Treating C3 glomerulopathy with eculizumab

Thomas Welte,Frederic Arnold,Julia Kappes,Elke Neumann-Haefelin,Gerd Walz,Karsten Häffner,Carsten Bergmann,Maximilian Seidl

doi:10.1186/s12882-017-0802-4

Thomas Welte, Frederic Arnold + Show 6 more

Open Access

https://doi.org/10.1186/s12882-017-0802-4

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Abstract

BackgroundC3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.MethodsSeven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.ResultsAfter treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.ConclusionsEculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.

Highlights

C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis
C3 glomerulopathy (C3G) is a recent description of a disease characterized by uncontrolled activation of the alternative complement pathway leading to predominantly glomerular deposition of complement C3 and C3 fragments [1,2,3,4] and characteristic histo-pathological features for membranoproliferative glomerulonephritis (MPGN)
Based on electron microscopy analysis, C3G can be subclassified as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)

Summary

Introduction

C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. C3 glomerulopathy (C3G) is a recent description of a disease characterized by uncontrolled activation of the alternative complement pathway leading to predominantly glomerular deposition of complement C3 and C3 fragments [1,2,3,4] and characteristic histo-pathological features for membranoproliferative glomerulonephritis (MPGN). Based on electron microscopy analysis, C3G can be subclassified as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Dysregulation of the alternative complement cascade plays a primary role in the pathogenesis of C3G and A cohort study with 80 patients identified age > 16 years, DDD subtype, and crescentic GN as predictors for ESRD [6].

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