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 by 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, CFHR5, CFI, DGKE, THBD, and VTN.
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: Eculizumab prophylaxis may prevent disease recurrences in those with pathogenic variants in genes encoding 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:
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
In relatives with the pathogenic variant following exposure to potential triggering events.
Agents/circumstances to avoid: Plasma therapy is contraindicated in those with aHUS induced by Streptococcus pneumoniae because antibodies in the plasma of adults may exacerbate the disease. Individuals with known aHUS should avoid pregnancy if possible and the following drugs that are known precipitants of aHUS: chemotherapeutic agents (e.g., mitomycin, cisplatin, daunorubicin, bleomycin, cytosine arabinoside, gemcitabine); immunotherapeutic agents (e.g., cyclosporin, tacrolimus, muromonab-CD3, interferon, quinidine); antiplatelet agents (e.g., ticlopidine, clopidogrel); oral contraceptives, and anti-inflammatory agents.
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.
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.
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 associated with pathogenic variants in C3, CD46, CFB, CFH (including CFH hybrid genes), CFHR5, CFI, THBD, or VTN is typically inherited in an autosomal dominant manner with reduced penetrance. Atypical HUS associated with pathogenic variants in DGKE is typically inherited in an autosomal recessive manner. Deletions of CFHR3/CFHR1 and CFHR1/CFHR4 are inherited in an autosomal recessive manner. Polygenic inheritance is also reported in rare families.
Autosomal dominant inheritance. Almost all individuals with autosomal dominant aHUS inherited an aHUS-related pathogenic variant from a heterozygous (typically unaffected) parent. Each child of an individual with autosomal dominant aHUS has a 50% chance of inheriting the pathogenic variant; offspring who inherit the pathogenic variant may or may not develop aHUS.
Autosomal recessive inheritance. If both parents are known to be heterozygous for an autosomal recessive aHUS-related pathogenic variant, each sib of a proband 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.
Once the aHUS-related pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for the familial pathogenic variant(s) are possible.
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