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


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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    • "In general, the question why the glomerular endothelium is the main target of TMA is still unsolved. It is speculated that the specific fenestration of the glomerular endothelial cells leads to a higher susceptibility to complement activation and makes it more vulnerable to complement dysregulation as the glomerular basement membrane lacks surface bound complement regulators (2, 4, 12, 17). Moreover, the glomerular endothelial cell was shown to depend on vascular endothelial growth factor (VEGF) produced and secreted by podocytes allowing vascular endothelial regeneration and maintaining endothelial health (4, 18) (Figure 1). "
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    ABSTRACT: Thrombotic microangiopathies (TMA) are rare but severe disorders, characterized by endothelial cell activation and thrombus formation leading to hemolytic anemia, thrombocytopenia, and organ failure. Complement over activation in combination with defects in its regulation is described in an increasing number of TMA and if primary for the disease denominated as atypical hemolytic-uremic syndrome. Although TMA predominantly affects the renal microvasculature, extra-renal manifestations are observed in 20% of patients including involvement of the central nerve system, cardiovascular system, lungs, skin, skeletal muscle, and gastrointestinal tract. Prompt diagnosis and treatment initiation are therefore crucial for the prognosis of disease acute phase and the long-term outcome. This review summarizes the available evidence on extra-renal TMA manifestations and discusses the role of acute and chronic complement activation by highlighting its complex interaction with inflammation, coagulation, and endothelial homeostasis.
    Full-text · Article · Sep 2014 · Frontiers in Pediatrics
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    • "For example, recurrence among patients who had infection related variant of TMA (typical HUS) seems low. On the other hand, higher rates of recurrence are associated with the noninfection related or atypical variant of HUS (aHUS), where a clear link has been established to defects in regulation of the alternate complement pathway [8]. Mutations have been identified in complement factor H (CFH), complement factor I (CFI), matrix cofactor protein, and thrombomodulin [9]. "
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    ABSTRACT: In order to decrease the time on the deceased donor kidney wait list and to have more organs available, criteria for acceptable organs for transplant could be made less stringent. There are reports of successful recipient outcomes using kidney donors presenting with disseminated intravascular coagulation (DIC). We report a unique circumstance where two patients received kidneys from the same deceased donor who had DIC; one patient developed thrombotic microangiopathy (TMA) while the other did not. This difference in outcome may indicate that both donor and recipient factors contribute to the development of posttransplant TMA.
    Full-text · Article · Jun 2014
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    • "In a majority of non-pneumococcal aHUS cases, abnormal complement activation is responsible for the TMA, which can be efficiently controlled with daily or even twice-daily PE.21,77 Therefore, when aHUS is suspected, PE should be instituted immediately, as the diagnostic workup may be quite lengthy.21 "
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    ABSTRACT: Acute renal failure associated with a fulminant, life-threatening systemic disease is rare in previously healthy young children; however, when it occurs, the most common cause is hemolytic-uremic syndrome (HUS). In most cases (90%), this abrupt and devastating illness is a result of ingestion of food or drink contaminated with pathogens that produce very potent toxins. Currently, there are no proven treatment options that can directly inactivate the toxin or effectively interfere with the cascade of destructive events triggered by the toxin once it gains access to the bloodstream and binds its receptor. However, HUS is self-limited, and effective supportive management during the acute phase is proven to be a life saver for children affected by HUS. A minority of childhood HUS cases, approximately 5%, are caused by various genetic mutations causing uncontrolled activation of the complement system. These children, who used to have a poor prognosis leading to end-stage renal disease, now have access to exciting new treatment options that can preserve kidney function and avoid disease recurrences. This review provides a summary of the current knowledge on the epidemiology, pathophysiology, and clinical presentation of childhood HUS, focusing on a practical approach to best management measures.
    Full-text · Article · Jun 2014 · International Journal of Nephrology and Renovascular Disease
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