title: Dynamics of complement activation in aHUS and how to monitor eculizumab therapy.
abstract: Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Miriam
authors.initials: M
authors.lastname: Galbusera
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Gastoldi
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Macor
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Banterla
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Bresin
authors.affiliation: Tumor Immunology Unit, Human Pathology Section, Department of Health Sciences, University of Palermo, Palermo, Italy;
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Serena
authors.initials: S
authors.lastname: Bettoni
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Valoti
authors.affiliation: IRCCS, Istituto Auxologico Italiano, Milan, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Tedesco
authors.affiliation: Unit of Nephrology, Dialysis and Transplantation, Regina Margherita University Hospital, Turin, Italy; and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Amore
authors.affiliation: Unit of Nephrology, Dialysis and Transplantation, Regina Margherita University Hospital, Turin, Italy; and.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Coppo
authors.affiliation: Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
authors.affiliation: Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Gotti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy and "Centro Anna Maria Astori" Science and Technology Park Kilometro Rosso, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D065766:Atypical Hemolytic Uremic Syndrome; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D006463:Hemolytic-Uremic Syndrome / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008991:Monitoring, Physiologic; D012074:Remission Induction; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D000246:Adenosine Diphosphate Ribose; C481642:eculizumab