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      Long-term outcomes of the Atypical Hemolytic Uremic Syndrome after kidney transplantation treated with eculizumab as first choice

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          Abstract

          Introduction

          The treatment of choice for Atypical Hemolytic Uremic Syndrome (aHUS) is the monoclonal antibody eculizumab. The objective of this study was to assess the efficacy and safety of eculizumab in a cohort of kidney transplant patients suffering from aHUS.

          Methods

          Description of the prospective cohort of all the patients primarily treated with eculizumab after transplantation and divided into the therapeutic (onset of aHUS after transplantation) and prophylactic use (patients with previous diagnosis of aHUS undergoing kidney transplantation).

          Results

          Seven cases were outlined: five of therapeutic use and two, prophylactic. From the five cases of therapeutic use, there was improvement of the thrombotic microangiopathy in the 48 hours following the start of the drug and no patient experienced relapse during an average follow-up of 21 months in the continuous use of eculizumab (minimum of 6 and maximum of 42 months). One patient died at 6 months, due to Aspergillus infection. From the two cases of prophylactic use, one patient experienced relapsed thrombotic microangiopathy after 4 months and another patient remained asymptomatic after 16 months of follow-up, both on chronic treatment.

          Discussion

          The therapeutic use of eculizumab showed to be effective, with improvement of the microangiopathy parameters and persisting up to the end of the follow-up, without relapses. The additional risk of immunosuppression, leading to opportunistic infections, was well tolerated. The prophylactic use showed to be effective and safe; however, the doses and intervals should be individualized in order to avoid relapsed microangiopathy, especially in patients with factor H mutation.

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          Most cited references28

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          Atypical hemolytic-uremic syndrome.

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

            Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non-Shiga toxin-associated HUS (non-Stx-HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx-HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.
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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

                Contributors
                Role: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curation
                Role: Data curation
                Role: Formal analysis
                Role: Data curation
                Role: Writing – review & editing
                Role: Data curation
                Role: Writing – review & editing
                Role: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 November 2017
                2017
                : 12
                : 11
                : e0188155
                Affiliations
                [1 ] Department of Internal Medicine, University São Paulo State(UNESP), Botucatu, São Paulo State, Brazil
                [2 ] Department of Internal Medicine, Hospital Estadual de Bauru, Bauru, São Paulo State, Brazil
                [3 ] Department of Internal Medicine, University of São Paulo (USP), São Paulo, São Paulo State, Brazil
                [4 ] Department of Internal Medicine, University of Campinas (UNICAMP), Campinas, São Paulo State, Brazil
                University of Toledo, UNITED STATES
                Author notes

                Competing Interests: Palma LMP is a speaker for Alexion Pharma. Chagas KDN is Associate Medical Director of Alexion Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                [¤]

                Current address: Department of Internal Medicine, University São Paulo State (UNESP), Botucatu/SP, Brazil

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-0230-0766
                Article
                PONE-D-17-15507
                10.1371/journal.pone.0188155
                5685617
                29136640
                461a538d-e08b-4545-804a-3b298a27fb22
                © 2017 de Andrade et al

                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 author and source are credited.

                History
                : 21 April 2017
                : 1 November 2017
                Page count
                Figures: 1, Tables: 3, Pages: 14
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Renal Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Urinary System Procedures
                Renal Transplantation
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Public and Occupational Health
                Preventive Medicine
                Prophylaxis
                Medicine and Health Sciences
                Infectious Diseases
                Opportunistic Infections
                Medicine and Health Sciences
                Urology
                Urinary Tract Infections
                Biology and Life Sciences
                Genetics
                Gene Identification and Analysis
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Biology and Life Sciences
                Biochemistry
                Proteins
                Hemoglobin
                Custom metadata
                All relevant data are within the paper and in the Supporting Information files.

                Uncategorized
                Uncategorized

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