6533b7dafe1ef96bd126d8f9
RESEARCH PRODUCT
Dynamics of complement activation in aHUS and how to monitor eculizumab therapy.
Paolo MacorMarina NorisFederica BanterlaElena BresinSerena BettoniClaudio TripodoAlessandro AmoreRosanna CoppoMiriam GalbuseraElisabetta ValotiGiuseppe RemuzziFrancesco TedescoPiero RuggenentiEliana GottiSara GastoldiRoberta Donadellisubject
MaleTime FactorsClinical Trials and ObservationsComplement Membrane Attack Complexurologic and male genital diseasesBiochemistryGlomerulonephritisInside BLOOD Commentaryhemic and lymphatic diseasesMembranoproliferative glomerulonephritisMonoclonalHumanizedComplement ActivationAtypical Hemolytic Uremic SyndromeEndothelial CellHematologyRemission Inductionfood and beveragesHematologyComplement C3Eculizumabmedicine.anatomical_structureFactor HFemalecomplementaHUS eculizumabmedicine.drugMembranoproliferativeHumanmedicine.medical_specialtyEndotheliumMonitoringTime FactorGlomerulonephritis MembranoproliferativeImmunologyBiologyAntibodies Monoclonal HumanizedAntibodiesInternal medicineAtypical hemolytic uremic syndromemedicineHumansPhysiologicMonitoring PhysiologicAdenosine Diphosphate RiboseEndothelial CellsCell Biologymedicine.diseaseComplement systemImmunologyAdenosine Diphosphate Ribose; Antibodies Monoclonal Humanized; Atypical Hemolytic Uremic Syndrome; Complement Activation; Complement C3; Complement Membrane Attack Complex; Endothelial Cells; Female; Glomerulonephritis Membranoproliferative; Hemolytic-Uremic Syndrome; Humans; Male; Remission Induction; Time Factors; Monitoring Physiologic; Hematology; Biochemistry; Cell Biology; ImmunologyHemolytic-Uremic SyndromeComplement membrane attack complexdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-09-11 | Blood |