Atypical Hemolytic-Uremic Syndrome

Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
DOI: 10.1056/NEJMra0902814 In book: GeneReviews™, Publisher: University of Washington, Seattle, Editors: Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam
Source: PubMed

ABSTRACT 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 a disease-causing mutation(s) is identified in one of the nine genes in which mutations are known to be associated with aHUS, irrespective of familial history. The nine genes are: CFH (encoding complement factor H), accounting for an estimated 30% of aHUS; CD46 (MCP) (encoding membrane cofactor protein) accounting for approximately 12% of aHUS; CFI (encoding complement factor I), accounting for an estimated 5%-10% of aHUS; C3 (encoding the third component of complement C3) accounting for 5% of aHUS; rarely, CFB (encoding complement factor B); and THBD (encoding thrombomodulin) accounting for about 5% of aHUS. Deletions involving CFHR1 and CFHR3 or CFHR1 and CFHR4 account for 5%-15% of aHUS.
Treatment of manifestations: Plasma manipulation (plasma infusion or exchange) to reduce mortality; however, plasma resistance or plasma dependence is possible. Bilateral nephrectomy when extensive renal microvascular thrombosis, refractory hypertension, and signs of hypertensive encephalopathy are not responsive to conventional therapies including plasma manipulation. 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 mutation-positive relatives 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. Evaluation of relatives at risk: While it is appropriate to offer molecular genetic testing to at-risk family members 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 mutations but not in those with CFH, CFI, 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) has (have) been identified in the family.

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    ABSTRACT: Thrombotic microangiopathies (TMAs) comprise a group of distinct disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. For many years distinction between these TMAs, especially between thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), remained purely clinical and hard to make. Recent discoveries shed light on different pathogenesis of TTP and HUS. Ultra-large von Willebrand factor (UL-VWF) platelet thrombi, resulting from the deficiency of cleavage protease which is now known as ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), were found to cause TTP pathology, while Shiga toxins or abnormalities in regulation of the complement system cause microangiopathy and thrombosis in HUS. TMAs may appear in various conditions such as pregnancy, inflammation, malignancy, or exposure to drugs. These conditions might cause acquired TTP, HUS, or other TMAs, or might be a trigger in individuals with genetic predisposition to ADAMTS-13 or complement factor H deficiency. Differentiation between these TMAs is highly important for urgent initiation of appropriate therapy. Measurement of ADAMTS-13 activity and anti-ADAMTS-13 antibody levels may advance this differentiation resulting in accurate diagnosis. Additionally, assessment of ADAMTS-13 levels can be a tool for monitoring treatment efficacy and relapse risk, allowing consideration of therapy addition or change. In the past few years, great improvements in ADAMTS-13 assays have been made, and tests with increased sensitivity, specificity, reproducibility, and shorter turnaround time are now available. These new assays enable ADAMTS-13 measurement in routine clinical diagnostic laboratories, which may ultimately result in improvement of TMA management.
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    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) can be distinguished from typical or Shiga-like toxin-induced HUS. The clinical outcome is unfavorable; up to 50% of affected patients progress to end-stage renal failure and 25% die during the acute phase. Multiple conditions have been associated with aHUS, including infections, drugs, autoimmune conditions, transplantation, pregnancy, and metabolic conditions. aHUS in the nontransplant postsurgical period, however, is rare. An 8-month-old boy underwent surgical repair of tetralogy of Fallot. Neurological disturbances, acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia developed 25 days later, and aHUS was diagnosed. Further evaluation revealed that his complement factor H (CFH) level was normal and that anti-FH antibodies were not detected in his plasma. Sequencing of his CFH, complement factor I, membrane cofactor protein, complement factor B, and thrombomodulin genes was normal. His ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin-1 repeats 13) activity was also normal. However, he had a potentially causative mutation (R425C) in complement component C3. Restriction fragment length polymorphism analysis revealed that his father and aunt also had this mutation; however, they had no symptoms of aHUS. We herein report a case of aHUS that developed after cardiovascular surgery and was caused by a complement C3 mutation.
    Case reports in nephrology. 01/2014; 2014:784943.
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    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by over-activation and dysregulation of the alternative complement pathway. Its estimated prevalence is 1-2 per million. The disease is characterized by thrombotic microangiopathy, which causes anemia, thrombocytopenia, and acute renal failure. aHUS has more severe course compared to typical (infection-induced) HUS and is frequently characterized by relapses that leads to end stage renal disease. For a long time, kidney transplantation for these patients was contraindicated because of high rate of recurrence and subsequent renal graft loss. The post-kidney transplantation recurrence rate largely depends on the pathogenetic mechanisms involved. However, over the past several years, advancements in the understanding and therapeutics of aHUS have allowed successful kidney transplantation in these patients. Eculizumab, which is a complement C5 antibody that inhibits complement factor 5a and subsequent formation of the membrane-attack complex, has been used in prevention and treatment of post-transplant aHUS recurrence. In this paper, we present two new cases of aHUS patients who underwent successful kidney transplantation in our center with the use of prophylactic and maintenance eculizumab therapy that have not been published before. The purpose of reporting these two cases is to emphasize the importance of using eculizumab as a prophylactic therapy to prevent aHUS recurrence post-transplant in high-risk patients. We will also review the current understanding of the genetics of aHUS, the pathogenesis of its recurrence after kidney transplantation, and strategies for prevention and treatment of post-transplant aHUS recurrence.
    Frontiers in medicine. 01/2014; 1:52.

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