title: Eculizumab for dense deposit disease and C3 glomerulonephritis.
abstract: OBJECTIVE
  The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial.
  
  
  METHODS
  In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark.
  
  
  RESULTS
  The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.
  
  
  CONCLUSIONS
  Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.
authors.affiliation: Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York, USA. asb68@columbia.edu
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bomback
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Smith
authors.forename: Gaetano R
authors.initials: GR
authors.lastname: Barile
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Eliot C
authors.initials: EC
authors.lastname: Heher
authors.forename: Leal
authors.initials: L
authors.lastname: Herlitz
authors.forename: M Barry
authors.initials: MB
authors.lastname: Stokes
authors.forename: Glen S
authors.initials: GS
authors.lastname: Markowitz
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: Pietro A
authors.initials: PA
authors.lastname: Canetta
authors.forename: Jai
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Appel
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D011415:Complement Factor B / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D017244:Complement Factor I / Q000235:genetics; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics; D003404:Creatinine / Q000097:blood; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics; D011507:Proteinuria / Q000209:etiology / Q000652:urine; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C497857:CD46 protein, human; C432223:CFHR5 protein, human; D003182:Complement C5; D015938:Complement Membrane Attack Complex; D051916:Membrane Cofactor Protein; D017242:Complement Factor H; D003165:Complement System Proteins; C481642:eculizumab; D003404:Creatinine; D017244:Complement Factor I; D011415:Complement Factor B