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      Genetic atypical hemolytic uremic syndrome in children: a 20-year experience from a tertiary center Translated title: Síndrome hemolítica urêmica atípica genética em crianças: uma experiência de 20 anos a partir de um centro terciário

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          Abstract

          Introduction:

          Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, which primarily affects preschool-aged children. This study’s aim was to describe the clinical profile, management, and long-term outcome of the genetic aHUS patients admitted to a tertiary care pediatric nephrology center during 20 years.

          Methods:

          We performed a retrospective analysis of the clinical records of all aHUS patients younger than 18 years with identified genetic mutations. Data on clinical features, genetic study, therapeutic interventions, and long-term outcomes were reviewed.

          Results:

          Five cases of aHUS with an identified genetic mutation were included; all were inaugural cases with the youngest being 4 months old. Complement factor H gene mutation was identified in four patients. Therapeutic plasma exchange was performed for acute management in 4 patients, one of whom also needed acute renal replacement therapy (peritoneal dialysis). All patients went on complete remission, 2 had more than one relapse but only 1 of these progressed to chronic kidney disease during the follow-up period (median (25th-75th percentile), 136 (43.5-200.5) months).

          Conclusion:

          In children, the prognosis of renal function seems to be strongly dependent on the genetic background, thus being crucial to perform genetic study in all aHUS cases. In our cohort, 2 patients presented genetic mutations not previously described. Recent innovations on the genetic field leading to the identification of new mutations has lead to a better understanding of aHUS pathogenesis, but further studies, focusing on the genotype-phenotype correlation, with longer follow-up periods, are needed.

          Resumo

          Introdução:

          A síndrome hemolítica urêmica atípica (SHUa) é um distúrbio raro caracterizado pela tríade de anemia hemolítica microangiopática, trombocitopenia e lesão renal aguda, afetando principalmente crianças em idade pré-escolar. O objetivo deste estudo foi descrever perfil clínico, manejo e desfecho em longo prazo dos pacientes com SHUa genética admitidos em um centro terciário de nefrologia pediátrica durante 20 anos.

          Métodos:

          Realizamos análise retrospectiva dos registros clínicos de todos os pacientes com SHUa menores de 18 anos com mutações genéticas identificadas. Revisaram-se dados sobre características clínicas, estudo genético, intervenções terapêuticas e desfechos em longo prazo.

          Resultados:

          Incluíram-se cinco casos de SHUa com uma mutação genética identificada; sendo todos casos inaugurais, o mais jovem tendo 4 meses de idade. A mutação no gene do fator H do complemento foi identificada em quatro pacientes. Plasmaférese terapêutica foi realizada para tratamento agudo em 4 pacientes, um dos quais também necessitou terapia renal substitutiva aguda (diálise peritoneal). Todos os pacientes tiveram remissão completa, 2 mais de uma recidiva, mas apenas 1 evoluiu para doença renal crônica durante acompanhamento (mediana (percentil 25°-75°), 136 (43,5-200,5) meses).

          Conclusão:

          Em crianças, o prognóstico da função renal parece ser fortemente dependente do histórico genético, sendo crucial realizar estudo genético em todos os casos de SHUa. Em nossa coorte, 2 pacientes apresentaram mutações genéticas não descritas anteriormente. Inovações recentes no campo genético que levaram à identificação de novas mutações conduziram a um melhor entendimento da patogênese SHUa, mas são necessários mais estudos, focando na correlação genótipo-fenótipo, com períodos de acompanhamento mais longos.

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          Most cited references19

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          Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents

          These pediatric hypertension guidelines are an update to the 2004 "Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents." Significant changes in these guidelines include (1) the replacement of the term "prehypertension" with the term "elevated blood pressure," (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.
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            New equations to estimate GFR in children with CKD.

            The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.
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              An international consensus approach to the management of atypical hemolytic uremic syndrome in children.

              Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.
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                Author and article information

                Journal
                J Bras Nefrol
                J Bras Nefrol
                jbn
                Jornal Brasileiro de Nefrologia
                Sociedade Brasileira de Nefrologia
                0101-2800
                2175-8239
                12 May 2021
                Jul-Sep 2021
                : 43
                : 3
                : 311-317
                Affiliations
                [1 ]Hospital de Braga, Departamento de Pediatria, Braga, Portugal.
                [2 ]Centro Hospitalar Tondela-Viseu, Departamento de Nefrologia, Viseu, Portugal.
                [3 ]Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do Norte, Departamento de Pediatria, Porto, Portugal.
                [4 ]Centro Hospitalar do Tâmega e Sousa, Departamento de Pediatria, Penafiel, Portugal.
                [5 ]Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do Norte, Unidade de Nefrologia Pediátrica, Porto, Portugal.
                [6 ]Universidade do Porto, Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal.
                [7 ]Universidade do Porto, Instituto de Saúde Pública, Porto, Portugal.
                [8 ]Universidade Nova de Lisboa, REQUIMTE, Unidade de Investigação em Biociências Moleculares Aplicadas, Porto, Portugal.
                Author notes
                Correspondence to: Cristiana Maximiano. E-mail: cristiana.maximiano@ 123456gmail.com

                Author’s Contribution

                Cristiana Maximiano principal Project Leader, conceived study, participated in design and coordination, read and approved the final manuscript. Andreia Silva, Inês Duro, Tiago Branco, Liane Correia-Costa, Ana Teixeira, Liliana Rocha, Teresa Costa, Paula Matos participated in design and coordination, undertook interviews, helped to draft the manuscript, read and approved the final manuscript. Maria do Sameiro Faria, Conceição Mota, Alberto Caldas Afonso analyzed the data and approved the final manuscript.

                Conflict of Interest

                No conflict of interest has been declared by the author(s).

                Author information
                http://orcid.org/0000-0001-9916-925X
                http://orcid.org/0000-0002-5417-2188
                http://orcid.org/0000-0002-1870-2727
                http://orcid.org/0000-0002-2825-4606
                http://orcid.org/0000-0002-8216-090X
                http://orcid.org/0000-0001-5211-2467
                http://orcid.org/0000-0002-1393-852X
                http://orcid.org/0000-0003-2230-6871
                http://orcid.org/0000-0003-1819-5275
                http://orcid.org/0000-0002-8061-9289
                http://orcid.org/0000-0002-4741-0002
                http://orcid.org/0000-0001-6776-9883
                Article
                10.1590/2175-8239-JBN-2020-0199
                8428634
                33988670
                ba1b014c-d91d-4dc9-b3c4-21690daef3a8

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 September 2020
                : 23 February 2021
                Categories
                Original Article

                atypical hemolytic uremic syndrome,child,genetic testing,thrombotic microangiopathies,síndrome hemolítico-urêmica atípica,criança,testes genéticos,microangiopatias trombóticas

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