Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Abstract

SummaryBackground 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, & measurementsIn 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. ResultsThe 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.

Eculizumab in Pediatric Dense Deposit Disease

“…Eculizumab is registered for use in paroxysmal nocturnal hematuria (11) and atypical hemolytic uremic syndrome (HUS) (12). Recent reports have described the use of eculizumab in DDD, with varying results (13)(14)(15)(16)(17)(18)(19)(20)(21).…”

A rare case: childhood-onset C3 glomerulonephritis due to homozygous factor H deficiency

“…Observation of similar cases suggests that there might be a good prognosis in the long term [4,7]. In case of aggravation of symptoms, treatment with agents that block the alternative or the terminal complement pathway such as eculizumab might be a plausible treatment option, as suggested also by Bomback et al [15,16] in a recent study.…”

American Society of Nephrology Clinical Pathological Conference

“…There is no good evidence that any of these therapies reliably alters renal survival in most patients with DDD, even when used for prolonged periods (26,43,44). The Kidney Disease Improving Global Outcomes clinical guidelines to treat children and adults with idiopathic MPGN accompanied by nephritis and progression of disease with "oral cyclophosphamide or MMF [mycophenolate mofetil] plus low dose daily or alternate day corticosteroids with initial therapy limited to less than 6 months" is based on insubstantial evidence and is not supported by recent experience (45)(46)(47).…”

“…Bomback et al performed a trial of eculizumab in C3 glomerulopathy (46). This open-label, proof-of-concept, efficacy, and safety study evaluated three patients with DDD (one with a renal transplant) and three patients with C3GN (two with a renal transplant).…”