Publications by authors named "Veronique Frémeaux-Bacchi"

241 Publications

Ex Vivo Complement Activation on Endothelial Cells: Research and Translational Value.

Trends Mol Med 2021 Feb 26. Epub 2021 Feb 26.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France. Electronic address:

The spectrum of human diseases with complement contribution is ever increasing. Tools to study the complement contribution and the potential interest of novel complement inhibitors in clinical practice are lacking. Here we discuss a functional ex vivo assay to monitor complement activation on endothelial cells, which can answer to this need.
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http://dx.doi.org/10.1016/j.molmed.2021.01.008DOI Listing
February 2021

Inherited Kidney Complement Diseases.

Clin J Am Soc Nephrol 2021 Feb 3. Epub 2021 Feb 3.

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

In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.
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http://dx.doi.org/10.2215/CJN.11830720DOI Listing
February 2021

Identification of Distinct Immunophenotypes in Critically Ill Coronavirus Disease 2019 Patients.

Chest 2020 Dec 11. Epub 2020 Dec 11.

Medical Intensive Care Unit, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France. Electronic address:

Background: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causes direct lung damage, overwhelming endothelial activation, and inflammatory reaction, leading to acute respiratory failure and multi-organ dysfunction. Ongoing clinical trials are evaluating targeted therapies to hinder this exaggerated inflammatory response. Critically ill coronavirus disease 2019 (COVID-19) patients have shown heterogeneous severity trajectories, suggesting that response to therapies is likely to vary across patients.

Research Question: Are critically ill COVID-19 patients biologically and immunologically dissociable based on profiling of currently evaluated therapeutic targets?

Study Design And Methods: We did a single-center, prospective study in an ICU department in France. Ninety-six critically ill adult patients admitted with a documented SARS-CoV-2 infection were enrolled. We conducted principal components analysis and hierarchical clustering on a vast array of immunologic variables measured on the day of ICU admission.

Results: We found that patients were distributed in three clusters bearing distinct immunologic features and associated with different ICU outcomes. Cluster 1 had a "humoral immunodeficiency" phenotype with predominant B-lymphocyte defect, relative hypogammaglobulinemia, and moderate inflammation. Cluster 2 had a "hyperinflammatory" phenotype, with high cytokine levels (IL-6, IL-1β, IL-8, tumor necrosis factor-alpha [TNF⍺]) associated with CD4+ and CD8+ T-lymphocyte defects. Cluster 3 had a "complement-dependent" phenotype with terminal complement activation markers (elevated C3 and sC5b-9).

Interpretation: Patients with severe COVID-19 exhibiting cytokine release marks, complement activation, or B-lymphocyte defects are distinct from each other. Such immunologic variability argues in favor of targeting different mediators in different groups of patients and could serve as a basis for patient identification and clinical trial eligibility.
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http://dx.doi.org/10.1016/j.chest.2020.11.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831685PMC
December 2020

Malignant hypertension and thrombotic microangiopathy: complement as a usual suspect.

Nephrol Dial Transplant 2020 Dec 10. Epub 2020 Dec 10.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie and Paris University, Paris, France.

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http://dx.doi.org/10.1093/ndt/gfaa362DOI Listing
December 2020

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

Atypical HUS relapse triggered by COVID-19.

Kidney Int 2021 01 11;99(1):267-268. Epub 2020 Nov 11.

Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1016/j.kint.2020.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657017PMC
January 2021

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study.

EClinicalMedicine 2020 Nov 5;28:100590. Epub 2020 Nov 5.

Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation - U1173, School of Medicine Simone Veil, University Versailles Saint Quentin - University Paris Saclay, INSERM, Garches, France.

Background: Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19.

Methods: All patients ( = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed.

Findings: At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test,  = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%).

Interpretation: Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed.

Funding: Programme d'Investissements d'Avenir: ANR-18-RHUS60004.
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http://dx.doi.org/10.1016/j.eclinm.2020.100590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644240PMC
November 2020

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis.

Kidney Int 2021 03 1;99(3):581-597. Epub 2020 Nov 1.

Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France. Electronic address:

Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney, likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.
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http://dx.doi.org/10.1016/j.kint.2020.09.033DOI Listing
March 2021

Atypical hemolytic and uremic syndrome due to C3 mutation in pancreatic islet transplantation: a case report.

BMC Nephrol 2020 09 19;21(1):405. Epub 2020 Sep 19.

Service de Néphrologie et Transplantation, Hôpital Civil, Strasbourg, France.

Background: We here report on the first observation of a C3 mutation that is related to atypical hemolytic and uremic syndrome (aHUS), which occurred in a pancreatic islet transplant patient. Immunosuppressive treatments, such as calcineurin inhibitors, have been linked to undesirable effects like nephrotoxicity.

Case Presentation: A 40-year-old man with brittle diabetes, who was included in the TRIMECO trial, became insulin-independent 2 months after pancreatic islet transplantation. About 15 months after islet transplantation, the patient exhibited acute kidney injury due to aHUS. Despite plasma exchange and eculizumab treatment, the patient developed end-stage renal disease. A genetic workup identified a missense variant (p.R592Q) in the C3 gene. In vitro, this C3 variant had defective Factor I proteolytic activity with membrane proteins as cofactor proteins, which was thus classified as pathogenic. About 1 year after the aHUS episode, kidney transplantation was carried out under the protection of the specific anti-C5 monoclonal antibody eculizumab. The patient had normal kidney function, with preserved pancreatic islet function 4 years later.

Conclusions: Pancreatic islet transplantation could have triggered this aHUS episode, but this link needs to be clarified. Although prophylactic eculizumab maintains kidney allograft function, its efficacy still needs to be studied in larger populations.
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http://dx.doi.org/10.1186/s12882-020-02062-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501718PMC
September 2020

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis.

Front Immunol 2020 7;11:1772. Epub 2020 Aug 7.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France.

Intravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to hemolysis-mediated AKI. Acute systemic hemolysis was induced in mice lacking liver expression of FH (hepatoFH, ~20% residual FH) and in WT controls, by phenylhydrazine injection. The impaired complement regulation in hepatoFH mice resulted in a delayed but aggravated phenotype of hemolysis-related kidney injuries. Plasma urea as well as markers for tubular (NGAL, Kim-1) and vascular aggression peaked at day 1 in WT mice and normalized at day 2, while they increased more in hepatoFH compared to the WT and still persisted at day 4. These were accompanied by exacerbated tubular dilatation and the appearance of tubular casts in the kidneys of hemolytic hepatoFH mice. Complement activation in hemolytic mice occurred in the circulation and C3b/iC3b was deposited in glomeruli in both strains. Both genotypes presented with positive staining of FH in the glomeruli, but hepatoFH mice had reduced staining in the tubular compartment. Despite the clear phenotype of tubular injury, no complement activation was detected in the tubulointerstitium of the phenylhydrazin-injected mice irrespective of the genotype. Nevertheless, phenylhydrazin triggered overexpression of C5aR1 in tubules, predominantly in hepatoFH mice. Moreover, C5b-9 was deposited only in the glomeruli of the hemolytic hepatoFH mice. Therefore, we hypothesize that C5a, generated in the glomeruli, could be filtered into the tubulointerstitium to activate C5aR1 expressed by tubular cells injured by hemolysis-derived products and will aggravate the tissue injury. Plasma-derived FH is critical for the tubular protection, since pre-treatment of the hemolytic hepatoFH mice with purified FH attenuated the tubular injury. Worsening of acute tubular necrosis in the hepatoFH mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.
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http://dx.doi.org/10.3389/fimmu.2020.01772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426730PMC
August 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

Neisseria meningitidis inside neutrophils, revealing properdin deficiency.

Int J Infect Dis 2020 10 25;99:117-118. Epub 2020 Jul 25.

Service d'Hématologie Biologique, Centre Hospitalier Universitaire, Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2020.07.040DOI Listing
October 2020

Ockham's razor defeated: about two atypical cases of hemolytic uremic syndrome.

BMC Nephrol 2020 07 11;21(1):269. Epub 2020 Jul 11.

Service d'urgences néphrologiques et transplantation rénale, hôpital Tenon, Paris, France.

Background: Medical investigation is a favorite application of Ockham's razor, in virtue of which when presented with competing hypotheses, the solution with the fewest assumptions should be privileged. Hemolytic uremic syndrome (HUS) encompasses diseases with distinct pathological mechanisms, such as HUS due to shiga-like toxin-producing bacteria (STEC-HUS) and atypical HUS, linked to defects in the alternate complement pathway. Other etiologies such as Parvovirus B19 infection are exceptional. All these causes are rare to such extent that we usually consider them mutually exclusive. We report here two cases of HUS that could be traced to multiple causes.

Cases Presentation: Case 1 presented as vomiting and diarrhea. All biological characteristics of HUS were present. STEC was found in stool (by PCR and culture). After initial remission, a recurrence occurred and patient was started on Eculizumab. Genetic analysis revealed the heterozygous presence of a CFHR1/CFH hybrid gene. The issue was favorable under treatment. In case 2, HUS presented as fever, vomiting and purpura of the lower limbs. Skin lesions and erythroblastopenia led to suspect Parvovirus B19 primo-infection, which was confirmed by peripheral blood and medullar PCR. Concurrently, stool culture and PCR revealed the presence of STEC. Evolution showed spontaneous recovery.

Conclusions: Both cases defy Ockham's razor in the sense that multiple causes could be traced to a single outcome; furthermore, they invite us to reflect on the physiopathology of HUS as they question the classical distinction between STEC-HUS and atypical HUS. We propose a two-hit mechanism model leading to HUS. Indeed, in case 1, HUS unfolded as a result of the synergistic interaction between an infectious trigger and a genetic predisposition. In case 2 however, it is the simultaneous occurrence of two infectious triggers that led to HUS. In dissent from Ockham's razor, an exceptional disease such as HUS may stem from the sequential occurrence or co-occurrence of several rare conditions.
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http://dx.doi.org/10.1186/s12882-020-01926-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353709PMC
July 2020

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties.

Kidney Int 2020 11 3;98(5):1135-1148. Epub 2020 Jul 3.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie and Paris University, Paris, France.

In recent years, a substantial body of experimental and clinical work has been devoted to C3 glomerulopathy and Ig-mediated membranoproliferative glomerulonephritis. Despite the rapid accumulation of data, several uncertainties about these 2 rare forms of nephropathies persist. They concern their pathophysiology, classification, clinical course, relevance of biomarkers and of pathology findings, and assessment of the efficacy of the available therapies. The present review discusses the impact of these uncertainties on the clinical management of patients.
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http://dx.doi.org/10.1016/j.kint.2020.05.053DOI Listing
November 2020

Analysis of protein missense alterations by combining sequence- and structure-based methods.

Mol Genet Genomic Med 2020 04 25;8(4):e1166. Epub 2020 Feb 25.

INSERM U973, Laboratory MTi, University Paris Diderot, Paris, France.

Background: Different types of in silico approaches can be used to predict the phenotypic consequence of missense variants. Such algorithms are often categorized as sequence based or structure based, when they necessitate 3D structural information. In addition, many other in silico tools, not dedicated to the analysis of variants, can be used to gain additional insights about the possible mechanisms at play.

Methods: Here we applied different computational approaches to a set of 20 known missense variants present on different proteins (CYP, complement factor B, antithrombin and blood coagulation factor VIII). The tools that were used include fast computational approaches and web servers such as PolyPhen-2, PopMusic, DUET, MaestroWeb, SAAFEC, Missense3D, VarSite, FlexPred, PredyFlexy, Clustal Omega, meta-PPISP, FTMap, ClusPro, pyDock, PPM, RING, Cytoscape, and ChannelsDB.

Results: We observe some conflicting results among the methods but, most of the time, the combination of several engines helped to clarify the potential impacts of the amino acid substitutions.

Conclusion: Combining different computational approaches including some that were not developed to investigate missense variants help to predict the possible impact of the amino acid substitutions. Yet, when the modified residues are involved in a salt-bridge, the tools tend to fail, even when the analysis is performed in 3D. Thus, interactive structural analysis with molecular graphics packages such as Chimera or PyMol or others are still needed to clarify automatic prediction.
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http://dx.doi.org/10.1002/mgg3.1166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196459PMC
April 2020

Anti-Factor B Antibodies and Acute Postinfectious GN in Children.

J Am Soc Nephrol 2020 04 7;31(4):829-840. Epub 2020 Feb 7.

Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France;

Background: The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis.

Methods: This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia.

Results: All children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity , confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity.

Conclusions: These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy.
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http://dx.doi.org/10.1681/ASN.2019080851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191928PMC
April 2020

Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy.

Am J Hematol 2020 05 19;95(5):456-464. Epub 2020 Feb 19.

INSERM U955 équipe 2, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est-Créteil (UPEC), Créteil, France; and Laboratoire d'excellence GR-Ex, Paris, France.

The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for complement over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing complement activation in SCD has not been elucidated. Here, we observe that the plasma concentration of sC5b-9, a reliable marker for terminal complement activation, is increased at steady state in 61% of untreated SCD patients. We show that greater complement activation in vitro is promoted by SCD erythrocytes compared to normal ones, although no significant differences were observed in the regulatory proteins CD35, CD55, and CD59 in whole blood. Complement activation is positively correlated with the percentage of dense sickle cells (DRBCs). The expression levels of CD35, CD55, and CD59 are reduced in DRBCs, suggesting inefficient regulation when cell density increases. Moreover, the surface expression of the complement regulator CD46 on granulocytes was inversely correlated with the plasma sC5b-9. We also show increased complement deposition in cultured human endothelial cells incubated with SCD serum, which is diminished by the addition of the heme scavenger hemopexin. Treatment of SCD patients with hydroxyurea produces substantial reductions in complement activation, measured by sC5b-9 concentration and upregulation of CD46, as well as decreased complement activation on RBCs in vitro. In conclusion, complement over activation is a common pathogenic event in SCD that is associated with formation of DRBCs and hemolysis. And, it affects red cells, leukocytes and endothelial cells. This complement over activation is partly alleviated by hydroxyurea therapy.
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http://dx.doi.org/10.1002/ajh.25742DOI Listing
May 2020

C3 glomerulonephritis in a patient treated with anti-PD-1 antibody.

Eur J Cancer 2020 01 12;125:46-48. Epub 2019 Dec 12.

Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.

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http://dx.doi.org/10.1016/j.ejca.2019.11.011DOI Listing
January 2020

Monitoring Complement Activation: The New Conundrum in Thrombotic Microangiopathies.

Clin J Am Soc Nephrol 2019 12 6;14(12):1682-1683. Epub 2019 Nov 6.

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

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http://dx.doi.org/10.2215/CJN.12111019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895483PMC
December 2019

Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome in solid organ transplant recipients.

Kidney Int 2019 12;96(6):1423-1424

Centre de Recherche en Transplantation et en Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2019.08.024DOI Listing
December 2019

Atypical hemolytic uremic syndrome and hypertensive crisis.

Kidney Int 2019 11;96(5):1239

Assistance Publique-Hôpitaux de Paris, Laboratoire d'immunologie, Hôpital Européen Georges Pompidou, Paris, France; INSERM UMR S1138, Inflammation Complément et Cancer, Centre de recherche des Cordeliers, Paris, France.

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http://dx.doi.org/10.1016/j.kint.2019.07.023DOI Listing
November 2019

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

Glomerulonephritis With Isolated C3 Deposits as a Manifestation of Subtotal Factor I Deficiency.

Kidney Int Rep 2019 Sep 31;4(9):1354-1358. Epub 2019 May 31.

Assistance Publique des Hôpitaux de Paris (AP-HP), Groupe Hospitalier Henri-Mondor/ Albert Chenevier, Service de Néphrologie et Transplantation, Créteil, France.

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http://dx.doi.org/10.1016/j.ekir.2019.05.1156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732777PMC
September 2019

Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System.

Front Immunol 2019 22;10:2007. Epub 2019 Aug 22.

Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.

Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.
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http://dx.doi.org/10.3389/fimmu.2019.02007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713926PMC
September 2020

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies.

Front Immunol 2019 8;10:1936. Epub 2019 Aug 8.

Assistance Publique - Hôpitaux de Paris (AP-HP), Laboratoire d'Immunologie, Hôpital Européen Georges-Pompidou, Paris, France.

The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [β ( = 1), ( = 3), ( = 2), ( = 12), ( = 5), C5 ( = 12), ( = 9), ( = 17), β ( = 7), ( = 3), ( = 7), ( = 18), ( = 10), ( = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (, and ). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.
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http://dx.doi.org/10.3389/fimmu.2019.01936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694794PMC
September 2020

The authors reply.

Kidney Int 2019 08;96(2):517-518

Unité Mixte de Recherche 1064, Centre de Recherche en Transplantation et Immunologie, Institut National de la Santé et de la Recherche Médicale, Université de Nantes, Nantes, France; Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2019.04.010DOI Listing
August 2019

Haemolytic uraemic syndrome associated with non shiga toxin-producing Escherichia coli bacteraemia: a case report.

BMC Nephrol 2019 05 7;20(1):157. Epub 2019 May 7.

Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou (AP-HP), 20 rue Leblanc, 75 908, Paris, Cedex 15, France.

Background: Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by predominant renal involvement. Several types of HUS can be distinguished: the most frequent « typical » HUS, due to shiga toxin producing Escherichia coli (STEC), "atypical" HUS due to complement alternative pathway dysregulation and "secondary" HUS associated with various diseases/conditions, the classification of which is still subject to debate.

Case Presentation: We report a case of HUS following E.coli prostatitis and bacteraemia in an adult male. He presented with severe renal and neurological involvement. Initially considered as a "typical" HUS, the condition was treated by antibiotics. No other specific treatment for HUS was administered. The outcome was favorable. We eventually identified a non shiga toxin producing E.coli. Genetic testing of the complement alternative pathway revealed a rare - potentially pathogenic - variant of factor H. This constitutes a possible factor of susceptibility for atypical HUS, suggesting that E.coli infection may be the trigger.

Conclusion: This case raises the question of complement exploration for HUS associated with infections, in order to classify such cases of HUS in accordance with their underlying pathophysiological mechanisms.
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http://dx.doi.org/10.1186/s12882-019-1357-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505115PMC
May 2019

Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors.

Kidney Int 2019 06 15;95(6):1443-1452. Epub 2019 Mar 15.

Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France; Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

Secondary hemolytic uremic syndrome (HUS) is a heterogeneous group of thrombotic microangiopathies associated with various underlying conditions. Whether it belongs to the spectrum of complement-mediated HUS remains controversial. We analysed the presentation, outcome, and frequency of complement gene rare variants in a cohort of 110 patients with secondary HUS attributed to drugs (29%), autoimmune diseases (24%), infections (17%), malignancies (10%), glomerulopathies (9%), extra-renal organ transplantation (8%), and pancreatitis (3%). The frequency of complement gene rare variants was similar in patients with secondary HUS (5%) and in healthy individuals (6% and 8% in French and European controls, respectively). At diagnosis, 40% of patients required dialysis and 18% had neurological manifestations. Fifty percent of patients received plasmatherapy and 35% were treated with eculizumab. Haematological and complete renal remission was achieved in 80% and 24% of patients, respectively. Thirty-nine percent of patients progressed to chronic kidney disease (stages 3-4) and an additional 37% reached end-stage renal disease. Eleven percent of patients died, most often from complications of the underlying cause of HUS. Only one patient experienced an HUS relapse. Patients treated with eculizumab presented with more severe HUS and were more likely to require dialysis at the time of diagnosis as compared to patients not treated with eculizumab. Rates of hematological remission, chronic kidney disease (stages 3-4), and end-stage renal disease were similar in the two groups. Secondary HUS is an acute nonrelapsing form of HUS, not related to complement dysregulation. The efficacy of eculizumab in this setting is not yet established.
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http://dx.doi.org/10.1016/j.kint.2019.01.023DOI Listing
June 2019