Deficiency of CFHR plasma proteins and autoantibody positive hemolytic uremic syndrome: treatment rationale, outcomes, a
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REVIEW
Deficiency of CFHR plasma proteins and autoantibody positive hemolytic uremic syndrome: treatment rationale, outcomes, and monitoring Franca Iorember 1
&
Anjali Nayak 1
Received: 29 February 2020 / Revised: 30 May 2020 / Accepted: 4 June 2020 # IPNA 2020
Abstract Deficiency of Complement Factor H Related (CFHR) plasma proteins and Autoantibody Positive Hemolytic Uremic Syndrome (DEAP-HUS) is a subtype of atypical hemolytic uremic syndrome, known to be associated with significant morbidity. Its pathogenesis is linked to the production of IgG autoantibodies against complement factor H, a regulator of the alternative complement pathway. The binding of the autoantibodies to the C terminal of complement factor H interferes with its regulatory function, leading to increased activation of the alternative complement pathway and consequent endothelial cellular damage. Early diagnosis and initiation of appropriate therapy is reported to lead to favorable outcomes. Institution of plasma exchange therapy within 24 h of diagnosis has been shown to rapidly lower antibody levels, leading to clinical improvement. Adjunctive immunosuppression therapy suppresses antibody production and helps in maintaining long-term clinical remission of the disease. Available data advocates a treatment regimen that combines plasma therapy (preferably plasma exchange) and immunosuppression to halt disease process and sustain long-term disease remission. Keywords DEAP-HUS . Alternative complement pathway . Complement activation . Hemolytic uremic syndrome
Introduction Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The atypical form of the disease, aHUS, often refers to the non-Shiga toxin, non-streptococcal infection–associated HUS. Up to 60% of cases of aHUS have been linked to uncontrolled complement activation due to either genetic mutations in the alternative complement pathway or the presence of autoantibodies to complement factor H (CFH) [1, 2]. Autoantibodies to CFH are responsible for approximately 10% of cases [2], although prevalence greatly varies among countries, with up to 50% in India, 29% in the Korean population, and 5–25% in European cohorts [3, 4]. Gene mutations in the activators or regulators of the alternative complement
* Franca Iorember [email protected] 1
Division of Nephrology, Phoenix Children’s Hospital, Phoenix, AZ, USA
pathway including CFH, membrane cofactor protein (CD46), factors I and B, C3 convertase components and C3, may occur [5–8]. Mutations in the thrombomodulin gene have been recently reported to also lead to aHUS [9]. The effect of these gene mutations on regulatory proteins leads to dysregulation of the alternative complement pathway, causing HUS. A unique subtype of aHUS is the deficiency of CFHR plasma proteins and factor H autoantibody positive hemolytic uremic syndrome (DEAP–HUS), which is unique in that a deletion of genes encoding FH-related proteins
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