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Article: Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19.

Leone, Valentina Fanny / Imeraj, Amantia / Gastoldi, Sara / Mele, Caterina / Liguori, Lucia / Condemi, Carmelita / Ruggenenti, Piero / Remuzzi, Giuseppe / Carrara, Camillo

Frontiers in pharmacology

2022 Volume 13, Page(s) 842473

Abstract: Hemolytic uremic syndrome (HUS) is a rare life-threatening disease of unrestrained complement system dysregulation, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure in genetically predisposed individuals. In this report, we ... ...

Abstract	Hemolytic uremic syndrome (HUS) is a rare life-threatening disease of unrestrained complement system dysregulation, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure in genetically predisposed individuals. In this report, we describe two cases of SARS-CoV-2-associated HUS treated with eculizumab, a C5-blocking monoclonal antibody reported to be remarkably effective in the treatment of HUS. Detailed biochemical and genetic complement system analysis is reported, and the prompt clinical response after C5 pharmacological blockade is documented. Our report provides the rationale and supports the use of terminal complement pathway inhibition for the treatment of SARS-CoV-2-associated HUS.
Language	English
Publishing date	2022-02-28
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.842473
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Article ; Online: An

Gastoldi, Sara / Aiello, Sistiana / Galbusera, Miriam / Breno, Matteo / Alberti, Marta / Bresin, Elena / Mele, Caterina / Piras, Rossella / Liguori, Lucia / Santarsiero, Donata / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

Frontiers in immunology

2023 Volume 14, Page(s) 1112257

Abstract: Introduction: Comprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains ... ...

Abstract	Introduction: Comprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains challenging owing to the complexity of functional studies with mutant proteins. This study was designed: 1) To identify a tool for rapid functional determination of complement gene variants; 2) To uncover inherited complement dysregulation in aHUS patients who do not carry identified gene variants. Methods: To address the above goals, we employed an ex-vivo assay of serum-induced C5b-9 formation on ADP-activated endothelial cells in 223 subjects from 60 aHUS pedigrees (66 patients and 157 unaffected relatives). Results: Sera taken from all aHUS patients in remission induced more C5b-9 deposition than control sera, independently from the presence of complement gene abnormalities. To avoid the possible confounding effects of chronic complement dysregulation related to aHUS status, and considering the incomplete penetrance for all aHUS-associated genes, we used serum from unaffected relatives. In control studies, 92.7% of unaffected relatives with known pathogenic variants exhibited positive serum-induced C5b-9 formation test, documenting a high sensitivity of the assay to identify functional variants. The test was also specific, indeed it was negative in all non-carrier relatives and in relatives with variants non-segregating with aHUS. All but one variants in aHUS-associated genes predicted in-silico as likely pathogenic or of uncertain significance (VUS) or likely benign resulted as pathogenic in the C5b-9 assay. At variance, variants in putative candidate genes did not exhibit a functional effect, with the exception of a Discussion: In conclusion, the serum-induced C5b-9 formation test in unaffected relatives of aHUS patients may be a tool for rapid functional evaluation of rare complement gene variants. When combined with exome sequencing the assay might be of help in variant selection, to identify new aHUS-associated genetic factors.
MeSH term(s)	Humans ; Complement Membrane Attack Complex/genetics ; Complement Membrane Attack Complex/metabolism ; Endothelial Cells/metabolism ; Atypical Hemolytic Uremic Syndrome/diagnosis ; Atypical Hemolytic Uremic Syndrome/genetics ; Complement System Proteins/genetics ; Complement System Proteins/therapeutic use ; Pedigree
Chemical Substances	Complement Membrane Attack Complex ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2023-02-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1112257
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Article ; Online: SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation.

Perico, Luca / Morigi, Marina / Galbusera, Miriam / Pezzotta, Anna / Gastoldi, Sara / Imberti, Barbara / Perna, Annalisa / Ruggenenti, Piero / Donadelli, Roberta / Benigni, Ariela / Remuzzi, Giuseppe

Frontiers in immunology

2022 Volume 13, Page(s) 827146

Abstract: Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been ... ...

Abstract	Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage. Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Angiotensin-Converting Enzyme 2 ; COVID-19 ; Complement System Proteins/metabolism ; Endothelial Cells/metabolism ; Humans ; Platelet Aggregation ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Complement System Proteins (9007-36-7) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2022-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.827146
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Article ; Online: Case Report: Effects of Anti-SARS-CoV-2 Convalescent Antibodies Obtained With Double Filtration Plasmapheresis.

Curtò, Diego / Tomatis, Federica / Gastoldi, Sara / Galbusera, Miriam / Noris, Marina / Raimondi, Federico / Lorini, Ferdinando Luca / Falanga, Anna / Marchetti, Marina / Remuzzi, Giuseppe / Ruggenenti, Piero

Frontiers in immunology

2021 Volume 12, Page(s) 711915

Abstract: Passive antibody therapy has been used to treat outbreaks of viral disease, including the ongoing pandemic of severe respiratory acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) or COVID-19. However, the real benefits of the procedure are ... ...

Abstract	Passive antibody therapy has been used to treat outbreaks of viral disease, including the ongoing pandemic of severe respiratory acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) or COVID-19. However, the real benefits of the procedure are unclear. We infused a concentrated solution of neutralizing anti-SARS-CoV-2 antibodies obtained from a convalescent donor with a single session of double filtration plasmapheresis (DFPP) into a 56-year-old woman with long history of unremitting, severe COVID-19. She was unable to establish an adequate antiviral immune response because of previous chemotherapy, including the infusion of the anti-CD20 monoclonal antibody rituximab, administered to treat a diffuse large B-cell lymphoma. The disease promptly recovered despite evidence of no endogenous anti-SARS-CoV-2 antibody production. The observation that passive antibody therapy might prove particularly effective in immunodepressed COVID-19 patients requires evaluation in prospective randomized controlled trial.
MeSH term(s)	Antibodies, Neutralizing/therapeutic use ; Antibodies, Viral/therapeutic use ; Antineoplastic Agents, Immunological/adverse effects ; Antiviral Agents/therapeutic use ; COVID-19/immunology ; COVID-19/therapy ; COVID-19/virology ; Female ; Humans ; Immunity/drug effects ; Immunization, Passive/methods ; Immunocompromised Host ; Immunoglobulin G/therapeutic use ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Middle Aged ; Plasmapheresis/methods ; RNA, Viral/genetics ; Rituximab/adverse effects ; SARS-CoV-2/genetics ; Treatment Outcome
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Antineoplastic Agents, Immunological ; Antiviral Agents ; Immunoglobulin G ; RNA, Viral ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2021-06-30
Publishing country	Switzerland
Document type	Case Reports ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.711915
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Article ; Online: C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19.

Aiello, Sistiana / Gastoldi, Sara / Galbusera, Miriam / Ruggenenti, Piero / Portalupi, Valentina / Rota, Stefano / Rubis, Nadia / Liguori, Lucia / Conti, Sara / Tironi, Matteo / Gamba, Sara / Santarsiero, Donata / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

Blood advances

2021 Volume 6, Issue 3, Page(s) 866–881

Abstract: Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, ... ...

Abstract	Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.
MeSH term(s)	Atypical Hemolytic Uremic Syndrome ; COVID-19 ; Endothelial Cells ; Humans ; Platelet Aggregation ; SARS-CoV-2
Language	English
Publishing date	2021-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021005246
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Article: Molecular Studies and an

Piras, Rossella / Iatropoulos, Paraskevas / Bresin, Elena / Todeschini, Marta / Gastoldi, Sara / Valoti, Elisabetta / Alberti, Marta / Mele, Caterina / Galbusera, Miriam / Cuccarolo, Paola / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

Frontiers in medicine

2020 Volume 7, Page(s) 579418

Abstract: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal impairment and is associated with dysregulation of the alternative complement pathway on the microvascular ... ...

Abstract	Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal impairment and is associated with dysregulation of the alternative complement pathway on the microvascular endothelium. Outcomes have improved greatly with pharmacologic complement C5 blockade. Abnormalities in complement genes (
Language	English
Publishing date	2020-11-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2020.579418
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Article ; Online: Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study.

PloS one

2021 Volume 16, Issue 12, Page(s) e0261113

Abstract: Background: Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome.: Methods: In this single-centre, academic, unblinded study two ... ...

Abstract	Background: Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. Methods: In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. Results: Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. Conclusions: In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.
MeSH term(s)	Aged ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/therapeutic use ; COVID-19/drug therapy ; COVID-19/mortality ; COVID-19/physiopathology ; COVID-19/therapy ; Case-Control Studies ; Complement Membrane Attack Complex/analysis ; Continuous Positive Airway Pressure ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Thrombosis/drug therapy ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; Complement Membrane Attack Complex ; eculizumab (A3ULP0F556)
Language	English
Publishing date	2021-12-20
Publishing country	United States
Document type	Controlled Clinical Trial ; Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0261113
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Article ; Online: A complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumab.

Schalk, Gesa / Kirschfink, Michael / Wehling, Cyrill / Gastoldi, Sara / Bergmann, Carsten / Hoppe, Bernd / Weber, Lutz T

Pediatric nephrology (Berlin, Germany)

2015 Volume 30, Issue 6, Page(s) 1039–1042

Abstract: Background: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is ... ...

Abstract	Background: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is increased, particularly in the first year of the disease. Therapeutic options include plasma therapy and terminal complement blockade using the anti-C5 monoclonal antibody eculizumab. Eculizumab prevents activation of the terminal sequence of the complement cascade and formation of the potentially lytic terminal complement complex (C5b-9). Case-diagnosis/treatment: We report a 3-year-old boy with aHUS due to a novel heterozygous truncating complement Factor H mutation in combination with other changes known to be associated with an increased risk for aHUS. Despite eculizumab treatment and maximal suppression of the classical and alternative complement pathways, C3d and sC5b-9 remained consistently elevated and the patient showed repeated relapses. Conclusions: Not every patient with aHUS and uncontrolled complement activation shows optimal therapeutic response to eculizumab with the recommended or even increased dosing regimen. Reliable outcome measures to determine the efficacy of treatment have to be defined.
MeSH term(s)	Antibodies, Monoclonal, Humanized/therapeutic use ; Atypical Hemolytic Uremic Syndrome/diagnosis ; Atypical Hemolytic Uremic Syndrome/drug therapy ; Atypical Hemolytic Uremic Syndrome/genetics ; Atypical Hemolytic Uremic Syndrome/immunology ; Child, Preschool ; Complement Factor H/genetics ; Complement Factor H/immunology ; Genetic Predisposition to Disease ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Mutation ; Phenotype ; Recurrence ; Time Factors ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; CFH protein, human ; Immunosuppressive Agents ; Complement Factor H (80295-65-4) ; eculizumab (A3ULP0F556)
Language	English
Publishing date	2015-03-10
Publishing country	Germany
Document type	Case Reports ; Journal Article
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-015-3078-6
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Zs.A 2196: Show issues

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Article ; Online: ADAMTS13 Secretion and Residual Activity among Patients with Congenital Thrombotic Thrombocytopenic Purpura with and without Renal Impairment.

Rurali, Erica / Banterla, Federica / Donadelli, Roberta / Bresin, Elena / Galbusera, Miriam / Gastoldi, Sara / Peyvandi, Flora / Underwood, Mary / Remuzzi, Giuseppe / Noris, Marina

Clinical journal of the American Society of Nephrology : CJASN

2015 Volume 10, Issue 11, Page(s) 2002–2012

Abstract: Background and objectives: Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease ...

Abstract	Background and objectives: Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease that cleaves von Willebrand factor [VWF] multimers), a substantial percentage of whom develop CKD during follow-up. Design, setting, participants, & measurements: Here we investigated whether, in 18 patients with congenital recruited from 1996 to 2013 who fulfilled inclusion criteria, acute renal involvement occurred during bouts segregated with lower secretion and activity levels of ADAMTS13 mutants. We performed expression studies and a sensitive recombinant VWF (rVWF) A1-A2-A3 cleavage test (detection limit, 0.78% of normal ADAMTS13 activity). Results: A higher risk of acute renal impairment during bouts was observed in patients with childhood (<18 years) onset (odds ratio [OR], 24.6 [95% confidence interval (CI), 1.11 to 542.44]) or a relapsing (≥1 episode per year) disease (OR, 54.6 [95% CI, 2.25 to 1326.28]) than in patients with adulthood onset or long-lasting remission, respectively. Whatever the age at onset, patients with acute renal impairment had mutations different from those in patients without renal involvement. Moreover, mutations in patients with acute renal impairment compared with those in patients without renal involvement caused lower in vitro rADAMTS13 secretion (1.33% versus 12.5%; P<0.001) and residual activity (0.11% versus 3.47%; P=0.003). rADAMTS13 secretion ≤3.75% and residual activity ≤0.4% best discriminated patients with renal impairment (receiver-operating characteristic curve sensitivity, 100% and 100%; specificity, 100% and 83.3%, respectively; logistic regression OR, 325 [95% CI, 6 to 18339] and 91.7 [95% CI, 3.2 to 2623.5], respectively). All mutations found in patients with childhood onset or relapsing disease were associated with acute renal impairment during bouts, confirming the link between acute renal impairment and early onset or a relapsing course. ADAMTS13 activity levels in vivo, measured in patients' serum by rVWF A1-A2-A3 cleavage test, correlated with in vitro rADAMTS13 mutant activity (r=0.95; P<0.001). Conclusions: In congenital TTP, renal impairment and relapsing disease might be predicted by measurements of in vitro rADAMTS13 secretion and activity levels and in vivo serum ADAMTS13 activity.
MeSH term(s)	ADAM Proteins/genetics ; ADAM Proteins/physiology ; ADAM Proteins/secretion ; ADAMTS13 Protein ; Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Mutation ; Purpura, Thrombotic Thrombocytopenic/blood ; Purpura, Thrombotic Thrombocytopenic/complications ; Purpura, Thrombotic Thrombocytopenic/genetics ; Renal Insufficiency/complications ; Young Adult
Chemical Substances	ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2015-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2226665-3
ISSN	1555-905X ; 1555-9041
ISSN (online)	1555-905X
ISSN	1555-9041
DOI	10.2215/CJN.01700215
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Article ; Online: An Ex Vivo Test of Complement Activation on Endothelium for Individualized Eculizumab Therapy in Hemolytic Uremic Syndrome.

Galbusera, Miriam / Noris, Marina / Gastoldi, Sara / Bresin, Elena / Mele, Caterina / Breno, Matteo / Cuccarolo, Paola / Alberti, Marta / Valoti, Elisabetta / Piras, Rossella / Donadelli, Roberta / Vivarelli, Marina / Murer, Luisa / Pecoraro, Carmine / Ferrari, Elisa / Perna, Annalisa / Benigni, Ariela / Portalupi, Valentina / Remuzzi, Giuseppe

American journal of kidney diseases : the official journal of the National Kidney Foundation

2019 Volume 74, Issue 1, Page(s) 56–72

Abstract: Rationale & objective: Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the ... ...

Abstract	Rationale & objective: Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the usefulness of an ex vivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment. Study design: Case series. Setting & participants: 121 patients with primary aHUS and 28 with secondary aHUS. Serum samples were collected during acute episodes, following remission, and during eculizumab treatment and were assessed using a serum-induced ex vivo C5b-9 endothelial deposition test. Results: Serum-induced C5b-9 deposition on cultured microvascular endothelium was quantified by calculating the endothelial area covered by C5b-9 staining; values were expressed as percentage of C5b-9 deposits induced by a serum pool from healthy controls. Testing with adenosine diphosphate-activated endothelium demonstrated elevated C5b-9 deposits for all untreated patients with aHUS independent of disease activity, while testing with unstimulated endothelium demonstrated deposits only in active disease. Similar findings were observed in secondary aHUS. Serum-induced C5b-9 deposits on activated and unstimulated endothelium normalized during eculizumab treatment. 96% (22/23) of patients receiving eculizumab at extended 3- or 4-week dosing intervals demonstrated normal C5b-9 deposits on activated endothelium, despite most patients having CH50Eq (serum complement activity) > 20 UEq/mL, indicating that adequate complement control was achieved even with incomplete blockade of circulating C5. During eculizumab dosage tapering or after treatment discontinuation, all patients experiencing relapses versus only 6% (1/17) of those in stable remission had elevated C5b-9 deposits on unstimulated endothelium. Limitations: The C5b-9 endothelial deposition test can be performed in only specialized laboratories. Findings on eculizumab dosage tapering need to be confirmed with longitudinal monitoring of C5b-9 deposition. Conclusions: The C5b-9 endothelial deposition assay may represent an advance in our ability to monitor aHUS activity and individualize therapy.
MeSH term(s)	Adult ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Atypical Hemolytic Uremic Syndrome/blood ; Atypical Hemolytic Uremic Syndrome/drug therapy ; Complement Activation/drug effects ; Complement Factor H/analysis ; Complement Factor H/genetics ; Complement Inactivating Agents/administration & dosage ; Complement Inactivating Agents/pharmacokinetics ; Complement Membrane Attack Complex/analysis ; Dose-Response Relationship, Drug ; Drug Monitoring/methods ; Endothelium, Vascular/metabolism ; Female ; Humans ; In Vitro Techniques/methods ; Male ; Reproducibility of Results ; Secondary Prevention/methods ; Secondary Prevention/statistics & numerical data
Chemical Substances	Antibodies, Monoclonal, Humanized ; CFH protein, human ; Complement Inactivating Agents ; Complement Membrane Attack Complex ; Complement Factor H (80295-65-4) ; eculizumab (A3ULP0F556)
Language	English
Publishing date	2019-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2018.11.012
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