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Atypical Hemolytic-Uremic Syndrome.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2007 Nov 16 [updated 2013 Aug 08].



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. Typical (acquired) HUS is triggered by infectious agents such as strains of E. coli (Stx-E. coli) that produce powerful Shiga-like exotoxins, whereas atypical HUS (aHUS) can be genetic, acquired, or idiopathic (of unknown cause). Onset of atypical HUS ranges from prenatal to adulthood. Individuals with genetic atypical HUS frequently experience relapse even after complete recovery following the presenting episode. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD).


Atypical HUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when disease-causing mutation(s) are identified in one of the ten genes in which mutations are known to be associated with aHUS, irrespective of familial history. The genes: CFH (encoding complement factor H and accounting for ~30% of aHUS; CD46 (MCP) (encoding membrane cofactor protein and accounting for ~12% of aHUS); CFI (encoding complement factor I; ~5%-10% of aHUS), C3 (encoding the third component of complement C3; ~5% of aHUS); CFB (encoding complement factor B; rare); THBD (encoding thrombomodulin; ~3%-5% of aHUS); DGKE (encoding diacylglycerol kinase; ~27% of aHUS manifesting before age 1 year) . CFHR3, CFHR1, and CFHR4; deletions involving CFHR1 and CFHR3 or CFHR1 and CFHR4 account for ~5%-15% of aHUS.


Treatment of manifestations: Eculizumab (a human anti-C5 monoclonal antibody) to treat aHUS and to induce remission of aHUS refractory or dependent to plasma therapy; plasma manipulation (plasma infusion or exchange) to reduce mortality; however, plasma resistance or plasma dependence is possible. Plasma manipulation and eculizumab therapy may not be beneficial to those with aHUS caused by mutations 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 it usefulness. Prevention of primary manifestations: Plasma exchange prophylaxis may prevent disease recurrences in those with mutation in CFH. Prevention of secondary complications: Eculizumab therapy may prevent thrombotic microangiopathic events and prophylactic treatment may prevent post-tranplantation aHUS recurrence; vaccination against Neisseria meningitidies, Streptococcus pneumonia, and Haemophilus influenza type B is required prior to eculizumab therapy; prophylactic antibiotics may be needed if vaccination against Neisseria meningitidies 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 mutation 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: anti-cancer molecules (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 aHUS flare during pregnancy and even a greater risk in the post-partum 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 disease-associated mutations have been identified, predictive testing based on a predisposing factor (as opposed to a causative mutation) is problematic as it is one of only several risk factors required for disease causation. 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 mutations but not in those with CFH, CFI, C3, THBD, or CFB mutations; however, simultaneous kidney and liver transplantation in young children with aHUS and CFH mutations may correct the genetic defect and prevent disease recurrence.


Predisposition to atypical HUS (aHUS) is inherited in an autosomal recessive or autosomal dominant manner with incomplete penetrance. Rarely digenic inheritance and uniparental isodisomy are observed. Autosomal recessive inheritance: Heterozygotes (carriers) are usually asymptomatic; however, rarely carriers have developed aHUS in adulthood. At conception, each sib of an individual with autosomal recessive aHUS has a 25% chance of inheriting two disease-causing mutations, a 50% chance of inheriting one mutation and being a carrier, and a 25% chance of inheriting neither mutation. 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 disease-causing mutation in an asymptomatic parent, early death of a parent, late onset in a parent (or close relative), or a de novo mutation in the proband. Each child of an individual with autosomal dominant aHUS has a 50% chance of inheriting the mutation. In both genetic types, clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression and outcome cannot be predicted. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-associated mutation(s) have been identified in the family.

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