Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

Caprioli, Jessica; Noris, Marina; Brioschi, Simona; Pianetti, Gaia; Castelletti, Federica; Bettinaglio, Paola; Mele, Caterina; Bresin, Elena; Cassis, Linda; Gamba, Sara; Porrati, Francesca; Bucchioni, Sara; Monteferrante, Giuseppe; Fang, Celia J.; Liszewski, M. Kathryn; Kavanagh, David; Atkinson, John P.; Remuzzi, Giuseppe

doi:10.1182/blood-2005-10-007252

Cited by 667 publications

(821 citation statements)

References 51 publications

Supporting

Mentioning

736

Contrasting

Unclassified

Order By: Relevance

“…In mutation carriers, aHUS penetrance is approximately 50%, suggesting that other genetic or environmental modifiers are needed for disease expression (3). Identification of mutations or autoantibodies is important owing to differences in renal survival, outcome of renal transplantation, and mortality (14,15).…”

Section: H Emolytic Uremic Syndrome (Hus) Is a Clinical Triad Ofmentioning

confidence: 99%

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Mache

Acham-Roschitz

Frémeaux‐Bacchi

et al. 2009

Clinical Journal of the American Society of Nephrology

143

103

View full text Add to dashboard Cite

Background and objectives: Atypical hemolytic uremic syndrome (aHUS) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage. Eculizumab, a humanized mAb against complement protein C5, inhibits activation of the terminal complement pathway.Design, setting, participants, & measurements: We report an adolescent with relapsing unclassified aHUS. On admission, a high plasma creatinine level indicated a poor prognosis, and hemodialysis had to be started. Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk. Subsequently, plasma exchanges (three times per week) failed to prevent ongoing aHUS activity and progressive renal failure. After 12 wk, aHUS treatment was switched to eculizumab.Results: Eculizumab was effective in terminating the microangiopathic hemolytic process in two aHUS relapses; however, after normalization of complement activity, aHUS recurred and ultimately led to anuric end-stage renal failure.Conclusions: In this patient, complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity. Nevertheless, renal damage as a result of preceding and subsequent aHUS activity resulted in end-stage renal failure; therefore, therapeutic success may depend on early administration of eculizumab. The optimal duration of treatment may be variable and remains to be determined.

show abstract

Section: H Emolytic Uremic Syndrome (Hus) Is a Clinical Triad Ofmentioning

confidence: 99%

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Mache

Acham-Roschitz

Frémeaux‐Bacchi

et al. 2009

Clinical Journal of the American Society of Nephrology

143

103

View full text Add to dashboard Cite

show abstract

“…Penetrance is also incomplete in aHUS, and seems to be 40%-50% among carriers of CFH, membrane cofactor protein (MCP), and CFI mutations [25]; healthy carriers of C3 and CFB mutations have also been described [26,27]. There are numerous reports describing the onset of aHUS symptoms in association with an environmental trigger.…”

Section: Epidemiology and Clinical Presentationmentioning

confidence: 99%

“…There are numerous reports describing the onset of aHUS symptoms in association with an environmental trigger. Infectious diseases have been associated with 22%-55% of clinical cases of patients with mutations in CFH, MCP, CFI or C3 25 and diarrhoea (including STEC diarrhoea) may also precede aHUS in as many as 30% of cases [28,29]. Pregnancy, drugs, malignancy, connective tissue disorders and specific metabolic defects are also known triggers [30].…”

Section: Epidemiology and Clinical Presentationmentioning

confidence: 99%

“…Age of initial onset of aHUS is approximately equal in adults and children [28,29] and distribution is similar between males and females, although there is a slight predominance in females among adult onset patients [28]. Prognosis is poor with a mortality up to 25% and over half of patients developing ESRD after the first presentation of aHUS [12,17,25,46,47].…”

Section: Hus: Stec-hus and Ahusmentioning

confidence: 99%

“…While PE initially manages haematological symptoms in some patients, up to 65% of aHUS patients require dialysis, develop permanent kidney damage or die within 1 year despite PE or plasma infusion (PI) [25]. However, haematologic improvement does not mean that TMA is not ongoing in organs, and unlike in the treatment of TTP, it has been demonstrated that the use of PE in aHUS is mostly ineffective [46].…”

Section: Treatment Treatment Of Ahusmentioning

confidence: 99%

See 2 more Smart Citations

Atypical hemolytic uremic syndrome: from diagnosis to treatment

Franchini¹

2015

Clinical Chemistry and Laboratory Medicine (CCLM)

View full text Add to dashboard Cite

Thrombotic microangiopathy (TMA) is a relatively rare condition but a medical urgency requiring immediate intervention to avoid irreversible organ damage or death. Symptoms on presentation include microangiopathic haemolytic anaemia, thrombocytopenia and organ damage. The most frequent direct causes of TMA are thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). The most common form of HUS is related to Shiga toxin producing Escherichia coli (STEC) infection while approximately 10% of cases are due to dysregulation of the complement pathway (atypical haemolytic uremic syndrome, aHUS). Optimal treatment regimens differ depending on the underlying cause; however, differential diagnosis may be difficult. The most accurate method of diagnosis is based on exclusion and should consider, beyond the symptoms common to TMA, ADAMTS13 activity levels and STEC infection status. For the management of TTP, plasma exchange (PE) is the most important acute intervention and is associated with lower mortality and better outcomes than plasma infusion. In most patients with STEC-HUS, the course of disease is selflimiting although management of acute kidney injury is often required. Until recently, the management of aHUS consisted of early and intensive PE, although this was mostly ineffective in protecting from subsequent organ damage. Eculizumab, an inhibitor of the alternative complement pathway, produces a rapid and sustained inhibition of the TMA process, with significant improvements in long-term clinical outcomes. Due to the significant improvement achieved, eculizumab has subsequently been approved as first-line therapy when an unequivocal diagnosis of aHUS has been made.

show abstract

Clinical Evaluation of 3 Families With Basal Laminar Drusen Caused by Novel Mutations in the Complement Factor H Gene

Ven¹,

Boon²,

Fauser³

et al. 2012

Arch Ophthalmol

View full text Add to dashboard Cite

Elucidation of the clinical BLD phenotype will facilitate identification of individuals predisposed to developing disease-related comorbidity, such as membranoproliferative glomerulonephritis type II. Moreover, with upcoming treatment modalities targeting specific components of the complement system, early identification of patients with BLD and detection of the genetic defect become increasingly important.

show abstract

Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

Cited by 667 publications

References 51 publications

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome: from diagnosis to treatment

Clinical Evaluation of 3 Families With Basal Laminar Drusen Caused by Novel Mutations in the Complement Factor H Gene

Contact Info

Product

Resources

About