Factor I Autoantibodies in Patients with Atypical Hemolytic Uremic Syndrome

Kavanagh, David; Pappworth, Isabel Y.; Anderson, Holly E.; Hayes, Christine; Moore, Iain; Hunze, Eva Maria; Bennaceur, K.; Roversi, Pietro; Lea, Susan M.; Strain, Lisa; Ward, Roy; Plant, Nick; Nailescu, Corina; Goodship, Timothy H.J.; Marchbank, Kevin J.

doi:10.2215/cjn.05750611

Cited by 58 publications

(36 citation statements)

References 52 publications

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“…It predominantly presents in childhood, frequently with a gastrointestinal prodrome. Autoantibodies against FI have also been reported, but they are rare and their functional relevance remains to be established (23).…”

Section: Acquired Complement-mediated Ahusmentioning

confidence: 99%

Thrombotic Microangiopathy and the Kidney

Brocklebank

Wood

Kavanagh

2017

CJASN

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289

288

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Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive management and, in some cases, effective specific treatment can result in good outcomes. This review considers the classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, and outlines a pragmatic approach to diagnosis and management.

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Section: Acquired Complement-mediated Ahusmentioning

confidence: 99%

Thrombotic Microangiopathy and the Kidney

Brocklebank

Wood

Kavanagh

2017

CJASN

Self Cite

289

288

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“…Some antibodies bind to other regions or FH and the significance of these in disease are less certain (79). Antibodies have been described against FI in a few cases (80). The functional significance of these has not been confirmed.…”

Section: Limitations Of Eculizumab In Pnhmentioning

confidence: 99%

Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome

Wong

Kavanagh

2015

Translational Research

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The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor somatic mutations lead to a population of peripheral blood cells that are deficient in complement regulators resulting in hemolysis and thrombosis. In aHUS, germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation resulting in thrombotic microangiopathy and renal failure. Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS.

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“…Screening for C autoantibodies was undertaken using ELISA as described previously. 37,38 Genetic Analysis and Multiplex Ligation-Dependent Probe Amplification…”

Section: Assaysmentioning

confidence: 99%

Thrombotic Microangiopathy in Inverted Formin 2–Mediated Renal Disease

Challis¹,

Ring

Xu³

et al. 2016

JASN

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The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-« have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had CharcotMarie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionallysignificant mutation in INF2. In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.

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Factor I Autoantibodies in Patients with Atypical Hemolytic Uremic Syndrome

Cited by 58 publications

References 52 publications

Thrombotic Microangiopathy and the Kidney

Thrombotic Microangiopathy and the Kidney

Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome

Thrombotic Microangiopathy in Inverted Formin 2–Mediated Renal Disease

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