Eculizumab Therapy for Dense Deposit Disease and C3 Nephropathy

Dense deposit disease (DDD), also called membranoproliferative glomerulonephritis (MPGN) type II, is a rare form of glomerulonephritis named because of the characteristic appearance of electron-dense material in the glomerular basement membrane observed on kidney biopsy. The principle immune defect in DDD is excessive activation of the alternative complement pathway, with deposition of complement components in the glomerular basement membrane. Hence, by immunofluorescence microscopy, there is heavy C3 deposited along the basement membrane. Some patients have been found to have deficiencies of Factor H or Factor I, inhibitors of C3 activation. Others have a C3 nephritic factor, an antibody that activates the alternative complement cascade. It has recently been recognized that C3 nephropathy, a rare glomerular disease with mesangial cell proliferation and C3 deposition by immunofluorescence microscopy, is associated with similar over-activation of the alternative complete cascade.

While DDD affects mostly children and young adults, in the series of 32 patients from Columbia with DDD whose biopsies were read from 1977-2007, 18 patients (56%) were older than 16 years of age at the time of diagnosis, and about 40% of patients were over 30 years old. The age division is important for two reasons. First, in the Columbia series, children appeared to have better clinical outcomes than adults. While 25.9% of all patients had a complete remission, there was a significant distinction between adults, of whom only 7.1% achieved complete remission, and children, of whom 46.1% achieved complete remission. Of the remaining patients who did not achieve remission, 42.9% of adults, compared to only 7.7% of children, progressed to end stage renal disease (ESRD) over a mean follow-up of over 5 years. Second, as there are no large clinical trials to guide specific interventions for DDD and the role of immunomodulatory therapies still remains controversial, many nephrologists advocate using immunomodulatory therapy only in selected adult patients.

Immunomodulatory therapies not specifically targeted to DDD, such as corticosteroids, cyclophosphamide, and calcineurin inhibitors, have either been unsuccessful or not studied in a meaningful number of patients to warrant routine use. However, as the principal defect underlying DDD is excessive activation of the alternative complement pathway, with deposition of complement components in the glomerular basement membrane, a therapy that directly targets the alternative complement pathway may prove particularly beneficial for this disease.

Eculizumab is a humanized monoclonal antibody that binds with high affinity to C5. The drug is FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria (in which mutations of complement regulatory proteins on hematopoietic cells lead to alternative complement pathway-mediated hemolysis). It is currently being studied for use in atypical hemolytic uremic syndrome, a rare disease marked by diffuse micro-thromboses related to activation of the alternative complement system. Eculizumab prevents cleavage of C5, thereby precluding formation of C5a, which has been implicated in glomerular inflammation in animal models of DDD. Moreover, by inhibiting the activation of C5, it prevents the formation of the membrane attack complex C5-9. Speculatively, this drug could provide effective, targeted therapy for patients with DDD.