Eculizumab and Refractory Membranoproliferative Glomerulonephritis

Radhakrishnan, Seetha; Lunn, Andrew; Kirschfink, Michael; Thorner, Paul; Hébert, Diane; Langlois, Valérie S.; Pluthero, Fred G.; Licht, Christoph

doi:10.1056/nejmc1106619

Cited by 108 publications

(73 citation statements)

References 5 publications

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“…By these measures, the study was a clear success. Moreover, their results have recently been corroborated by several other case reports (9,10,18,19).…”

supporting

confidence: 75%

Monoclonal Antibodies for the Treatment of the C3 Glomerulopathies

Beck

2012

Clinical Journal of the American Society of Nephrology

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“…By these measures, the study was a clear success. Moreover, their results have recently been corroborated by several other case reports (9,10,18,19).…”

supporting

confidence: 75%

Monoclonal Antibodies for the Treatment of the C3 Glomerulopathies

Beck

2012

Clinical Journal of the American Society of Nephrology

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“…This agent is a humanized monoclonal antibody that binds with great affinity to C5 proteins, inhibiting cleaving into C5a and C5b and blocking production of the C5b-9 membrane attack complex. Reports of individual cases showed that Ig 2 C3 1 MPGN improved after treatment, with reduced serum creatinine and proteinuria (43)(44)(45)(46). In an illustrative case, a 16-year-old girl with renal biopsy indicated MPGN and low C3 levels; plasma complement FH-related protein 1 was absent by immunoblotting.…”

Section: Treatmentmentioning

confidence: 99%

“…Treatment with eculizimab was initiated with dramatic results. Renal function normalized rapidly (43). In a series of six patients with DDD or C3GN, Bomback et al (47) found eculizimab to result in either clinical or pathologic benefits in four subjects.…”

Section: Treatmentmentioning

confidence: 99%

Update on Membranoproliferative GN

Masani

Jhaveri²,

Fishbane³

2014

Clinical Journal of the American Society of Nephrology

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Membranoproliferative GN represents a pattern of injury seen on light microscopy. Historically, findings on electron microscopy have been used to further subclassify this pathologic entity. Recent advances in understanding of the underlying pathobiology have led to a proposed classification scheme based on immunofluorescence findings. Dysregulation of the complement system has been shown to be a major risk factor for the development of a membranoproliferative GN pattern of injury on kidney biopsy. Evaluation and treatment of this complex disorder rest on defining the underlying mechanisms.

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“…To generate C3dg, the iC3b surface was treated with successive cycles of soluble CR1 (50 μg/ml; gift from T Cell Sciences) and FI (10 μg/ml) until no further loss of mass (C3c) was evident. To assess binding to C3b, iC3b, or C3dg, samples were injected explain why treatment of C3G patients with eculizumab, a humanized mAb blocking C5 activation, led to an improvement in renal parameters in only approximately half of patients (23)(24)(25)(26)(27). The pathophysiological heterogeneity of C3G means that the appropriate complement-inhibiting strategy will be determined by the underlying mechanism of complement dysregulation.…”

Section: Mlpa Analysis and High-density Cgh Arraysmentioning

confidence: 99%

C3 glomerulopathy–associated CFHR1 mutation alters FHR oligomerization and complement regulation

Tortajada¹,

Yébenes²,

et al. 2013

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C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H-related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo-and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G.

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Eculizumab and Refractory Membranoproliferative Glomerulonephritis

Cited by 108 publications

References 5 publications

Monoclonal Antibodies for the Treatment of the C3 Glomerulopathies

Monoclonal Antibodies for the Treatment of the C3 Glomerulopathies

Update on Membranoproliferative GN

C3 glomerulopathy–associated CFHR1 mutation alters FHR oligomerization and complement regulation

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