Eculizumab for dense deposit disease and C3 glomerulonephritis

Abstract

Background and objectives: 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.

Design, setting, participants, & measurements: 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.

Figure 1.

Drusen formation in C3 glomerulopathies. Drusen are characteristically seen in age-related macular degeneration but have also been reported in individuals with dense deposit disease (DDD), suggesting a common underlying etiology for deposits in the glomerular basement membrane and retina. A shows pretreatment drusen deposition in subject DDD3. B shows pretreatment drusen deposition in subject C3GN2; to our knowledge, this case is the first reported case of drusen in C3GN, although a prior case report of drusen in membranoproliferative glomerulonephritis type I may, in retrospect, have been a case of C3GN (18). Neither subject showed qualitative change in drusen deposition over the 1-year course of therapy despite clinical and/or histopathologic improvements in renal disease.