Publications by authors named "Chantal Loirat"

116 Publications

Eculizumab discontinuation in children and adults with atypical haemolytic uremic syndrome: a prospective multicentric study.

Blood 2020 Dec 3. Epub 2020 Dec 3.

Assistance Publique - Hôpitaux de Paris, paris, France.

The optimal duration of eculizumab treatment in patients with atypical haemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicentric open-label study in order to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean duration of treatment, 16.5 months). Twenty-eight (51%) patients had complement gene rare variants, mostly in MCP (n= 12, 22%), CFH (n= 6, 11%) and CFI (n=6, 10%) genes. At eculizumab discontinuation, 17 (30%) and 4 (7%) patients had chronic kidney disease stage 3 and 4, respectively. During follow-up, 13 (23%) patients (6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female gender and the presence of a rare complement gene variant were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during previous episodes of acute aHUS was not. In addition, an increased soluble C5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers of complement gene rare variants, in log rank test and in multivariable analysis. Among the 13 relapsing patients, who were all restarted on eculizumab, 11 regained their baseline renal function and two had a worsening of their pre-existing chronic kidney disease, including one patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. Trail registration number: NCT02574403.
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http://dx.doi.org/10.1182/blood.2020009280DOI Listing
December 2020

Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group.

Blood 2020 Nov;136(19):2103-2117

Maternité Port-Royal, Hôpital Cochin, Université de Paris/AP-HP, Fighting Prematurity University Hospital Federation (FHU PREMA), INSERM UMR 1139, Paris, France.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.
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http://dx.doi.org/10.1182/blood.2020005221DOI Listing
November 2020

Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome.

J Am Soc Nephrol 2019 12 1;30(12):2449-2463. Epub 2019 Oct 1.

French Study Group of Atypical Hemolytic Uremic Syndrome, France.

Background: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.

Methods: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (=397) between 2007 and 2016.

Results: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.

Conclusions: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.
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http://dx.doi.org/10.1681/ASN.2019040331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900783PMC
December 2019

Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing , an overview of 10 years of surveillance in France, 2007 to 2016.

Euro Surveill 2019 Feb;24(8)

Santé publique France, Saint Maurice, France.

IntroductionHaemolytic uraemic syndrome (HUS) related to Shiga toxin-producing (STEC) is the leading cause of acute renal failure in young children. In France, HUS surveillance in children aged < 15 years was implemented starting from 1996.AimWe present the results of this surveillance between 2007 and 2016.MethodsA voluntary nationwide network of 32 paediatric departments notifies cases. Two national reference centres perform microbiological STEC confirmation.ResultsOver the study period, the paediatric HUS incidence rate (IR) was 1.0 per 100,000 children-years, with a median of 116 cases/year. In 2011, IR peaked at 1.3 per 100,000 children-years, and decreased to 1.0 per 100,000 children-years in 2016. STEC O157 associated HUS peaked at 37 cases in 2011 and decreased to seven cases in 2016. Cases of STEC O26-associated HUS have increased since 2010 and STEC O80 associated HUS has emerged since 2012, with 28 and 18 cases respectively reported in 2016. Four STEC-HUS food-borne outbreaks were detected (three STEC O157 linked to ground beef and raw-milk cheese and one STEC O104 linked to fenugreek sprouts). In addition, two outbreaks related to person-to-person transmission occurred in distinct kindergartens (STEC O111 and O26).ConclusionsNo major changes in HUS IRs were observed over the study period of 10 years. However, changes in the STEC serogroups over time and the outbreaks detected argue for continuing epidemiological and microbiological surveillance.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.8.1800068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446949PMC
February 2019

Successful treatment of a associated haemolytic uraemic syndrome by eculizumab.

Clin Kidney J 2019 Feb 20;12(1):106-109. Epub 2018 Mar 20.

Department of Nephrology and Kidney Transplantation, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.

Haemolytic uraemic syndrome (HUS) is a rare complication of invasive infection by (SP-HUS), especially in adults. Here we report an unusual case of a 53-year-old man presenting SP-HUS with severe multivisceral involvement. After failure of supportive care and plasma exchanges, eculizumab (anti-C5 antibody) resulted in a favourable outcome.
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http://dx.doi.org/10.1093/ckj/sfy019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366139PMC
February 2019

Complement Gene Variants and Shiga Toxin-Producing -Associated Hemolytic Uremic Syndrome: Retrospective Genetic and Clinical Study.

Clin J Am Soc Nephrol 2019 03 23;14(3):364-377. Epub 2019 Jan 23.

Pediatric Nephrology Department.

Background And Objectives: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS.

Design, Setting, Participants, & Measurements: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project.

Results: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; =0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant.

Conclusions: Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.
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http://dx.doi.org/10.2215/CJN.05830518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419292PMC
March 2019

Anticomplement Treatment in Atypical and Typical Hemolytic Uremic Syndrome.

Semin Hematol 2018 07 20;55(3):150-158. Epub 2018 Apr 20.

Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address:

The dissection of the pathogenic mechanisms of the various forms of the hemolytic uremic syndrome (HUS) has paved the way for the design of specific efficacious treatments. Such mechanistic approach led to a revolution in the management of atypical HUS with the use of the first-in class C5 blocker, eculizumab. The availability of this anticomplement drug has also raised unsettled questions regarding the cost or burden and optimal duration of therapy and its use in secondary HUS. The efficacy of eculizumab in Shiga toxin producing Escherichia coli-associated HUS is not to date established and the results of ongoing prospective studies are eagerly awaited. Nevertheless, the emergence of anticomplement therapies (eculizumab and other drugs in development) has transformed our approach of HUS.
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http://dx.doi.org/10.1053/j.seminhematol.2018.04.009DOI Listing
July 2018

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy.

Am J Kidney Dis 2018 07 9;72(1):84-92. Epub 2018 Feb 9.

Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

Background: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab.

Study Design: Case series of C3 glomerulopathy.

Setting & Participants: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada.

Outcomes: Global or partial clinical renal response.

Measurements: Evolution of serum creatinine and proteinuria values.

Results: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders.

Limitations: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases.

Conclusions: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.
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http://dx.doi.org/10.1053/j.ajkd.2017.11.019DOI Listing
July 2018

Hemolytic Uremic Syndrome in Pregnancy and Postpartum.

Clin J Am Soc Nephrol 2017 Aug 8;12(8):1237-1247. Epub 2017 Jun 8.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background: Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation.

Design, Setting, Participants, & Measurements: We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome.

Results: Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the (30%) and genes (9%).

Conclusions: Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.
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http://dx.doi.org/10.2215/CJN.00280117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544502PMC
August 2017

Haemolytic uraemic syndrome.

Lancet 2017 Aug 25;390(10095):681-696. Epub 2017 Feb 25.

Assistance Publique-Hôpitaux de Paris, Department of Pediatric Nephrology, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address:

Haemolytic uraemic syndrome is a form of thrombotic microangiopathy affecting predominantly the kidney and characterised by a triad of thrombocytopenia, mechanical haemolytic anaemia, and acute kidney injury. The term encompasses several disorders: shiga toxin-induced and pneumococcus-induced haemolytic uraemic syndrome, haemolytic uraemic syndrome associated with complement dysregulation or mutation of diacylglycerol kinase ɛ, haemolytic uraemic syndrome related to cobalamin C defect, and haemolytic uraemic syndrome secondary to a heterogeneous group of causes (infections, drugs, cancer, and systemic diseases). In the past two decades, experimental, genetic, and clinical studies have helped to decipher the pathophysiology of these various forms of haemolytic uraemic syndrome and undoubtedly improved diagnostic approaches. Moreover, a specific mechanism-based treatment has been made available for patients affected by atypical haemolytic uraemic syndrome due to complement dysregulation. Such treatment is, however, still absent for several other disease types, including shiga toxin-induced haemolytic uraemic syndrome.
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http://dx.doi.org/10.1016/S0140-6736(17)30062-4DOI Listing
August 2017

Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation.

Clin J Am Soc Nephrol 2017 01 31;12(1):50-59. Epub 2016 Oct 31.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome.

Design, Setting, Participants & Measurements: Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse.

Results: Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (<7 days) hematologic remission and a return of serum creatinine to baseline level in a median time of 26 days. At last follow-up, renal function remained unchanged in nonrelapsing and relapsing patients compared with baseline values before eculizumab discontinuation.

Conclusions: Pathogenic variants in complement genes were associated with higher risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients.
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http://dx.doi.org/10.2215/CJN.06440616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220663PMC
January 2017

Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy.

Lancet Haematol 2016 Nov 3;3(11):e537-e546. Epub 2016 Oct 3.

Service d'Hématologie biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut Universitaire d'Hématologie-Hôpital Saint Louis, Université Paris Diderot, Paris, France. Electronic address:

Background: Thrombotic thrombocytopenic purpura is a rare thrombotic microangiopathy, related to a severe ADAMTS13 deficiency (a disintegrin and metalloprotease with thromboSpondin type 1 repeats, member 13; activity <10% of normal). Childhood-onset thrombotic thrombocytopenic purpura is very rare and initially often misdiagnosed, especially when ADAMTS13 deficiency is acquired (ie, not linked to inherited mutations of the ADAMTS13 gene). We aimed to investigate initial presentation, management, and outcome of acquired thrombotic thrombocytopenic purpura in children.

Methods: Between Jan 1, 2000, and Dec 31, 2015, we studied a cohort of patients with child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura included in the French national registry for thrombotic microangiopathies at presentation and during follow up. The inclusion criteria were: first episode before age 18 years; ADAMTS13 activity less than 10% of normal at presentation; positive anti-ADAMTS13 autoantibodies during an episode, or a recovery of ADAMTS13 activity in remission, or both. ADAMTS13 activity and anti-ADAMTS13 autoantibodies were investigated by a central laboratory, and medical records were extensively reviewed to collect clinical and biological features with a standardised form. This study is registered with ClinicalTrials.gov, number NCT00426686.

Findings: We enrolled 973 patients with childhood-onset thrombotic microangiopathy, of whom 74 had a severe ADAMTS13 deficiency (activity <10%) at presentation. 24 patients had an inherited thrombotic thrombocytopenic purpura also known as Upshaw-Schulman syndrome and five did not have follow-up data available, thus 45 children had acquired thrombotic thrombocytopenic purpura and were included in our database at presentation. 25 (56%) patients had idiopathic disease and 20 (44%) had miscellaneous associated clinical conditions. At diagnosis, median age was 13 years (IQR 7-16, range 4 months-17 years), with a sex ratio of 2·5 girls to 1 boy. Anti-ADAMTS13 autoantibodies were positive in 37 (82%) of 45 patients (24 [96%] of 25 idiopathic cases and 13 [65%] of 20 non-idiopathic cases). 39 (87%) of 45 patients were given plasma therapy and 21 (47%) received additional rituximab. Four (9%) children died after the first thrombotic thrombocytopenic purpura episode. Long-term follow up of the 41 survivors showed that ten (24%) patients relapsed and systemic lupus erythematosus occurred in two (5%) patients. Preemptive rituximab was used in seven (17%) of 41 patients with acquired thrombotic thrombocytopenic purpura.

Interpretation: Our study shows that child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura have specific clinical, biological and therapeutic features. Long-term follow-up is crucial to prevent relapses of the disease, to identify the occurrence of autoimmune disorders, and to evaluate consequences on social life. Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura is a crucial diagnosis in the field of paediatric haematologic cytopenias because it is a life-threatening disease requiring a specific management.

Funding: Assistance Publique-Hôpitaux de Paris, France.
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http://dx.doi.org/10.1016/S2352-3026(16)30125-9DOI Listing
November 2016

Observations of a large Dent disease cohort.

Kidney Int 2016 08 22;90(2):430-439. Epub 2016 Jun 22.

INSERM, UMR970, Paris-Cardiovascular Research Center, Paris, France; Reference Centre of Hereditary Renal Disease of the Child and Adult (MARHEA), Paris, France; Assistance Publique-Hôpitaux de Paris, European Georges Pompidou University Hospital, Genetics Department, Paris, France.

Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.
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http://dx.doi.org/10.1016/j.kint.2016.04.022DOI Listing
August 2016

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1.

Hum Mutat 2015 Aug 11;36(8):743-52. Epub 2015 Jun 11.

Assistance Publique-Hôpitaux de Paris, Service de Génétique, Hôpital Européen Georges Pompidou, Paris, France.

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.
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http://dx.doi.org/10.1002/humu.22804DOI Listing
August 2015

An international consensus approach to the management of atypical hemolytic uremic syndrome in children.

Pediatr Nephrol 2016 Jan 11;31(1):15-39. Epub 2015 Apr 11.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Laboratory of Immunology, INSERM UMRS 1138, Paris, France.

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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http://dx.doi.org/10.1007/s00467-015-3076-8DOI Listing
January 2016

Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies.

Kidney Int 2015 May 4;87(5):1061-73. Epub 2015 Feb 4.

Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Hôpital Robert-Debré, Paris, France.

Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.
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http://dx.doi.org/10.1038/ki.2014.423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424817PMC
May 2015

An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome.

Pediatr Nephrol 2014 Oct 11;29(10):1967-78. Epub 2014 May 11.

Great North Children's Hospital, Newcastle Upon Tyne, UK,

Background: In 2009, the European Paediatric Study Group for Haemolytic Uraemic Syndrome (HUS) published a clinical practice guideline for the investigation and initial therapy of diarrhea-negative HUS (now more widely referred to as atypical HUS, aHUS). The therapeutic component of the guideline (comprising early, high-volume plasmapheresis) was derived from anecdotal evidence and expert consensus, and the authors committed to auditing outcome.

Methods: Questionnaires were distributed to pediatric nephrologists across Europe, North America, and the Middle East, who were asked to complete one questionnaire per patient episode of aHUS between July 1, 2009 and December 31, 2010. Comprehensive, anonymous demographic and clinical data were collected.

Results: Seventy-one children were reported with an episode of aHUS during the audit period. Six cases occurred on a background of influenza A H1N1 infection. Of 71 patients, 59 (83 %) received plasma therapy within the first 33 days, of whom ten received plasma infusion only. Complications of central venous catheters occurred in 16 out of 51 patients with a catheter in-situ (31 %). Median time to enter hematological remission was 11.5 days, and eight of 71 (11 %) patients did not enter hematological remission by day 33. Twelve patients (17 %) remained dialysis dependent at day 33.

Conclusions: This audit provides a snapshot of the early outcome of a group of children with aHUS in the months prior to more widespread use of eculizumab.
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http://dx.doi.org/10.1007/s00467-014-2817-4DOI Listing
October 2014

Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better.

Kidney Int 2014 May;85(5):1019-22

1] Laboratory of Immunology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [2] INSERM Unité Mixte de Recherche en Santé 872, Paris, France.

Atypical hemolytic uremic syndrome (HUS) secondary to anti-factor H autoantibodies has a poor prognosis. The study by Sinha et al. of a large cohort of Indian children makes a substantial contribution to improved management of this form of HUS by showing that standardized titration of anti-factor H autoantibodies is applicable worldwide and that early treatment initiation and guidance of maintenance treatment by autoantibody titer monitoring significantly improve outcomes.
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http://dx.doi.org/10.1038/ki.2013.447DOI Listing
May 2014

A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: the Cystadrops OCT-1 study.

Mol Genet Metab 2014 Mar 9;111(3):314-320. Epub 2014 Jan 9.

Department of Pediatric Nephrology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Objective: To establish the safety and efficacy of a new gel formulation of cysteamine hydrochloride (CH) eye drops, for the treatment of corneal complications of nephropathic cystinosis.

Design: Open label dose response clinical trial.

Participants: Eight patients with infantile nephropathic cystinosis including 4 children, 3 adolescents, and 1 adult (mean age at inclusion, 12.1 ± 4.6 years) treated with CH 0.1% eye drops.

Intervention: Patients were treated, in both eyes, with the control CH 0.1% eye drop formulation on average 4 times daily for one month and then switched to Cystadrops® at the same dose frequency. Based on clinical ocular findings, the dose regimen was adapted at D30 and D90 in order to decrease the frequency of instillation. After D90, this dose frequency was maintained, except in cases of crystal density worsening. Patients had a follow-up visit every 6 months during 48 months.

Main Outcome Measures: Safety assessment consisted of adverse event and serious adverse event monitoring and recording at each visit. For the efficacy study, the primary endpoint was the corneal cystine crystal density measured with an in vivo confocal microscopy (IVCM) score.

Results: All patients completed the study. During the 4-year study period, neither serious adverse events nor significant adverse events related to the study drug were reported. After switching to Cystadrops®, the IVCM total score decreased from baseline to D90 by a mean of 28.6 ± 17.5% (p<0.001). From D90 to M48, the IVCM total score remained stable and significantly decreased as compared to that at D1 despite a reduced dose regimen from D90. At M48, the mean IVCM total score was 8.13 ± 4.15, decreased by a mean 29.9 ± 26.29% from D1 (p = 0.001), with a reduced number of instillations compared to that at D1. The IVCM total score and photophobia were significantly correlated (p = 0.04).

Conclusion: This study provides evidence that Cystadrops® gel is superior to the CH 0.1% formulation in terms of efficacy and has a good safety profile over a long follow-up period.
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http://dx.doi.org/10.1016/j.ymgme.2013.12.298DOI Listing
March 2014

Macrovascular involvement in a child with atypical hemolytic uremic syndrome.

Pediatr Nephrol 2014 Jul 19;29(7):1273-7. Epub 2013 Dec 19.

Vilnius University, Vilnius, Lithuania.

Background: Atypical hemolytic uremic syndrome (aHUS) is a disorder of the complement system which leads to thrombotic microangiopathy. It is caused by either acquired or hereditary defects in the activation or regulation of the alternative complement pathway and is therefore considered to be a disease of local complement dysregulation in microvasculature with predominantly renal involvement. However, extrarenal manifestations are observed in approximately one-fifth of aHUS patients, with the myocardium and central nervous system (CNS) being involved most often. Additionally, there have been a few reports of aHUS with cerebral artery stenoses or periphereal gangrene, suggesting the possibility of 'macrovascular' involvement in aHUS.

Case-diagnosis/treatment: We present a child with early onset aHUS and a C3 gain-of-function mutation who developed cerebral artery stenoses, leading ultimately to death due to a massive stroke 9 days after successful renal transplantation under prophylactic eculizumab treatment. Similar cases described in the literature are also briefly summarized.

Conclusions: The disease course in our patient with aHUS confirms that dysregulated complement activation can induce arterial steno-occlusive lesions in the absence of acute episodes of HUS. Further studies are required to document the frequency of such macrovascular complications and the role of eculizumab treatment in preventing their development and progression.
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http://dx.doi.org/10.1007/s00467-013-2713-3DOI Listing
July 2014

[Adult socioprofessional status of childhood kidney transplant recipients].

Bull Acad Natl Med 2013 Nov;197(8):1607-8

Service de néphrologic pédiatrique, CHU Paris - Hôpital Robert Debré, 48 boulevard Sérurier - 75019 Paris.

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November 2013

Adult social and professional outcomes of pediatric renal transplant recipients.

Transplantation 2014 Jan;97(2):196-205

1 Inserm, CIE 5, Paris, France. 2 Unité d'Epidémiologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France. 3 Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 4 Agence de la Biomédecine, Direction Médicale et Scientifique, Saint-Denis-La Plaine, France. 5 Service de Néphrologie, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France. 6 Address correspondence to: Chantal Loirat, M.D., Pediatric Nephrology Department, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France.

Background: Little is known about the socioprofessional situation of adult-aged kidney-transplanted children. This nationwide French cohort study documented the socioprofessional outcomes of adults who underwent kidney transplantation before age 16 years between 1985 and 2002.

Methods: Of 890 patients, 624 were eligible for a questionnaire and 374 completed it (response rate=60%; men=193 and women=181). The data were compared with the French general population using an indirect standardization matched for gender, age, and period.

Results: The median ages were 27.1 years at survey time and 12.3 years at first transplantation. Of the participants, 31.1% lived with a partner (vs. 52.2%; P<0.01) and 35.7% lived with their parents (vs. 21.0%; P<0.01). When standardized for parental educational level, fewer participants had a high-level degree (≥3-year university level) and fewer women had a baccalaureate degree. Professional occupations were similar to the French general population, but unemployment was higher (18.5% vs. 10.4%; P<0.01). Independent predictive factors for poor socioprofessional outcome were primary disease severity (onset in infancy or hereditary disease), the presence of comorbidities or sensorial disabilities, low educational level of the patient or his parents, female gender, and being on dialysis after graft failure.

Conclusions: Transplanted children, particularly girls and patients with low parental educational levels, require optimized educational, psychologic, and social support to reach the educational level of their peers. This support should be maintained during adulthood to help them integrate into the working population and build a family.
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http://dx.doi.org/10.1097/TP.0b013e3182a74de2DOI Listing
January 2014

Eculizumab in atypical hemolytic-uremic syndrome.

N Engl J Med 2013 10;369(14):1379-80

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http://dx.doi.org/10.1056/NEJMc1308826DOI Listing
October 2013

Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases.

Am J Kidney Dis 2014 Jan 8;63(1):40-8. Epub 2013 Sep 8.

Department of Immunology, Assistance Publique-Hôpitaux de Paris Hôpital Européen Georges Pompidou, Paris, France.

Background: Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. Despite plasma exchange, the standard treatment of aHUS for decades, the renal prognosis for patients with aHUS has remained poor. We assessed the off-trial use of eculizumab in adult patients with aHUS affecting the native kidneys.

Study Design: A retrospective study was conducted. aHUS was defined as the presence of 3 or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 μmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of thrombotic microangiopathy features in a kidney biopsy specimen. Patients who had received 4 or more weekly 900-mg infusions of eculizumab were included.

Setting & Participants: 19 patients were identified through a query sent to all French nephrology centers.

Outcomes & Measurements: Evolution of kidney function, hemolysis, and thrombocytopenia after the initiation of eculizumab therapy.

Results: All patients had acute kidney injury (serum creatinine range, 2.2-17.0 mg/dL) and 12 required hemodialysis. Thirteen patients carried a mutation in 1 complement gene and 1 had anti-factor H antibodies. For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab. Median time between aHUS onset and eculizumab therapy initiation was 6 (range, 1-60) days and median time to platelet count normalization after eculizumab therapy initiation was 6 (range, 2-42) days. At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent chronic kidney disease, and 7 had normalized kidney function. At last follow-up (range, 4-22 months), 3 patients remained dialysis dependent, 7 had non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate, 17-55 mL/min/1.73 m(2)), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls.

Limitations: Retrospective study and use of historical controls.

Conclusions: Our data indicate that eculizumab improves kidney disease outcome in patients with aHUS.
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http://dx.doi.org/10.1053/j.ajkd.2013.07.011DOI Listing
January 2014

Targeted strategies in the prevention and management of atypical HUS recurrence after kidney transplantation.

Transplant Rev (Orlando) 2013 Oct 12;27(4):117-25. Epub 2013 Aug 12.

Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Service de Transplantation Rénale adulte, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, France. Electronic address:

Atypical hemolytic and uremic syndrome (aHUS) is associated with a high rate of recurrence and poor outcomes after kidney transplantation. Fortunately, recent advances in the understanding of the pathogenesis of aHUS have permitted an individualized risk assessment of post-transplant recurrence. Acquired or inherited dysregulation of the alternative complement pathway, thought to be the driving force of the disease, is identified in most aHUS patients. Notably, depending on the mutations involved, the risk of recurrence greatly varies, highlighting the importance of undertaking etiological investigations prior to kidney transplantation. In those with moderate to high risk of recurrence, the use of a prophylactic therapy, consisting in either plasmapheresis or eculizumab therapies, represents a major stride forward in the prevention of aHUS recurrence after kidney transplantation. In those who experience aHUS recurrence, a growing number of observations suggest that eculizumab therapy outperforms curative plasma therapy. The optimal duration of both prophylactic and curative therapies remains an important, yet unaddressed, issue. In this respect, the kidney transplant recipients, continuously exposed to endothelial-insulting factors, referred here as to triggers, might have a sustained high risk of recurrence. A global therapeutic approach should thus attempt to reduce exposure to these triggers.
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http://dx.doi.org/10.1016/j.trre.2013.07.003DOI Listing
October 2013

Atypical hemolytic uremic syndrome: from the rediscovery of complement to targeted therapy.

Eur J Intern Med 2013 Sep 5;24(6):492-5. Epub 2013 Jun 5.

Department of Nephrology and Immunology, CHU de Nantes, ITUN and INSERM UMR S-1064, Nantes, France.

Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. In the last five years, we have finally witnessed a dramatic improvement in the management of aHUS patients, and three breakthroughs in our understanding of aHUS have led to such an improvement. The first breakthrough was the emergence of a new clinical picture of aHUS (frequency of adult cases, and overall poor renal prognosis despite plasma therapy). The second breakthrough was the identification of complement alternative pathway dysregulation as a major risk factor for aHUS. The third breakthrough was the availability in clinical practice of the first complement inhibitor, the anti-C5 monoclonal antibody, eculizumab. Available data from case series and prospective studies indicate that eculizumab use has dramatically improved the renal prognosis of aHUS. These breakthroughs have prompted the French working group on aHUS to propose a new algorithm for the management of aHUS in children and in adults. This algorithm will evolve as we gain new insights in the pathogenesis and evolution of aHUS in the eculizumab era.
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http://dx.doi.org/10.1016/j.ejim.2013.05.008DOI Listing
September 2013

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.

Nat Genet 2013 May 31;45(5):531-6. Epub 2013 Mar 31.

Department of Genetics, Yale University School of Medicine, and Howard Hughes Medical Institute, New Haven, Connecticut, USA.

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
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http://dx.doi.org/10.1038/ng.2590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719402PMC
May 2013

Post-partum atypical haemolytic-uraemic syndrome treated with eculizumab: terminal complement activity assessment in clinical practice.

Clin Kidney J 2013 Apr;6(2):243-4

Service de Néphrologie Transplantation Dialyse , Centre Hospitalier Universitaire de Bordeaux , Bordeaux , France ; Unité INSERM 1026 , Université Bordeaux Segalen , Bordeaux , France.

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http://dx.doi.org/10.1093/ckj/sfs185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432440PMC
April 2013

[Hemolytic uremic syndrome caused by Shiga-toxin-producing Escherichia coli].

Authors:
Chantal Loirat

Rev Prat 2013 Jan;63(1):11-6

Service de néphrologie, AP-HP, hôpital Robert-Debré, 75019 Paris, France.

Every year in France, approximately one hundred children, aged from 6 months to 3 years, develop hemolytic uremic syndrome (HUS) secondary to Shiga toxin-producing Escherichia coli (STEC) infection, mostly the O157:H7 serotype. Except during outbreaks, STEC-HUS is less frequent in adults. The main route of transmission is the consumption of undercooked ground beef or unpasteurized dairy products, or household contacts with STEC diarrhea. Mortality is 1 to 2%. Half of patients require dialysis at the acute phase, the majority will recover normal renal function but approximately 30% will suffer renal sequelae. The risk of sequelae is important if the duration of anuria has been more than 5 days. Treatment of STEC-HUS is mostly supportive. The efficacy of plasma exchanges is not demonstrated and that of eculizumab, a complement blocker, especially in case of central nervous system or cardiac involvement, uncertain. Prevention of STEC-HUS relies on simple methods, often unknown of parents of young children, with the French general population being scarcely informed. However, the surveillance of STEC-infections/HUS by the Institut de veille sanitaire and the Reference Center for E. coli infections allows the early detection of outbreaks and their source of contamination. This prevents the emergence of new cases by withdrawing the suspected food from the market and diffusing the information to the population (return of suspected food).
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January 2013