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.
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