Eculizumab for Treatment of Rapidly Progressive C3 Glomerulopathy

Quintrec, Moglie Le; Lionet, Arnaud; Kandel, Christine; Bourdon, Franck; Gnemmi, Viviane; Colombat, Magali; Goujon, Jean-Michel; Frémeaux‐Bacchi, Véronique; Fakhouri, Fádi

doi:10.1053/j.ajkd.2014.09.025

Cited by 92 publications

(70 citation statements)

References 16 publications

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“…Anti-complement therapies may be preferable in patients with genetic abnormalities because immunosuppressive treatment was not effective in our patient cohort. Complement blockade by the C5 inhibitor eculizumab has been tested in patients with persistent C3GP under immunosuppressive therapy and some patients responded to this treatment [9,10,11]. However, its use for the treatment of C3GP has not yet been approved and the results of an ongoing prospective study are expected [25].…”

Section: Discussionmentioning

confidence: 99%

“…Adult patients with C3GP, particularly those with DDD, appear to have more aggressive disease and worse prognosis compared with other primary glomerular diseases [4,5,6]. Thus, immunomodulatory therapy with corticosteroids [4,6], mycophenolate mofetil (MMF) [7], rituximab [8], calcineurin inhibitors, and complement blockade [9,10,11] have been used to alter the course of C3GP [6]. Although previous studies have reported a failure in response to steroids, MMF, and rituximab therapy [9,12], a recent study from the Spanish Group for the Study of Glomerular Diseases showed that immunosuppressive treatment, particularly corticosteroids plus MMF were beneficial in C3GN [7]; therefore, the treatment modalities of this entity are controversial.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunosuppressive Treatment in C3 Glomerulopathy: Is it Really Effective?

Çalışkan¹,

Torun²,

Tiryaki³

et al. 2017

Am J Nephrol

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Background: C3 glomerulopathy (C3GP) is a recently identified and described disease that has a high risk of progressing into end-stage renal disease. We aimed to evaluate the effects of various immunosuppressive regimens on C3GP progression because there are conflicting data on the treatment modalities. Methods: In this retrospective study of 66 patients with C3GP, 27 patients received mycophenolate mofetil (MMF)-based treatment, 23 received non-MMF-based treatment (prednisolone or cyclophosphamide), and 16 received conservative care. The study groups were compared with each other with specific focus on primary outcomes defined as (1) kidney failure and (2) estimated glomerular filtration rate (eGFR) decline ≥50% from the baseline value. Results: Overall, 17 (25.8%) patients reached the primary outcome after a median period of 28 months. The number of patients who reached the primary outcome were similar among the study groups (MMF-based: 8/27 [29.6%], non-MMF-based: 4/23 [17.4%], and conservative care: 5/16 [31.3%], p = 0.520). In the Cox regression analysis, age (HR 0.912, p = 0.006), eGFR (HR 0.945, p = 0.001), and proteinuria levels (HR 1.418, p = 0.015) at the time of biopsy, percentage of crescentic (HR 1.035, p = 0.001) and sclerotic glomeruli (HR 1.041, p = 0.006), severity of interstitial fibrosis (HR 1.981, p = 0.048), as well as no remission of proteinuria (HR 2.418, p = 0.002) predicted the primary outcome. Conclusion: Although patients receiving immunosuppressive treatments had higher proteinuria and lower serum albumin at baseline, there were no differences between these patients and those receiving conservative care alone in proteinuria remission or in the decline of renal function. Younger age, higher proteinuria, lower eGFR, and the presence of crescentic and sclerotic glomeruli, severity of interstitial fibrosis, and no remission of proteinuria predicted the progression of kidney disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunosuppressive Treatment in C3 Glomerulopathy: Is it Really Effective?

Çalışkan¹,

Torun²,

Tiryaki³

et al. 2017

Am J Nephrol

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“…4,5 Promising clinical results were also reported in several studies where eculizumab therapy was evaluated in other diseases with complement involvement. [6][7][8][9][10] Eculizumab binds C5 with picomolar affinity and inhibits its enzymatic activation by C5 convertases, possibly through steric hindrance. 11,12 However, a recent study indicates that eculizumab not only acts sterically, by blocking binding to the C5 convertase, but also prevents C5 to adopt a primed conformation that is susceptible to processing by the C5 convertase.…”

Section: Introductionmentioning

confidence: 99%

Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Harder

Kuhn

Schrezenmeier

et al. 2017

Blood

118

124

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• Strong complement activation overrides the terminal pathway inhibition by the anti-C5 antibody eculizumab.• The more powerful complement is activated, the less effective is terminal pathway inhibition by diverse anti-C5 agents.Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general. (Blood. 2017;129(8):970-980)

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“…Furthermore, in a recent study, three more patients affected by rapidly progressive C3G have been re ported [110] . All these patients responded to eculizumab with an improvement in renal function, a regression of proteinuria and an improvement of glomerular lesions.…”

Section: Inhibition Of Complement Activationmentioning

confidence: 99%

Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN

Salvadori¹,

Rosso²

2016

WJN

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This review revises the reclassification of the membranoproliferative glomerulonephritis (MPGN) after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and pathogenesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized: The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecific treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in finding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.

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Eculizumab for Treatment of Rapidly Progressive C3 Glomerulopathy

Cited by 92 publications

References 16 publications

Immunosuppressive Treatment in C3 Glomerulopathy: Is it Really Effective?

Immunosuppressive Treatment in C3 Glomerulopathy: Is it Really Effective?

Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN

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