The Rational Use of Complement Inhibitors in Kidney Diseases

Fakhouri, Fádi; Schwotzer, Nora; Golshayan, Déla; Frémeaux‐Bacchi, Véronique

doi:10.1016/j.ekir.2022.02.021

Cited by 24 publications

(24 citation statements)

References 114 publications

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“…The success of eculizumab in the treatment of PNH has kindled the pharmaceutical industry's interest in the clinical development of inhibitors that target the complement system at various levels 265,266 . Complement inhibition has dramatically transformed the outcome of aHUS, one of the most severe kidney diseases 88 . The availability of complement‐directed therapies has also opened promising new perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent.…”

Section: Discussionmentioning

confidence: 99%

“…In patients with aHUS, lifelong anti‐C5 treatment was initially recommended, based on the assumption that patients with aHUS have continuous, systemic complement activation and are hence at high risk of relapse in case of treatment discontinuation. However, there is no definite evidence to support this assumption 88 . When and how to discontinue C5 inhibition treatment remain unresolved questions.…”

Section: Two Prototypical Complement‐mediated Kidney Diseasesmentioning

confidence: 99%

“…265,266 Complement inhibition has dramatically transformed the outcome of aHUS, one of the most severe kidney diseases. 88 The availability of complement-directed therapies has also context are now registered (Table 1). However, clinical trials to test new therapeutics are difficult to carry out due to the rarity of these diseases.…”

Section: Con Clus Ionsmentioning

confidence: 99%

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Kidney diseases

Daina

Cortinovis

2022

Immunological Reviews

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The complement system, a central part of the innate immunity that serves as a first line of defense against foreign and altered host cells, is an extremely effective cell-killing and inflammation-provoking pathway. However, complement activation is a double-edged sword because uncontrolled stimulation can be highly detrimental to host tissues. [1][2][3] In order to avoid self-damage, a plethora of inhibitory mechanisms are known to prevent overwhelming activation at all stages of the complement cascade. The alternative pathway (AP) of complement is particularly significant for survival against invading pathogens and can be triggered by several other conditions, such as trauma, surgery, or pregnancy. Inappropriate AP activation may be

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Section: Discussionmentioning

confidence: 99%

Section: Two Prototypical Complement‐mediated Kidney Diseasesmentioning

confidence: 99%

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Kidney diseases

Daina

Cortinovis

2022

Immunological Reviews

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“…narsoplimab) 15 and inhibitors of the initial stages of the CP and LP are also available or undergoing clinical trials. 100 The role of C5 fragments in amplifying neutrophil responses further suggests that C5 inhibitors may be a potential benefit in both complementneutrophil-mediated inflammatory diseases. Prospective, randomized controlled trials are required to investigate the utility of anti-complement therapies in TMA associated with autoimmune diseases in more detail, to provide insights on which patients to treat and for how long in this complex and challenging area.…”

Section: Treatmentmentioning

confidence: 99%

The Role of Complement in Autoimmune Disease-Associated Thrombotic Microangiopathy and the Potential for Therapeutics

Java¹,

Kim

2023

J Rheumatol

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The complement system is a tightly regulated, cascading protein network representing a key component linking the innate and humoral immune systems. However, if misdirected or dysregulated, it can be similarly damaging to host-tissue. The role of complement dysregulation on vascular endothelial cells has been well established in atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and target organ injury. Yet a great deal of complexity exists around the role of complement in TMA associated with other diseases. A further complicating factor is the cross-talk between complement, neutrophils, and coagulation pathways in the pathophysiology of TMA. Advancements in the understanding of the etiopathogenesis of aHUS paved the way for the successful development of anti-complement therapies (complement C5 inhibitors), which have revolutionized the treatment of aHUS. Therefore, a clearer understanding of the role of the complement system in TMA associated with other conditions will help to identify patients who would benefit from these therapies. This review aims to provide an assessment of the nature and extent of complement involvement in TMA associated with autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and scleroderma renal crisis. Defining the role of complement in TMA in these conditions will help to guide timely diagnosis and management.

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“…Two additional inhibitors of the alternative pathway, Iptacopan and Danicopan [ 61 ], are available. Iptacopan (LNP023) is a new, oral, selective inhibitor of factor B, currently in a phase III trial in patients with aHUS (Efficacy and Safety of Iptacopan [LNP023] in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy; ClinicalTrials.gov.…”

Section: Complement System Involvementmentioning

confidence: 99%

Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy

et al. 2022

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Thrombotic microangiopathy (TMA) is a complication that may occur after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and is conventionally called transplant-associated thrombotic microangiopathy (TA-TMA). Despite the many efforts made to understand the mechanisms of TA-TMA, its pathogenesis is largely unknown, its diagnosis is challenging and the case-fatality rate remains high. The hallmarks of TA-TMA, as for any TMA, are platelet consumption, hemolysis, and organ dysfunction, particularly the kidney, leading also to hypertension. However, coexisting complications, such as infections and/or immune-mediated injury and/or drug toxicity, together with the heterogeneity of diagnostic criteria, render the diagnosis difficult. During the last 10 years, evidence has been provided on the involvement of the complement system in the pathophysiology of TA-TMA, supported by functional, genetic, and therapeutic data. Complement dysregulation is believed to collaborate with other proinflammatory and procoagulant factors to cause endothelial injury and consequent microvascular thrombosis and tissue damage. However, data on complement activation in TA-TMA are not sufficient to support a systematic use of complement inhibition therapy in all patients. Thus, it seems reasonable to propose complement inhibition therapy only to those patients exhibiting a clear complement activation according to the available biomarkers. Several agents are now available to inhibit complement activity: two drugs have been successfully used in TA-TMA, particularly in pediatric cases (eculizumab and narsoplimab) and others are at different stages of development (ravulizumab, coversin, pegcetacoplan, crovalimab, avacopan, iptacopan, danicopan, BCX9930, and AMY-101).

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The Rational Use of Complement Inhibitors in Kidney Diseases

Cited by 24 publications

References 114 publications

Kidney diseases

Kidney diseases

The Role of Complement in Autoimmune Disease-Associated Thrombotic Microangiopathy and the Potential for Therapeutics

Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy

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