, combined liver-renal transplantations have been proposed in patients with ESKD in whom there is a high likelihood of recurrent disease [134]. However, data are limited regarding patient outcome. A 2014 review reported 25 patients with complement-mediated HUS underwent combined liver-renal transplantation [140]. All five children who did not have a preparative regimen for complement regulation (eg, plasma therapy or eculizumab) suffered fatal complications, presumably due to uncontrolled complement activation. In the remaining 20 cases that were performed with either or both plasma therapy or eculizumab administration, transplantation was successful in 16 patients. There were three deaths, and in one patient, liver transplantation was successful, but the renal transplant never gained function. Of this group of 20 patients, 16 had CFH variants (14 successful outcomes), 1 with CFB variant (successful), 1 with C3 variant (unsuccessful), and 2 with CFH/CFHR1 hybrid variants (one successful).
The decision of combined liver-renal transplantation to definitively cure the disease is based on an evaluation that carefully weighs the risks and benefits for the individual patient. It should only be performed in pediatric centers with expertise in solid combined organ transplantation and with provision of preparative measures to control complement activation. The decision to perform combined liver-renal transplantation should be taken on a case-by-case basis, after discussion with the patient and families, taking into account the benefits and risks of each option and the cost of the long-term eculizumab treatment. In patients with high risk of recurrence and preserved renal function, isolated liver transplantation may be an option.
OUTCOME
Patient with complement antibodies — Outcome of patients with CFH antibodies varies as demonstrated by the following case series:
●In one case series, outcome data at a mean follow-up of 39 months were available for 44 of the 45 patients [21]. Four patients died (unknown cause in two patients, one from pulmonary arterial hypertension, and one from cardiac disease), 25 patients had relapses, 17 developed chronic kidney disease (CKD) including 12 who went on to end-stage kidney disease (ESKD), and 11 patients had no sequelae.
●In a study from the United Kingdom and Ireland, six patients progressed to ESKD (two who received only supportive care and four who also received plasma exchange), and the others regained kidney function, including six patients with sustained remission who were treated with eculizumab [26]. Five patients received kidney transplants without specific factor H autoantibody-targeted treatment, and recurrence occurred in one patient who also had a functionally significant CFI variant.
●A large case series of 138 patients from India reported mean follow-up at 14.5 months for patients who mostly were treated with early plasma exchange therapy and/or immunosuppressive therapy [141]. Plasma exchange was performed in 105 patients and 87 received immunosuppressive therapy, which included oral prednisolone with or without additional agents such as intravenous cyclophosphamide (n = 49) and rituximab (n = 18). The following outcomes were noted:
•58 patients had normal kidney function with hypertension and/or significant hematuria/proteinuria
•33 patients remained on dialysis
•20 deaths
•13 patients with normal kidney function and normal urinalysis
•10 patients with impaired kidney function, but not dialysis dependent
•3 patients underwent transplantation
●In a series of 19 children who were treated initially with plasma exchanges and only steroids for immunosuppression, relapses occurred 14 patients [29]. All patients had their first relapse during the first six months after diagnosis. Although 13 of 19 children required initial kidney replacement therapy, only 5 (26 percent) remained on dialysis at one- and two-year follow-up. After five years, two of these five children received a kidney transplant, two remained on dialysis, and one patient started on eculizumab was able to discontinue dialysis.
Patients with genetic variants — The clinical course and outcome vary depending on the affected complement component [34,50]. Without treatment, patients with variants of the gene for CFH have a high likelihood of progressing to ESKD; though the risk is substantially reduced with eculizumab treatment (see 'Complement blockade (eculizumab)' above). By contrast, few patients harboring variants that affect CD46 progress to ESKD, although relapse is common [50]. (See 'Genetic variants' 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)".)
SUMMARY AND RECOMMENDATIONS
●Definition ‒ Hemolytic uremic syndrome (HUS) is defined by the concurrent characteristic triad of HUS: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most common cause of HUS is due to Shiga toxin-producing Escherichia coli (STEC). Complement-mediated HUS accounts for most of the non-STEC-HUS.
●Epidemiology ‒ Complement-mediated HUS is a relatively rare disorder, with an estimated prevalence of seven per one million children in Europe. Most complement-mediated HUS cases are due to gene variants of complement factors, although acquired complement dysregulation due to antibodies to complement proteins occurs in 6 to 10 percent of patients with complement-mediated HUS. (See 'Epidemiology' above.)
●Pathogenesis ‒ The complement proteins associated with complement-mediated HUS are components of the alternative complement pathway. They include complement factors H, I, and B (CFH, CFI, and CFB), C3, CD46 (previously known as membrane cofactor protein [MCP]), and thrombomodulin (THBD). (See 'Genetic complement disorders' above and 'Genetic variants' above and 'Complement antibodies' above.)
The proposed pathogenesis of complement-mediated HUS is that a trigger (eg, infection) causes uninhibited continuous activation of the alternative complement pathway in a susceptible individual with either gene variants or antibodies to complement proteins. This results in renal endothelial damage leading to thrombotic microangiopathy. (See 'Pathogenesis' above.)
●Clinical features ‒ In addition to the clinical triad of HUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), patients with complement-mediated HUS typically will have a history of a triggering antecedent event (eg, upper respiratory infection or diarrheal illness). There is often a positive family history, and/or a history of a previous episode. Severe hypertension is a common clinical finding. (See 'Clinical manifestations' above.)
●Clinical course and outcome ‒ The clinical course and outcome vary depending on the affected complement component. (See 'Clinical course and outcome' above.)
•Patients with CFH variants generally have a poor prognosis with most patients progressing to end-stage kidney disease (ESKD) or death within the first year of presentation. (See 'Factor H' above.)
•In contrast, patients with variants of CD46 do not usually progress to ESKD, although relapse is common. (See 'CD46' above.)
•Patients with CFI variants have an intermediate course between those with CFH and CD46 variants, with one-half of patients progressing to ESKD or death within two years of presentation. (See 'Factor I' above.)
●Evaluation ‒ The diagnostic evaluation consists of laboratory studies that differentiate complement-mediated HUS from other conditions that have similar presentations. This includes testing for STEC, cultures of blood and other pertinent bodily fluids (eg, cerebral spinal fluid, urine, or sputum), complement studies, ADAMTS13 activity, and occasionally kidney biopsy. (See 'Evaluation' above and "Overview of hemolytic uremic syndrome in children", section on 'Evaluation to identify underlying etiology' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●Diagnosis ‒ The diagnosis of complement-mediated HUS is based upon the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, plus demonstration of complement dysregulation, either due to a genetic variant or antibodies to complement factors. Laboratories that offer complement genotyping for complement-mediated HUS can be found from the National Center for Biotechnology Information website. (See 'Diagnosis' above.)
●Differential diagnosis ‒ The differential diagnosis of complement-mediated HUS includes other forms of HUS (eg, STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and inborn errors of vitamin B12. (See 'Differential diagnosis' above.)
●Management ‒ (See 'Treatment' above.)
•The initial management of complement-mediated HUS is supportive and similar to the approach used for STEC-HUS. (See 'Supportive care' above and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Supportive therapy'.)
•For patients in with severe forms of complement-mediated HUS (eg, patients with CFH and CFI variants), we recommend eculizumab (Grade 1B). If eculizumab therapy is not available, plasma therapy is an alternative treatment option. (See 'Complement blockade (eculizumab)' above and 'Plasma therapy' above.)
•For patients with HUS due to CFH antibodies, we suggest initial treatment with plasma exchange followed by immunosuppressive therapy (Grade 2C). (See 'Patients with complement antibodies' above.)
•For patients with HUS who progress to ESKD and undergo evaluation for kidney transplantation, complement genotyping should be performed if it was not already done. Complement genotyping will identify the presence and nature of an underlying gene, which informs the risk of recurrent disease in the allograft. (See 'Kidney transplantation' above.)
•In our center, living-related donor transplantation is not performed unless donor genetic testing has been completed to ensure that the same variant is not present in the potential living donor. (See 'Kidney transplantation' above.)
•For kidney transplant recipients who are at risk for recurrent disease in the allograft, we suggest prophylactic administration of eculizumab rather than plasma therapy or no treatment (Grade 2C). At-risk patients include those with with an identified variant in CFH, CFI, C3, or CFB, those with high titers of CFH antibodies, and those with a previous post-transplant episode of recurrent disease. If eculizumab is not available (eg, due to cost constraints), plasma therapy is an acceptable alternative.
•Combined liver-renal transplantation provides a definitive cure for complement-mediated HUS with variants of CFH, CFI, CFB, and C3. However, this procedure carries a risk of death in the postoperative period. It should only be performed in pediatric centers with expertise in solid combined organ transplantation and after careful consideration of the risks and benefits for the individual patient. (See 'Combined liver-renal transplantation' above.)
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