• Factor H, FHL1
• alternative pathway
• complement mediated diseases
• complement therapy

• DFG

• clinical nephrology
• clinical trial
• complement
• kidney disease
• molecular biology
• nephrology
• nephropathy

• CRC 1192 Deutsche Forschungsgemeinschaft CRC 1192

• AH50
• Activity assays
• Alternative pathway
• CH50
• Classical pathway
• Complement
• Functional testing
• Lectin pathway
• Serology

• Humans
• Complement System Proteins/immunology
• Complement System Proteins/metabolism
• Complement Activation
• Reproducibility of Results
• Laboratories, Clinical/standards
• Predictive Value of Tests

• CSL040
• Complement
• Pharmacodynamics
• Receptor
• Safety
• Toxicokinetics

• Animals
• Female
• Male
• Rats
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Injections, Intravenous
• Macaca fascicularis
• No-Observed-Adverse-Effect Level
• Rats, Wistar
• Recombinant Proteins/toxicity
• Recombinant Proteins/pharmacokinetics
• Recombinant Proteins/pharmacology
• Recombinant Proteins/administration & dosage

• C3 glomerulopathy
• C5
• factor H

• Animals
• Disease Models, Animal
• Mice
• Complement C5/immunology
• Complement C5/antagonists & inhibitors
• Mice, Transgenic
• Complement C3/metabolism
• Complement C3/immunology
• Humans
• Recombinant Fusion Proteins/therapeutic use
• Recombinant Fusion Proteins/pharmacology
• Recombinant Fusion Proteins/genetics
• Antibodies, Monoclonal
• Complement Factor H/genetics
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antibodies, Monoclonal, Humanized/pharmacology
• Glomerulonephritis/drug therapy
• Glomerulonephritis/immunology
• Glomerulonephritis, Membranoproliferative/drug therapy
• Glomerulonephritis, Membranoproliferative/immunology
• Complement Pathway, Alternative/drug effects

• R01 AI148797 NIAID NIH HHS
• RO1-AI146162 NIH HHS
• Kira Pharmaceuticals
• R01 AI146162 NIAID NIH HHS
• National Institutes of Health

• AH50
• Activity assays
• Alternative pathway
• CH50
• Classical pathway
• Complement,
• Functional testing
• Lectin pathway
• Serology

• cardiovascular disease
• chronic kidney disease
• differential diagnosis
• glomerular disease

• complement
• glomerular disease
• gn
• glomerulopathy
• histopathology
• kidney transplantation
• pathology
• renal pathology
• transcriptional profiling
• transplant pathology

• Adult
• Female
• Humans
• Male
• Middle Aged
• Biopsy
• Complement C3/analysis
• Glomerulonephritis/pathology
• Kidney Transplantation/adverse effects
• Recurrence
• Time Factors

• R01 DK135671 NIDDK NIH HHS
• R01DK135671-01 National Institute of Diabetes and Digestive and Kidney Diseases,Fundación Alfonso Martín Escudero
• R01DK135671-01 NIDDK NIH HHS

• Humans
• Animals
• Mice
• Rheumatology
• Complement System Proteins
• Complement Activation
• Autoimmune Diseases/drug therapy

• BK virus
• C3 glomerulonephritis
• C3 glomerulopathy
• graft biopsy
• kidney transplantation

• HR22C1832 Korea Health Industry Development Institute
• 2021R1I1A3047973 National Research Foundation of Korea
• 2021R1I1A3059702 National Research Foundation of Korea

• C3 glomerulopathy
• complement alternative pathway
• infection-related glomerulonephritis
• membranoproliferative glomerulonephritis
• nephritis-associated plasmin receptor

• C3 glomerulonephritis
• C3 glomerulopathy
• dense deposit disease

Since the re-classification of membranoproliferative glomerulonephritis the new disease entity C3 glomerulopathy is diagnosed if C3 deposition is clearly dominant over immunoglobulins in immunohistochemistry or immunofluorescence. Although this new definition is more orientated at the pathophysiology as mediated by activity of the alternative complement pathway C3 glomerulopathy remains a heterogenous group of disorders. Genetic or autoimmune causes are associated in several but not in all patients with this disease. However, prognosis is poorly predictable, and clinicians cannot directly identify patients that might benefit from therapy. Moreover, therapy may range from supportive care alone, unspecific immune suppression, plasma treatment, or plasma exchange to complement inhibition. The current biopsy based diagnostic approaches sometimes combined with complement profiling are not sufficient to guide clinicians neither (i) whether to treat an individual patient, nor (ii) to choose the best therapy. With this perspective, we propose an interdisciplinary diagnostic approach, including detailed analysis of the kidney biopsy for morphological alterations and immunohistochemical staining, for genetic analyses of complement genes, complement activation patterning in plasma, and furthermore for applying novel approaches for convertase typing and complement profiling directly in renal tissue. Such a combined diagnostic approach was used here for a 42-year-old female patient with a novel mutation in the Factor H gene, C3 glomerulopathy and signs of chronic endothelial damage. We present here an approach that might in future help to guide therapy of renal diseases with relevant complement activation, especially since diverse new anti-complement agents are under clinical investigation.

• C3 glomerulopathy
• FHL1
• complement
• eculizumab
• factor H
• membranoproliferative glomerulonephritis

Thrombotic microangiopathy (TMA) can sometimes manifest only histologically. Our aim was to retrospectively compare biopsy-proven adult TMA patients showing only histological (h-TMA) or both histological and clinical (c-TMA) TMA in 2006–2017. All native kidney biopsies with TMA were included. Biopsies were re-evaluated by light and electron microscopy, and immunofluorescence. Clinical characteristics, laboratory variables, and treatments were recorded from the electronic medical database. Patients were categorized into h-TMA and c-TMA and these groups were compared. In total, 30 biopsy-proven cases among 7943 kidney biopsies were identified and, of these, 15 had h-TMA and 15 c-TMA. Mean follow-up was 6.3 y, and 73.3% had secondary hemolytic uremic syndrome (HUS) and the rest were atypical HUS. Patient characteristics, treatments, and kidney, and patient survival in the groups were similar. Statistically significant differences were found in histological variables. Vascular myxoid swelling and vascular onion-skinning were almost exclusively detected in c-TMA and, thus, vascular occlusive changes indicate clinically apparent rather than merely histological TMA. In addition, regardless of clinical presentation, kidney and patient survival times were similar in the patient groups highlighting the importance of a kidney biopsy in the case of any kidney-related symptoms.

• atypical HUS
• clinical TMA
• histological TMA
• kidney biopsy
• secondary HUS
• thrombotic microangiopathy

• FH deficiency
• case report
• curcumin
• experimental treatment
• lupus
• translational medicine

• C3 glomerulonephritis
• C3 glomerulopathy
• C3 nephritic factor
• Children
• Complement system
• Dense deposit disease

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses.

The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy.

The online version contains supplementary material available at 10.1007/s00109-021-02102-1.

• Alternative complement pathway
• Atypical uremic syndrome
• C3 glomerulopathy
• Genetic testing
• Thrombotic microangiopathy

Complement is an evolutionarily conserved system which is important in the defense against microorganisms and also in the elimination of modified or necrotic elements of the body. Complement is activated in a cascade type manner and activation and all steps of cascade progression are tightly controlled and regulatory interleaved with many processes of inflammatory machinery. Overshooting of the complement system due to dysregulation can result in the two prototypes of primary complement mediated renal diseases: C3 glomerulopathy and thrombotic microangiopathy. Apart from these, complement also is highly activated in many other inflammatory native kidney diseases, such as membranous nephropathy, ANCA-associated necrotizing glomerulonephritis, and IgA nephropathy. Moreover, it likely plays an important role also in the transplant setting, such as in antibody-mediated rejection or in hematopoietic stem cell transplant associated thrombotic microangiopathy. In this review, these glomerular disorders are discussed with regard to the role of complement in their pathogenesis. The consequential, respective clinical trials for complement inhibitory therapy strategies for these diseases are described.

• C3 Convertase testing
• C3 glomerulopathy
• Complement
• Complement diagnostics
• Glomerular diseases
• Thrombotic microangiopathy

The complement system, a network of highly-regulated proteins, represents a vital part of the innate immune response. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement-modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including seven complement proteins, complement regulatory factors, IL-8, and RANTES in MERS-CoV infected patients without underlying chronic medical conditions. Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a, and C3a was positively correlated with IL-8, RANTES, and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P, suggesting positive regulation of the complement during MERS-CoV infection. High levels of lung C5a, C3a, factor P, IL-8, and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8, and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the prediction of functional partners (proteins) of highly expressed proteins (C5a, C3a, factor P, IL-8, and RANTES), the computational protein–protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.

• Chemokine
• Complement system
• Cytokine
• Immunopathology
• Lung
• MERS-CoV infection

• Complement activation
• Complement biomarkers
• Complement mediated diseases
• Complement system
• Complement therapeutics

• Complement system
• complement deficiency
• complement dysregulation
• laboratory testing

• Atypical hemolytic uremic syndrome
• Avacopan
• Complement 3 glomerulopathy
• Eculizumab

• C2 KO
• C3 glomerulopathy
• C3b
• C5
• CFH mAbs
• accelerated kidney disease
• humanized C3 mice
• liver phenotype
• mouse model

• Animals
• Complement C3/genetics
• Complement C3/metabolism
• Complement Pathway, Alternative/genetics
• Disease Models, Animal
• Exons
• Gene Expression Regulation
• Glomerulonephritis, Membranoproliferative/genetics
• Glomerulonephritis, Membranoproliferative/metabolism
• Humans
• Kidney Diseases/genetics
• Kidney Diseases/metabolism
• Liver/metabolism
• Male
• Mice
• Mice, Knockout
• Microscopy, Fluorescence
• Phenotype
• Polymorphism, Single Nucleotide
• Renal Insufficiency/genetics
• Renal Insufficiency/metabolism

• complement
• factor H-related protein 1
• inflammation

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

• ANCA-associated vasculitis
• C3 glomerulopathy
• C5 antagonist
• C5aR1 antagonist
• IgA nephropathy
• aHUS
• complement system
• lupus nephritis

• Clinical examination
• Complement
• Complement-related diseases
• Complement-related factors
• Genetic abnormalities

• Autoantibodies
• C1 inhibitor
• C1q
• C3 nephritic factor
• Complement
• Factor H

• Alternative complement pathway
• C3 glomerulopathy
• mycophenolate mofetil

• C3 glomerulonephritis
• alternative pathway
• complement mutations
• membranoproliferative glomerulonephritis
• proteinuria

• Alternative complement pathway
• C3 glomerulonephritis
• Dense deposit disease
• Mycophenolate mofetil

• Complement Factor H related
• complement
• glomerular disease
• glomerulonephritis
• hemolytic uremic syndrome

• Atypical Hemolytic Uremic Syndrome/etiology
• Atypical Hemolytic Uremic Syndrome/genetics
• Complement C3/analysis
• Complement Factor H/chemistry
• Complement Factor H/genetics
• Complement Factor H/physiology
• DNA Copy Number Variations
• Genetic Predisposition to Disease
• Genetic Variation
• Glomerulonephritis, Membranoproliferative/etiology
• Glomerulonephritis, Membranoproliferative/genetics
• Humans
• Kidney/pathology
• Multigene Family

• C3 glomerulopathy
• eculizumab
• end stage renal disease
• mycophenolate mofetil

Defective complement action is a cause of several human glomerular diseases including atypical hemolytic uremic syndrome (aHUS), anti-neutrophil cytoplasmic antibody mediated vasculitis (ANCA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, ischemic reperfusion injury, lupus nephritis, membranous nephropathy, and chronic transplant mediated glomerulopathy. Here we summarize ongoing clinical trials of complement inhibitors in nine glomerular diseases and show which inhibitors are used in trials for these renal disorders (http://clinicaltrials.gov).

• ANCA
• C3 glomerulopathy
• aHUS
• clinical trials
• complement
• glomerular disease
• inhibitors

• Alternative pathway
• Autoantibodies
• C3 glomerulopathy
• Complement
• Membranoproliferative glomerulonephritis
• Nephritic factor

C3 glomerulopathy (C3G) is an umbrella classification for severe renal diseases characterized by predominant staining for complement component C3 in the glomeruli. The disease is caused by a dysregulation of the alternative pathway (AP) of the complement system. In more than half of C3G patients C3 nephritic factors (C3NeFs) are found. These autoantibodies bind to the AP C3 convertase, prolonging its activity. C3NeFs can be dependent or independent of the complement regulator properdin for their convertase-stabilizing function. However, studies to determine the properdin-dependency of C3NeFs are rare and not part of routine patient workup. Until recently, only supportive treatments for C3G were available. Complement-directed therapies are now being investigated. We hypothesized that patients with properdin-dependent C3NeFs may benefit from properdin-inhibiting therapy to normalize convertase activity. Therefore, in this study we validated two methods to distinguish between properdin-dependent and properdin-independent C3NeFs. These methods are hemolytic assays for measuring convertase activity and stability in absence of properdin. The first assay assesses convertase stabilization by patient immunoglobulins in properdin-depleted serum. The second assay measures convertase stabilization directly in patient serum supplemented with the properdin-blocking agent Salp20. Blood samples from 13 C3NeF-positive C3G patients were tested. Three patients were found to have properdin-dependent C3NeFs, whereas the C3NeF activity of the other ten patients was independent of properdin. The convertase-stabilizing activity in the samples of the patients with properdin-dependent C3NeFs disappeared in absence of properdin. These data indicate that inhibition of properdin in patients with properdin-dependent C3NeFs can normalize convertase activity and could represent a novel therapy for normalizing AP hyperactivity. Our assays provide a tool for identifying C3G patients who may benefit from properdin-inhibiting therapy and can be incorporated into standard C3G laboratory investigations.

• C3 glomerulopathy
• C3 nephritic factor
• Salp20
• alternative pathway
• complement system
• convertase
• properdin
• therapy

• C3 glomerulopathy
• C3NeF
• C5Nef
• Eculizumab
• complement

• Atypical hemolytic uremic syndrome
• C3 glomerulopathy
• Complement system
• Complement-inhibiting therapy
• Properdin
• Proteinuria-induced tubulointerstitial injury

• Autoimmunity
• autoantibody
• glomerulonephritis
• immunotherapy
• kidney

• C3 glomerulonephritis
• children
• clinic-pathological findings
• epidemiology
• predictive factors for poor outcome

• C3 glomerulonephritis (C3GN)
• C3 glomerulopathy (C3G)
• allograft recurrence
• case series
• complement dysregulation
• dense deposit disease (DDD)
• eculizumab
• glomerulonephritis (GN)
• kidney transplantation
• recurrent glomerular disease

For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy (a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases. Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.

• Complement-related diseases
• Kidney transplantation
• De novo
• Recurrent diseases