Abstract
Background
Hyperactivity of the alternative complement pathway is the principle defect in C3 glomerulopathies (C3G). Eculizumab, a monoclonal antibody that binds C5 to prevent formation of the membrane attack complex, has been shown to be beneficial in some patients with this disease.
Methods
In this open-label, proof-of-concept efficacy-and-safety study, a patient with the initial diagnosis of dense deposit disease (DDD) and allograft recurrence of C3 glomerulonephritis (C3GN) was treated with eculizumab every other week for 1 year. The patient had pathological evidence of C3GN and proteinuria >1 g/day at enrollment. He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months.
Results
Although no mutations were identified in complement genes, functional studies were positive for C3 nephritic factors and elevated levels of soluble membrane attack complex (sMAC). On therapy, sMAC levels normalized and although proteinuria initially decreased, it increased reaching pre-treatment levels at 12 months. Although serum creatinine remained stable, repeat allograft biopsies showed progression of disease.
Conclusions
Clinical and histopathologic data suggest a partial response to eculizumab in this patient. While eculizumab blocked activation of the terminal complement cascade, persistent dysregulation of the alternative pathway remained, indicating eculizumab alone cannot control disease in this patient. Additional research is required to identify effective anticomplement therapy for this group of C3G patients.
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Acknowledgments
We are grateful to Helen Mundy and Cheryle Ludwig for assistance with the conduct of this study at the Division of Pediatric Nephrology at UMDNJ. This research was supported, in part, by the National Institutes of Health Grant DK074409 (to R.J.S.).
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The investigators were responsible for study design, implementation, data analysis, and manuscript preparation.
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Gurkan, S., Fyfe, B., Weiss, L. et al. Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol 28, 1975–1981 (2013). https://doi.org/10.1007/s00467-013-2503-y
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DOI: https://doi.org/10.1007/s00467-013-2503-y