Genetic Atypical Hemolytic-Uremic Syndrome

Clinical characteristics.

Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).

Diagnosis/testing.

The diagnosis of genetic aHUS is established in a proband with aHUS and identification of a pathogenic variant(s) in one or more of the genes known to be associated with genetic aHUS. The genes associated with genetic aHUS include C3, CD46 (MCP), CFB, CFH, CFHR1, CFHR3, CFHR4, CFI, DGKE, and THBD.

Management.

Treatment of manifestations: Eculizumab (a human anti-C5 monoclonal antibody) to treat aHUS and to induce remission of aHUS refractory to plasma therapy; plasma manipulation (plasma infusion or exchange) to reduce mortality; however, plasma resistance or plasma dependence is possible. Eculizumab therapy may not be beneficial to those with aHUS caused by pathogenic variants in DGKE. Treatment with ACE inhibitors or angiotensin receptor antagonists helps to control blood pressure and reduce renal disease progression. Bilateral nephrectomy when extensive renal microvascular thrombosis, refractory hypertension, and signs of hypertensive encephalopathy are not responsive to conventional therapies, including plasma manipulation. Renal transplantation may be an option, although recurrence of disease in the graft limits its usefulness.

Prevention of primary manifestations: Plasma exchange and eculizumab prophylaxis may prevent disease recurrences in those with mutation of circulating factors (CFH, C3, CFB, and CFI).

Prevention of secondary complications: Eculizumab therapy may prevent thrombotic microangiopathic events and prophylactic treatment may prevent post-transplantation aHUS recurrence; vaccination against Neisseria meningitidis, Streptococcus pneumonia, and Haemophilus influenza type B is required prior to eculizumab therapy; prophylactic antibiotics may be needed if vaccination against Neisseria meningitidis is not possible at least two weeks prior to eculizumab therapy.

Surveillance: Serum concentration of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin: (1) every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for those with normal renal function or chronic renal insufficiency as they are at risk for relapse; and (2) in relatives with the pathogenic variant following exposure to potential triggering events.

Agents/circumstances to avoid: Those with known aHUS should avoid if possible pregnancy and the following drugs that are known precipitants of aHUS: chemotherapeutic agents (including mitomycin C, cisplatin, daunorubimicin, cytosine arabinoside); immunotherapeutic agents (including cyclosporin and tacrolimus); and antiplatelet agents (including ticlopidine and clopidogrel). Plasma therapy is contraindicated in those with aHUS induced by Streptococcus pneumoniae because antibodies in the plasma of adults may exacerbate the disease.

Pregnancy management: Women with a history of aHUS are at increased risk for an aHUS flare during pregnancy and even a greater risk in the postpartum period; the risk for pregnancy-associated aHUS (P-aHUS) is highest during the second pregnancy. Women with complement dysregulation should be informed of the 20% risk for P-aHUS, and any pregnancy in these women should be closely monitored.

Evaluation of relatives at risk: While it is appropriate to offer molecular genetic testing to at-risk relatives of persons in whom pathogenic variants have been identified, predictive testing based on a predisposing factor (as opposed to a pathogenic variant) is problematic as it is only one of several risk factors required for aHUS.

Other: Live-related renal transplantation for individuals with aHUS should also be avoided in that disease onset can be precipitated in the healthy donor relative. Evidence suggests that kidney graft outcome is favorable in those with CD46 and DGKE pathogenic variants but not in those with C3, CFB, CFH, CFI, or THBD pathogenic variants; however, simultaneous kidney and liver transplantation in young children with aHUS and CFH pathogenic variants may correct the genetic defect and prevent disease recurrence.

Genetic counseling.

Predisposition to aHUS is inherited in an autosomal recessive or autosomal dominant manner with incomplete penetrance. Rarely, polygenic inheritance and uniparental isodisomy are observed.

Autosomal recessive inheritance: Heterozygotes are usually asymptomatic; however, in rare cases, heterozygotes develop aHUS in adulthood. At conception, each sib of an individual with autosomal recessive aHUS has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant.

Autosomal dominant inheritance: Some individuals diagnosed with autosomal dominant aHUS have an affected parent or an affected close relative, but in the majority the family history is negative because of reduced penetrance of the pathogenic variant in an asymptomatic parent, early death of a parent, late onset in a parent (or close relative), or a de novo pathogenic variant in the proband. Each child of an individual with autosomal dominant aHUS has a 50% chance of inheriting the pathogenic variant.

In both genetic types, clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression and outcome cannot be predicted. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in the family.

Suggestive Findings

Genetic atypical hemolytic-uremic syndrome (aHUS) should be suspected in a proband with a diagnosis of aHUS in addition to ONE of the following criteria:

• Two or more members of the same family have been diagnosed with aHUS at least six months apart and exposure to a common triggering infectious agent has been excluded.
• An individual has an HUS relapse even after complete recovery from the presenting episode.
• An underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins can be identified.

For information about laboratory findings and renal histology related to typical and atypical HUS, click here.

Establishing the Diagnosis

The diagnosis of genetic aHUS is confirmed in a proband with aHUS and identification of a pathogenic variant(s) in one or more of the genes known to be associated with genetic aHUS (see Table 1). Genetic predisposition to aHUS can be inherited in an autosomal dominant or autosomal recessive manner by a pathogenic variant(s) in a single gene; or, rarely, inheritance can be polygenic. To date, the reported mechanisms include the following:

• Heterozygous pathogenic variant in C3, CD46, CFB, CFH, CFI, or THBD
• Homozygous or compound heterozygous pathogenic variants in DGKE
• Pathogenic variants in two or three of the following genes: C3, CD46, CFB, CFH, CFI, and THBD
• Homozygous deletion of CFHR1 and an additional pathogenic variant in C3, CD46, CFH, or CFI

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing should be considered in individuals with aHUS presenting before age one year, particularly if the family history reveals consanguinity or evidence of autosomal recessive inheritance; consider sequence analysis of DGKE first. If sequence analysis of DGKE does not identify biallelic pathogenic variants, a multigene panel should be performed.
• A multigene panel that includes C3, CD46, CFB, CFH, CFI, DGKE, and THBD should be considered in individuals with aHUS presenting after age one year. Testing specifically designed to detect CFH/CFHR1 and CFHR1/CFH hybrid alleles and deletions of CHFR1/CHFR4 and CHFR3/CHFR1 should also be considered. Note: The high degree of sequence identity between CFH and its downstream CFH-related genes (CFHR1-CFHR4) results in susceptibility to nonallelic homologous recombination (NAHR) events, and consequently, in large-scale deletions or duplications (copy number variation) and generation of hybrid CFH genes. Molecular assays must be specifically designed to detect deletions resulting from gene conversion in this region.
  A multigene panel that includes other genes of interest (see Differential Diagnosis) may also be considered.
  Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of aHUS.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The onset of atypical hemolytic-uremic syndrome (aHUS) ranges from the neonatal period to adulthood. Collectively, aHUS is associated with poor outcome. Individuals with genetic aHUS frequently relapse even after complete recovery following the presenting episode [Ruggenenti et al 2001, Taylor et al 2004]. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD) [Noris et al 2010].

Genetic aHUS accounts for an estimated 60%of all aHUS [Nester et al 2015]. It is likely that mutation of C3, CD46, CFB, CFH, CFI, and THBD confers a predisposition to developing aHUS, rather than directly causing the disease. Conditions that trigger complement activation may precipitate an acute event in those with the predisposing genetic background [Caprioli et al 2006, Noris et al 2010].

Triggers for acquired aHUS include non-enteric bacterial and viral infections, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions:

• Infection caused by Streptococcus pneumoniae accounts for 40% of aHUS. The clinical picture is usually severe, with respiratory distress, neurologic involvement, and coma; the mortality rate is 12.3% [Copelovitch & Kaplan 2008].
• Drugs most frequently reported to trigger aHUS include: chemotherapeutic agents (e.g., mitomycin, cisplatin, bleomycin, gemcitabine), immunotherapeutic agents (e.g., cyclosporine, tacrolimus, OKT3, interferon, and quinidine), antiplatelet agents (e.g., ticlopidine, clopidogrel), and a variety of common medications (e.g., oral contraceptives, anti-inflammatory agents).
• Malignancy-associated aHUS occurs in almost 6% of individuals with metastatic carcinoma. Gastric cancer accounts for approximately half of such cases.
• Post-transplantation aHUS may occur in individuals who have not had aHUS before or may affect those whose primary cause of ESRD was aHUS.
• Pregnancy-associated aHUS may occasionally develop as a complication of preeclampsia. Some women progress to a life-threatening variant of preeclampsia with severe thrombocytopenia, microangiopathic hemolytic anemia, renal failure, and liver involvement (HELLP syndrome). Complete remission usually follows prompt delivery. Postpartum aHUS usually manifests in women within three months of delivery. The outcome is usually poor: ESRD or death in 50%-60%; residual renal dysfunction and hypertension are the rule in those who survive the acute episode.
• Underlying medical conditions include autoimmune disease (e.g., scleroderma, anti-phospholipid syndrome, systemic lupus erythematosus).

Phenotype Correlations by Gene

The phenotype of aHUS ranges from mild (with complete recovery of renal function) to severe (resulting in ESRD or death). The course and outcome of the disease are influenced by the gene in which pathogenic variants occur.

• C3. Atypical HUS associated with C3 pathogenic variants presents in childhood in about 50% of individuals. More than 60% of affected individuals will develop ESRD.
• CD46. Atypical HUS associated with CD46 pathogenic variants typically presents in childhood with a milder acute episode. Eighty percent of individuals experience complete remission. Recurrences are frequent but have little effect on long-term outcome; 60%-70% of individuals remain dialysis free even after several recurrences. A subgroup of individuals, however, lose renal function either during the first episode or later in life.
• CFB. Atypical HUS associated with CFB pathogenic variants shows variable onset, presenting both in childhood and adulthood [Frémeaux-Bacchi et al 2013], and intrafamilial variability [Funato et al 2014]. Seventy percent of individuals eventually develop ESRD [Nester et al 2015].
• CFH. Atypical HUS associated with CFH pathogenic variants presents early in childhood in approximately 70% of affected individuals and in adulthood in approximately 30%. Irrespective of the pattern of inheritance, there is a high rate of relapse and a 60%-80% rate of ESRD or death.
• CFI. Atypical HUS associated with CFI pathogenic variants is variable. The onset is in childhood in 50% of affected individuals. Fifty-eight percent develop ESRD.
• DGKE. Atypical HUS associated with biallelic pathogenic variants in DGKE presents before age one year in all affected individuals [Lemaire et al 2013]. Affected individuals show persistent hypertension, hematuria, and proteinuria (sometimes in nephrotic range). Relapsing episodes are reported before age five years. Chronic kidney disease occurs by the second decade of life.
• THBD. Atypical HUS associated with THBD pathogenic variants presents in childhood in about 90% of individuals. More than 50% of individuals will eventually develop ESRD.

Polygenic inheritance. CFH, CFI, and C3 pathogenic variants may have an additive effect and lead to a more severe aHUS phenotype in individuals with CD46-associated aHUS, including an increased incidence of ESRD and graft loss [Bresin et al 2013].

Penetrance

C3, CD46, CFH, CFI, and THBD. Penetrance for pathogenic variants in these genes is: C3: 56%; CD46: 53%; CFH: 48%; CFI: 50%; and THBD: 64% [Caprioli et al 2006, Noris et al 2010], indicating that additional genetic and environmental factors contribute to disease development in affected individuals with pathogenic variants in these genes [Rodríguez de Córdoba et al 2014].

DGKE. Penetrance was complete in nine kindreds with homozygous or compound heterozygous pathogenic variants in DGKE [Lemaire et al 2013].

Nomenclature

Genetic aHUS is also referred to as hereditary HUS, familial aHUS, and complement mutation-associated HUS.

Prevalence

Genetic aHUS accounts for an estimated 60% of all aHUS.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with genetic atypical hemolytic-uremic syndrome (aHUS), the following evaluations are recommended:

• Renal function
  • Creatinine clearance (i.e., glomerular filtration rate [GFR])
  • Serum concentration of creatinine resources
  • Urinalysis
• Hematologic status
  • Platelet count
  • Erythrocyte count
  • Search for schistocytes in the blood smear.
  • Leukocyte count
• Other
  • Serum LDH concentration
  • Haptoglobin
  • Serum C3 and C4 concentrations
  • Plasma concentrations of Bb and sC5b-9
• Measure serum concentrations of CFH and CFI.
• Assessment of CD46 expression on leukocytes
• Testing for CFH autoantibodies because affected individuals who have autoantibodies could benefit from an immunosuppressive therapy (see Treatment of Manifestations)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Eculizumab has been shown to induce remission of acute episodes of aHUS refractory to plasma therapy and is now widely used as a first-line therapy to treat aHUS. Eculizumab should be considered as a first-line therapy when the diagnosis of aHUS is unequivocal, since this treatment has the potential to rescue renal function when administered early after onset of the disease [Zuber et al 2012a, Fakhouri et al 2013].

For further information about eculizumab, click here.

Plasma infusion or exchange guidelines have been published for children [Ariceta et al 2009] and adults [Taylor et al 2010]. Cohort data show that response to plasma therapy was in part related to the genetic background of the treated patient [Noris et al 2010]. Despite the variability in response to therapy, plasma therapy is the only therapy with near-complete global availability and therefore it remains an important treatment for aHUS. Plasma therapy should be started as soon as aHUS is suspected and continued until resolution of thrombotic microangiopathy. In individuals who respond, plasma exchange can be gradually withdrawn, although a significant proportion will require continued plasma exchange to maintain remission. There is minimal evidence to suggest the superiority of either plasma exchange or plasma infusion, and instead the selected option should be based on individual tolerance, local expertise, and resources (e.g., a neonatal benefit from infusion vs exchange) [Nester et al 2015].

• Plasma exchange usually involves exchanging 1-2 plasma volumes (40 mL/kg) per session in adults and 50-100 mL/kg in children. Typically, plasma exchange is undertaken daily initially; the duration and frequency of treatment is then determined by the clinical response.
  Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma.
• Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes.

Platelet count and serum LDH concentration are the most sensitive markers for monitoring response to plasma therapy. Plasma treatment should be continued until platelet count and serum LDH concentration remain normal after therapy is discontinued. Discontinuation of plasma therapy is the only way to know if complete remission has been achieved. Immediate exacerbation of disease activity, principally manifested by falling platelet count that requires the resumption of daily plasma therapy, occurs in 29%-82% of individuals after treatment is discontinued. Thus, many cycles of stopping and resuming plasma therapy may occur, in which case therapy with eculizumab should be considered.

Genetic characterization of persons with aHUS has the potential to optimize the treatment:

• C3. Response to plasma treatment in persons with C3 pathogenic variants was comparable (57%) to that in persons with CFH pathogenic variants [Noris et al 2010]. It is hypothesized that plasma exchange could remove mutated hyperactive C3 and also provide regulatory plasma proteins to counteract complement activation induced by mutated C3.
• CFB. Limited data are available on response of individuals with CFB pathogenic variants to treatment with plasma. Remission with plasma exchange or infusion has been reported in five individuals [Goicoechea de Jorge et al 2007, Roumenina et al 2009, Tawadrous et al 2010, Funato et al 2014].
• CD46. The rationale for using plasma in individuals with CD46 pathogenic variants is not so clear, since the CD46 protein (also known as MCP) is a transmembrane protein and, theoretically, plasma infusion or plasma exchange would not compensate for the MCP defect. Published data indicate that the majority (80%-90%) of individuals undergo remission following plasma infusion or exchange [Richards et al 2003, Caprioli et al 2006]; however, complete recovery from the acute episode was also observed in 100% of individuals not treated with plasma [Noris et al 2010]. The decision whether to treat with plasma should be based on the clinical severity of the acute episode.
• CFH. Plasma infusion or exchange has been used in individuals with aHUS and CFH pathogenic variants with the rationale of providing normal CFH to compensate for the genetic deficiency, as CFH is a circulating plasma protein. In published studies, some individuals with CFH pathogenic variants did not respond at all to plasma therapy and died or developed ESRD. Others required infusion of plasma at weekly intervals in order to raise CFH plasma levels enough to maintain remission [Landau et al 2001].
  Stratton and Warwicker [2002] were able to induce sustained remission in a patient with a CFH pathogenic variant by three months of weekly plasma exchange in conjunction with intravenous immunoglobulins. One year after discontinuation of plasma therapy, the patient remained disease free and dialysis independent.
  A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [Loirat et al 2016].
  In the authors' series [Caprioli et al 2006, Noris et al 2010], approximately 60% of individuals with CFH pathogenic variants treated with plasma underwent either complete or partial remission (hematologic normalization with renal sequelae). However, the remaining individuals did not respond at all to plasma and 20% died during the acute episode.
  In the French cohort [Frémeaux-Bacchi et al 2013] progression to ESRD during the first episode of aHUS was similar in children and adults with CFH pathogenic variants who received high-intensity plasma therapy compared to those who did not.
• CFH autoantibodies. In individuals with anti-CFH autoantibodies, plasma treatment induced complete or partial remission (normalization of hematologic parameters with renal sequelae) of 75% of episodes [Noris et al 2010]. Persons with anti-CFH autoantibodies benefit from treatment with steroids or other immunosuppressants in conjunction with plasma exchange.
• CFI. Theoretically one should expect a good response to plasma therapy in individuals with CFI pathogenic variants because CFI (like CFH) is a circulating protein; the results, however, suggest that a larger quantity of plasma is required to provide sufficient wild type CFH or CFI to compensate for the genetic deficiency [Caprioli et al 2006]. Indeed, remission was achieved in only 25% of episodes treated with plasma in persons with CFI pathogenic variants [Noris et al 2010].
• DGKE. Absence of evidence linking DGKE deficiency to the complement cascade and relapses of acute aHUS in affected individuals with pathogenic variants in DGKE while receiving plasma therapy suggest that this treatment may not benefit individuals with DGKE pathogenic variants [Lemaire et al 2013].
• THBD. Plasma treatment induced disease remission in about 80% of acute episodes in persons with THBD pathogenic variants [Noris et al 2010].

Treatment with ACE inhibitors or angiotensin receptor antagonists helps to reduce renal disease progression to end-stage renal failure, while at the same time controlling blood pressure levels.

Bilateral nephrectomy may serve as rescue therapy in selected individuals with extensive microvascular thrombosis at renal biopsy, refractory hypertension, and signs of hypertensive encephalopathy, in whom conventional therapies including plasma manipulation are not adequate to control the disease (i.e., persistent severe thrombocytopenia and hemolytic anemia). Follow up has been excellent in some individuals [Ruggenenti et al 2001].

Renal transplantation outcome is determined largely by the underlying genetic abnormality. An important advance has been the development of transplant protocols integrating eculizumab treatment [Nester et al 2011]. Eculizumab therapy may be used to treat post-transplantation aHUS recurrence, as reported in individuals with pathogenic variants in C3, CFH, and CFI [Zuber et al 2012b]. Eculizumab prophylactic therapy may also prevent post-transplantation aHUS recurrence (see Prevention of Secondary Complications).

Molecular genetic testing can help to define graft prognosis; thus, all affected individuals should undergo such testing prior to transplantation.

• C3, CFB, and CFI. Graft failures secondary to recurrences occurred in one individual with a CFB pathogenic variant and in70% of individuals with CFI pathogenic variants. The percentage of graft failure was slightly lower (50%) in individuals with C3 pathogenic variants [Noris et al 2010].
• CD46. Four individuals with isolated CD46 pathogenic variants have undergone renal transplantation with no disease recurrence [Noris & Remuzzi 2005, Noris et al 2010]. The strong theoretic rationale is that because the CD46 protein (MCP) is a transmembrane protein that is highly expressed in the kidney, transplantation of a kidney expressing normal MCP corrects the defect.
• CFH. In individuals with CFH pathogenic variants the graft outcome is poor. Recurrence ranges from 30% to 100% and is significantly higher than in individuals without CFH pathogenic variants [Noris & Remuzzi 2010]. As CFH is mainly produced by the liver, kidney transplantation does not correct the CFH genetic defect in these individuals.
  Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and CFH pathogenic variants [Noris & Remuzzi 2005]. However, following transplantation