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Urinary Biomarker Analysis of the SANCTUARY Trial: Insights into IgA Nephropathy Pathophysiology and Ravulizumab Mechanism of Action.

BACKGROUND: Complement activation in IgA nephropathy (IgAN) drives inflammation, nephron loss, and progressive kidney damage. We evaluated urinary biomarkers among participants with IgAN treated with ravulizumab (terminal complement C5 inhibitor) versus placebo in the Phase 2 SANCTUARY trial and healthy donors. METHODS: This exploratory analysis evaluated data from 60 participants with IgAN from SANCTUARY (NCT04564339) and 25 healthy donors. Spot urine samples were collected pre-dose on days 1, 15, 71, 127, and 183, and thereafter Q8W. Urinary biomarkers of complement activation (soluble C5b-…

Post-Acute Sequelae of COVID-19 Persist Over 3 Years in Acute Lung Injury/Acute Respiratory Distress Syndrome Survivors But Are Not Associated With Persistent Thromboinflammation or Endothelial Dysfunction.

IMPORTANCE: Inflammation, endothelial dysfunction, and complement activation are associated with COVID-19 acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). OBJECTIVES: We hypothesized that higher levels of inflammation, endothelial dysfunction, and complement activation implicated in more severe COVID-19 ALI/ARDS are associated with post-acute sequelae of COVID-19 (PASC) phenotypes in the 3 years after hospitalization. DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective cohort of 150 adult survivors of severe and critical COVID-19 from the first wave of the p

A case report of atypical hemolytic uremic syndrome with a CFH mutation complicated by recurrent posterior reversible encephalopathy syndrome.

RATIONALE: Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction, particularly affecting the kidneys and the central nervous system. It is caused by genetic variants or autoantibodies involved in dysregulation of the complement system. Pathogenic variants of the complement factor H (CFH) gene are associated with severe disease and may lead to life-threatening multiorgan failure during the acute phase. We report a case of CFH mutation-positive aHUS complicated by recurrent

Molecular characterization and expression analysis of complement component 3 in dojo loach (Misgurnus anguillicaudatus).

The complement component 3 (C3) is a central component of complement system. All three pathways converge at formation of C3 convertases and share the terminal pathways of membrane attack complex (MAC) formation. In this study, three isoforms of C3 were discovered in Misgurnus anguillicaudatus, named "C3-1", "C3-2" and "C3-3", respectively. The full-length of C3-1 cDNA sequence was firstly identified and analyzed from dojo loach (Misgurnus anguillicaudatus). The Ma-C3-1 cDNA sequence comprised of 4509 bp encoding 1454 amino acids with a putative signal peptide of 20 amino acid residues. The ded

Efficacy and safety of eculizumab in adult patients with atypical hemolytic uremic syndrome: A single center experience from Turkey.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, which develops as a result of defective activity of the alternative complement pathway and excessive complement activation due to genetic or acquired factors. No satisfactory responses were obtained by plasmapheresis, corticosteroids and fresh frozen plasma (FFP) transfusion. However, promising results are obtained in recent years by eculuzimab treatment, which inhibits C5 activation. OBJECTIVE: To evaluate the efficacy, safety and effect of eculizumab on quality of life of adult aHUS patients followed in

Scleroderma Renal Crisis Debute with Thrombotic Microangiopathy: A Successful Case Treated with Eculizumab.

We had the challenged to treat a 40-year-old female with Systemic Scleroderma who was showing unspecific symptoms. During her time at the hospital she rapidly develops renal dysfunction, associated with hypertension. She required renal replacement therapy initiation and we observed a decline in hemoglobin and platelets numbers. We confirm a microangiopathic hemolytic anemia and rule out other immune diseases or thrombotic thrombocytopenic purpura. Systemic Sclerosis is a chronic immune disorder of unknown origin that it is not completely understood. It is believed that environmental factors ma

Investigational drugs in development to prevent neuromyelitis optica relapses.

INTRODUCTION: In the short time since 2014, three pivotal, worldwide studies in neuromyelitis optica spectrum disorders have been launched: eculizumab, SA237 and inebelizumab, each based on a unique mechanism. AREAS COVERED: In this review, we provide a discussion on the trial data available for each drug, a brief description of the trial design, and our expert opinion on the potential benefits and risks. EXPERT OPINION: Eculizumab, a C5 complement inhibitor, may prove useful in the treatment of intractable cases of NMOSD, but physicians must be aware of the known risk of meningococcal infec

Pregnancy-induced atypical haemolytic uremic syndrome: A new era with eculizumab.

Pregnancy is a well-recognised trigger of atypical haemolytic syndrome (P-aHUS) and often occurs in the post-partum period. Similar to atypical haemolytic uremic syndrome, it carries a poor prognosis with high morbidity particularly in the form of renal failure. Early recognition and intervention is crucial in its management particularly with the recent availability of eculizumab, a humanized monoclonal antibody to complement component C5, which has demonstrated drastic improvement in prognosis. The issue, however, is arriving at a timely diagnosis given the considerable amount of overlap in t

Long-term successful liver-kidney transplantation in a child with atypical hemolytic uremic syndrome caused by homozygous factor H deficiency.

BACKGROUND: Rational options for the treatment of end-stage renal disease (ESRD) due to atypical hemolytic uremic syndrome (aHUS) in children are still open to discussion. In the case of human complement factor H (CFH) deficiency, the choice is either kidney transplantation in combination with eculizumab, a humanized anti-C5 monoclonal antibody, or a combined liver-kidney transplantation. CASE-DIAGNOSIS/TREATMENT: A child with a homozygous CFH deficiency underwent a successful liver-kidney transplantation. CFH levels normalized within days. After 6 years of follow-up, the graft function (Cock

Complement activation and fibrinolysis dysregulation drive contrast-induced acute kidney injury: a 4D proteomics rat study.

Contrast-induced acute kidney injury (CI-AKI) is a major cause of hospital-acquired AKI, but its molecular pathogenesis remains incompletely understood. In this study, we used quantitative 4D proteomics, integrating ion mass-to-charge ratio (m/z), retention time, ion intensity, and ion mobility, to profile renal tissues from a novel rat CI-AKI model based on renal venous congestion and contrast exposure, with sham-operated rats as controls. Differentially expressed proteins were identified and analyzed using pathway enrichment and protein-protein interaction (PPI) network approaches, followed

Analysis of adverse drug reactions associated with ravulizumab: a retrospective pharmacovigilance study utilizing the FAERS database.

BACKGROUND: Ravulizumab is a long-acting C5 complement inhibitor that provides sustained suppression of the complement pathway. It is currently approved by the US Food and Drug Administration (FDA) for the treatment of generalized myasthenia gravis, paroxysmal nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome. With its increasing clinical use, concerns regarding Ravulizumab-associated adverse drug reactions have grown. METHODS: This study utilized a dataset extracted from the Adverse Event Reporting System (FAERS) database, comprising adverse event reports from the fourth quart

TEP-1, a glial thioester protein is required for cilia organization and intraflagellar transport in ensheathed sensory neurons in Caenorhabditis elegans.

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by progressive degeneration of retinal photoreceptors. Traditional disease models suggest that defective repression of thioester protein C3 activity by complement factor H (CFH) is a major contributor to pathogenesis in AMD and a related disease, early-onset drusen maculopathy (EODM). Our previous study identified novel functions for human CFH and Caenorhabditis elegans CFH-1 in the maintenance of inversin compartment integrity in photoreceptors and mechanosensory neurons, indicating that CF

The Path to Accessible Care: Development and Impact of Eculizumab Biosimilars for Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome.

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thro…

Aggressive and Refractory Attack of AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder Treated With Ravulizumab: A Case Report.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune astrocytopathy mediated by aquaporin-4-immunoglobulin G (AQP4-IgG) antibodies, leading to complement-mediated neural injury. While ravulizumab, a long-acting C5 inhibitor, is approved for relapse prevention in AQP4-IgG-positive NMOSD, its role in acute attacks remains unestablished. We report a 58-year-old woman with a highly relapsing course of AQP4-IgG-positive NMOSD who developed a fulminant attack with bilateral corticospinal tract involvement, resulting in asymmetrical tetraparesis. Despite high-dose intravenous methylp

Structure and function of therapeutic antibodies approved by the US FDA in 2023.

In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities, of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Among the 12 therapeutic antibodies approved by the US FDA, 8 were relatively standard IgG formats, 3 were bivalent, bispecific antibodies and 1 was a trivalent, bispecific antibody. In 2023, no new antibody-drug conjugates, immunocytokin

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… Finally, one of the newly approved antibodies targets the well-known protein complement C5. One of the aspects driving differentiation of those antibodies approved this year was the engineered features incorporated into many of them, as noted in Table 1 and as follows. …

Hot Spot of Complement Factor I Rare Variant p.Ile357Met in Patients With Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease due to a dysregulation of the complement alternative pathway. Complement factor I (CFI) negatively regulates the alternative pathway and CFI gene rare variants have been associated to aHUS with a low disease penetrance. We report 10 unrelated cases of HUS associated to a rare CFI variant, p.Ile357Met (c.1071T>G). All patients with isolated p.Ile357Met CFI missense variant were retrospectively identified among patients included between January 2007 and January 2022 in the French HUS Registry. We identified 10 unrelated patients

Hope for patients with neuromyelitis optica spectrum disorders - from mechanisms to trials.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe o … our effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies: the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mecha …

Novel insights into pathophysiology and therapeutic possibilities reveal further differences between AQP4-IgG- and MOG-IgG-associated diseases.

PURPOSE OF REVIEW: This review summarizes recent insights into the pathogenesis and therapeutic options for patients with MOG- or AQP4-antibodies. RECENT FINDINGS: Although AQP4-IgG are linked to NMOSD, MOG-IgG-associated diseases (MOGAD) include a broader clinical spectrum of autoimmune diseases of the central nervous system (CNS). Details of membrane assembly of AQP4-IgG required for complement activation have been uncovered. Affinity-purified MOG-IgG from patients were shown to be pathogenic by induction of demyelination when the blood--brain barrier (BBB) was breached and by enhancement o

Complement activation on neutrophils initiates endothelial adhesion and extravasation.

Neutrophils are essential to the pathogenesis of many inflammatory diseases. In the autoantibody-mediated K/BxN model of inflammatory arthritis, the alternative pathway (AP) of complement and Fc gamma receptors (FcγRs) are required for disease development while the classical pathway is dispensable. The reason for this differential requirement is unknown. We show that within minutes of K/BxN serum injection complement activation (CA) is detected on circulating neutrophils, as evidenced by cell surface C3 fragment deposition. CA requires the AP factor B and FcγRs but not C4, implying that engage

Selected IgG rapidly induces Lambert-Eaton myasthenic syndrome in mice: complement independence and EMG abnormalities.

Antibodies in individual patients with the Lambert-Eaton myasthenic syndrome (LES) differ in their reactivity with mouse motor nerve terminals. Of 26 LES patients' sera injected a single time into mice, 3 caused a highly significant reduction in stimulus-dependent quantal release (m) of acetylcholine (ACh) (to 6, 33, and 42 quanta per impulse at 1 Hz, respectively; mean for 10 control sera, 100 quanta at 1 Hz). The most potent serum (LES-A) was fully effective in mice deficient in complement component C5 and in mice depleted of complement components C3----C9 by cobra venom factor. A single i.v