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      Atypical hemolytic uremic syndrome in Brazil: clinical presentation, genetic findings and outcomes of a case series in adults and children treated with eculizumab

      research-article
      1 , 2 , 3 , 4 , 5 , the Brazilian Thrombotic Microangiopathy and Atypical Hemolytic Uremic Syndrome Study Group (aHUS Brazil)
      Clinical Kidney Journal
      Oxford University Press
      atypical hemolytic uremic syndrome, eculizumab, plasma exchange, thrombotic microangiopathy

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          Abstract

          Background

          Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and kidney injury caused by a dysregulation of the alternative complement pathway.

          Methods

          We conducted a multicenter nonregistry study aimed at collecting clinical, laboratory and genetic information of patients with aHUS in Brazil. Demographic data, genetic findings, treatments and outcomes are presented.

          Results

          Thirty-four patients were included, 62% were female and 67% were Caucasian. Half of the patients had the first manifestation of aHUS before the age of 18 years (pediatric group). Among the 17 patients who had the first manifestation after the age of 18 years (adult group), 6 were kidney transplant patients. Overall, 22 patients (65%) received plasma exchange/plasma infusion (PE/PI) and 31 patients (91%) received eculizumab. Eculizumab was started later in the adult group compared with the pediatric group. Two patients stopped dialysis after PE/PI and 19 patients stopped dialysis after eculizumab despite a late start. A pathogenic/likely pathogenic variant was found in 24.3% of patients. A coexisting condition or trigger was present in 59% of patients (infections, pregnancy, hypertension, autoimmune disease and transplant), especially in the adult group. There was a 30% relapse rate after stopping eculizumab, irrespective of genetic status.

          Conclusion

          This is the largest case series of aHUS in Brazil involving a wide range of patients for which eculizumab was the main treatment. Although eculizumab was started later than advised in the guidelines, most patients were able to stop dialysis at variable intervals. Discontinuation of eculizumab was associated with a 30% relapse of aHUS.

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          Most cited references43

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            Atypical hemolytic-uremic syndrome.

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              Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

              In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
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                Author and article information

                Journal
                Clin Kidney J
                Clin Kidney J
                ckj
                Clinical Kidney Journal
                Oxford University Press
                2048-8505
                2048-8513
                April 2021
                22 June 2020
                22 June 2020
                : 14
                : 4
                : 1126-1135
                Affiliations
                [1 ] Pediatric Nephrology, State University of Campinas , Campinas, Brazil
                [2 ] Department of Nephrology, Hospital Moinhos de Vento , Porto Alegre, Brazil
                [3 ] Pediatric Nephrology, Hospital Barão de Lucena , Recife, Brazil
                [4 ] Pediatric Nephrology, Hospital Materno-Infantil , Goiania, Brazil
                [5 ] Department of Nephrology, Hospital Federal de Bonsucesso , Rio de Janeiro, Brazil
                Author notes
                Correspondence to: Lilian Monteiro Pereira Palma; E-mail: lilianp@ 123456unicamp.br
                Author information
                http://orcid.org/0000-0002-0334-8470
                Article
                sfaa062
                10.1093/ckj/sfaa062
                8023178
                33841858
                46e52b63-2802-4544-a96b-8eec1b27d115
                © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 02 January 2019
                : 27 March 2020
                Page count
                Pages: 10
                Categories
                Original Articles
                AcademicSubjects/MED00340

                Nephrology
                atypical hemolytic uremic syndrome,eculizumab,plasma exchange,thrombotic microangiopathy

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